Том 8, Номер 2

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Introduction

Over last decade, the issue of PD-1 and PD-1 ligand (PD-L1) is being actively studied due to attempted clinical usage of their inhibitors in cancer treatment. In particular, PD-1 inhibitory drugs (e.g., nivolumab) have elicited good response in Hodgkin’s disease patients [1] if also applied in the setting of hematopoietic stem cell transplantation (HSCT). Activation of antitumor T cell populations is considered the main reason for success in anti-PD-1 treatment. However, only a part of patients are responding to the PD-1 inhibitors, thus suggesting individual differences of PD-1/PD-L1 regulation. These patient-specific differences should be better described at the levels of PD-1 production, PD-1/PD-L1 binding, and resulting stimulation of anticancer immunity in distinct clinical disorders. Hence, the immune regulation mechanisms of PD-1 and other immune checkpoint molecules are still poorly understood in many aspects. We tried to summarize the latest data on PD-1 receptor immunology and its potential role in the development of antitumor response.

CD8+ T cells present the key effector population of antitumor adaptive immune response. A lot of positive and negative factors are known to participate in their regulation. At the present time, the so-called “double-signal” model is used to describe a TCR-mediated recognition by naïve T lymphocyte of MHC/antigen on antigen-presenting cell. This recognition event results either into activation of T cells, or its anergy.

To achieve effective activation of antigen-specific T lymphocytes, a signal from the TcR/MHC complex should be accomplished by additional antigen-independent (or costimulatory) signal from other receptors on the responding T cells. However, certain factors may down-regulate the T cell activation. These suppressive effects are performed via appropriate receptors on T cells (e.g. PD-L1 and PD-L2) functioning as immune checkpoints [2]. Under normal conditions, this inhibitory mechanism prevents excessive activation of T cell populations, e.g., adverse autoimmune reactions, thus maintaining a peripheral immune tolerance [3]. The opposite task, i.e., promotion of T cell-mediated antitumor activity requires inhibition of the PD-1 receptors, performed by specific anti-PD-1 monoclonal antibodies now proposed for clinical use.

Hence, special attention is drawn to these costimulatory and coinhibitory interactions, since appropriate pathways are involved in immune escape of malignant tissues or virus-infected cells, as well as in development of autoimmune reactions [4]. The costimulatory and inhibitory receptors are not limited to naïve T cells, being also active in regulatory, effector and memory T cells. The most studied costimulatory pathway includes CD80(B7-1)/CD86(B7-2) receptors on the surface of antigen-presenting cells that interact with CD28 Ig-like molecules on T lymphocytes. There are both costimulatory receptors (CD28, ICOS), and inhibitory molecules (CTLA-4, PD-1, BTLA) on lymphocytes (Fig. 1).

Figure 1. Main molecules and interactions during T cell activation. CD28 family receptors and their ligands on the membranes of
T lymphocytes (bottom) during their contacts with ligand molecules on the antigen-presenting cells (top)

PD-1 molecule is a member of CD28 family, but, like as its main ligand (PD-L1), it is considered a separate player at these signal pathways participating in T cell activation. Initial therapeutic interest was connected with an opportunity to augment the immune response via the costimulatory signal receptors. However, with discovery of immune checkpoints, the research was focused on these inhibitory molecules thus providing impressive results in therapy of some malignant diseases and a Nobel Prize 2018 for J. P. Allison (studies in PD-1/PD-L1) and T. Honjo (discovery of CTLA4 receptor). The both inhibitory receptors are involved into APC-T cell interactions (Fig. 2). The targeted CTLA-4 inhibition by Ipilimumab was initially used for antitumor immune therapy, proving its efficiency in melanoma and other epithelial carcinomas. Monoclonal antibodies to PD-L1 were developed later, and numerous clinical trials have shown its efficiency in some malignancies, especially, Hodgkin lymphoma and melanoma, thus giving some promise for usage of PD-1/PD-L1 inhibitors in clinical oncology [5].

Figure 2. Mechanism of CTLA 4 and PD-1/PD-L1 inhibition. The activation of T cells is mediated by the interaction of T cell receptor and the CD28 receptor with class II major histocompatibility complex and B7 costimulatory molecule. The interaction of CTLA-4 with B7 molecule delivers an inhibitory signal, effectively checked by CTLA-4 inhibitors. The negative regulation of T cells resulting from PD-1/PD-L1 interaction between T cells and tumor cells is prevented by PD-1/PD-L1 inhibitors (Chae et al., 2018) [5]

PD-1: molecular structure

The Programmed Death-1 receptor (PD-1, CD279) is expressed on the surface membrane of some immune cell populations. As many other membrane receptors, PD-1 is a transmembrane protein (type 1) from the immunoglobulin superfamily, with extracellular IgV domain. PD-1 is broadly represented on different leukocyte populations and it can be detected on Т, B, NK, and natural killer T cells (NKT cells), as well as on monocytes, dendritic cells, thymocytes. The protein consists of 288 amino acids and includes an Ig-variable domain, a "stem" of ca. 20 amino acids, as well as transmembrane and cytoplasmic domains. The latter includes tyrosine-based inhibitory signal motifs (ITIM), a similar tyrosine-based switch motif (ITSM). PD-1 is encoded by the Pdcd1 gene mapped at the chromosome 2 in humans (in mice, at chromosome 1). Pdcd1 contains 5 protein-coding exons, i.e.: exon 1 encodes signal sequence; exon 2 for the IgV domain; exon3, for transmembrane domain; exons 4 and 5 encode cytoplasmic domain with ITIM- and ITSM motifs. Four additional protein variants may exist, due to alternative mRNA splicing. The soluble PD-1 form is encoded by the Pdcd1 variant with missed exon 3 [6]. The Pdcd1 transcription is regulated by several transcription factors, i.e., NFATc1 [7], IRF9 [8], FoxO1 [9], Notch signaling [10]. T-bet and Blimp-1 factors are known to inhibit PD-1 expression [11, 12].

PD-1 is able to bind some specific ligands, i.e., PD-L1 (B7-H1, CD274), or PD-L2 (B7-DC, CD273). These inhibitory molecules are necessary for induction of immunological tolerance and suppression of excessive tissue damage in the inflammatory foci in peripheral tissues, and, probably, escape of tumor cells from immune surveillance. Affinity of PD-L2 for PD-1 is 2 to 6-fold higher than PD-L1/PD-1 binding [13]. However, most studies deal with PD1/PDL1 interactions that are primarily caused by broad PD-1 distribution and ability of its expression on various hematopoietic cells and other tissues. On the contrary, PD-L2 expression is mostly limited by dendritic cells, macrophages and lung cells. PD-1 ligands exhibit additional receptors. PD-L1 interacts with B7-1 (CD80) and participates in transduction of inhibitory signal [14]. Hence, B7-1 represents a common ligand for the three receptor types: CD28, CTLA-4, PD-L1 (Fig. 3). Moreover, PD-L2 may bind the RGMB (Repulsive Guidance Molecule B) expressed on lung macrophages, and on alveolar epithelium, thus participating in maintenance of local immune tolerance [15].

Figure 3. Main molecular interactions connected with PD-1 pathway

Methodology of PD-1/PD-L1 detection in tumor samples

There are some conventional laboratory methods of PD-1/PDL-1 diagnostics and appropriate semi-quantitative assays based on detection of specific protein or mRNAs. Immunohistochemical (IHC) testing has some problems with different quality of biopsies as well with cutoff values. Despite of these issues, several IHS commercial systems are now used and intercompared. Moreover, detection of soluble PD-L1 (sPD-L1) is feasible in blood sera of the patients with solid cancer, showing some correlation with response to PD-1 inhibitors [16].

In general, however, the PD-1 receptors and their ligands in tissue samples are detected by immunohistochemical techniques at single-cell level, as it was performed by Zaya et al. [17]. The workers studied expression of PD-1/PD-1L in different specimens of malignant tissue from the patients with nodal peripheral T-cell lymphomas. The slices from formalin-fixed paraffin-embedded blocks were used for immunostaining, and the ratios of antigen-positive cells were scored at 0 to 4. Their quite heterogenous results for different lymphoma types have shown great complexity of PD-1/PDL1 expression which, probably, may impact on clinical response to PD-1 and PD-1L inhibitors.

To study systemic malignancies (e.g., leukemias), or to assess leukocyte populations, flow cytometric methods may be applied as it was performed by Zhang et al. [18]. The authors studied PD-1 expression on the surface of CD4+, CD8+ lymphocytes and PDL-1 on the monocytes of cervical cancer patients. Such approach may be also applied to the patients with myelo- and lymphoproliferative disorders in case of appropriate trials with PD-1 inhibitors.

FISH techniques allow of determining PDL-1 gene copy numbers in malignant cells, i.e. specific gene amplification in the cells of interest. As shown with lung cancer specimens, this parameter seems to correlate with PDL-1 protein expression, as well as overall survival of the patients [19].

PD-1 expression and functioning of T cells

PD-1 is an antagonist of signals coming from the T cell receptor. Therefore, its expression research has aroused great practical interest. PD-1 expression on T cells is a consequence of cell activation, showing a distinct kinetics. Along with TcR/antigen contact, it may be induced by cytokines with common γ-chain, e.g., IL-2, IL-7, IL-15 [20], IFNα [8], and, to lesser degree, with IL-21.

PD-1 is absent or low on the surface of resting T cells. However, its expression levels are drastically increasing within several hours after stimulation [21]. E.g., the PD-1 levels on T helpers from peripheral blood showed a four-fold increase as soon as 24 h after their in vitro exposure to standard cell stimulants (PMA or ionomycin) [22]. Experiments with in vitro activation of murine lymph node lymphocytes have shown PD-1 expression detectable in 1/3 of the CD4+ and CD8+ cells having been activated for 24 hours [23]. PD-1 expression level in T and B cells from mouse spleen was also increased following stimulation with anti-CD3 antibodies, or ConA and anti-IgM antibodies [24]. Differential effects are shown for distinct agents, e.g., bacterial LPS or dexamethasone did not affect PD-1 levels, whereas PMA/ionomycin caused an increase of this receptor on the surface of murine T and B lymphocytes. Hence, the inhibitory effects of PD-1 may be exhibited as soon as upon their early activation.

When studying the inhibitory effects of PD-1 upon T cell functions, an association was revealed between the rate of signal, resulting from the ligand-receptor interactions, and ability of cells for cytokine production, proliferation and cytotoxic activities in response to antigenic stimulation [25]. E.g., the PD-1 stimulation did not exert sufficient effects upon IFNγ and β-chemokine production, associated with full inhibition of IL-2 and TNFα secretion.

Meanwhile, the cytotoxic T cells that expressed PD-1 at very high rates, were able to trigger a reaction cascade switching the in vitro apoptosis [26]. Introduction of antibodies to PD-1 into the cell cultures promoted apoptosis only in the cell populations with PD-1^high++CD3+CD8+ phenotype, without any sufficient effect upon cytotoxic T cells expressing PD-1 at low density.

A similar trend was noted for the virus-specific Т cells, when the PD-1/PD ligand interaction was followed by apoptosis, but not effector attack towards virus-infected cells. When studying chronic virus choriomeningitis in mice, blockage of PD-1/PD-L1 pathway during early activation of naïve T cells resulted into stronger effects of cytotoxic T cells against the virus-infected cells [27]. Exponential clonal T cell expansion was also observed, with TcR re-expression within 2 weeks and accumulation of antigen-specific cells able to express cytotoxic properties. [28]. In case of PD-L1 pathway blockade, a population of hyperactivated proinflammatory TCR^highСD8+ T cells, able to exhibit and augment antitumor immune response along with probable autoimmune lesions in the model of mice lymphoma [28, 29].

PD-1 expression on T cells depends on their differentiation state

Normally, PD-1 is detected on ca. 10% of peripheral T cells, with similar rates for CD4+ and CD8+ T lymphocytes [30]. PD-1 expression levels sufficiently differ at distinct stages of T cell differentiation and besides show some special features for the high- and low-PD1 populations. E.g., when assaying PD-1 expression on peripheral cytotoxic T cells from healthy donors, this receptor was revealed on 40-80% memory T cells, being absent on naïve cells [31,32]. Among mature cytotoxic cells, PD-1 was revealed on 60% of the memory effector cells with CD45RA–CCR7–, whereas this value did not exceed 25% for the central memory cells. Higher expression of mRNAs for CD28 and CD27 costimulators and inhibitory CTLA-4 receptors, as well as homing-mediating chemokine receptors CXCR6, CXCR4 и CCR5, and Granzyme К were characteristic for the PD-1hi cells. If compared with PD-1-negative cytotoxic T cells, the low KIR «killer cell Ig-like receptors» expression, as well as low Granulysin and Granzyme B expression were revealed in the given population. Notably, presence of PD-1 on the cell surface was associated with decreased levels of mRNAs for cell adhesion molecules, i.e., CD11b, CD11c and CD56 [31].

urface phenotypic analysis of PD-1^hi and PD-1^low CD8+ memory T cell populations has shown that CD127 expression is higher at the PD-1hi cell surface whereas more perforin was revealed in the granules of PD-1low cells. Moreover, the PD-1 positivity was accompanied by increased CD95/Fas levels and decreased anti-apoptotic factor Bcl-2, if compared to the PD-1-negative cells [33].

Worth of note, the PD-1 expression is sometimes used as an additional marker of T cell differentiation. E.g., the phenotype of central memory T cells could be described as CCR7+CD27+CD28+CD45RA–CD57–KLRG1–PD1– cells. In the course of further differentiation into the effector memory cells, they acquire CCR7–CD27+/–CD28+/–CD45RA–CD57+/–KLRG1+/–PD1+ profile, whereas differentiated TEMRA effector cells are described as CCR7–CD27–CD28–CD45RA+CD57+KLRG1+PD1+/– subpopulation [34]. This approach allows to consider PD-1, along with CD57 and KLRG1, as markers of late differentiation T lymphocyte aging.

PD-1 expression in different subpopulations of immune cells

Regulatory T cells
The PD-1/PD-L1 interactions are highly important for differentiation of naïve T cells towards induced regulatory cells (iTregs) and for their functional support [35, 36]. E.g., the TGFβ-mediated transition from naïve T cells to Tregs proceeded much more efficient in contact with PD-L1 than in absence of this ligand. Also it was shown for Th1 polarization towards Tregs [37]. Moreover, the contacts between PD-1 on regulatory Т cells and PD-L1 on cytotoxic T cells are quite necessary for suppressory effect of CD8+ T cells, as shown for the virus-specific immune response [38]. After blockade of PD-1, but not PD-L1 separately on murine Treg cells in vitro, a decreased suppressor activity of this population was observed with respect to cytotoxic T cell proliferation and IFNγ production. Such features of PD-1/PD-L1 signaling towards Tregs may be considered as a special mechanism causing insufficiency of, e.g., antitumor immune response, in case of excessive PD-L1 production by malignant cells [39].

NK cells
PD-1 expression shows some specific features in natural killer (NK) cell populations. When studying CMV-seropositive donors and patients with ovarian cancer, the PD-1 receptor was highly expressed on CD56^dim, but not on CD56^bright blood lymphocytes with mature NK phenotype (NKG2A–KIR+CD57+) [39]. The PD-1-specific mRNA expression was also higher in CD56^dim than in CD56^bright NK cells, and the specific protein was detected in all NK cells by means of confocal microscopy [41]. PD-1 expression on NK cells was also shown in other cancers, e.g. Kaposi sarcoma myeloma and gastrointestinal cancers [42, 43, 44]. Studying the effects of PD-1/PD-L1 blockage in various in vitro systems and murine cancer models has demonstrated a significance of this signal pathway for inhibition of NK cell functions, as well as their recovery in case of its blockade [45, 46]. However, real significance of the PD1/PDL1 pathway in antitumor immune response, and in particular, antitumor activity against malignant cells with acquired MHC-1 loss is not clear so far.Therefore, the NK activation mechanisms when using PD-1/PD-L1 inhibitors remain unclear and deserve further studies. E.g., one may suggest induced PD-L1 expression by tumor cells in response to IFNγ secretion by NK cell, with subsequent attraction of PD-1+ Т cells and Tregs expansion [46].

Invariant NKT cells (iNKT)
PD-1/PD-L1 signaling is important for invariant NKT cells both in cancer and chronic viral diseases. E.g., peripheral iNKT cells in patients with non-small-cell lung cancer expressed PD-1 at sufficiently higher levels than in healthy donors [47]. In vitro stimulation of iNKT cells by α-galactosyl ceramide caused increased PD-1 expression, whereas PD-1/PD-L1 blockage prevented anergy of this population and induced Th1-cytokines, thus leading to NK cell activation [47, 48, 49].

Myeloid suppressor cells (MDSC)
MDSC population is able to inhibit T and NK cell activity, thus being considered as a suppressor population. The MDSC level and PD-1 expression are increased under permanent antigenic stimulation. E.g., the patients with chronic hepatitis B exhibited higher levels of MDSC (CD14+HLA-DR–^/low) in peripheral blood, as well as PD-1 expression on these cells. The suppressor effects of this population against cytotoxic T cells could be caused by the PD-1-induced IL-10 production [50]. In mice with mammary tumors, a largely increased PD-1 expression was revealed in tumor-infiltrating MDSCs (CD11b+Gr1+), when compared to expression in bone marrow and spleen. Moreover, the PD-1+ MDSC population showed higher proliferation rates than the PD-1-negative MDSCs [51]. MDSCs may influence the efficiency of anticancer immune therapy with PD-1/PD-L1 inhibitors [52], and contents of this population may be regarded as a potential prognostic marker in this treatment mode [53].

PD-1 expression on T cells in malignant diseases

The inhibitors of PD-1/PD-L1 have yielded impressive results in clinics when treating several cancer diseases, despite still unclear immunological effects produced by these agents. However, efficiency of such therapeutic option proved to be maximal in cancer with high mutation burden, or in tumors with very high expression of PD-L1. In general, the rate of PD-L1 expression in tumors is limited to 20 per cent of cases, but the therapeutic effects are not limited by only absence or presence of PD-L1 or PD-1 expression on malignant cells or tumor-associated lymphocytes [54]. In recent years, clinical research is directed towards combined anticancer therapy including PD-1/PD-L1 inhibitors, in order to improve clinical outcomes [55].

PD-L1, a natural PD-1 ligand, was subject to a number of studies in the field of cancer therapy. PD-L1 expression is normally absent in benign tissues, but it is observed in malignant cells. Increased PD-L1 expression seems to be induced by IFNγ, a physiological response limiting the inflammation area and preventing tissue damage [56, 57]. Cancer cells and their microenvironment may develop PD-L1 expression, due to attraction of lymphocytes, i.e., IFNγ-producing T cells. In melanoma patients, the melanocytes are grouped around PD-1+ tumor-infiltrating lymphocytes [58]. The Т cells expressing PD-1 (and, probably, B7-1) seem to become dysfunctional when binding PD-L1, and they lose their effector abilities, thus leading to escape of tumor cells from immune surveillance, causing the so-called adaptive resistance [59].

Current predictive diagnostics of the PD-1/PD-L1 blocker efficiency is based on this presumption, by determining PD-L1 expression in malignant tissue by means of immunohistochemistry. More recently, a number of works suggest low efficiency of this index as a marker of therapeutic response [60]. Moreover, a constitutively high PD-L1 expression is found in some cancers which does not depend on presence of tumor-infiltrating lymphocytes, e.g., in Hodgkin lymphoma [61, 62]. Hence, the patients with PD-L1 negative tumors can still respond to immune checkpoint blockade, however a subgroup of PD-L1+ patients still do not respond, as shown for some common solid cancers [63].

PD-1 expression is increased on the surface of T cells in the wide range of oncological diseases [64, 65]. Expression of this molecule in melanoma was sufficiently higher on the tumor-infiltrating CD4+ and CD8+ Т cells as compared to normal blood cells and tissues. Antigen-specific T cells showed the same feature. PD1-positive intratumor СD8+ Т cells were characterized by the so-called “exhausted” phenotype: they expressed CTLA-4, showed low cytokine production in response to PMA/ionomycin, but being mostly positive for HLA-DR and CD127-negative [65].

In breast cancer, PD-1 expression in tumor-infiltrating CD8+ T cells was also increased. However, the intratumor T cells had different phenotype and functional properties, i.e, TIM-3 and 2B4 proved to be more expressed on CD8+ T cells from melanoma patients, whereas CD8+ T cells from breast cancer patients retained their degranulation ability, IFNγ, TNFα and IL-2 production, and could be therefore regarded as functional cell population [66]. Similar situation is noted for other malignant diseases including oncohematological diseases, e.g AML [67]. Hence, an increased PD-1-expression on CD8+ T cells could not be considered a common feature of cellular dysfunction which may develop in response to a variety of microenvironmental factors in distinct tumor types.

Hence, PD-1 expression in T lymphocytes, being induced by many biologically active factors, is the least reliable predictor of clinical response to PD-1 inhibitors. So far, the major predictive markers for checkpoint inhibitor response include PD-L1 expression, and indirect markers, such as high tumor mutational burden, microsatellite instability, CD8 infiltrates etc. [63].

Conclusion

PD-1 is an inhibitory receptor of cellular immune response expressed on different immune cell populations. There are sufficient features of PD-1 expression and regulation of antitumor response, being dependent on PD-1 ligands (PDL-1), costimulatory molecules and target tumor antigens.

We have considered some features of PD-1 expression in normal cells and malignancies which show great variability when studied in experimental models and under clinical conditions. This functional heterogeneity may explain wide variability of individual response in clinical studies of PD-1 inhibitors in different human malignancies. Further search for more reliable and immediate laboratory predictors of response to PD-1 inhibitors deserve future studies.

Conflict of interest

No conflict of interests is declared.

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Duraiswamy J, Ibegbu CC, Masopust D, Miller JD, Araki K, Doho GH, Tata P, Gupta S, Zilliox MJ, Nakaya HI, Pulendran B, Haining WN, Freeman GJ, Ahmed R. Phenotype, function, and gene expression profiles of programmed death-1(hi) CD8 T cells in healthy human adults. J Immunol. 2011; 186(7):4200-4212.
Kudryavtsev IV, Borisov AG, Vasilyeva EV, Krobinets II, Savchenko AA, Serebriakova MK, Totolian AA. Phenotypic characterization of peripheral blood cytotoxic T lymphocytes: regulatory and effector molecules. Medical Immunology. 2018; 20(2):227-240 (in Russian).
Petrovas C, Chaon B, Ambrozak DR, Price DA, Melenhorst JJ, Hill BJ, Geldmacher C, Casazza JP, Chattopadhyay PK, Roederer M, Douek DC, Mueller YM, Jacobson JM, Kulkarni V, Felber BK et al. Differential association of programmed death-1 and CD57 with ex vivo survival of CD8+ T cells in HIV infection. J Immunol. 2009; 183(2):1120-1132.
Larbi A, Fulop T. From "truly naïve" to "exhausted senescent" T cells: when markers predict functionality. Cytometry A. 2014; 85(1):25-35.
Gotot J, Gottschalk C, Leopold S, Knolle PA, Yagita H, Kurts C, Ludwig-Portugall I. Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo. PNAS. 2012; 109(26):10468-10473.
Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009; 206(13):3015-3029.
Amarnath S, Mangus CW, Wang JC, Wei F, He A, Kapoor V, Foley JE, Massey PR, Felizardo TC, Riley JL, Levine BL, June CH, Medin JA, Fowler DH. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med. 2011; 3(111):111ra120.
Park HJ, Park JS, Jeong YH, Son J, Ban YH, Lee BH, Chen L, Chang G, Chung DH, Choi I, Ha SJ. PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells. J Immunol. 2015; 194:5801-5811.
Penaloza-MacMaster P, Kamphorst AO, Wieland A, Araki K, Iyer SS, West EE, O'Mara L, Yang S, Konieczny BT, Sharpe AH, Freeman GJ, Rudensky AY, Ahmed R. Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med. 2014; 211(9):1905-1918.
Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, Moretta L, Moretta A, Marcenaro E. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J Allergy Clin Immunol. 2017; 139(1) :335-346.
Mariotti FR, Petrini S, Ingegnere T, Tumino N, Besi F, Scordamaglia F, Munari E, Pesce S, Marcenaro E, Moretta A, Vacca P, Moretta L. PD-1 in human NK cells: evidence of cytoplasmic mRNA and protein expression. Oncoimmunology. 2019; 8(3):1557030.
Beldi-Ferchiou A, Lambert M, Dogniaux S, Vely F, Vivier E, Olive D, Dupuy S, Levasseur F, Zucman D, Lebbe C, Sene D, Hivroz C, Caillat-Zucman S. PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget. 2016; 7(45):72961-72977.
Benson DM, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK, Greenfield CN, Porcu P, Devine SM, Rotem-Yehudar R, Lozanski G, Byrd JC, Caligiuri MA. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood. 2010; 116(13):2286-2294.
Liu Y, Cheng Y, Xu Y, Wang Z, Du X, Li C, Peng J, Gao L, Liang X, Ma C. Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers. Oncogene. 2017; 36(44):6143-6153.
Hsu J, Hodgins JJ, Marathe M, Nicolai CJ, Bourgeois-Daigneault MC, Trevino TN, Azimi CS, Scheer AK, Randolph HE, Thompson TW, Zhang L, Iannello A, Mathur N, Jardine KE, Kirn GA, Bell JC, McBurney MW, Raulet DH, Ardolino M. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Invest. 2018; 128(10):4654-4668.
Oyer JL, Gitto SB, Altomare DA, Copik AJ. PD-L1 blockade enhances anti-tumor efficacy of NK cells. Oncoimmunology. 2018; 7(11):e1509819.
Kamata T, Suzuki A, Mise N, Ihara F, Takami M, Makita Y, Horinaka A, Harada K, Kunii N, Yoshida S, Yoshino I, Nakayama T, Motohashi S. Blockade of programmed death-1/programmed death ligand pathway enhances the antitumor immunity of human invariant natural killer T cells. Cancer Immunol Immunother. 2016; 65(12):1477-1489.
Chang WS, Kim JY, Kim YJ, Kim YS, Lee JM, Azuma M, Yagita H, Kang CY. Cutting edge: Programmed death-1/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy. J Immunol. 2008; 181:6707-6710.
Parekh VV, Lalani S, Kim S, Halder R, Azuma M, Yagita H, Kumar V, Wu L, Kaer LV. PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells. J Immunol. 2009; 182:2816-2826.
Huang A, Zhang B, Yan W, Wang B, Wei H, Zhang F, Wu L, Fan K, Guo Y. Myeloid-derived suppressor cells regulate immune response in patients with chronic hepatitis B virus infection through PD-1-induced IL-10. J Immunol. 2014; 193:5461-5469.
Nam S, Lee A, Lim J, Lim JS. Analysis of the Expression and Regulation of PD-1 Protein on the Surface of Myeloid-Derived Suppressor Cells (MDSCs). Biomol Ther. 2019; 27(1):63-70.
Weber R, Fleming V, Hu X, Nagibin V, Groth C, Altevogt P, Utikal J, Umansky V. Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors. Front Immunol. 2018; 9:1310.
Krieg C, Nowicka M, Guglietta S, Schindler S, Hartmann FJ, Weber LM. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat Med. 2018; 24:144-53.
Xu-Monette Z, Zhang M, Li J, Young K. PD-1/PD-L1 Blockade: Have we found the key to unleash the antitumor immune response? Front Immunol. 2017; 8:1597.
Song M, Chen X, Wang L, Zhang Y. Future of anti-PD-1/PD-L1 applications: Combinations with other therapeutic regimens. Chin J Cancer Res. 2018; 30(2):157-172.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Files DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002; 8(8):793-800.
Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013; 5(200):200ra116.
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012. 4(127):127ra37.
Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest. 2015; 125(9):3384-3391.
Shen X, Zhao B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ. 2018; 262:k3529.
Parsa AT, Waldron JS, Paanner A, Crane CA, Parney CA, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007; 13(1):84-88.
Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest. 2014; 94(1):107-116.
Khagi Y, Kurzrock R, Patel SP. Next generation predictive biomarkers for immune checkpoint inhibition. Cancer Metastasis Rev. 2017; 36(1):179-190. doi: 10.1007/s10555-016-9652-y.
Wong RM, Scotland RR, Lau RL, Wang C, Korman AJ, Kast WM, Weber JS. Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int Immunol. 2007; 19:1223-1234.
Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009; 114(8):1537-1544.
Egelston CA, Avalos C, Tu TY, Simons DL, Jimenez G, Jung JY, Melstrom L, Margolin K, Yim JH, Kruper L, Mortimer J, Lee PP. Human breast tumor-infiltrating CD8+ T cells retain polyfunctionality despite PD-1 expression. Nat Commun. 2018; 9(1):4297.
Schnorfeil FM, Lichtenegger FS, Emmerig K. T cells are functionally not impaired in AML: increased PD‐1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment [serial online]. J Hematol Oncol. 2015; 8:93.

" ["~DETAIL_TEXT"]=> string(42318) "

Introduction

PD-1: molecular structure

Figure 3. Main molecular interactions connected with PD-1 pathway

Methodology of PD-1/PD-L1 detection in tumor samples

PD-1 expression and functioning of T cells

PD-1 expression on T cells depends on their differentiation state

PD-1 expression in different subpopulations of immune cells

PD-1 expression on T cells in malignant diseases

Conclusion

Conflict of interest

No conflict of interests is declared.

References

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Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, Moretta L, Moretta A, Marcenaro E. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J Allergy Clin Immunol. 2017; 139(1) :335-346.
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Beldi-Ferchiou A, Lambert M, Dogniaux S, Vely F, Vivier E, Olive D, Dupuy S, Levasseur F, Zucman D, Lebbe C, Sene D, Hivroz C, Caillat-Zucman S. PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget. 2016; 7(45):72961-72977.
Benson DM, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK, Greenfield CN, Porcu P, Devine SM, Rotem-Yehudar R, Lozanski G, Byrd JC, Caligiuri MA. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood. 2010; 116(13):2286-2294.
Liu Y, Cheng Y, Xu Y, Wang Z, Du X, Li C, Peng J, Gao L, Liang X, Ma C. Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers. Oncogene. 2017; 36(44):6143-6153.
Hsu J, Hodgins JJ, Marathe M, Nicolai CJ, Bourgeois-Daigneault MC, Trevino TN, Azimi CS, Scheer AK, Randolph HE, Thompson TW, Zhang L, Iannello A, Mathur N, Jardine KE, Kirn GA, Bell JC, McBurney MW, Raulet DH, Ardolino M. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Invest. 2018; 128(10):4654-4668.
Oyer JL, Gitto SB, Altomare DA, Copik AJ. PD-L1 blockade enhances anti-tumor efficacy of NK cells. Oncoimmunology. 2018; 7(11):e1509819.
Kamata T, Suzuki A, Mise N, Ihara F, Takami M, Makita Y, Horinaka A, Harada K, Kunii N, Yoshida S, Yoshino I, Nakayama T, Motohashi S. Blockade of programmed death-1/programmed death ligand pathway enhances the antitumor immunity of human invariant natural killer T cells. Cancer Immunol Immunother. 2016; 65(12):1477-1489.
Chang WS, Kim JY, Kim YJ, Kim YS, Lee JM, Azuma M, Yagita H, Kang CY. Cutting edge: Programmed death-1/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy. J Immunol. 2008; 181:6707-6710.
Parekh VV, Lalani S, Kim S, Halder R, Azuma M, Yagita H, Kumar V, Wu L, Kaer LV. PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells. J Immunol. 2009; 182:2816-2826.
Huang A, Zhang B, Yan W, Wang B, Wei H, Zhang F, Wu L, Fan K, Guo Y. Myeloid-derived suppressor cells regulate immune response in patients with chronic hepatitis B virus infection through PD-1-induced IL-10. J Immunol. 2014; 193:5461-5469.
Nam S, Lee A, Lim J, Lim JS. Analysis of the Expression and Regulation of PD-1 Protein on the Surface of Myeloid-Derived Suppressor Cells (MDSCs). Biomol Ther. 2019; 27(1):63-70.
Weber R, Fleming V, Hu X, Nagibin V, Groth C, Altevogt P, Utikal J, Umansky V. Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors. Front Immunol. 2018; 9:1310.
Krieg C, Nowicka M, Guglietta S, Schindler S, Hartmann FJ, Weber LM. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat Med. 2018; 24:144-53.
Xu-Monette Z, Zhang M, Li J, Young K. PD-1/PD-L1 Blockade: Have we found the key to unleash the antitumor immune response? Front Immunol. 2017; 8:1597.
Song M, Chen X, Wang L, Zhang Y. Future of anti-PD-1/PD-L1 applications: Combinations with other therapeutic regimens. Chin J Cancer Res. 2018; 30(2):157-172.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Files DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002; 8(8):793-800.
Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013; 5(200):200ra116.
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012. 4(127):127ra37.
Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest. 2015; 125(9):3384-3391.
Shen X, Zhao B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ. 2018; 262:k3529.
Parsa AT, Waldron JS, Paanner A, Crane CA, Parney CA, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007; 13(1):84-88.
Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest. 2014; 94(1):107-116.
Khagi Y, Kurzrock R, Patel SP. Next generation predictive biomarkers for immune checkpoint inhibition. Cancer Metastasis Rev. 2017; 36(1):179-190. doi: 10.1007/s10555-016-9652-y.
Wong RM, Scotland RR, Lau RL, Wang C, Korman AJ, Kast WM, Weber JS. Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int Immunol. 2007; 19:1223-1234.
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Schnorfeil FM, Lichtenegger FS, Emmerig K. T cells are functionally not impaired in AML: increased PD‐1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment [serial online]. J Hematol Oncol. 2015; 8:93.

Дмитрий С. Елезов ¹, Игорь В. Кудрявцев ^2,3,4

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¹ НИИ детской онкологии, гематологии и трансплантологии им. Р. М.Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
² Отдел иммунологии, Институт экспериментальной медицины, Санкт-Петербург, Россия
³ Отдел онкоиммунологии, Национальный медицинский научно-исследовательский центр онкологии им. Н. Н. Петрова, Санкт-Петербург, Россия
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В последнее десятилетие к PD-1 и его лиганду PD-L1 приковано большое внимание в связи с высокой эффективностью терапии ряда опухолевых заболеваний блокаторами PD-1/PD-L1. В рамках данного обзора обобщены данные по экспрессии рецептора PD-1 на различных популяциях Т-клеток и его потенциальной роли в противоопухолевом иммунном ответе.
Кроме общего описания молекулярной структуры и межмолекулярных взаимодействий, основное внимание в обзоре уделено особенностям экспрессии PD-1 на популяции СD8+ T-клеток, которая играет центральную роль в противоопухолевом иммунном ответе. Общие закономерности изменений уровня экспрессии PD-1 в ходе процессов клеточной активации и дифференцировки были рассмотрены в основном относительно этой клеточной популяции. Экспрессия PD-1 отмечается также на поверхности Т-регуляторных, NK-, инвариантных NKT-, миелоидных супрессорных клеток, что, вероятно, имеет важную роль в ходе противоопухолевого иммунного ответа, и имело отражение в данном обзоре. При проведении терапии ингибиторами PD-1/PD-L1 вышеперечисленные популяции могут влиять на формировании резистентности к данному виду терапии. В связи с этим, многие современные исследования направлены на выяснение их вовлеченности в процесс иммунорегуляции и возможности использования их в качестве биомаркеров оценки эффективности терапии ингибиторами иммунных контрольных точек.

Ключевые слова

PD-1, PD-L1, экспрессия, T-клетки, противоопухолевая терапия, ингибиторы иммунных контрольных точек.

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Dmitry S. Elezov ¹, Igor V. Kudryavtsev ^2,3,4

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¹ Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
² Department of Immunology, Institute of Experimental Medicine, St. Petersburg, Russia
³ Department of Oncoimmunology, N. N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russia
⁴ Department of Fundamental Medicine, Far Eastern Federal University, Vladivostok, Russia

PD-1 is among key receptors conveying an inhibitory signal to T cells. Over last decade, PD-1 and its ligand PD-L1 draw much attention, due to high efficiency of therapy with PD-1/PD-L1 inhibitors in a number of malignant disorders. In this review article, we aimed to summarize current data on the PD-1 receptor expression in different immune cell subpopulations, like as its potential role in cellular antitumor response. Along with molecular structure and receptor-ligand interactions, the main attention is drawn to special features of PD-1 expression on the СD8+ T cell population which plays a key role in antitumor immune response. Some common changes of PD-1 expression levels during the cell activation and differentiation are considered, mainly, for the CD8+ T cells. Moreover, we discuss PD-1 expression on the surface of regulatory T cells, NK cells, invariant NKT cells, myeloid suppressor cells which may play an important role for anticancer immune response. When performing current therapy with PD-1/PD-L1 inhibitors, the mentioned populations may influence development of resistance to this mode of immune treatment. Therefore, a number of recent studies are directed for studying the PD-1/PD-L1 involvement into the immune regulation and to test prospects of their usage as biomarkers for clinical immune checkpoint therapy.

Keywords

PD-1, PD-L1, expression, T cells, antitumor therapy, checkpoint inhibitors.

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Elezov 1, Igor V. Kudryavtsev 2,3,4 " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(80) "

Dmitry S. Elezov ¹, Igor V. Kudryavtsev ^2,3,4

Keywords

PD-1, PD-L1, expression, T cells, antitumor therapy, checkpoint inhibitors.

Keywords

PD-1, PD-L1, expression, T cells, antitumor therapy, checkpoint inhibitors.

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Дмитрий С. Елезов ¹, Игорь В. Кудрявцев ^2,3,4

Ключевые слова

PD-1, PD-L1, экспрессия, T-клетки, противоопухолевая терапия, ингибиторы иммунных контрольных точек.

Ключевые слова

PD-1, PD-L1, экспрессия, T-клетки, противоопухолевая терапия, ингибиторы иммунных контрольных точек.

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "22074" ["VALUE"]=> array(2) { ["TEXT"]=> string(1046) "1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М.Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия 2 Отдел иммунологии, Институт экспериментальной медицины, Санкт-Петербург, Россия 3 Отдел онкоиммунологии, Национальный медицинский научно-исследовательский центр онкологии им. Н. Н. Петрова, Санкт-Петербург, Россия 4 Отдел фундаментальной медицины, Дальневосточный федеральный университет, Владивосток, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(974) "

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective treatment method for lymphoid, haematopoietic and related tissue malignancies as well as non-malignant disorders. In 2017, 18.281 number of allo-HSCT were performed in Europe and associated countries reported by 683 centers in 50 countries, with acute leukemia being the main indication [1]. The approachability and outcome of allo-HSCT are steadily improving due to wide application of reduced-intensity conditioning (RIC), new methods of graft-versus-host disease (GvHD) prophylaxis, haploidentical transplantation, and introduction of novel molecules and drugs for bridge therapy before allo-HSCT, along with prevention and treatment of relapses after allo-HSCT both in adults and pediatric patients [2-8] Invasive fungal disease (IFD) is a common infectious complication during remission-induction and/or consolidation chemotherapy for aggressive hematologic malignancies. The patients with acute leukemia and high-risk myelodysplastic syndrome are also at high risk for IFD [9-10]. Some patients with relapsed/refractory lymphoma could be, under some circumstances, also attributed to the high-risk group [11]. Introducing new antifungal drugs and diagnostic procedures has improved prognosis of IFD in hematological disorders. Many of these patients will subsequently be referred for allo-HSCT because of high-risk hematological malignances. The number of patients with IFD who are candidates for allo-HSCT has been also increased, and the problems related to the transplant procedure are pressing now. An observational study of the Transplant Associated Infection Surveillance Network (TRANSNET) suggests that the post-transplant IFD remains problematic, with cumulative incidence rates varying between 5.8 and 7.7% [12]. The role of IFD revealed prior to allo-HSCT is still a subject of controversy. Historically, IFD has been a major barrier for allo-HSCT. Previous studies have shown that invasive aspergillosis (IA) may have a significant role in clinical outcome of allo-HSCT [13-15]. Fukuda et al. have summarized the 10-year experience of Fred Hutchinson Cancer Research Center, having shown that the post-transplant IA occurred in 13 of 45 patients with a pre-transplant IA history (29%) [16]. Nine infectious events were considered to be recurrent by anatomic site and timing. Compared with all other patients who received allo-HSCT over the same period, the patients with IA history had lower 1-year overall survival rate (56% versus 77%; P=0.0001), and higher transplant-related mortality (38% versus 21%; P=0.0001) by 100 days after HSCT, associated mainly with IA and other pulmonary complications. The CIBMTR data also confirm that 5-year overall survival was 30% (95% Confidence interval (CI): 26-34%) at 5 years in patients with pre-transplant IFD versus 45% (95% CI: 44-46%) in control population (p <0.0001). The lower overall survival seems to be a composite result of higher relapse rates and higher non-relapse mortality in the patients with pre-existing IFD [17].

Historically, pre-transplant IFD was considered a relative contraindication to HSCT. However, recent studies have demonstrated a controversial point, e.g., a single-center study on behalf of CIC 725 suggested that IA prior to allo-HSCT did not impair the outcome of transplantation procedure with effective diagnosis and secondary prophylaxis of IFD, as reported at the 41^st Annual EBMT Meeting and 57^th Annual ASH Meeting in 2015 [18, 19]. A retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties concerning influence of pre-existing invasive aspergillosis upon allo-HSCT outcome in acute leukemia patients (published online in October 2015 in Bone Marrow Transplantation) confirm our data that, in general, a history of IA should not be a contraindication when considering allo-HSCT in acute leukemia patients [20]. Penack O. et al. found only a trend toward lower overall survival (P=0.078, hazard ratio (HR) [95% confidence interval (CI): 1.16 (0.98, 1.36)], and higher non-relapse mortality [P=0.150, HR (95% CI): 1.19 (0.94, 1.50)] in allo-HSCT recipients with pre-existing IA [20]. So far, there are no available data on clinical effects of other then IA pre-existing IFD and in pediatric allo-HSCT recipients.

The aim of this study was to estimate impact of prior proven or probable invasive fungal diseases on clinical outcome of allo-HSCT in children and adults.

Patients and methods

We have conducted a prospective single center study, where 504 allo-HSCT recipients were included from Jan 2013 to Jul 2016, with median follow-up time of 20 months and median age of 24 y.o. [2 months to 76 years]. The study cohort included 164 children (<18 yo), 340 adults, 52% were males. Most patients had high-risk acute leukemia (74.6%). Allo-HSCT from MUD was performed in 58.5%; MRD, 22.5%; haplo-HSCT, 19%. Reduced-intensity conditioning regimens (RIC) were predominant (67% of the cases). General characteristics of patients, donors and transplants are outlined in Tables 1, 2. The patients with lymphoid, haematopoietic and related tissue malignancies as well as non-malignant disorders received primary chemotherapy and other treatment in various regions of Russian Federation, from where most of the data including history of prior IFD were collected. All the patients with CT-detectable lesions at the time of transplantation were subjected to diagnostic bronchoscopy with bronchoalveolar lavage (BAL) microscopy, microbiological cultures and galactomannan (GM) test. EORTC/MSG 2008 criteria were used for the diagnosis of proven and probable IFD as well as to evaluate response to therapy. An “active” invasive fungal disease means IFD diagnosed just before allo-HSCT during examination at <1 month before starting the conditioning regimen.

The following primary endpoints were used: incidence of pre-existing IFD, incidence of relapse or progression of IFD after allo-HSCT, and overall survival (OS). The secondary endpoints included influence of pre-existing IFD on other outcomes of allo-HSCT, i.e., acute GvHD, chronic GvHD, relapse of underlying disease.

Overall survival was estimated using the Kaplan–Meier method. Mortality due to any cause was considered as a distinct event. Patients alive at the end of the follow-up were censored at this date. Patients with pre-existing IFD and without pre-existing IFD will be compared by the log-rank test. A Cox regression was applied, in order to compare the outcomes the study groups.

Results

The overall incidence of IFD before allo-HSCT was 15% (n=76). According to EORTS/MSG 2008 criteria 90.8% of patients had probable IFD, and 9.2% exhibited proven fungal invasion. Patients with lymphoma, as well as those with acute myeloid leukemia had a higher rate of pre-existing IFD at the time of allo-HSCT (Fig. 1).

The pathogens detected in IFD prior to allo-HSCT were as follows: invasive aspergillosis, 75%; invasive candidiasis (IC), 13%; mucormycosis (Mu), 4%; Pneumocystis pneumoniae (PCP), 1,3%; combination of IA with Mu was found in 2 patients, IC in one case, and PCP, in one another case (Fig. 2). The main sites of infection were lungs (95%), other affected sites were predominantly combined with lung lesions, i.e., maxillary or frontal sinuses, 9%; spleen, 6%; liver, 6%, and soft tissues, 3% (Fig. 3).

The median time from IFD to allo-HSCT was 86 days [1 day to 4.5 years]. Antifungal therapy before allo-HSCT was administered in 75% patients. The median duration of antifungal therapy before allo-HSCT was 65 days [1 day-11 months]. Complete response to antifungal treatment was achieved in 38.2% patients, partial response or stabilization were observed in 35.5%, and 26.3% patients had “active IFD”. After allo-HSCT, all the patients received antifungal therapy or secondary prophylaxis according to the IFD etiology, with median duration of clinical effect for 78 [21-217] days, and median therapy length for 166 [32 to 394 days].

Cumulative incidence of relapse or progression of IFD after allo-HSCT was 14.5% (Fig. 4). Active underlying disease at the moment of HSCT was the only risk factor for relapse or progression of IFD after allo-HSCT (11.5% vs 21.1%, p=0.03) (Fig. 5). We detected no significant differences in cumulative incidence of acute or chronic GVHD, and relapse rates in the study group as compared to the patients without history of IFD. Patients and HSCT characteristics, CMV reactivation, graft hypofunction did not show any significant association with incidence of relapse, or progression of IFD after allo-HSCT. The characteristics related to pre-existing IFD (status of IFD at the HSCT, time from IFD to HSCT, duration of antifungal therapy before HSCT) also had no impact on probability of relapse or progression of IFD after allo-HSCT.

Three-year OS after allo-HSCT was 67.5%. The impact of prior IFD upon overall survival in allo-HSCT recipients was not statistically significant in the entire group (60.5% vs 68.7%, p=0.1) (Fig. 6). Similar results were obtained for the separate groups of children (50.0% vs 57.4%, p=0.3), and adults (63.3% vs 74.6%, p=0.09). The main outcomes of allo-HSCT are presented in Table 3.

The worst outcome was observed in patients with “active IFD” and active underlying disease at the moment of allo- HSCT (3-year OS – 20%, p<0.001; HR (95% CI): 5.81 (2.81 – 11.87)). However, OS values in patients with “active IFD” and remission of underlying disease were similar to survival rate of patients without history of IFD (80% vs 68.7%, p=0.2, p=0.57, HR [(95% CI): 0.67 (0.16 – 2.71)] (Fig. 7).

Table 3. The main outcomes of allo-HSCT in patients with history of prior IFD as compared to patients without history of IFD

Discussion

In the present study, we analyzed large data set of patients with different hematological malignancies and non-malignant disorders undergoing allo-HSCT between 2013 and 2016 in a single BMT center (CIC 725). We would highlight the real-life character of study. The entire cohort of allo-HSCT recipients was included in the observation period without exception of any patients, regardless of underlying disease or status at the moment of allo-HSCT. Also we would emphasize the participation of pediatric cohort that was presented by 164 children.

In our population of allo-HSCT recipients, 15% had proven and probable invasive fungal disease before transplantation. Moreover, most of them (>60%) had signs of the infection at the moment of allo-HSCT. We believe that there are several factors that could contribute to our results. Out BMT team has wide diagnostic opportunities and an active diagnostic strategy related to infections, and is able to perform the on-place assessment of infectious state of the patient before allo-HSCT, because of lacking necessary diagnostic procedures in most regions where the patients were initially treated. Due to successful implementation of such strategy, we are more often prone for active treatment and avoiding delays with allo-HSCT. An unexpected result for us is the fact that a quarter of patients with lymphomas had IFD before allo-HSCT. This result may be due to high pre-treatment burden in these patients, most of them were patients with Hodgkin lymphoma who underwent more than 6 lines of chemotherapy before allo-HSCT.

Our study has also shown that the cumulative incidence of relapse or progression of invasive fungal disease after allo-HSCT was 14.5%. The only risk factor for relapse or progression of IFD was lack of complete remission of the underlying disease at the moment of HSCT. That result corresponded to the earlier reported data [16], but we didn’t find any additional risk factors associated with bone marrow transplant procedure or antifungal treatment before allo-HSCT.

In the present study, we demonstrated that invasive fungal disease prior to the allo-HSCT did not impact on outcome of this treatment in children and adults. We suggest that there are several features that may have endow to obtained results.

Firstly, our study included allo-HSCT recipients who have been transplanted over recent years, in comparison with published studies [13-16, 20]. An overall better supportive care management was applied over last years, thus improving, specifically the outcome of allo-HSCT in patients with infectious complications including IFD. We believe that active diagnostic strategy and wide implementation of modern medications for secondary prophylaxis in our center played a role in improving the outcome of allo-HSCT in the patients with pre-existing IFD. It has been shown in several trials that secondary antifungal prophylaxis with voriconazole leads to considerably lower IA relapse rates as compared with those reported in historical controls, since Aspergillus spp. is a prevailing pathogen in pre-transplant IFD in our study [21-23].

Secondly, this study demonstrated the central role of the underlying disease status upon outcome of the allo-HSCT, and influence on the course of the infectious complications after HSCT, IFD in our case. Active underlying disease at the moment of HSCT was the only risk factor for relapse or progression of IFD and impaired outcome of allo-HSCT. This hypothesis is supported by publications from a French-Belgium study group, demonstrating that the outcome of severe infectious complications in patients with hematological malignancies has been considerably improved during the last decade and is mostly determined by the status of the underlying disease [24-25].

Thirdly, our study has limitations due to relatively small study cohort from a single center data. That is why the result may be not accurate enough to evaluate the effect of IFD upon allo-HSCT outcome. At the same time, it reflects the situation during certain time which significantly affects the results obtained. Therefore, we cannot exclude the possibility that pre-existing IFD has a higher adverse impact on allo-HSCT outcome than our data may suggest.

In conclusion, we found out no significant impact upon important allo-HSCT transplant outcomes, such as survival, GvHD and relapse. Our data suggest that a history of IFD should not be considered a contraindication for allo-HSCT. We are currently continuous an observational prospective study to be able to more precisely investigate the impact of IFD on allo-HSCT.

Acknowledgments

The authors would like to acknowledge all medical staff at our University’ BMT clinic CIC725. Special thanks to our ICU department, our transplant nurses’ team for their particular care of our patients. Many thanks to specialists of Department of Clinical Microbiology at the First Pavlov State Medical University of Saint-Petersburg, especially to dr. Olga Pinegina and Chief of the Department, and special gratitude to patients and their relatives.

Conflict of interest

No conflict of interests is declared.

References

Passweg JR, Baldomero H, Basak GW, Chabannon C, Corbacioglu S, Duarte R, Kuball J, Lankester A, Montoto S, de Latour RP, Snowden JA, Styczynski J, Yakoub-Agha I, Arat M, Mohty M, Kröger N; European Society for Blood and Marrow Transplantation (EBMT). The EBMT activity survey report 2017: a focus on allogeneic HCT for nonmalignant indications and on the use of non-HCT cell therapies. Bone Marrow Transplant 2019, Feb 6. doi: 10.1038/s41409-019-0465-9.
Afanasyev BV, Zubarovskaya LS, Semenova EV, Ivanova NE, Alyanskiy AL, Morozova EV, Mikhailova NB, Darskaya EI, Estrina MA, Golovacheva AA, Babenko EV, Bondarenko SN, Ganapiev AA, Bogomolny MP. The experience in non-relative allogenic transplantation of stem hemopoietic cells in the clinic of bone marrow transplantation at I. P. Pavlov St. Petersburg Medical Academy. Terapevticheskii Arkhiv 2007, 79 (7):36-43 (In Russian).
Bondarenko SN, Moiseev IS, Slesarchuk OA, Darskaya EI, Ekushev KA, Smirnova AG, Alyanskiy AL, Gindina TL, Babenko EV, Kuzmich EV, Semenova EV, Kulagin AD, Zubarovskaya LS, Afanasyev BV. Allogeneic hematopoietic stem cell transplantation in children and adults with acute lymphoblastic leukemia. Cell Ther Transplant. 2016, 5 (2):12-20.
Afanasyev BV, Zubarovskaya LS, Moiseev IS. Allogeneic hematopoietic stem cell transplantation in children: now, problems and prospects. Russian Journal of Children Hematology and Oncology. 2015, 2: 28-42 (In Russian).
Baron F, Labopin M, Peniket A, Jindra P, Afanasyev B, Sanz M.A, Deconinck E, Nagler A, Mohty M. Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Cancer 2015; 121(7): 1048-1055.
Moiseev IS, Pirogova OV, Babenko EV, Gindina TL, Darskaya EI, Morozova EV, Bondarenko SN, Afanasyev BV. Single-agent post-transplantation cyclophosphamide versus calcineurin-based graft-versus-host disease prophylaxis in matched related bone marrow transplantation. Cell Ther Transplant. 2017; 6 (4): 52-59.
Bykova TA, Borovkova AS, Osipova AA, Ovechkina VN, Sheveleva PV, Nadzhafava KU, Yager VU, Paina OV, Kozhokar PV, Alyanskyi AL, Kulagin AD, Semenova EV, Smirnov BI, Zubarovskaya LS, Afanasyev BV. Acute GvHD prophylaxis with posttransplant cyclophosphamide after hematopoietic stem cell transplantation (HSCT) for non-malignant disorders. Pediatric Hematology/Oncology and Immunopathology 2018, 17 (2), pp. 51-58 (In Russian).
Moiseev IS, Darskaya EI, Bykova TA, Morozova EV, Alyanskiy AL, Babenko EV, Bondarenko SN, Markova IV, Afanasyev BV. Different risk factors of acute and chronic graft-versus-host disease with conventional prophylaxis and posttransplantation cyclophosphamide in matched related and unrelated donor transplantation. Cell Ther Transplant. 2018; 7 (4): 29-37. DOI: 10.18620/ctt-1866-8836-2018-7-4-29-37.
Shadrivova OV, Khostelidi SN, Chudinovskikh YA, Zabirov VS, Borzova YV, Desyatik EA, Volkova AG, Popova MO, Markova IV, Uspenskaya OS, Ruzhinskaya OS, Shneyder TV, Bogomolova TS, Ignatyeva SM, Zubarovskaya LS, Afanasyev BV, Klimko NN. Invasive aspergillosis and mucormycosis in oncohematological patients. Oncohematology 2018, 13(2):39-47. DOI: 10.17650/1818-8346-2018-13-2-39-47. (In Russian).
Klimko NN, Khostelidi SN, Volkova AG, Popova MO, Bogomolova TS, Zubarovskaya LS, Kolbin AS, Medvedeva NV, Zuzgin IS, Simkin SM, Vasilyeva NV. Afanasyev BV. Mucormycosis in haematological patients: case report and results of prospective study in Saint Petersburg, Russia. Mycoses 2014, 57: 91-96. doi:10.1111/myc.12247.
Teng JC, Slavin MA, Teh BW, Lingaratnam SM, Ananda-Rajah MR, Worth LJ, Seymour JF, Thursky KA. Epidemiology of invasive fungal disease in lymphoproliferative disorders. Haematologica. 2015; 100(11):e462-6. doi: 10.3324/haematol.2015.126698.
Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, Ito J, Andes DR, Baddley JW, Brown JM, Brumble LM, Freifeld AG, Hadley S, Herwaldt LA, Kauffman CA, Knapp K, Lyon GM, Morrison VA, Papanicolaou G, Patterson TF, Perl TM, Schuster MG, Walker R, Wannemuehler KA, Wingard JR, Chiller TM, Pappas PG. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: overview of the transplant-associated infection surveillance network (TRANSNET) database. Clin Infect Dis. 2010, 50:1091–1100. DOI: 10.1086/651263.
Martino R, Lopez R, Sureda A, Brunet S, Domingo-Albos A. Risk of reactivation of a recent invasive fungal infection in patients with hematological malignancies undergoing further intensive chemo-radiotherapy. A single-center experience and review of the literature. Haematologica. 1997; 82:297–304.
Offner F, Cordonnier C, Ljungman P, Prentice HG, Engelhard D, De Bacquer D, Meunier F, De Pauw B. Impact of previous aspergillosis on the outcome of bone marrow transplantation. Clin Infect Dis. 1998, 26:1098–1103. DOI: 10.1086/520274.
Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002;34: 909-917. DOI: 10.1086/339202.
Fukuda T, Boeckh M, Guthrie KA, Mattson DK, Owens S, Wald A, Sandmaier BM, Corey L, Storb RF, Marr KA. Invasive aspergillosis before allogeneic hematopoietic stem cell transplantation: 10-year experience at a single transplant center. Biol Blood Marrow Transplant. 2004; 10: 494-503. DOI: 10.1016/j.bbmt.2004.02.006.
Maziarz RT, Brazauskas R, Chen M, McLeod AA, Martino R, Wingard JR, Aljurf M, Battiwalla M, Dvorak CC, Geroge B, Guinan EC, Hale GA, Lazarus HM, Lee JW, Liesveld JL, Ramanathan M, Reddy V, Savani BN, Smith FO, Strasfeld L, Taplitz RA, Ustun C, Boeckh MJ, Gea-Banacloche J, Lindemans CA, Auletta JJ, Riches ML. Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study. Bone Marrow Transplant. 2017; 52(2):270-278. DOI: 10.1038/bmt.2016.259.
Popova MO, Volkova A, Elias Soulaiman S, Vavilov V, Bondarenko S, Slesarchuk O, Smirnova A, Shadrivova O, Khostelidi S, Ignatyeva S, Bogomolova T, Zubarovskaya L, Klimko N, Afanasyev B. Allogeneic hematopoietic stem cell transplantation in patients with invasive aspergillosis. Bone Marrow Transplantation. 2015, Volume 50, Supplement 1, S33.
Popova MO, Volkova AG, Soulaiman SE, Pinegina ON, Ignatyeva SM, Bogomolova TS, Smirnova AG, Vladovskaya M D, Bondarenko SN, Zubarovskaya LS, Klimko NN, Afanasyev BV. Outcome of allogeneic hematopoietic stem cell transplantation in patients with prior invasive aspergillosis. Blood. 2015; 126(23):3123; DOI: https://doi.org/
Penack O, Tridello G, Hoek J, Socié G, Blaise D, Passweg J, Chevallier P, Craddock C, Milpied N, Veelken H, Maertens J, Ljungman P, Cornelissen J, Thiebaut-Bertrand A, Lioure B, Michallet M, Iacobelli S, Nagler A, Mohty M, Cesaro S. Influence of pre-existing invasive aspergillosis on allo-HSCT outcome: a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties. Bone Marrow Transplant. 2016; 51(3):418-23. doi: 10.1038/bmt.2015.237.
Allinson K, Kolve H, Gumbinger HG, Vormoor HJ, Ehlert K, Groll AH. Secondary antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell recipients. J Antimicrob Chemother. 2008;61:734-742.
Cordonnier C, Maury S, Pautas C, Bastie JN, Chehata S, Castaigne S, Kuentz M, Bretagne S, Ribaud P. Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients. Bone Marrow Transplant. 2004;33(9):943-948.
Cordonnier C, Rovira M, Maertens J, Olavarria E, Faucher C, Bilger K, Pigneux A, Cornely OA, Ullmann AJ, Bofarull RM, de la Cámara R, Weisser M, Liakopoulou E, Abecasis M, Heussel CP, Pineau M, Ljungman P, Einsele H. Voriconazole for secondary prophylaxis of invasive fungal infections in patients with allogeneic stem cell transplants recipients: results of the VOSIFI Study Group; Infectious Diseases Working Party, European Group for Blood and Marrow Transplantation. Haematologica. 2010; 95(10):1762-1768. doi:10.3324/haematol.2009.020073.
Azoulay E, Mokart D, Pène F, Lambert J, Kouatchet A, Mayaux J, Vincent F, Nyunga M, Bruneel F, Laisne LM, Rabbat A, Lebert C, Perez P, Chaize M, Renault A, Meert AP, Benoit D, Hamidfar R, Jourdain M, Darmon M, Schlemmer B, Chevret S, Lemiale V. Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium – a groupe de recherche respiratoire en reanimation onco-hematologique study. J Clin Oncol. 2013;31(22):2810-2818. doi: 10.1200/JCO.2012.47.2365.
Legrand M, Max A, Peigne V, Mariotte E, Canet E, Debrumetz A, Lemiale V, Seguin A, Darmon M, Schlemmer B, Azoulay E. Survival in neutropenic patients with severe sepsis or septic shock. Crit Care Med. 2012;40(1):43-9. doi: 10.1097/CCM.0b013e31822b50c2.

" ["~DETAIL_TEXT"]=> string(26455) "

Introduction

The aim of this study was to estimate impact of prior proven or probable invasive fungal diseases on clinical outcome of allo-HSCT in children and adults.

Patients and methods

Results

Table 3. The main outcomes of allo-HSCT in patients with history of prior IFD as compared to patients without history of IFD

Discussion

Acknowledgments

Conflict of interest

No conflict of interests is declared.

References

Passweg JR, Baldomero H, Basak GW, Chabannon C, Corbacioglu S, Duarte R, Kuball J, Lankester A, Montoto S, de Latour RP, Snowden JA, Styczynski J, Yakoub-Agha I, Arat M, Mohty M, Kröger N; European Society for Blood and Marrow Transplantation (EBMT). The EBMT activity survey report 2017: a focus on allogeneic HCT for nonmalignant indications and on the use of non-HCT cell therapies. Bone Marrow Transplant 2019, Feb 6. doi: 10.1038/s41409-019-0465-9.
Afanasyev BV, Zubarovskaya LS, Semenova EV, Ivanova NE, Alyanskiy AL, Morozova EV, Mikhailova NB, Darskaya EI, Estrina MA, Golovacheva AA, Babenko EV, Bondarenko SN, Ganapiev AA, Bogomolny MP. The experience in non-relative allogenic transplantation of stem hemopoietic cells in the clinic of bone marrow transplantation at I. P. Pavlov St. Petersburg Medical Academy. Terapevticheskii Arkhiv 2007, 79 (7):36-43 (In Russian).
Bondarenko SN, Moiseev IS, Slesarchuk OA, Darskaya EI, Ekushev KA, Smirnova AG, Alyanskiy AL, Gindina TL, Babenko EV, Kuzmich EV, Semenova EV, Kulagin AD, Zubarovskaya LS, Afanasyev BV. Allogeneic hematopoietic stem cell transplantation in children and adults with acute lymphoblastic leukemia. Cell Ther Transplant. 2016, 5 (2):12-20.
Afanasyev BV, Zubarovskaya LS, Moiseev IS. Allogeneic hematopoietic stem cell transplantation in children: now, problems and prospects. Russian Journal of Children Hematology and Oncology. 2015, 2: 28-42 (In Russian).
Baron F, Labopin M, Peniket A, Jindra P, Afanasyev B, Sanz M.A, Deconinck E, Nagler A, Mohty M. Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Cancer 2015; 121(7): 1048-1055.
Moiseev IS, Pirogova OV, Babenko EV, Gindina TL, Darskaya EI, Morozova EV, Bondarenko SN, Afanasyev BV. Single-agent post-transplantation cyclophosphamide versus calcineurin-based graft-versus-host disease prophylaxis in matched related bone marrow transplantation. Cell Ther Transplant. 2017; 6 (4): 52-59.
Bykova TA, Borovkova AS, Osipova AA, Ovechkina VN, Sheveleva PV, Nadzhafava KU, Yager VU, Paina OV, Kozhokar PV, Alyanskyi AL, Kulagin AD, Semenova EV, Smirnov BI, Zubarovskaya LS, Afanasyev BV. Acute GvHD prophylaxis with posttransplant cyclophosphamide after hematopoietic stem cell transplantation (HSCT) for non-malignant disorders. Pediatric Hematology/Oncology and Immunopathology 2018, 17 (2), pp. 51-58 (In Russian).
Moiseev IS, Darskaya EI, Bykova TA, Morozova EV, Alyanskiy AL, Babenko EV, Bondarenko SN, Markova IV, Afanasyev BV. Different risk factors of acute and chronic graft-versus-host disease with conventional prophylaxis and posttransplantation cyclophosphamide in matched related and unrelated donor transplantation. Cell Ther Transplant. 2018; 7 (4): 29-37. DOI: 10.18620/ctt-1866-8836-2018-7-4-29-37.
Shadrivova OV, Khostelidi SN, Chudinovskikh YA, Zabirov VS, Borzova YV, Desyatik EA, Volkova AG, Popova MO, Markova IV, Uspenskaya OS, Ruzhinskaya OS, Shneyder TV, Bogomolova TS, Ignatyeva SM, Zubarovskaya LS, Afanasyev BV, Klimko NN. Invasive aspergillosis and mucormycosis in oncohematological patients. Oncohematology 2018, 13(2):39-47. DOI: 10.17650/1818-8346-2018-13-2-39-47. (In Russian).
Klimko NN, Khostelidi SN, Volkova AG, Popova MO, Bogomolova TS, Zubarovskaya LS, Kolbin AS, Medvedeva NV, Zuzgin IS, Simkin SM, Vasilyeva NV. Afanasyev BV. Mucormycosis in haematological patients: case report and results of prospective study in Saint Petersburg, Russia. Mycoses 2014, 57: 91-96. doi:10.1111/myc.12247.
Teng JC, Slavin MA, Teh BW, Lingaratnam SM, Ananda-Rajah MR, Worth LJ, Seymour JF, Thursky KA. Epidemiology of invasive fungal disease in lymphoproliferative disorders. Haematologica. 2015; 100(11):e462-6. doi: 10.3324/haematol.2015.126698.
Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, Ito J, Andes DR, Baddley JW, Brown JM, Brumble LM, Freifeld AG, Hadley S, Herwaldt LA, Kauffman CA, Knapp K, Lyon GM, Morrison VA, Papanicolaou G, Patterson TF, Perl TM, Schuster MG, Walker R, Wannemuehler KA, Wingard JR, Chiller TM, Pappas PG. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: overview of the transplant-associated infection surveillance network (TRANSNET) database. Clin Infect Dis. 2010, 50:1091–1100. DOI: 10.1086/651263.
Martino R, Lopez R, Sureda A, Brunet S, Domingo-Albos A. Risk of reactivation of a recent invasive fungal infection in patients with hematological malignancies undergoing further intensive chemo-radiotherapy. A single-center experience and review of the literature. Haematologica. 1997; 82:297–304.
Offner F, Cordonnier C, Ljungman P, Prentice HG, Engelhard D, De Bacquer D, Meunier F, De Pauw B. Impact of previous aspergillosis on the outcome of bone marrow transplantation. Clin Infect Dis. 1998, 26:1098–1103. DOI: 10.1086/520274.
Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002;34: 909-917. DOI: 10.1086/339202.
Fukuda T, Boeckh M, Guthrie KA, Mattson DK, Owens S, Wald A, Sandmaier BM, Corey L, Storb RF, Marr KA. Invasive aspergillosis before allogeneic hematopoietic stem cell transplantation: 10-year experience at a single transplant center. Biol Blood Marrow Transplant. 2004; 10: 494-503. DOI: 10.1016/j.bbmt.2004.02.006.
Maziarz RT, Brazauskas R, Chen M, McLeod AA, Martino R, Wingard JR, Aljurf M, Battiwalla M, Dvorak CC, Geroge B, Guinan EC, Hale GA, Lazarus HM, Lee JW, Liesveld JL, Ramanathan M, Reddy V, Savani BN, Smith FO, Strasfeld L, Taplitz RA, Ustun C, Boeckh MJ, Gea-Banacloche J, Lindemans CA, Auletta JJ, Riches ML. Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study. Bone Marrow Transplant. 2017; 52(2):270-278. DOI: 10.1038/bmt.2016.259.
Popova MO, Volkova A, Elias Soulaiman S, Vavilov V, Bondarenko S, Slesarchuk O, Smirnova A, Shadrivova O, Khostelidi S, Ignatyeva S, Bogomolova T, Zubarovskaya L, Klimko N, Afanasyev B. Allogeneic hematopoietic stem cell transplantation in patients with invasive aspergillosis. Bone Marrow Transplantation. 2015, Volume 50, Supplement 1, S33.
Popova MO, Volkova AG, Soulaiman SE, Pinegina ON, Ignatyeva SM, Bogomolova TS, Smirnova AG, Vladovskaya M D, Bondarenko SN, Zubarovskaya LS, Klimko NN, Afanasyev BV. Outcome of allogeneic hematopoietic stem cell transplantation in patients with prior invasive aspergillosis. Blood. 2015; 126(23):3123; DOI: https://doi.org/
Penack O, Tridello G, Hoek J, Socié G, Blaise D, Passweg J, Chevallier P, Craddock C, Milpied N, Veelken H, Maertens J, Ljungman P, Cornelissen J, Thiebaut-Bertrand A, Lioure B, Michallet M, Iacobelli S, Nagler A, Mohty M, Cesaro S. Influence of pre-existing invasive aspergillosis on allo-HSCT outcome: a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties. Bone Marrow Transplant. 2016; 51(3):418-23. doi: 10.1038/bmt.2015.237.
Allinson K, Kolve H, Gumbinger HG, Vormoor HJ, Ehlert K, Groll AH. Secondary antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell recipients. J Antimicrob Chemother. 2008;61:734-742.
Cordonnier C, Maury S, Pautas C, Bastie JN, Chehata S, Castaigne S, Kuentz M, Bretagne S, Ribaud P. Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients. Bone Marrow Transplant. 2004;33(9):943-948.
Cordonnier C, Rovira M, Maertens J, Olavarria E, Faucher C, Bilger K, Pigneux A, Cornely OA, Ullmann AJ, Bofarull RM, de la Cámara R, Weisser M, Liakopoulou E, Abecasis M, Heussel CP, Pineau M, Ljungman P, Einsele H. Voriconazole for secondary prophylaxis of invasive fungal infections in patients with allogeneic stem cell transplants recipients: results of the VOSIFI Study Group; Infectious Diseases Working Party, European Group for Blood and Marrow Transplantation. Haematologica. 2010; 95(10):1762-1768. doi:10.3324/haematol.2009.020073.
Azoulay E, Mokart D, Pène F, Lambert J, Kouatchet A, Mayaux J, Vincent F, Nyunga M, Bruneel F, Laisne LM, Rabbat A, Lebert C, Perez P, Chaize M, Renault A, Meert AP, Benoit D, Hamidfar R, Jourdain M, Darmon M, Schlemmer B, Chevret S, Lemiale V. Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium – a groupe de recherche respiratoire en reanimation onco-hematologique study. J Clin Oncol. 2013;31(22):2810-2818. doi: 10.1200/JCO.2012.47.2365.
Legrand M, Max A, Peigne V, Mariotte E, Canet E, Debrumetz A, Lemiale V, Seguin A, Darmon M, Schlemmer B, Azoulay E. Survival in neutropenic patients with severe sepsis or septic shock. Crit Care Med. 2012;40(1):43-9. doi: 10.1097/CCM.0b013e31822b50c2.

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Увеличилось число пациентов с ИМ, кандидатов на аллогенную трансплантацию гемопоэтических стволовых клеток (алло-ТГСК). Роль ИМ, развившихся до алло-ТГСК, по-прежнему не определена. Нет опубликованных данных о результатах алло-ТГСК у педиатрических пациентов с предшествующим ИМ. Цель исследования – оценить влияние предшествующего ИМ на результаты алло-ТГСК. <h3>Пациенты и методы</h3> В проспективное исследование были включены 504 реципиента алло-ТГСК в период с января 2013 года по июль 2016 года. Средний возраст составил 24 года (2 месяца – 76 лет), дети (<18 лет) – 164, взрослые – 340, мужчины – 52%. Преимущественно пациенты с диагнозом острый лейкоз группы высокого риска (74,6%). Алло-ТГСК от неродственного совместимого донора были выполнены у 58,5%, совместимого родственного донора – 22,5%, гаплоидентичного – 19%, преимущественно с использованием режима кондиционирования со сниженной интенсивностью (67%). Непосредственно перед алло-ТГСК всем пациентам с обнаруженными изменениями ткани легких, в результате компьютерной томографии органов грудной клетки, выполнялась бронхоскопия с исследованием жидкости бронхоальвеолярного лаважа: микроскопии, культуры и теста на галактоманнан. Для диагностики доказанного и вероятного ИМ и оценки ответа на терапию были использованы критерии EORTC/MSG 2008. «Активный ИМ» – ИМ, диагностированный непосредственно перед трансплантацией. Медиана наблюдения составила 20 месяцев. Основными конечными точками были общая выживаемость (ОВ), частота рецидива или прогрессирования ИМ после алло-ТГСК; вторичные точки – частота острой и хронической РТПХ, рецидива основного заболевания. <h3>Результаты</h3> Частота ИМ до алло-ТГСК составила 15% (n=76). Согласно критериям EORTS/MSG 2008, 90,8% пациентов имели вероятный и 9,2% доказанный ИМ. Этиология ИМ до трансплантации: инвазивный аспергиллез (ИА) – 75%, инвазивный кандидоз (ИК) – 13%, мукормикоз (М) – 4%, пневмоцистная пневмония (ПП) – 1,3% и комбинация ИА с М диагностирована у 2 пациентов, с ИК – 1, с ПП – 1. Основным органом поражения были легкие – 95%, другие локализации, преимущественно в сочетании с вовлечением легких: синусы – 9%, селезенка – 6%, печень – 6%, и мягкие ткани – 3%. Противогрибковая терапия перед алло-ТГСК применялась у 75% пациентов с медианой продолжительности – 2 месяца. Полный ответ на противогрибковую терапию был достигнут у 38,2% пациентов, частичный ответ или стабилизация – 35,5%, а у 26,3% пациентов был «активный ИМ». После алло-ТГСК все пациенты получали противогрибковую терапию или вторичную профилактику в соответствии с этиологией ИМ. Кумулятивная частота рецидива или прогрессирования ИМ после алло-ТГСК составила 14,5%. Отсутствие ремиссии основного заболевания в момент трансплантации был единственным фактором риска рецидива или прогрессирования ИМ после алло-ТГСК (11,5% против 21,1%, p=0,03). Существенных различий в кумулятивной частоте острой (p=0,28), хронической РТПХ (p=0,25) и рецидива (p=0,31) не было обнаружено в сравнении с группой пациентов без ИМ в анамнезе. 3-летняя ОВ после алло-ТГСК составила 67,5%. Общая выживаемость у реципиентов аллоТГСК без ИМ и имевших ИМ в анамнезе статистически не различалась во всех группах (60,5% против 68,7%, р=0,1), как отдельно у детей (50,0% против 57,4% , P=0,32) так и у взрослых (63,3% против 74,6%, p=0,09). Наихудший результат наблюдался у пациентов с «активным ИМ» и отсутствием ремиссии основного заболевания на момент трансплантации (3-летняя ОВ – 20%, р <0,001). Однако у пациентов с «активным ИМ» и ремиссией основного заболевания ОВ была аналогична выживаемости пациентов без ИМ в ананмнезе (80% против 68,7%, р=0,57). <h3>Выводы</h3> Пятнадцать процентов реципиентов алло-ТГСК имели инвазивный микоз в анамнезе. Кумулятивная частота рецидива или прогрессирования инвазивных микозов после алло-ТГСК составила 14,5%. Предшествующий инвазивный микоз не оказывал существенного влияния на результаты трансплантации и общую выживаемость детей и взрослых после алло-ТГСК. Отсутствие ремиссии основного заболевания на момент трансплантации было единственным фактором риска рецидива или прогрессирования инвазивного микоза, и ухудшения результатов алло-ТГСК. <h2>Ключевые слова</h2> Предшествующие инвазивные микозы, аллогенная трансплантация гемопоэтических стволовых клеток, дети и взрослые, клинические исходы." 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Попова 1, Алиса Г. Волкова 1, Инна В. Маркова 1, Оксана В. Айзсилниекс 1, Юлия А. Рогачева 1, Анастасия С. Фролова 1, Александр Н. Швецов 1, Илья Ю. Николаев 1, Светлана М. Игнатьева 2, Татьяна С. Богомолова 2, Асмик Г. Геворгян 1, Олеся В. Паина 1, Татьяна А. Быкова 1, Елена И. Дарская 1, Мария В. Владовская 1, Иван С. Моисеев 1, Людмила С. Зубаровская 1, Николай Н. Климко 1,2, Борис В. Афанасьев 1" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(907) "

Марина О. Попова ¹, Алиса Г. Волкова ¹, Инна В. Маркова ¹, Оксана В. Айзсилниекс ¹, Юлия А. Рогачева ¹, Анастасия С. Фролова ¹, Александр Н. Швецов ¹, Илья Ю. Николаев ¹, Светлана М. Игнатьева ², Татьяна С. Богомолова ², Асмик Г. Геворгян ¹, Олеся В. Паина ¹, Татьяна А. Быкова ¹, Елена И. Дарская ¹, Мария В. Владовская ¹, Иван С. Моисеев ¹, Людмила С. Зубаровская ¹, Николай Н. Климко ^1,2, Борис В. Афанасьев ¹

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¹ НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургсий государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
² НИИ Медицинской микологии им. П. Н. Кашкина, Северо-западный государственный медицинский университет им. И. И. Мечникова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "23052" ["VALUE"]=> array(2) { ["TEXT"]=> string(8272) "Внедрение новых противогрибковых средств и диагностических процедур улучшило прогноз гематологических пациентов с инвазивными микозами (ИМ). Увеличилось число пациентов с ИМ, кандидатов на аллогенную трансплантацию гемопоэтических стволовых клеток (алло-ТГСК). Роль ИМ, развившихся до алло-ТГСК, по-прежнему не определена. Нет опубликованных данных о результатах алло-ТГСК у педиатрических пациентов с предшествующим ИМ. Цель исследования – оценить влияние предшествующего ИМ на результаты алло-ТГСК. <h3>Пациенты и методы</h3> В проспективное исследование были включены 504 реципиента алло-ТГСК в период с января 2013 года по июль 2016 года. Средний возраст составил 24 года (2 месяца – 76 лет), дети (<18 лет) – 164, взрослые – 340, мужчины – 52%. Преимущественно пациенты с диагнозом острый лейкоз группы высокого риска (74,6%). Алло-ТГСК от неродственного совместимого донора были выполнены у 58,5%, совместимого родственного донора – 22,5%, гаплоидентичного – 19%, преимущественно с использованием режима кондиционирования со сниженной интенсивностью (67%). Непосредственно перед алло-ТГСК всем пациентам с обнаруженными изменениями ткани легких, в результате компьютерной томографии органов грудной клетки, выполнялась бронхоскопия с исследованием жидкости бронхоальвеолярного лаважа: микроскопии, культуры и теста на галактоманнан. Для диагностики доказанного и вероятного ИМ и оценки ответа на терапию были использованы критерии EORTC/MSG 2008. «Активный ИМ» – ИМ, диагностированный непосредственно перед трансплантацией. Медиана наблюдения составила 20 месяцев. Основными конечными точками были общая выживаемость (ОВ), частота рецидива или прогрессирования ИМ после алло-ТГСК; вторичные точки – частота острой и хронической РТПХ, рецидива основного заболевания. <h3>Результаты</h3> Частота ИМ до алло-ТГСК составила 15% (n=76). Согласно критериям EORTS/MSG 2008, 90,8% пациентов имели вероятный и 9,2% доказанный ИМ. Этиология ИМ до трансплантации: инвазивный аспергиллез (ИА) – 75%, инвазивный кандидоз (ИК) – 13%, мукормикоз (М) – 4%, пневмоцистная пневмония (ПП) – 1,3% и комбинация ИА с М диагностирована у 2 пациентов, с ИК – 1, с ПП – 1. Основным органом поражения были легкие – 95%, другие локализации, преимущественно в сочетании с вовлечением легких: синусы – 9%, селезенка – 6%, печень – 6%, и мягкие ткани – 3%. Противогрибковая терапия перед алло-ТГСК применялась у 75% пациентов с медианой продолжительности – 2 месяца. Полный ответ на противогрибковую терапию был достигнут у 38,2% пациентов, частичный ответ или стабилизация – 35,5%, а у 26,3% пациентов был «активный ИМ». После алло-ТГСК все пациенты получали противогрибковую терапию или вторичную профилактику в соответствии с этиологией ИМ. Кумулятивная частота рецидива или прогрессирования ИМ после алло-ТГСК составила 14,5%. Отсутствие ремиссии основного заболевания в момент трансплантации был единственным фактором риска рецидива или прогрессирования ИМ после алло-ТГСК (11,5% против 21,1%, p=0,03). Существенных различий в кумулятивной частоте острой (p=0,28), хронической РТПХ (p=0,25) и рецидива (p=0,31) не было обнаружено в сравнении с группой пациентов без ИМ в анамнезе. 3-летняя ОВ после алло-ТГСК составила 67,5%. Общая выживаемость у реципиентов аллоТГСК без ИМ и имевших ИМ в анамнезе статистически не различалась во всех группах (60,5% против 68,7%, р=0,1), как отдельно у детей (50,0% против 57,4% , P=0,32) так и у взрослых (63,3% против 74,6%, p=0,09). Наихудший результат наблюдался у пациентов с «активным ИМ» и отсутствием ремиссии основного заболевания на момент трансплантации (3-летняя ОВ – 20%, р <0,001). Однако у пациентов с «активным ИМ» и ремиссией основного заболевания ОВ была аналогична выживаемости пациентов без ИМ в ананмнезе (80% против 68,7%, р=0,57). <h3>Выводы</h3> Пятнадцать процентов реципиентов алло-ТГСК имели инвазивный микоз в анамнезе. Кумулятивная частота рецидива или прогрессирования инвазивных микозов после алло-ТГСК составила 14,5%. Предшествующий инвазивный микоз не оказывал существенного влияния на результаты трансплантации и общую выживаемость детей и взрослых после алло-ТГСК. Отсутствие ремиссии основного заболевания на момент трансплантации было единственным фактором риска рецидива или прогрессирования инвазивного микоза, и ухудшения результатов алло-ТГСК. <h2>Ключевые слова</h2> Предшествующие инвазивные микозы, аллогенная трансплантация гемопоэтических стволовых клеток, дети и взрослые, клинические исходы." 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Внедрение новых противогрибковых средств и диагностических процедур улучшило прогноз гематологических пациентов с инвазивными микозами (ИМ). Увеличилось число пациентов с ИМ, кандидатов на аллогенную трансплантацию гемопоэтических стволовых клеток (алло-ТГСК). Роль ИМ, развившихся до алло-ТГСК, по-прежнему не определена. Нет опубликованных данных о результатах алло-ТГСК у педиатрических пациентов с предшествующим ИМ. Цель исследования – оценить влияние предшествующего ИМ на результаты алло-ТГСК.

Пациенты и методы

В проспективное исследование были включены 504 реципиента алло-ТГСК в период с января 2013 года по июль 2016 года. Средний возраст составил 24 года (2 месяца – 76 лет), дети (<18 лет) – 164, взрослые – 340, мужчины – 52%. Преимущественно пациенты с диагнозом острый лейкоз группы высокого риска (74,6%). Алло-ТГСК от неродственного совместимого донора были выполнены у 58,5%, совместимого родственного донора – 22,5%, гаплоидентичного – 19%, преимущественно с использованием режима кондиционирования со сниженной интенсивностью (67%). Непосредственно перед алло-ТГСК всем пациентам с обнаруженными изменениями ткани легких, в результате компьютерной томографии органов грудной клетки, выполнялась бронхоскопия с исследованием жидкости бронхоальвеолярного лаважа: микроскопии, культуры и теста на галактоманнан. Для диагностики доказанного и вероятного ИМ и оценки ответа на терапию были использованы критерии EORTC/MSG 2008. «Активный ИМ» – ИМ, диагностированный непосредственно перед трансплантацией. Медиана наблюдения составила 20 месяцев. Основными конечными точками были общая выживаемость (ОВ), частота рецидива или прогрессирования ИМ после алло-ТГСК; вторичные точки – частота острой и хронической РТПХ, рецидива основного заболевания.

Результаты

Частота ИМ до алло-ТГСК составила 15% (n=76). Согласно критериям EORTS/MSG 2008, 90,8% пациентов имели вероятный и 9,2% доказанный ИМ. Этиология ИМ до трансплантации: инвазивный аспергиллез (ИА) – 75%, инвазивный кандидоз (ИК) – 13%, мукормикоз (М) – 4%, пневмоцистная пневмония (ПП) – 1,3% и комбинация ИА с М диагностирована у 2 пациентов, с ИК – 1, с ПП – 1. Основным органом поражения были легкие – 95%, другие локализации, преимущественно в сочетании с вовлечением легких: синусы – 9%, селезенка – 6%, печень – 6%, и мягкие ткани – 3%. Противогрибковая терапия перед алло-ТГСК применялась у 75% пациентов с медианой продолжительности – 2 месяца. Полный ответ на противогрибковую терапию был достигнут у 38,2% пациентов, частичный ответ или стабилизация – 35,5%, а у 26,3% пациентов был «активный ИМ». После алло-ТГСК все пациенты получали противогрибковую терапию или вторичную профилактику в соответствии с этиологией ИМ. Кумулятивная частота рецидива или прогрессирования ИМ после алло-ТГСК составила 14,5%. Отсутствие ремиссии основного заболевания в момент трансплантации был единственным фактором риска рецидива или прогрессирования ИМ после алло-ТГСК (11,5% против 21,1%, p=0,03). Существенных различий в кумулятивной частоте острой (p=0,28), хронической РТПХ (p=0,25) и рецидива (p=0,31) не было обнаружено в сравнении с группой пациентов без ИМ в анамнезе. 3-летняя ОВ после алло-ТГСК составила 67,5%. Общая выживаемость у реципиентов аллоТГСК без ИМ и имевших ИМ в анамнезе статистически не различалась во всех группах (60,5% против 68,7%, р=0,1), как отдельно у детей (50,0% против 57,4% , P=0,32) так и у взрослых (63,3% против 74,6%, p=0,09). Наихудший результат наблюдался у пациентов с «активным ИМ» и отсутствием ремиссии основного заболевания на момент трансплантации (3-летняя ОВ – 20%, р <0,001). Однако у пациентов с «активным ИМ» и ремиссией основного заболевания ОВ была аналогична выживаемости пациентов без ИМ в ананмнезе (80% против 68,7%, р=0,57).

Выводы

Пятнадцать процентов реципиентов алло-ТГСК имели инвазивный микоз в анамнезе. Кумулятивная частота рецидива или прогрессирования инвазивных микозов после алло-ТГСК составила 14,5%. Предшествующий инвазивный микоз не оказывал существенного влияния на результаты трансплантации и общую выживаемость детей и взрослых после алло-ТГСК. Отсутствие ремиссии основного заболевания на момент трансплантации было единственным фактором риска рецидива или прогрессирования инвазивного микоза, и ухудшения результатов алло-ТГСК.

Ключевые слова

Предшествующие инвазивные микозы, аллогенная трансплантация гемопоэтических стволовых клеток, дети и взрослые, клинические исходы.

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Marina O. Popova ¹, Alisa G. Volkova ¹, Inna V. Markova ¹, Oksana V. Ayzsilnieks ¹, Yulia A. Rogacheva ¹, Anastasia S. Frolova ¹, Aleksandr N. Shvetcov ¹, Ilya Y. Nikolaev ¹, Svetlana M. Ignatyeva ², Tatyana S. Bogomolova ², Asmic G. Gevorgian ¹, Olesya V. Paina ¹, Tatiana A. Bykova ¹, Elena I. Darskaya ¹, Maria V. Vladovskaya ¹, Ivan S. Moiseev ¹, Ludmila S. Zubarovskaya ¹, Nikolay N. Klimko ^1,2, Boris V. Afanasyev ¹

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¹ Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
² Dept. of Clinical Mycology, I. Mechnikov North-Western State Medical University, St. Petersburg, Russia

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Number of patients with IFD who are candidates for allogeneic hematopoietic stem cell transplant (allo-HSCT) increased. However, publications on the field are limited and there are no data on results of pediatric allo-HSCT patients with prior IFD. This study focuses on the outcomes of allo-HSCT in children and adults with prior IFD. <h3>Patients and methods</h3> In a prospective study, 504 allo-HSCT recipients were included from Jan 2013 to Jul 2016. The median age was 24 y.o. [2 months to 76 years] including 164 children (<18 yo) and 340 adults. The cohort included 52% male patients. Most patients (74.6%) were diagnosed with high-risk acute leukemia. Allo-HSCT from HLA-matched unrelated donors (MUD) was performed in 58.5%, from matched related donors (MRD), 22.5%; haploidentical HSCT was performed in 19% of patients, predominantly with RIC (67%). EORTC/MSG 2008 criteria for diagnosis and response to therapy were used. In the patients with pre-transplant lung lesions detected by CT scan, bronchoscopy with BAL was used. “Active IFD” means IFD diagnosed just before HSCT. <h3>Results</h3> Incidence of IFD before allo-HSCT was 15% (n=76). According to EORTS/MSG 2008 criteria, 90.8% of patients had probable and 9.2% presented with proven IFD. Etiology of IFD prior to HSCT was as follows: invasive aspergillosis (IA), 75%; invasive candidiasis (IC), 13%; mucormycosis (Mu), 4%; Pneumocystis pneumoniae (PCP), 1.3%, and combination of IA with Mu (2 cases), IC (n=1), PCP (n=1). The main sites of infection were lungs (95%), other localizations were predominantly combined with lung involvement: sinuses (9%), spleen (6%), liver (6%), and soft tissues (3%). Antifungal therapy before allo-HSCT was used in 75% patients with median duration of 2 months. Complete response to antifungal therapy was observed in 38.2% of the cases, partial response or stabilization was achieved in 35.5%, and “active IFD” was detected in 26.3% of the patients. After allo-HSCT, all the patients received antifungal therapy or secondary prophylaxis according to the IFD etiology. Cumulative incidence of relapse or progression of IFD after allo-HSCT was observed in 14.5%. Active underlying disease (hematology malignancy) at the moment of HSCT was the only risk factor for relapse or progression of IFD after allo-HSCT (11.5% vs 21.1%, p=0,03). We detected no significant differences in the cumulative incidence of acute, chronic GVHD and relapse in the study group as compared to the patients without history of IFD. 3-year overall survival (OS) after allo-HSCT was 67.5%. The impact of prior IFD on overall survival in allo-HSCT recipients was not statistically significant for the entire group (60.5% vs 68.7%, p=0.1), and, separately, for children (50.0% vs 57.4%, p=0,3) and adults (63.3% vs 74.6%, p=0.09). The worst outcome was observed in the patients with “active IFD” and active underlying disease at the moment of HSCT (3-year OS was 20%, p<0.001 compared to patients without history of IFD). However, in the patients with “active IFD” and remission of underlying disease, OS value was similar to survival rate of patients without history of IFD (80% vs 68.7%, p=0.2). <h3>Conclusion</h3> Incidence of IFD before allo-HSCT was 15%. Cumulative incidence of relapse or progression of IFD after allo-HSCT was 14.5%. Prior IFD had no significant impact on transplant-related complications and overall survival in children and adults undergoing allo-HSCT. Active underlying disease at the moment of HSCT was the only risk factor for relapse or progression of IFD and impaired outcome of allo-HSCT. <h2>Keywords</h2> Invasive fungal disease, pre-existing IFD, allogeneic hematopoietic stem cell transplantation, children and adults, clinical outcomes. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4216) "

Invasive fungal diseases (IFD) are a major cause of morbidity and mortality in hematological patients, but prognosis of IFD has improved recently, due to introduction of new antifungals and efficient diagnostic procedures. Number of patients with IFD who are candidates for allogeneic hematopoietic stem cell transplant (allo-HSCT) increased. However, publications on the field are limited and there are no data on results of pediatric allo-HSCT patients with prior IFD. This study focuses on the outcomes of allo-HSCT in children and adults with prior IFD.

Patients and methods

In a prospective study, 504 allo-HSCT recipients were included from Jan 2013 to Jul 2016. The median age was 24 y.o. [2 months to 76 years] including 164 children (<18 yo) and 340 adults. The cohort included 52% male patients. Most patients (74.6%) were diagnosed with high-risk acute leukemia. Allo-HSCT from HLA-matched unrelated donors (MUD) was performed in 58.5%, from matched related donors (MRD), 22.5%; haploidentical HSCT was performed in 19% of patients, predominantly with RIC (67%). EORTC/MSG 2008 criteria for diagnosis and response to therapy were used. In the patients with pre-transplant lung lesions detected by CT scan, bronchoscopy with BAL was used. “Active IFD” means IFD diagnosed just before HSCT.

Results

Incidence of IFD before allo-HSCT was 15% (n=76). According to EORTS/MSG 2008 criteria, 90.8% of patients had probable and 9.2% presented with proven IFD. Etiology of IFD prior to HSCT was as follows: invasive aspergillosis (IA), 75%; invasive candidiasis (IC), 13%; mucormycosis (Mu), 4%; Pneumocystis pneumoniae (PCP), 1.3%, and combination of IA with Mu (2 cases), IC (n=1), PCP (n=1). The main sites of infection were lungs (95%), other localizations were predominantly combined with lung involvement: sinuses (9%), spleen (6%), liver (6%), and soft tissues (3%). Antifungal therapy before allo-HSCT was used in 75% patients with median duration of 2 months. Complete response to antifungal therapy was observed in 38.2% of the cases, partial response or stabilization was achieved in 35.5%, and “active IFD” was detected in 26.3% of the patients. After allo-HSCT, all the patients received antifungal therapy or secondary prophylaxis according to the IFD etiology. Cumulative incidence of relapse or progression of IFD after allo-HSCT was observed in 14.5%. Active underlying disease (hematology malignancy) at the moment of HSCT was the only risk factor for relapse or progression of IFD after allo-HSCT (11.5% vs 21.1%, p=0,03). We detected no significant differences in the cumulative incidence of acute, chronic GVHD and relapse in the study group as compared to the patients without history of IFD. 3-year overall survival (OS) after allo-HSCT was 67.5%. The impact of prior IFD on overall survival in allo-HSCT recipients was not statistically significant for the entire group (60.5% vs 68.7%, p=0.1), and, separately, for children (50.0% vs 57.4%, p=0,3) and adults (63.3% vs 74.6%, p=0.09). The worst outcome was observed in the patients with “active IFD” and active underlying disease at the moment of HSCT (3-year OS was 20%, p<0.001 compared to patients without history of IFD). However, in the patients with “active IFD” and remission of underlying disease, OS value was similar to survival rate of patients without history of IFD (80% vs 68.7%, p=0.2).

Conclusion

Incidence of IFD before allo-HSCT was 15%. Cumulative incidence of relapse or progression of IFD after allo-HSCT was 14.5%. Prior IFD had no significant impact on transplant-related complications and overall survival in children and adults undergoing allo-HSCT. Active underlying disease at the moment of HSCT was the only risk factor for relapse or progression of IFD and impaired outcome of allo-HSCT.

Keywords

Invasive fungal disease, pre-existing IFD, allogeneic hematopoietic stem cell transplantation, children and adults, clinical outcomes.

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Popova 1, Alisa G. Volkova 1, Inna V. Markova 1, Oksana V. Ayzsilnieks 1, Yulia A. Rogacheva 1, Anastasia S. Frolova 1, Aleksandr N. Shvetcov 1, Ilya Y. Nikolaev 1, Svetlana M. Ignatyeva 2, Tatyana S. Bogomolova 2, Asmic G. Gevorgian 1, Olesya V. Paina 1, Tatiana A. Bykova 1, Elena I. Darskaya 1, Maria V. Vladovskaya 1, Ivan S. Moiseev 1, Ludmila S. Zubarovskaya 1, Nikolay N. Klimko 1,2, Boris V. Afanasyev 1" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(637) "

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "23075" ["VALUE"]=> array(2) { ["TEXT"]=> string(4452) "Invasive fungal diseases (IFD) are a major cause of morbidity and mortality in hematological patients, but prognosis of IFD has improved recently, due to introduction of new antifungals and efficient diagnostic procedures. Number of patients with IFD who are candidates for allogeneic hematopoietic stem cell transplant (allo-HSCT) increased. However, publications on the field are limited and there are no data on results of pediatric allo-HSCT patients with prior IFD. This study focuses on the outcomes of allo-HSCT in children and adults with prior IFD. <h3>Patients and methods</h3> In a prospective study, 504 allo-HSCT recipients were included from Jan 2013 to Jul 2016. The median age was 24 y.o. [2 months to 76 years] including 164 children (<18 yo) and 340 adults. The cohort included 52% male patients. Most patients (74.6%) were diagnosed with high-risk acute leukemia. Allo-HSCT from HLA-matched unrelated donors (MUD) was performed in 58.5%, from matched related donors (MRD), 22.5%; haploidentical HSCT was performed in 19% of patients, predominantly with RIC (67%). EORTC/MSG 2008 criteria for diagnosis and response to therapy were used. In the patients with pre-transplant lung lesions detected by CT scan, bronchoscopy with BAL was used. “Active IFD” means IFD diagnosed just before HSCT. <h3>Results</h3> Incidence of IFD before allo-HSCT was 15% (n=76). According to EORTS/MSG 2008 criteria, 90.8% of patients had probable and 9.2% presented with proven IFD. Etiology of IFD prior to HSCT was as follows: invasive aspergillosis (IA), 75%; invasive candidiasis (IC), 13%; mucormycosis (Mu), 4%; Pneumocystis pneumoniae (PCP), 1.3%, and combination of IA with Mu (2 cases), IC (n=1), PCP (n=1). The main sites of infection were lungs (95%), other localizations were predominantly combined with lung involvement: sinuses (9%), spleen (6%), liver (6%), and soft tissues (3%). Antifungal therapy before allo-HSCT was used in 75% patients with median duration of 2 months. Complete response to antifungal therapy was observed in 38.2% of the cases, partial response or stabilization was achieved in 35.5%, and “active IFD” was detected in 26.3% of the patients. After allo-HSCT, all the patients received antifungal therapy or secondary prophylaxis according to the IFD etiology. Cumulative incidence of relapse or progression of IFD after allo-HSCT was observed in 14.5%. Active underlying disease (hematology malignancy) at the moment of HSCT was the only risk factor for relapse or progression of IFD after allo-HSCT (11.5% vs 21.1%, p=0,03). We detected no significant differences in the cumulative incidence of acute, chronic GVHD and relapse in the study group as compared to the patients without history of IFD. 3-year overall survival (OS) after allo-HSCT was 67.5%. The impact of prior IFD on overall survival in allo-HSCT recipients was not statistically significant for the entire group (60.5% vs 68.7%, p=0.1), and, separately, for children (50.0% vs 57.4%, p=0,3) and adults (63.3% vs 74.6%, p=0.09). The worst outcome was observed in the patients with “active IFD” and active underlying disease at the moment of HSCT (3-year OS was 20%, p<0.001 compared to patients without history of IFD). However, in the patients with “active IFD” and remission of underlying disease, OS value was similar to survival rate of patients without history of IFD (80% vs 68.7%, p=0.2). <h3>Conclusion</h3> Incidence of IFD before allo-HSCT was 15%. Cumulative incidence of relapse or progression of IFD after allo-HSCT was 14.5%. Prior IFD had no significant impact on transplant-related complications and overall survival in children and adults undergoing allo-HSCT. Active underlying disease at the moment of HSCT was the only risk factor for relapse or progression of IFD and impaired outcome of allo-HSCT. <h2>Keywords</h2> Invasive fungal disease, pre-existing IFD, allogeneic hematopoietic stem cell transplantation, children and adults, clinical outcomes. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4216) "

Patients and methods

Results

Conclusion

Keywords

Invasive fungal disease, pre-existing IFD, allogeneic hematopoietic stem cell transplantation, children and adults, clinical outcomes.

Patients and methods

Results

Conclusion

Keywords

Invasive fungal disease, pre-existing IFD, allogeneic hematopoietic stem cell transplantation, children and adults, clinical outcomes.

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Popova" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "23052" ["VALUE"]=> array(2) { ["TEXT"]=> string(8272) "Внедрение новых противогрибковых средств и диагностических процедур улучшило прогноз гематологических пациентов с инвазивными микозами (ИМ). Увеличилось число пациентов с ИМ, кандидатов на аллогенную трансплантацию гемопоэтических стволовых клеток (алло-ТГСК). Роль ИМ, развившихся до алло-ТГСК, по-прежнему не определена. Нет опубликованных данных о результатах алло-ТГСК у педиатрических пациентов с предшествующим ИМ. Цель исследования – оценить влияние предшествующего ИМ на результаты алло-ТГСК. <h3>Пациенты и методы</h3> В проспективное исследование были включены 504 реципиента алло-ТГСК в период с января 2013 года по июль 2016 года. Средний возраст составил 24 года (2 месяца – 76 лет), дети (<18 лет) – 164, взрослые – 340, мужчины – 52%. Преимущественно пациенты с диагнозом острый лейкоз группы высокого риска (74,6%). Алло-ТГСК от неродственного совместимого донора были выполнены у 58,5%, совместимого родственного донора – 22,5%, гаплоидентичного – 19%, преимущественно с использованием режима кондиционирования со сниженной интенсивностью (67%). Непосредственно перед алло-ТГСК всем пациентам с обнаруженными изменениями ткани легких, в результате компьютерной томографии органов грудной клетки, выполнялась бронхоскопия с исследованием жидкости бронхоальвеолярного лаважа: микроскопии, культуры и теста на галактоманнан. Для диагностики доказанного и вероятного ИМ и оценки ответа на терапию были использованы критерии EORTC/MSG 2008. «Активный ИМ» – ИМ, диагностированный непосредственно перед трансплантацией. Медиана наблюдения составила 20 месяцев. Основными конечными точками были общая выживаемость (ОВ), частота рецидива или прогрессирования ИМ после алло-ТГСК; вторичные точки – частота острой и хронической РТПХ, рецидива основного заболевания. <h3>Результаты</h3> Частота ИМ до алло-ТГСК составила 15% (n=76). Согласно критериям EORTS/MSG 2008, 90,8% пациентов имели вероятный и 9,2% доказанный ИМ. Этиология ИМ до трансплантации: инвазивный аспергиллез (ИА) – 75%, инвазивный кандидоз (ИК) – 13%, мукормикоз (М) – 4%, пневмоцистная пневмония (ПП) – 1,3% и комбинация ИА с М диагностирована у 2 пациентов, с ИК – 1, с ПП – 1. Основным органом поражения были легкие – 95%, другие локализации, преимущественно в сочетании с вовлечением легких: синусы – 9%, селезенка – 6%, печень – 6%, и мягкие ткани – 3%. Противогрибковая терапия перед алло-ТГСК применялась у 75% пациентов с медианой продолжительности – 2 месяца. Полный ответ на противогрибковую терапию был достигнут у 38,2% пациентов, частичный ответ или стабилизация – 35,5%, а у 26,3% пациентов был «активный ИМ». После алло-ТГСК все пациенты получали противогрибковую терапию или вторичную профилактику в соответствии с этиологией ИМ. Кумулятивная частота рецидива или прогрессирования ИМ после алло-ТГСК составила 14,5%. Отсутствие ремиссии основного заболевания в момент трансплантации был единственным фактором риска рецидива или прогрессирования ИМ после алло-ТГСК (11,5% против 21,1%, p=0,03). Существенных различий в кумулятивной частоте острой (p=0,28), хронической РТПХ (p=0,25) и рецидива (p=0,31) не было обнаружено в сравнении с группой пациентов без ИМ в анамнезе. 3-летняя ОВ после алло-ТГСК составила 67,5%. Общая выживаемость у реципиентов аллоТГСК без ИМ и имевших ИМ в анамнезе статистически не различалась во всех группах (60,5% против 68,7%, р=0,1), как отдельно у детей (50,0% против 57,4% , P=0,32) так и у взрослых (63,3% против 74,6%, p=0,09). Наихудший результат наблюдался у пациентов с «активным ИМ» и отсутствием ремиссии основного заболевания на момент трансплантации (3-летняя ОВ – 20%, р <0,001). Однако у пациентов с «активным ИМ» и ремиссией основного заболевания ОВ была аналогична выживаемости пациентов без ИМ в ананмнезе (80% против 68,7%, р=0,57). <h3>Выводы</h3> Пятнадцать процентов реципиентов алло-ТГСК имели инвазивный микоз в анамнезе. Кумулятивная частота рецидива или прогрессирования инвазивных микозов после алло-ТГСК составила 14,5%. Предшествующий инвазивный микоз не оказывал существенного влияния на результаты трансплантации и общую выживаемость детей и взрослых после алло-ТГСК. Отсутствие ремиссии основного заболевания на момент трансплантации было единственным фактором риска рецидива или прогрессирования инвазивного микоза, и ухудшения результатов алло-ТГСК. <h2>Ключевые слова</h2> Предшествующие инвазивные микозы, аллогенная трансплантация гемопоэтических стволовых клеток, дети и взрослые, клинические исходы." 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Пациенты и методы

Результаты

Выводы

Ключевые слова

Пациенты и методы

Результаты

Выводы

Ключевые слова

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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most rapidly developing fields of medicine [1, 2, 3, 4]. Improvement of allo-HSCT technology allowed focusing on the new challenges. One of those issues is poor graft function (PGF). The incidence of PGF depends on many factors, e.g., diagnosis of the underlying disease, type of allo-HSCT, ABO-compatibility, viral reactivation, and varies between 5% and 20%, according to the most publications [5-8]. However, given the multifactorial nature of PGF, as well as frequent inability to perform etiological therapy, the treatment options are limited and poor standardized [9, 10].

Thrombopoietin is one of the main physiological regulators of platelet production and was initially considered as a linear growth factor for megakaryocytes. However, a number of studies have shown that Mpl expression is detected in 70% of hematopoietic stem cells. Thus, thrombopoietin alone or in combination with other cytokines stimulates the proliferation of early hematopoietic precursors [11, 12]. These data allowed the use of TPO-RA for the treatment of both idiopathic thrombocytopenic purpura and aplastic anemia with promising results [13-15]. The safety of using TPO-RA for malignant diseases has been questioned, however, it was analyzed in a large cohort study which showed TPO-RA therapy did not affect relapse of acute myeloid leukemia [16-18]. Recently, a number of studies have been conducted in order to expand the obtained experience to the setting of posttransplant cytopenias. TPO-RA has shown a positive effect in posttransplant thrombocytopenia, and there are some data suggesting functional improvement of other hematopoietic lineages.

Current study aims to summarize single-center experience of TPO-RA for treatment of posttransplant cytopenias, including PGF, following allo-HSCT. In this report, we present data on the efficacy of TPO-RA in a large single-center adult cohort with PGF.

Patients and methods

We have performed clinical analysis of thirty-one adult patients at the median age of 22 (18-56) years old who received TPO-RA for treatment of cytopenia after allo-HSCT in the R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I. Pavlov Medical University.

The inclusion criteria were as follows: 1) thrombocytopenia <20×10⁹/l with or without cytopenias in other hematopoietic lines; 2) complete of stable mixed donor chimerism ≥90%; 3) no signs of relapse of underlying disease, or hematopoietic graft rejection. The spectrum of disorders in which allo-HSCT was indicated is shown in Table 1.

Table 1. Characteristics of the patients

Conditioning regimen considered to be myeloablative (MAC) (n=11.38%) at the dosage of oral busulfan ≥10 mg/kg. Dose of busulfan in reduced intensity regimes (RIC) was 10 mg/kg (n=18, 62%). Depending on the severity of cytopenia, three groups were selected by the following criteria: 1) mild PGF: ANC 1.0-1.5×10⁹/l; platelets 50-100×10⁹/l; hemoglobin >100 g/l; 2) moderate PGF: ANC 0.5-1.0×10⁹/l; platelets 20-50×10⁹/l; hemoglobin 70-100 g/l, 3) severe PGF: ANC <0.5×10⁹/l; platelets <20×10⁹/l; hemoglobin <70 g/l.

The response to TPO-RA therapy was assessed according to the hemogram dynamics: complete response: ANC ≥1.0×10⁹/l, platelets ≥50×10⁹/l, hemoglobin ≥80g/l; partial response: ANC ≥0.5×10⁹/l, platelets ≥20×10⁹/l, hemoglobin ≥70 g/l; no response: ANC <0.5×10⁹/l, platelets <20×10⁹/l, hemoglobin <70 g/l. Clinical outcomes of PGF were considered as: 1) any response to therapy, 3) recurrence of a malignant disease, 3) death.

Statistical analysis

Descriptive tables were analyzed for patient-related factors, donor and transplantation. Fisher's exact test and Pearson's Chi-square were used to compare binary data. The cumulative response rate was calculated taking into account competing risks (death, relapse). Overall survival (OS) was estimated using the Kaplan-Meier method over the time from administration of TPO agonists to the date of the last contact, or the date of death. The log-rank test was used to evaluate statistical differences between curves. Statistical analysis was performed using SPSS Statistics v.17 software, EZR free statistical environment, version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

This data analysis included 31 patients treated with TPO-RA for PGF after the first or second allo-HSCT. The myeloid engraftment was documented in all cases at the median of 21 (11-48) days. Thrombocytopenia was the indication for the therapy in 7 cases, 10 and 13 patients received TPO-RA for bi- and trilineage cytopenias, respectively. Characteristics of patients and transplants are shown in Table 1.

Malignant diseases prevailed in the diagnosis landscape: 87% versus 13%, with a significant proportion in the group fell on acute leukemia (55%) and myeloproliferative diseases (26%). The majority of patients (n=17, 55%) were transplanted from unrelated HLA-matched donors. However, the number of allo-HSCT from haploidentical donors was also significant in this cohort (n=9, 29%). Bone marrow (BM) and peripheral blood stem cells (PBSC) were used as a source of graft in 41% and 48% of cases, respectively, whereas a combination of BM and PBSC was applied in 11% cases.

Majority of the patients were transplanted after RIC: 65% versus 35% treated with MAC regimens. GVHD prophylaxis depended on the type of donor and source of the graft. GVHD prophylaxis for all cases of haploidentical HSCTs except of one (n=8, 26%) consisted of posttransplant cyclophosphamide (ptCy) in combination with cyclosporine A, or tacrolimus and/or other immunosuppressants (mycophenolate mofetil or sirolimus). For HLA-matched HSCTs, ptCy, ATG in combination with CsA and methotrexate, and a combination of tacrolimus and mycophenolate mofetil was used in 2 cases, 1 case, and 1 case, respectively. Of the 17 unrelated HLA-matched HSCTs, ATG and ptCy were used in 7 and 10 cases, respectively. Thus, GVHD prophylaxis with ptCy was predominant in the analyzed group (61%, n=19). Allo-HSCT with a major AB0-incompatibility took place in 25% (n=7) cases. Most patients (81%, n=25) suffered viral reactivation (mainly cytomegalovirus) and received ganciclovir or valganciclovir at the doses of 5-10 mg/kg/day, or 450-900 mg/day, respectively. A total of 61% (n=19) of the patients had signs of acute infection at the time of starting TPO-RA therapy. The proportion of cases of acute GVHD grade III-IV was also significant (42%).

The median time from allo-HSCT to PGF was 54 days (18 to 664), with prevalence of early PGF (n=20, 65%), compared to late PGF (n=11, 35%). Severe PGF was the most frequent indication for therapy (n=24, 77%) vs posttransplant thrombocytopenia (n=7, 23%).

The median duration of PGF was 59 days (5-426). The median time from the diagnosis of PGF to the start of therapy with TPO-RA was 15 days (0-119). The median duration of the treatment was 3 (1-48) weeks. The median cumulative doses of romiplostim and eltrombopag were 15 (5-70) mg and 2100 (700-50400) mg, respectively.

TPO-RA drugs were well tolerated, with no detectable toxicity of grade 3-4. One case of hepatotoxicity grade 2 was documented with eltrombopag but didn’t require withdrawal of the drug.

TPO-RA were used in combination with other therapies in 26% of cases: rituximab in 5 cases, rituximab and infusion of donor lymphocytes in 3 cases, and a booster dose of CD34+ cells from the same donor was applied in one case.

A total of 16 (52 %) patients developed response to the TPO-RA. Complete response was documented in 4 cases (13 %), while 12 patients (39 %) showed partial response. The median of increase in ANC in responders was 1.7×10⁹/l (0.1-5.6), in platelet count – 20×109/l (2-205). The median cumulative dose of romiplostim in responders was 30 mg/kg (3.5-73), for eltrombopag it was 4900 mg (2100-50400). The median time of response for romiplostim and eltrombopag was 63 days (5-181) and 103 days (52-426), respectively. Combination therapy had no benefits in the response rate compared to monotherapy with TPO-RA. Overall response was similar for both medications. Our analysis showed no influence of infections (including viral), or acute GVHD grade 3-4 on the cumulative response to the TPO-RA therapy.

Figure 1. One-year overall survival (OS) curves for responders to TPO-RA drugs, and non-responding patients. Abscissa, time from start of the therapy, days; ordinate OS rates, % of total

Twelve of 16 responders were alive: 7 patients with time of response under median values and 5 patients with time to response exceeding median levels.

A total of 18 patients died. Infectious complications were the main cause of death in these cases (n=11), wherein 8 cases were classified as non-responders, and 3 patients showed longer time to response which exceeded median values. The disease relapse caused death in 4 cases, while aGVHD was associated with lethal outcome in 3 cases.

One-year OS from the start of therapy with TPO-RA was 60% (95% CI, 40-76). It was significantly different for responders and non-responders: 78% (95% CI, 47-93) versus 33% (95% CI, 12-56) (p=0.004), as seen from Fig. 1.

Discussion

Allogeneic hematopoietic stem cell transplantation is an effective method for treatment of a wide range of malignant and non-malignant diseases of the blood system. With improving the HSCT technology, most transplanted patients achieve engraftment, but the so-called “poor graft function”, i.e., posttransplant cytopenia of various origin with preservation of donor chimerism still remains a challenge. Poor graft function is one of factors significantly worsening the outcome of allo-HSCT [5].

The impairment of hematopoietic stem cell (HSC) compartments after HSCT has been demonstrated by reduced numbers of hematopoietic progenitors under the in vitro culture conditions [19]. The graft functioning might be influenced by the underlying disease, donor and recipient HLA compatibility, the dose of transplanted CD34+ cells, as well as by accompanying complications (GVHD, infections, including viral activation). However, most of the cases remain idiopathic [20, 21, 22]. Most likely, a combination of these factors creates an immune-active environment that hampers the normal development and functioning of transplanted HSCs [23, 24, 25]. Moreover, several post-HSCT conditions (e.g., myelotoxic drugs, inflammatory events, and infections) provide well-established mechanisms impairing hematopoiesis.

TPO-RA drugs, in the context of PGF therapy, may present a promising option, especially, concerning eltrombopag. There are several mechanisms by which eltrombopag may provide effect in the bone marrow failure syndromes. Eltrombopag works as a trigger for HSCs and promotes active proliferation of HSCs after HSCT. Also eltrombopag has an immunomodulatory effect on the T-regulatory cell function [26]. Furthermore, abolition of inhibitory effect produced by interferon-γ upon HSCs may be another potential mechanism of eltrombopag action which has been recently explained. Eltrombopag, by its binding directly to c-MPL, activates its intracellular signal transduction pathway, irrespectively of interferon-γ presence [27].

Since it is impossible to separate the only etiological factor, the choice of a single approach to the therapy of PGF is complicated. However, given the data on the efficacy of TPO agonists in various bone marrow failure syndromes and other diseases associated with cytopenia, and the safety of their use in malignant diseases, as well as its ability to overcome the immune mechanisms of suppressing hematopoiesis, TPO-RA seem to be good candidates for management of PGF. Recently, the several groups published the experience of TPO-RA administration in post-transplant setting [28, 29, 30]. Nevertheless, the precise analysis of efficiency of this therapy is complicated, due to small number of patients and different inclusion criteria in these studies.

We analyzed the results of the use of TPO-RA in our BMT center. The special feature of our cohort was the predominance of patients with severe trilineage cytopenia, as well as high proportion of patients with severe acute GVHD. Our experience showed the safety of TPO-RA: there was only one case of hepatotoxicity of grade 1, which did not require discontinuation of the drug. Neither the drug used, nor the duration of therapy, nor the cumulative dose of each agent didn’t influence overall response in our study. However, there are reports that the cumulative dose for romiplostim plays a role for the overall response to therapy [31].

In our study, there was no statistically significant correlations between the overall response rates to TPO-RA, and clinical complications associated with PGF (sepsis, aGVHD, viral infections), thus being in accordance with results from other centers. However, there is some evidence that a better response could be obtained in the absence of active GVHD [32].

Facing a problem of prolonged cytopenia in the posttransplant period, only booster CD34-cell infusions are considered more or less standardized therapy. TPO-RA used as monotherapy, or in combination with other methods, seem to be quite effective for PGF after allo-HSCT, regardless of its etiology.

Conclusion

TPO-RA showed promising efficacy and low toxicity in adult patients with PGF after allo-HSCT. Considering multifactorial origin of PGF, TPO-RA might be a reasonable approach that could be applied early and irrespectively of PGF cause. However, the optimal dose and duration of the administration, as well as the criteria for discontinuation of these drugs remain uncertain. Multicenter prospective studies are needed to resolve these problems.

Conflict of interest

The authors report no conflicts of interest.

References

Duarte RF, Labopin M, Bader Р, Basak GW, Bonini Ch, Chabannon Ch, Corbacioglu S, Dreger P, Dufour C, Andrew R. Gennery AR, Kuball J, Lankester AC, Lanza F, Montoto S, Nagler A, Peffault de Latour R, Snowden JA, Styczynski J, Yakoub-Agha I, Kröger N, Mohty M,for the European Society for Blood and Marrow Transplantation (EBMT). Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019. Bone Marrow Transplant. 2019 https://doi.org/10.1038/s41409-019-0516-2.
Majhail NS, Farnia SH, Carpenter PA, Champlin RE, Crawford S, Marks DI, Omel JL, Orchard PJ, Palmer J, Saber W, Savani BN, Veys PA, Bredeson ChN, Giralt SA, LeMaistre ChF. Indications for autologous and allogeneic hematopoietic cell transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015; 21(11): 1863–1869.
Savchenko VG, Liubimova LS, Parovichnikova EN, Mendeleeva LP, Mamotiuk KS, Demidova IA, Gribanova EO, Gal'tseva IV, Pokrovskaia OS, Kuz'mina LA, Zhelnova EI, Kliasova GA, Glasko EN, Kaplanskaia IB, Poreshina LP, et al. Transplantations of allogenic and autologous hemopoietic stem cells in acute leukemia (results of 20-year experience). Terapevticheskiy arkhiv. 2007;79 (7):30-35. (In Russian).
Afanasyev BV, Zubarovskaya LS, Moiseev IS. Allogeneic hematopoietic stem cell transplantation in children: now, problems and prospects. Russian Journal of Children Hematology and Oncology. 2015;2(2):28-42. (In Russian).
Rudakova TA, Kulagin AD, Klimova OU, et al. Severe "poor graft function" after allogeneic hematopoietic stem cell transplantation in adult patients: incidence, risk Factors, and outcomes. Clinical Oncohematology. 2019;12(3):309-318 (In Russian).
Olsson R, Remberger M, Schaffer M, Berggren DM, Svahn BM, Mattsson J, Ringden O. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48: 537-543.
Alchalby H, Yunus DR, Zabelina T, Ayuk F, Kröger N. Incidence and risk factors of poor graft function after allogeneic stem cell transplantation for myelofibrosis. Bone Marrow Transplant. 2016;51(9):1223-1227.
Stasia A, Ghiso A, Galaverna F, Raiola AM, Gualandi F, Luchetti S, Pozzi S, Varaldo R, Lamparelli T, Bregante S, Van Lint MT, diGrazia C, Bacigalupo A. CD34+ selected cells for the treatment of poor graft function after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20:1440–1443.
Gale RP. Early and late graft-failure after transplants. Bone Marrow Transplant. 2016;51:182-183.
Valcárcel D, Sureda A. Graft failure. The EBMT Handbook (2019). doi.org/10.1007/978-3-030-02278-5_41.
Solar GP, Kerr WG, Zeigler FC, Hess D, Donahue Ch, de Sauvage FJ, Eaton DL. Role of c-mpl in Early Hematopoiesis. Blood. 1998; 92(1):4-10.
Ninos JM, Jefferies LC, Cogle ChR, Kerr WG. The thrombopoietin receptor, c-Mpl, is a selective surface marker for human hematopoietic stem cells. J Transl Med. 2006;4:9. doi: 10.1186/1479-5876-4-9.
Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007; 29;357(22):2237-2247.
Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011; 29; 377(9763):393-402.
Winkler T, Fan X, Cooper J, Desmond R, Young DJ, Townsley DM. Eltrombopag for refractory severe aplastic anemia: dosing, duration, long term outcomes and clonal evolution. Blood, 2019.
Ecsedi M, Lengline É, Knol-Bout C, Bosman P, Eikema DJ, Afanasyev B, Maschan A, Dreger P, Halkes CJM, Drexler B, Cortelezzi A, Drénou B, Patriarca A, Bruno B, Onofrillo D, Lanino E, Pulanic D, Serventi-Seiwerth R, Garnier A, Ljungman P, Bonifazi F, Giammarco S, Tournilhac O, Pioltelli P, Rovó A, Risitano AM, de Latour RP, Dufour C, Passweg J. Use of eltrombopag in aplastic anemia in Europe. Ann Hematol. 2019; 98(6):1341-1350.
Mittelman M, Platzbecker U, Afanasyev B, Grosicki S, Wong RSM, Anagnostopoulos A, Brenner B, Denzlinger C, Rossi G, Nagler A, Garcia-Delgado R, Portella MSO, Zhu Z, Selleslag D. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial. Lancet Haematol. 2018;5(1):e34-e43. DOI: 10.1016/S2352-3026(17)30228-4.
Oliva EN, Alati C, Santini V, Poloni A, Molteni A, Niscola P, Salvi F, Sanpaolo G, Balleari E, Germing U, Fenaux P, Stamatoullas A, Palumbo GA, Salutari P, Impera S et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017;4:e127-e136. DOI: 10.1016/S2352-3026(17)30012-1.
Kong Y, Wang YT, Hu Y, Han W, Chang YJ, Zhang XH, Jiang ZF, Huang XJ. The bone marrow microenvironment is similarly impaired in allogeneic hematopoietic stem cell transplantation patients with early and late poor graft function. Bone Marrow Transplant. 2016;51:249-255.
Rondón G, Saliba RM, Khouri I, Giralt S, Chan K, Jabbour E, McMannis J, Champlin R, Shpall E. Long-term follow up of patients who experienced graft failure post allogeneic progenitor cell transplantation. Results of a single institution analysis. Biol Blood Marrow Transplant. 2008; 14(8): 859–866.
Kröger N, Holler E, Kobbe G, Bornhäuser M, Schwerdtfeger R, Baurmann H, Nagler A, Bethge W, Stelljes M, Uharek L, Wandt H, Burchert A, Corradini P, Schubert J, Kaufmann M, Dreger P, Wulf GG, Einsele H, Zabelina T, Kvasnicka HM, Thiele J, Brand R, Zander AR, Niederwieser D, de Witte TM. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation Blood. 2009;114(26):5264-5270.
Dominietto A, Raiola AM, van Lint MT, Lamparelli T, Gualandi F, Berisso G, Bregante S, Frassoni F, Casarino L, Verdiani S and Bacigalupo A. Factors influencing haematological recovery after allogeneic haemopoietic stem cell transplants: graft-versus-host disease, donor type, cytomegalovirus infections and cell dose. Br J Haematol. 2001;112:219-227.
Yu J-M, Emmons RV, Hanazono Y, Sellers S, Young NS, Dunbar CE. Expression of interferon-γ by stromal cells inhibits murine long-term repopulating hematopoietic stem cell activity. Exp Hematol. 1999;27(5):895-903.
Kong Y, Wang Yu-Tong , Cao Xie-Na , Song Yang , Chen Yu-Hong , Sun Yu-Qian , Wang Yu , Zhang Xiao-Hui , Xu Lan-Ping, Huang Xiao-Jun. Aberrant T cell responses in the bone marrow microenvironment of patients with poor graft function after allogeneic hematopoietic stem cell transplantation. J Transl Med. 2017;15:57. doi: 10.1186/s12967-017-1159-y.
Rudakova TA, Eismont YuA, Moiseev IS, Zubarovskaya LS, Kulagin AD, Afanasyev BV. Role of polyomavirus in emerging secondary hypofunction of marrow graft following allogeneic bone marrow transplantation in adults. Cellular Therapy and Transplantation. 2016;5(3):79–82. DOI: 10.18620/ctt-1866-8836-2016-5-3-79-82.
Bao W, Bussel JB, Heck S, He W, Karpoff M, Boulad N, Yazdanbakhsh K. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116:4639–4645.
Alvarado LJ, Andreoni A, Huntsman HD, Cheng H, Knutson JR, Larochelle A. Heterodimerization of TPO and IFNγ impairs human hematopoietic stem/progenitor cell signaling and survival in chronic inflammation. Blood. 2017;130:4.
Lisukov IA, Uspenskaya OS, Kulagin AD, Bondarenko SN, Rudakova TA, Slesarchuk O.A., Afanasyev BV. Romiplostim in thrombocytopenia treatment after allogeneic bone marrow transplantation. Oncohematology. 2012;7(1):29–34. (In Russian).
Marotta S, Marano L, Ricci P, Cacace F, Frieri C, Simeone L, Trastulli F, Vitiello S, Cardano F, Pane F, Risitano AM. Eltrombopag for post-transplant cytopenias due to poor graft function. Bone Marrow Transplant. 2019;54(8):1346-1353.
Tang C, Chen F, Kong D, Ma Q, Dai H, Yin J, Li Zh, Chen Ji, Zhu X, Mao X, Wu D, Tang X. Successful treatment of secondary poor graft function post allogeneic hematopoietic stem cell transplantation with Eltrombopag. J Hematol Oncol. 2018 ;11:103 https://doi.org/10.1186/s13045-018-0649-6.
Liga M. Romiplostim for the treatment of thrombocytopenia after allogeneic stem cell transplantation. The 45th Annual Meeting of EBMT (Physicians, Poster Session). Bone Marrow Transplantation. 2019;54:144–619, P143.
Aguirre L. Eltrombopag (EPAG) induces a high percentage of responses in patients with post allo-HSCT poor graft function (PGF) and no active GVHD. The 45th Annual Meeting of EBMT (Physicians, Poster Session). Bone Marrow Transplantation. 2019;54:144–619, P133.

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Introduction

Patients and methods

Table 1. Characteristics of the patients

Statistical analysis

Results

TPO-RA drugs were well tolerated, with no detectable toxicity of grade 3-4. One case of hepatotoxicity grade 2 was documented with eltrombopag but didn’t require withdrawal of the drug.

Figure 1. One-year overall survival (OS) curves for responders to TPO-RA drugs, and non-responding patients. Abscissa, time from start of the therapy, days; ordinate OS rates, % of total

Twelve of 16 responders were alive: 7 patients with time of response under median values and 5 patients with time to response exceeding median levels.

Discussion

Conclusion

Conflict of interest

The authors report no conflicts of interest.

References

Duarte RF, Labopin M, Bader Р, Basak GW, Bonini Ch, Chabannon Ch, Corbacioglu S, Dreger P, Dufour C, Andrew R. Gennery AR, Kuball J, Lankester AC, Lanza F, Montoto S, Nagler A, Peffault de Latour R, Snowden JA, Styczynski J, Yakoub-Agha I, Kröger N, Mohty M,for the European Society for Blood and Marrow Transplantation (EBMT). Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019. Bone Marrow Transplant. 2019 https://doi.org/10.1038/s41409-019-0516-2.
Majhail NS, Farnia SH, Carpenter PA, Champlin RE, Crawford S, Marks DI, Omel JL, Orchard PJ, Palmer J, Saber W, Savani BN, Veys PA, Bredeson ChN, Giralt SA, LeMaistre ChF. Indications for autologous and allogeneic hematopoietic cell transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015; 21(11): 1863–1869.
Savchenko VG, Liubimova LS, Parovichnikova EN, Mendeleeva LP, Mamotiuk KS, Demidova IA, Gribanova EO, Gal'tseva IV, Pokrovskaia OS, Kuz'mina LA, Zhelnova EI, Kliasova GA, Glasko EN, Kaplanskaia IB, Poreshina LP, et al. Transplantations of allogenic and autologous hemopoietic stem cells in acute leukemia (results of 20-year experience). Terapevticheskiy arkhiv. 2007;79 (7):30-35. (In Russian).
Afanasyev BV, Zubarovskaya LS, Moiseev IS. Allogeneic hematopoietic stem cell transplantation in children: now, problems and prospects. Russian Journal of Children Hematology and Oncology. 2015;2(2):28-42. (In Russian).
Rudakova TA, Kulagin AD, Klimova OU, et al. Severe "poor graft function" after allogeneic hematopoietic stem cell transplantation in adult patients: incidence, risk Factors, and outcomes. Clinical Oncohematology. 2019;12(3):309-318 (In Russian).
Olsson R, Remberger M, Schaffer M, Berggren DM, Svahn BM, Mattsson J, Ringden O. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48: 537-543.
Alchalby H, Yunus DR, Zabelina T, Ayuk F, Kröger N. Incidence and risk factors of poor graft function after allogeneic stem cell transplantation for myelofibrosis. Bone Marrow Transplant. 2016;51(9):1223-1227.
Stasia A, Ghiso A, Galaverna F, Raiola AM, Gualandi F, Luchetti S, Pozzi S, Varaldo R, Lamparelli T, Bregante S, Van Lint MT, diGrazia C, Bacigalupo A. CD34+ selected cells for the treatment of poor graft function after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20:1440–1443.
Gale RP. Early and late graft-failure after transplants. Bone Marrow Transplant. 2016;51:182-183.
Valcárcel D, Sureda A. Graft failure. The EBMT Handbook (2019). doi.org/10.1007/978-3-030-02278-5_41.
Solar GP, Kerr WG, Zeigler FC, Hess D, Donahue Ch, de Sauvage FJ, Eaton DL. Role of c-mpl in Early Hematopoiesis. Blood. 1998; 92(1):4-10.
Ninos JM, Jefferies LC, Cogle ChR, Kerr WG. The thrombopoietin receptor, c-Mpl, is a selective surface marker for human hematopoietic stem cells. J Transl Med. 2006;4:9. doi: 10.1186/1479-5876-4-9.
Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007; 29;357(22):2237-2247.
Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011; 29; 377(9763):393-402.
Winkler T, Fan X, Cooper J, Desmond R, Young DJ, Townsley DM. Eltrombopag for refractory severe aplastic anemia: dosing, duration, long term outcomes and clonal evolution. Blood, 2019.
Ecsedi M, Lengline É, Knol-Bout C, Bosman P, Eikema DJ, Afanasyev B, Maschan A, Dreger P, Halkes CJM, Drexler B, Cortelezzi A, Drénou B, Patriarca A, Bruno B, Onofrillo D, Lanino E, Pulanic D, Serventi-Seiwerth R, Garnier A, Ljungman P, Bonifazi F, Giammarco S, Tournilhac O, Pioltelli P, Rovó A, Risitano AM, de Latour RP, Dufour C, Passweg J. Use of eltrombopag in aplastic anemia in Europe. Ann Hematol. 2019; 98(6):1341-1350.
Mittelman M, Platzbecker U, Afanasyev B, Grosicki S, Wong RSM, Anagnostopoulos A, Brenner B, Denzlinger C, Rossi G, Nagler A, Garcia-Delgado R, Portella MSO, Zhu Z, Selleslag D. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial. Lancet Haematol. 2018;5(1):e34-e43. DOI: 10.1016/S2352-3026(17)30228-4.
Oliva EN, Alati C, Santini V, Poloni A, Molteni A, Niscola P, Salvi F, Sanpaolo G, Balleari E, Germing U, Fenaux P, Stamatoullas A, Palumbo GA, Salutari P, Impera S et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017;4:e127-e136. DOI: 10.1016/S2352-3026(17)30012-1.
Kong Y, Wang YT, Hu Y, Han W, Chang YJ, Zhang XH, Jiang ZF, Huang XJ. The bone marrow microenvironment is similarly impaired in allogeneic hematopoietic stem cell transplantation patients with early and late poor graft function. Bone Marrow Transplant. 2016;51:249-255.
Rondón G, Saliba RM, Khouri I, Giralt S, Chan K, Jabbour E, McMannis J, Champlin R, Shpall E. Long-term follow up of patients who experienced graft failure post allogeneic progenitor cell transplantation. Results of a single institution analysis. Biol Blood Marrow Transplant. 2008; 14(8): 859–866.
Kröger N, Holler E, Kobbe G, Bornhäuser M, Schwerdtfeger R, Baurmann H, Nagler A, Bethge W, Stelljes M, Uharek L, Wandt H, Burchert A, Corradini P, Schubert J, Kaufmann M, Dreger P, Wulf GG, Einsele H, Zabelina T, Kvasnicka HM, Thiele J, Brand R, Zander AR, Niederwieser D, de Witte TM. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation Blood. 2009;114(26):5264-5270.
Dominietto A, Raiola AM, van Lint MT, Lamparelli T, Gualandi F, Berisso G, Bregante S, Frassoni F, Casarino L, Verdiani S and Bacigalupo A. Factors influencing haematological recovery after allogeneic haemopoietic stem cell transplants: graft-versus-host disease, donor type, cytomegalovirus infections and cell dose. Br J Haematol. 2001;112:219-227.
Yu J-M, Emmons RV, Hanazono Y, Sellers S, Young NS, Dunbar CE. Expression of interferon-γ by stromal cells inhibits murine long-term repopulating hematopoietic stem cell activity. Exp Hematol. 1999;27(5):895-903.
Kong Y, Wang Yu-Tong , Cao Xie-Na , Song Yang , Chen Yu-Hong , Sun Yu-Qian , Wang Yu , Zhang Xiao-Hui , Xu Lan-Ping, Huang Xiao-Jun. Aberrant T cell responses in the bone marrow microenvironment of patients with poor graft function after allogeneic hematopoietic stem cell transplantation. J Transl Med. 2017;15:57. doi: 10.1186/s12967-017-1159-y.
Rudakova TA, Eismont YuA, Moiseev IS, Zubarovskaya LS, Kulagin AD, Afanasyev BV. Role of polyomavirus in emerging secondary hypofunction of marrow graft following allogeneic bone marrow transplantation in adults. Cellular Therapy and Transplantation. 2016;5(3):79–82. DOI: 10.18620/ctt-1866-8836-2016-5-3-79-82.
Bao W, Bussel JB, Heck S, He W, Karpoff M, Boulad N, Yazdanbakhsh K. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116:4639–4645.
Alvarado LJ, Andreoni A, Huntsman HD, Cheng H, Knutson JR, Larochelle A. Heterodimerization of TPO and IFNγ impairs human hematopoietic stem/progenitor cell signaling and survival in chronic inflammation. Blood. 2017;130:4.
Lisukov IA, Uspenskaya OS, Kulagin AD, Bondarenko SN, Rudakova TA, Slesarchuk O.A., Afanasyev BV. Romiplostim in thrombocytopenia treatment after allogeneic bone marrow transplantation. Oncohematology. 2012;7(1):29–34. (In Russian).
Marotta S, Marano L, Ricci P, Cacace F, Frieri C, Simeone L, Trastulli F, Vitiello S, Cardano F, Pane F, Risitano AM. Eltrombopag for post-transplant cytopenias due to poor graft function. Bone Marrow Transplant. 2019;54(8):1346-1353.
Tang C, Chen F, Kong D, Ma Q, Dai H, Yin J, Li Zh, Chen Ji, Zhu X, Mao X, Wu D, Tang X. Successful treatment of secondary poor graft function post allogeneic hematopoietic stem cell transplantation with Eltrombopag. J Hematol Oncol. 2018 ;11:103 https://doi.org/10.1186/s13045-018-0649-6.
Liga M. Romiplostim for the treatment of thrombocytopenia after allogeneic stem cell transplantation. The 45th Annual Meeting of EBMT (Physicians, Poster Session). Bone Marrow Transplantation. 2019;54:144–619, P143.
Aguirre L. Eltrombopag (EPAG) induces a high percentage of responses in patients with post allo-HSCT poor graft function (PGF) and no active GVHD. The 45th Annual Meeting of EBMT (Physicians, Poster Session). Bone Marrow Transplantation. 2019;54:144–619, P133.

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(3) "100" ["~SORT"]=> string(3) "100" ["CODE"]=> string(100) "agonisty-retseptora-trombopoetina-dlya-lecheniya-gipofunktsii-transplantata-posle-allogennoy-transpl" ["~CODE"]=> string(100) "agonisty-retseptora-trombopoetina-dlya-lecheniya-gipofunktsii-transplantata-posle-allogennoy-transpl" ["EXTERNAL_ID"]=> string(4) "1663" ["~EXTERNAL_ID"]=> string(4) "1663" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(278) "Агонисты рецептора тромбопоэтина для лечения гипофункции трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток у взрослых" ["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(414) "Агонисты рецептора тромбопоэтина для лечения гипофункции трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток у взрослыхThrombopoietin receptor agonists for treatment of poor graft function after allogeneic hematopoietic stem cell transplantation in adults" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(6044) "Посттрансплантационные цитопении в структуре гипофункции трансплантата являются жизнеугрожающим осложнением аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Общепринятые терапевтические опции для лечения ограничены повторными инфузиями гемопоэтических стволовых клеток. Однако миметики тромбопоэтина (ТПО), показавшие свою эффективность при идиопатической апластической анемией и тромбоцитопении (ромиплостим, элтромбопаг), могут рассматриваться в качестве возможной альтернативной стратегии терапии гипофункции трансплантата после алло-ТГСК. В данной работе представлен опыт использования агонистов рецептора тромбопоэтина для лечения посттрансплантационных цитопений, в том числе критериальной тяжелой гипофункции трансплантата после алло-ТГСК в нашем центре. В общей сложности 31 пациент (15 мужчин, 16 женщин) со средним возрастом 22 года (18-57) получили терапию агонистами рецептора ТПО (АР-ТПО) для посттрансплантационной тромбоцитопении <20×109/л (n=7) и ГФТ (n=24). Для терапии использовался ромиплостим (n=17) со средней дозой 5 мкг/кг в неделю (3-5) или элтромбопаг (n=14) со средней дозой 50 мг/день (50-150). Критериями тяжелой гипофункции трансплантата (тГФТ) были: цитопения в двух или более миелоидных линиях (тромбоциты <20×109/л, абсолютное число нейтрофилов (АЧН) <0,5×109/л, гемоглобин <70 г/л в любое время после документированного приживления, полный или стабильный смешанный донорский химеризм >90% без признаков рецидива основного заболевания. Общий ответ включал полный ответ (ПО) (тромбоциты ≥100×109/л, АЧН ≥1,5×109/л, гемоглобин ≥100 г/л) и частичный ответ (ЧО) (тромбоциты >20×109/л, АЧН ≥0,5×109/л, гемоглобин >70 г/л). Медиана времени от постановки диагноза тГФТ до начала терапии АР-ТПО составила 14 дней (0-119), медиана продолжительности терапии АР-ТПО составила 3 недели (1-43). Переносимость АР-ТПО была удовлетворительной, без признаков токсичности II-IV степени. В общей сложности в 8 случаях (28%) АР-ТПО использовались в комбинации с ритуксимабом (n=4), ритуксимабом и инфузиями донорских лимфоцитов (ИДЛ) (n=3), а также с инфузиями CD34-клеток (n=1). Всего 14 (48%) пациентов достигли ответа (ПО: n=4, 14%; ЧО: n=10, 34%). Комбинированная терапия не показала преимущества в скорости ответа по сравнению с АР-ТПО в монорежиме. Медиана прироста АЧН у ответивших на терапию составила 3,4×109/л (0,8-6,0), тромбоцитов – 48×109/л (21-205). В общей сложности 15 пациентов (3 ответивших, 12 не ответивших на терапию) умерли от инфекции (n=10), рецидива (n=2) и острой реакции «трансплантат-против-хозяина» (оРТПХ) III-IV степени (n=3). Однолетняя общая выживаемость (ОВ) от начала терапии составила 60% (95% ДИ, 40-76), при этом наблюдалась существенная разница между ответившими и неответившими на АР-ТПО: 79% (95% ДИ, 47-93) против 39% (95% ДИ, 14-63) (р=0,01). Наше исследование показало многообещающую эффективность и удовлетворительную безопасность АР-ТПО у пациентов с тГФТ после алло-ТГСК. Необходимо проведение многоцентровых проспективных исследований для установления оптимальной дозы и продолжительности приема, а также критериев отмены этих препаратов. <h2>Ключевые слова</h2> Алло-ТГСК, гипофункция трансплантата, агонисты рецепторов тромбопоэтина." 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Рудакова, Александр Д. Кулагин, Иван С. Моисеев, Татьяна А. Быкова, Сергей Н. Бондаренко, Мария В. Барабанщикова, Анастасия В. Бейнарович, Анна А. Осипова, Варвара Н. Овечкина, Александр Л. Алянский, Елена И. Дарская, Елена В. Морозова, Борис В. Афанасьев" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(477) "

Татьяна А. Рудакова, Александр Д. Кулагин, Иван С. Моисеев, Татьяна А. Быкова, Сергей Н. Бондаренко, Мария В. Барабанщикова, Анастасия В. Бейнарович, Анна А. Осипова, Варвара Н. Овечкина, Александр Л. Алянский, Елена И. Дарская, Елена В. Морозова, Борис В. Афанасьев

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "22295" ["VALUE"]=> array(2) { ["TEXT"]=> string(367) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(355) "

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Россия

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Посттрансплантационные цитопении в структуре гипофункции трансплантата являются жизнеугрожающим осложнением аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Общепринятые терапевтические опции для лечения ограничены повторными инфузиями гемопоэтических стволовых клеток. Однако миметики тромбопоэтина (ТПО), показавшие свою эффективность при идиопатической апластической анемией и тромбоцитопении (ромиплостим, элтромбопаг), могут рассматриваться в качестве возможной альтернативной стратегии терапии гипофункции трансплантата после алло-ТГСК. В данной работе представлен опыт использования агонистов рецептора тромбопоэтина для лечения посттрансплантационных цитопений, в том числе критериальной тяжелой гипофункции трансплантата после алло-ТГСК в нашем центре.

В общей сложности 31 пациент (15 мужчин, 16 женщин) со средним возрастом 22 года (18-57) получили терапию агонистами рецептора ТПО (АР-ТПО) для посттрансплантационной тромбоцитопении <20×10⁹/л (n=7) и ГФТ (n=24). Для терапии использовался ромиплостим (n=17) со средней дозой 5 мкг/кг в неделю (3-5) или элтромбопаг (n=14) со средней дозой 50 мг/день (50-150). Критериями тяжелой гипофункции трансплантата (тГФТ) были: цитопения в двух или более миелоидных линиях (тромбоциты <20×10⁹/л, абсолютное число нейтрофилов (АЧН) <0,5×10⁹/л, гемоглобин <70 г/л в любое время после документированного приживления, полный или стабильный смешанный донорский химеризм >90% без признаков рецидива основного заболевания. Общий ответ включал полный ответ (ПО) (тромбоциты ≥100×10⁹/л, АЧН ≥1,5×109/л, гемоглобин ≥100 г/л) и частичный ответ (ЧО) (тромбоциты >20×10⁹/л, АЧН ≥0,5×10⁹/л, гемоглобин >70 г/л). Медиана времени от постановки диагноза тГФТ до начала терапии АР-ТПО составила 14 дней (0-119), медиана продолжительности терапии АР-ТПО составила 3 недели (1-43). Переносимость АР-ТПО была удовлетворительной, без признаков токсичности II-IV степени. В общей сложности в 8 случаях (28%) АР-ТПО использовались в комбинации с ритуксимабом (n=4), ритуксимабом и инфузиями донорских лимфоцитов (ИДЛ) (n=3), а также с инфузиями CD34-клеток (n=1). Всего 14 (48%) пациентов достигли ответа (ПО: n=4, 14%; ЧО: n=10, 34%). Комбинированная терапия не показала преимущества в скорости ответа по сравнению с АР-ТПО в монорежиме. Медиана прироста АЧН у ответивших на терапию составила 3,4×10⁹/л (0,8-6,0), тромбоцитов – 48×10⁹/л (21-205). В общей сложности 15 пациентов (3 ответивших, 12 не ответивших на терапию) умерли от инфекции (n=10), рецидива (n=2) и острой реакции «трансплантат-против-хозяина» (оРТПХ) III-IV степени (n=3). Однолетняя общая выживаемость (ОВ) от начала терапии составила 60% (95% ДИ, 40-76), при этом наблюдалась существенная разница между ответившими и неответившими на АР-ТПО: 79% (95% ДИ, 47-93) против 39% (95% ДИ, 14-63) (р=0,01). Наше исследование показало многообещающую эффективность и удовлетворительную безопасность АР-ТПО у пациентов с тГФТ после алло-ТГСК. Необходимо проведение многоцентровых проспективных исследований для установления оптимальной дозы и продолжительности приема, а также критериев отмены этих препаратов.

Ключевые слова

Алло-ТГСК, гипофункция трансплантата, агонисты рецепторов тромбопоэтина.

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Tatiana A. Rudakova, Alexander D. Kulagin, Ivan S. Moiseev, Tatyana A. Bykova, Sergey N. Bondarenko, Maria V. Barabanshikova, Anastasia V. Beinarovich, Anna A. Osipova, Varvara N. Ovechkina, Alexander L. Alyanskiy, Elena I. Darskaya, Elena V. Morozova, Boris V. Afanasyev

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "22331" ["VALUE"]=> array(2) { ["TEXT"]=> string(3345) "Posttransplant cytopenias due to poor graft function (PGF) are a severe complication of allogeneic transplantation of hematopoietic stem cells (allo-HSCT). Conventional therapeutic options for poor graft function are limited to infusions of CD34-selected cells. However, having shown encouraging results in idiopathic thrombocytopenia and aplastic anemia, thrombopoietin receptor agonists (TPO-RA) romiplostim and eltrombopag might be a possible alternative treatment strategy for PGF after allo-HSCT. Current study aims to summarize single-center experience of TPO-RA for treatment of posttransplant cytopenias including PGF after allo-HSCT. A total of 31 patients (15 males, 16 females) with median age of 22 years (18-57) received therapy with TPO agonists for posttransplant thrombocytopenia <20×109/l (n=7) and PGF (n=24). Romiplostim (n=17) with the median dose 5 mkg/kg weekly (3-5) or eltrombopag (n=14) with the median dose 50 mg/day (50-150) were used. Criteria for severe poor graft function (sPGF) were the following: cytopenia in two or more myeloid lineages (platelets <20×109/l, absolute neutrophil count (ANC) <0.5×109/l, hemoglobin <70 g/l) any time after documented engraftment, full or stable mixed donor chimerism >90% without signs of relapse of underlying disease. Overall response included complete response (CR) (platelets ≥100×109/l, ANC ≥1.5×109/l, hemoglobin ≥100 g/l) and partial response (PR) (platelets >20×109/l, ANC ≥0.5×109/l, hemoglobin >70 g/l). Median time from diagnosis of sPGF to the start of TPO-RA therapy was 14 days (0-119), median length of TPO-RA therapy was 3 weeks (1-43). TPO-RA was well tolerated, with no signs of II-IV grade toxicity. In a total of 8 cases (28%) TPO-RA were used in combination with rituximab (n=4), rituximab and donor lymphocyte infusions (DLI) (n=3), as well as CD34-cell infusions (n=1). A total of 14 (48%) patients achieved response (CR: n=4, 14%; PR: n=10, 34%). Combination therapy showed no advantage in response rate compared to TPO-RA alone. Median increase of ANC in responders was 3.4×109/l (0.8-6.0), platelets – 48×109/l (21-205). A total of 15 patients (3 responders, 12 non-responders) died of infection (n=10), relapse (n=2) and acute graft-versus-host disease (aGVHD) III-IV grade (n=3). One-year overall survival (OS) from the therapy start was 60% (95% CI, 40-76), with a significant difference between responders and non-responders: 79% (95% CI, 47-93) vs 39% (95% CI, 14-63) (p=0.01). Our study showed a promising efficacy and safety of TPO-RA in patients with sPGF after allo-HSCT. Multicenter prospective studies are needed to establish optimal dose and duration of the drug administration, as well as the criteria for discontinuation of these drugs. <h2>Keywords</h2> Allo-HSCT, poor graft function, thrombopoietin receptor agonists." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3104) "

Posttransplant cytopenias due to poor graft function (PGF) are a severe complication of allogeneic transplantation of hematopoietic stem cells (allo-HSCT). Conventional therapeutic options for poor graft function are limited to infusions of CD34-selected cells. However, having shown encouraging results in idiopathic thrombocytopenia and aplastic anemia, thrombopoietin receptor agonists (TPO-RA) romiplostim and eltrombopag might be a possible alternative treatment strategy for PGF after allo-HSCT. Current study aims to summarize single-center experience of TPO-RA for treatment of posttransplant cytopenias including PGF after allo-HSCT.

A total of 31 patients (15 males, 16 females) with median age of 22 years (18-57) received therapy with TPO agonists for posttransplant thrombocytopenia <20×10⁹/l (n=7) and PGF (n=24). Romiplostim (n=17) with the median dose 5 mkg/kg weekly (3-5) or eltrombopag (n=14) with the median dose 50 mg/day (50-150) were used. Criteria for severe poor graft function (sPGF) were the following: cytopenia in two or more myeloid lineages (platelets <20×10⁹/l, absolute neutrophil count (ANC) <0.5×10⁹/l, hemoglobin <70 g/l) any time after documented engraftment, full or stable mixed donor chimerism >90% without signs of relapse of underlying disease. Overall response included complete response (CR) (platelets ≥100×10⁹/l, ANC ≥1.5×10⁹/l, hemoglobin ≥100 g/l) and partial response (PR) (platelets >20×10⁹/l, ANC ≥0.5×10⁹/l, hemoglobin >70 g/l). Median time from diagnosis of sPGF to the start of TPO-RA therapy was 14 days (0-119), median length of TPO-RA therapy was 3 weeks (1-43). TPO-RA was well tolerated, with no signs of II-IV grade toxicity. In a total of 8 cases (28%) TPO-RA were used in combination with rituximab (n=4), rituximab and donor lymphocyte infusions (DLI) (n=3), as well as CD34-cell infusions (n=1). A total of 14 (48%) patients achieved response (CR: n=4, 14%; PR: n=10, 34%). Combination therapy showed no advantage in response rate compared to TPO-RA alone. Median increase of ANC in responders was 3.4×10⁹/l (0.8-6.0), platelets – 48×10⁹/l (21-205). A total of 15 patients (3 responders, 12 non-responders) died of infection (n=10), relapse (n=2) and acute graft-versus-host disease (aGVHD) III-IV grade (n=3). One-year overall survival (OS) from the therapy start was 60% (95% CI, 40-76), with a significant difference between responders and non-responders: 79% (95% CI, 47-93) vs 39% (95% CI, 14-63) (p=0.01).

Our study showed a promising efficacy and safety of TPO-RA in patients with sPGF after allo-HSCT. Multicenter prospective studies are needed to establish optimal dose and duration of the drug administration, as well as the criteria for discontinuation of these drugs.

Keywords

Allo-HSCT, poor graft function, thrombopoietin receptor agonists.

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Keywords

Allo-HSCT, poor graft function, thrombopoietin receptor agonists.

Keywords

Allo-HSCT, poor graft function, thrombopoietin receptor agonists.

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Rudakova" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "22296" ["VALUE"]=> array(2) { ["TEXT"]=> string(6044) "Посттрансплантационные цитопении в структуре гипофункции трансплантата являются жизнеугрожающим осложнением аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Общепринятые терапевтические опции для лечения ограничены повторными инфузиями гемопоэтических стволовых клеток. Однако миметики тромбопоэтина (ТПО), показавшие свою эффективность при идиопатической апластической анемией и тромбоцитопении (ромиплостим, элтромбопаг), могут рассматриваться в качестве возможной альтернативной стратегии терапии гипофункции трансплантата после алло-ТГСК. В данной работе представлен опыт использования агонистов рецептора тромбопоэтина для лечения посттрансплантационных цитопений, в том числе критериальной тяжелой гипофункции трансплантата после алло-ТГСК в нашем центре. В общей сложности 31 пациент (15 мужчин, 16 женщин) со средним возрастом 22 года (18-57) получили терапию агонистами рецептора ТПО (АР-ТПО) для посттрансплантационной тромбоцитопении <20×109/л (n=7) и ГФТ (n=24). Для терапии использовался ромиплостим (n=17) со средней дозой 5 мкг/кг в неделю (3-5) или элтромбопаг (n=14) со средней дозой 50 мг/день (50-150). Критериями тяжелой гипофункции трансплантата (тГФТ) были: цитопения в двух или более миелоидных линиях (тромбоциты <20×109/л, абсолютное число нейтрофилов (АЧН) <0,5×109/л, гемоглобин <70 г/л в любое время после документированного приживления, полный или стабильный смешанный донорский химеризм >90% без признаков рецидива основного заболевания. Общий ответ включал полный ответ (ПО) (тромбоциты ≥100×109/л, АЧН ≥1,5×109/л, гемоглобин ≥100 г/л) и частичный ответ (ЧО) (тромбоциты >20×109/л, АЧН ≥0,5×109/л, гемоглобин >70 г/л). Медиана времени от постановки диагноза тГФТ до начала терапии АР-ТПО составила 14 дней (0-119), медиана продолжительности терапии АР-ТПО составила 3 недели (1-43). Переносимость АР-ТПО была удовлетворительной, без признаков токсичности II-IV степени. В общей сложности в 8 случаях (28%) АР-ТПО использовались в комбинации с ритуксимабом (n=4), ритуксимабом и инфузиями донорских лимфоцитов (ИДЛ) (n=3), а также с инфузиями CD34-клеток (n=1). Всего 14 (48%) пациентов достигли ответа (ПО: n=4, 14%; ЧО: n=10, 34%). Комбинированная терапия не показала преимущества в скорости ответа по сравнению с АР-ТПО в монорежиме. Медиана прироста АЧН у ответивших на терапию составила 3,4×109/л (0,8-6,0), тромбоцитов – 48×109/л (21-205). В общей сложности 15 пациентов (3 ответивших, 12 не ответивших на терапию) умерли от инфекции (n=10), рецидива (n=2) и острой реакции «трансплантат-против-хозяина» (оРТПХ) III-IV степени (n=3). Однолетняя общая выживаемость (ОВ) от начала терапии составила 60% (95% ДИ, 40-76), при этом наблюдалась существенная разница между ответившими и неответившими на АР-ТПО: 79% (95% ДИ, 47-93) против 39% (95% ДИ, 14-63) (р=0,01). Наше исследование показало многообещающую эффективность и удовлетворительную безопасность АР-ТПО у пациентов с тГФТ после алло-ТГСК. Необходимо проведение многоцентровых проспективных исследований для установления оптимальной дозы и продолжительности приема, а также критериев отмены этих препаратов. <h2>Ключевые слова</h2> Алло-ТГСК, гипофункция трансплантата, агонисты рецепторов тромбопоэтина." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5849) "

Ключевые слова

Алло-ТГСК, гипофункция трансплантата, агонисты рецепторов тромбопоэтина.

Ключевые слова

Алло-ТГСК, гипофункция трансплантата, агонисты рецепторов тромбопоэтина.

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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the standard treatment option in a significant proportion of patients suffering from malignant (acute and chronic leukemias, lymphomas, primary myelofibrosis, myelodysplastic syndrome, etc.) and non-malignant blood diseases (aplastic anemia, primary immunodeficiency, inherited metabolic disorders, hemoglobinopathies, etc.) [1-4]. Despite high therapeutic efficacy, allo-HSCT is associated with the risk of disability and death caused by various post-transplant complications such as graft-versus-host disease (GVHD), severe organ toxicity, infections, and worsening of concomitant diseases causing nonrelapse mortality (NRM). Careful donor selection, flexible conditioning regimens, using of novel strategies for GVHD prevention and prophylaxis of infectious complications reduce the risk of the allo-HSCT procedure [5, 6]. Nevertheless, the problem of NRM remains relevant what determines the need to evaluate all potential pre-transplant risk factors associated with both the underlying disease and its treatment, as well as with comorbid conditions.

In 1987 M. Charlson proposed a comorbidity index, in order to stratify the risk of post-transplant complications. The Charlson Comorbidity Index (CCI) was being used for a long time, but it had several significant limitations and low sensitivity [7]. In 2005, M. Sorror and colleagues modified the CCI and proposed the first specific Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) which was amended in 2014 [8, 9]. HCT-CI differed from CCI, e.g., in grading the severity of pulmonary comorbidities by introducing specific parameters of pulmonary function test (PFT), i.e., forced expiratory volume in one second (FEV1) and diffusing capacity of carbon monoxide (CO) (DLco). The Fred Hutchinson Cancer Research Center study demonstrated high prognostic significance of these PFT parameters in relation to the risk of severe respiratory failure development and mortality within the first 120 days after HSCT [10]. Importantly, the described cohort consisted by 95% of patients given myeloablative conditioning (MAC). At the same time, in a number of studies using reduced intensity conditioning (RIC), the total lung capacity (TLC) and the forced vital capacity (FVC) had a more prognostic significance rather than FEV1 and DLco parameters [11].

The evolving concept of evaluating comorbidities during HSCT is to identify subclinical organ dysfunctions, which cannot be evaluated by means of HCT-CI index. The most progress in this area has been reached in evaluation and prediction of acute kidney injury and cardiotoxicity using highly sensitive biomarkers [12, 13]. However, currently there are not such biomarkers for detection of subclinical lung injury in the context of HSCT [14].

The frequency of detection and prognostic significance of abnormal pulmonary functional tests (PFT) during HSCT was significantly increased due to implication of novel diagnostic criteria. In the original retrospective study of M. Sorror et al., among 347 patients with moderate or high severity of pulmonary comorbidity, 122 patients died without signs of relapse, including 24% of deaths directly from the toxic lung injury [9].

Currently, all potential allo-HSCT recipients are undergoing PFTs. However, the pre-transplant examination in real clinical practice is limited to the screening level, often with incorrect spirometry manoeuvres, and the data are interpreted without taking into account all the potential factors that compromise pulmonary health before allo-HSCT procedure. Previous pulmonary infections, an extremely wide range of medical drugs are able to induce pulmonary toxicity, history of mediastinal radiation therapy, lung involvement due to underlying diseases, and other factors, along with chronic obstructive pulmonary disease (COPD) and bronchial asthma (BA) are of importance in the risk of post-transplantation pulmonary complications and NRM. At the same time, a novel unexplored landscape of pulmonary comorbidity is being observed in the context of expanding indications for allo-HSCT, new treatment modalities before allo-HSCT, increasing age limit for recipients, widespread usage of non-myeloablative conditioning and GVHD prophylaxis based on post-transplant cyclophosphamide.

Hence, the aim of our work was to perform a comprehensive evaluation of all potential pre-transplant factors of lung injury and integral PFT data in a large cohort of adult allo-HSCT patients suffering from malignant and non-malignant blood diseases.

Patients and methods

The present study was carried out at the Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation, M. Chernorutskiy Department of Hospital Therapy, and Department of Functional Diagnostics № 2 at Scientific and Clinical Research Center of the Fist St. Petersburg State I. Pavlov Medical University. The study was approved by the local ethics committee. All the patients gave written informed consent.

The study was both retrospective (data analysis until December 31, 2017) and prospective (data analysis after January 1, 2017). The analysis included patients with various malignant and non-malignant blood diseases who underwent allo-HSCT (in retrospective phase) or were scheduled for it (in prospective phase). The inclusion criteria for the study were as follows: 1. Patients’ age at the time of allo-HSCT over 18 years old; 2. Availability of sufficient anamnestic data about previous respiratory diseases, or risk factors for bronchopulmonary system; 3. Presence of pre-transplant PFT results.

The study was based on real clinical practice, so it was not limited by the characteristics of the donor (HLA-matched sibling, unrelated, haploidentical), graft source (bone marrow, peripheral blood), conditioning regimen (MAC, RIC), and regimen of GVHD prophylaxis.

Identification of pre-transplant risk factors for lung injury was based on a detailed history taking and analysis of available medical records (case histories, outpatient records, etc.). Pulmonary symptoms within one month before the start of conditioning (shortness of breath, cough, etc.), history of BA, COPD, previous pulmonary infections, administration of drugs causing potential pulmonary toxicity (bleomycin, carmustine, cytosine arabinoside, methotrexate) and immune checkpoint inhibitors (nivolumab, pembrolizumab), previous mediastinal radiation therapy, proven or suspected specific lung involvement and the status of the underlying blood disease at the moment of allo-HSCT were documented.

The data analysis included results of PFTs performed within 4 weeks before the allo-HSCT procedure. PFTs included spirometry and DLco measurement. All the PFTs were performed with MasterScreen equipment (CareFusion 234 GmbH, Erich Jaeger, Höchberg, Germany) according to the standards of the American Thoracic Society and European Respiratory Society (ATS/ERS) [15]. DLco measurement was performed with single-breath hold technique, using a gas mixture consisting of CO (0.25-0.30%), helium (8.9-10.0%) and synthetic air. DLco value was adjusted for hemoglobin concentration at the time of PFTs performance [16, 17]. The analyzed PFT parameters included spirometric vital capacity (VC), FVC, FEV1, FEV1/VC ratio (Tiffeneau index), DLco (adjusted for hemoglobin concentration), alveolar volume (Va), carbon monoxide transfer coefficient (Krogh factor, Kco). The absolute values of the PFT parameters and their percentage to predicted values were evaluated using formulas for predicted PFT values by R. Clement et al. [18].

Severity of pulmonary comorbidity was evaluated according to criteria of HCT-CI [8, 9]. Mild pulmonary comorbidity was defined as DLco and/or FEV1 values of 81%-90%, or dyspnea at moderate physical activity. Moderate pulmonary comorbidity was defined as DLco and/or FEV1 values of 66%-80%, or dyspnea at minimal activity. Severe pulmonary comorbidity was defined as DLco and/or FEV1 values of ≤65% or dyspnea at rest, or requirement for oxygen therapy.

Statistical evaluation of the cohort and outcomes of allo-HSCT was performed as of May 1, 2019. Descriptive characteristics included the number of observations and proportions for discrete factors, medianes, range of values, interquartile ranges and 95% confidence intervals (CI) for continuous values. Differences between the analyzed groups were evaluated using Kruskal-Wallis test (quantitative characteristics), Fisher's exact test and Pearson chi-square (categorical characteristics).

The cumulative incidence of mechanical ventilation (MV) and NRM rates were calculated from the date of allo-HSCT to the date of the beginning of the MV and death unrelated to the relapse of the underlying disease, respectively. Death prior to the onset of mechanical ventilation and relapses were considered competing risks. Prognostic value of the severity of pulmonary comorbidity and other potential risk factors for NRM (age, diagnosis, disease status at the time of HSCT, type of donor, protocol of GVHD prophylaxis, year of HSCT, severe acute GVHD) was performed in the Fine-Gray regression model for competing events. Overall survival (OS) was estimated using the Kaplan-Meier method from the date of allo-HSCT to the date of death, or the last contact with the patient. Comparison of survival was performed using the log-rank test.

The two-sided alternative testing hypothesis was applied, being statistically significant at the p-value of <0.05. Statistical analysis was performed using EZR statistical software, version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Clinical characteristics

As of May 1, 2019, 355 patients were included in the study, among them 206 (58%) and 149 (42%) in the retrospective and prospective phases, respectively. The basic demographic and clinical characteristics of the patient cohort are presented in Table 1.

In terms of age, gender, diagnosis and clinical indications for allo-HSCT, donor characteristics, conditioning regimens, the analyzed cohort appears to be representative and generally reflects the current transplant activity in adult patients.

Table 1. The basic demographic and clinical characteristics of patient cohort

Baseline factors of pulmonary comorbidity

At the first stage of the study, we analyzed the baseline potential risk factors and causes of pulmonary comorbidity in the entire patient cohort, as listed in Table 2.

Table 2. Risk factors for pulmonary comorbidity

Tobacco smoking, including high pack-year rates (> 20) for every fourth smoker was most frequent (32%) among the basic risk factors unrelated to the underlying disease and its treatment. A documented diagnosis of COPD and BA was present in, respectively, 15 (4.2%) and 4 (1.1%) of HSCT recipients. It should be noted that the majority of COPD patients (13/15) had a mild-severity disease, and intermittent BA was diagnosed in all 4 cases. The leading group of lung diseases reported before allo-HSCT was presented by pulmonary infections (44.9%), dominated by clinically proven pneumonia (35.8%). In general, microbiological verification of the pathogens in available medical documentation was low, and to a greater extent concerned only invasive mycoses with lung involvement (16%). Ten patients (2.8%) had the history of pulmonary tuberculosis, or radiological signs of previous tuberculosis which required secondary prophylaxis with tuberculostatic drugs.

Frequently used medical drugs with known lung toxicity, e.g., cytarabine (65%), as well as bleomycin (8.2%) and carmustine (5.2%) applied in anticancer chemotherapy before allo-HSCT were also identified as potential risk factors. In addition, 30 (8.5%) and 22 (6.2%) patients had the history of high-dose chemotherapy followed by autologous HSCT and mediastinal therapeutic irradiation, respectively. Use of immune checkpoint inhibitors was considered another particular potential risk factor of pre-HSCT pulmonary injury (5.4% of entire cohort).

In general, statistical evaluation of the potential factors predisposing for pulmonary compromise allowed us to identify two of the most characteristic disease-specific profiles associated with clinical course of the underlying disease and its treatment. The greatest number of risk factors for pulmonary comorbidity was revealed among the patients with lymphomas who received treatment with bleomycin, carmustine, cytarabine, immune checkpoint inhibitors, radiation therapy and autologous HSCT. The second group was represented by patients with acute leukemia and a part of MDS patients who received chemotherapy with cytarabine and showed high incidence of neutropenic pulmonary infections before allo-HSCT. Patients with AA did not exhibit specific drug pulmonary toxicity in anamnesis. However, this group of patients had an increased risk of iron overload, having been associated with multiple blood transfusions.

The proportion of smokers was higher among the patients with lymphomas (41%) and myeloproliferative diseases, and MDS (39%) compared with acute leukemia (30%) and, especially, AA group (19%). However, 48% of smokers with MPD and MDS had a smoking index of more than 20 pack-years, which was significantly higher than for with acute leukemia (22%) and lymphoma patients (21%) (p=0.0461). The frequency of concomitant COPD was significantly higher among patients with MPD and MDS, i.e., 7/54 (13%), compared with 0/27 (0%), 5/215 (2%) and 3/59 (5%) with AA, acute leukemia and lymphomas respectively (p=0.0038).

These patterns are partly explained by differences in the age and the duration of the disease at the time of allo-HSCT. The median age was 28, 32, 37 and 45 years in patients with SAA, acute leukemia, lymphomas and MPD and MDS respectively (p <0.0001). Accordingly, the median time between the diagnosis and allo-HSCT was 1.9, 1.1, 3.6, and 1.4 years (p <0.0001).

Table 3. Frequency of individual pulmonary CT symptoms before allo-HSCT (n=270)

Chest computed tomography (CT) findings at the time of allo-HSCT were available in 270 (76%) patients. Pathological changes in lung structures were documented in 190 (70.6%) of the examined patients (Table 3). The signs of local pulmonary fibrosis and focal changes were the most frequent CT symptoms detected in more than 50% and 30% of patients, respectively.

Pulmonary function tests (PFT)

At the next step of our study, we analyzed data from a pre-HSCT PFT with a focus on the key FEV1 and DLco parameters which are included in HCT-CI comorbidity criteria. Testing of FEV1 and other standard spirometry parameters covered the entire cohort (n=355), while the data on the pulmonary diffusing capacity, including DLco were obtained from 76 patients, predominantly in the prospective phase of the study. The main parameters of spirometry and pulmonary diffusing capacity are presented in Table 4.

FEV1 varied within 49-145% of predicted, the median was 100.6%, the interquartile range was 90-109.6%. According to HCT-CI criteria, 90 (25%) patients had low FEV1 value, including 14%, 9% and 2% of mild, moderate and severe grade respectively.

When verifying alterations of the pulmonary diffusing capacity, two methods were used to adjust the obtained DLco values for the hemoglobin levels. The median hemoglobin level at the time of DLco testing was 10.3 g/dL (5.8-16.4). There was decreased hemoglobin level in 80% of women and 57% of men. Frequency of diffusion disorders by the DLco values seems to be definitely overestimated (96%) when using the Cotes hemoglobin correction method, which is routinely recommended by ATS/ERS experts and used by default in pulmonary practice. The Dinakara method aiming to adjust DLco for hemoglobin levels provided a more accurate assessment and showed DLco disorders in 69% of the examined patients, including 29%, 28% and 12% frequency rates for mild-, moderate- and severe-grade alterations respectively.

Table 4. Pulmonary function tests characteristics before allo-HSCT

When analyzing PFT data in patients with different diagnoses, more frequent bronchial obstruction according to the FEV1/VC parameter was found in the patients with MPD and MDS, whereas disorders of pulmonary diffusing capacity according to the adjusted DLco were more pronounced in patients with lymphomas (Table 5). Other tested parameters did not show significant dependence on the underlying disease.

Table 5. Pulmonary function tests before allo-HSCT according to the diagnosis

In general, taking into account the maximum contribution of FEV1 or DLco data 68 (19%), 49 (14%) and 14 (4%) patients corresponded to the criteria for mild, moderate and severe pulmonary comorbidity, respectively (Table 6).

Table 6. Severity of pulmonary function abnormalities before allo-HSCT

Figure 1. NRM with stratification of patients according to the severity of pulmonary comorbidity

Figure 2. Cumulative incidence of mechanical ventilation with stratification of patients according to the severity of pulmonary comorbidity

Figure 3. Overall survival after allo-HSCT with stratification of patients according to the severity of pulmonary comorbidity

Prognostic value of pulmonary comorbidity for the outcome of allo-HSCT

The prognostic value of pulmonary comorbidity parameters was tested by its analyzing against cumulative incidence of NRM and overall survival (OS) after allo-HSCT. In the whole cohort, NRM and cumulative incidence of relapse in 2 years were 21.0% (95% CI, 16.4-25.9) and 10.5% (95% CI, 7.3-14.3).

Stratification of patients according to the severity of pulmonary comorbidity revealed significant differences in NRM (Fig. 1). The cumulative incidence of death without signs of relapse of the underlying disease within 12 months after allo-HSCT was 13.8% (CI 95%, 9.5-18.9), 14.1% (CI 95%, 6.4-24.7), 26.7% (CI 95%, 14.5-40.4) and 53.2% (CI 95%, 22.1-76.9) with pulmonary comorbidity 0, 1, 2, 3 degrees respectively (p=0.0004).

The value of pulmonary comorbidity was further evaluated by a surrogate criterion of severe respiratory failure with need for mechanical ventilation (MV). Indications for MV occurred in 34 (9.6%) and 54 (15.2%) patients during the first 100 days and 1 year after allo-HSCT, respectively. In two other cases, MV was performed later. In order to reduce the significance of the primary disease relapse, further analysis was carried out for patients who developed severe respiratory failure during the first 100 days after allo-HSCT.

Stratification of patients according to the pulmonary comorbidity revealed a significant increased risk of switching to MV in high-risk patients (Fig. 2). Cumulative incidence of the MV within 100 days from allo-HSCT was 7.2% (CI 95%, 3.8-10.6), 10.9% (CI 95%, 2.9-18.2), 16.7% (CI 95%, 5.4-26.6) and 22.1% (CI 95%, 0-41.3) in patients with pulmonary comorbidity of 0, 1, 2 and 3 degree, respectively (p=0.0176).

Prognostic significance of the degree of pulmonary comorbidity for the risk of NRM was confirmed in a multivariate analysis, using the Fine-Gray regression model for competing events (Table 7). Other factors associated with increased risk of NRM were: primary diagnosis (maximum risk for MPD and MDS, minimum for SAA), lack of remission at the time of allo-HSCT, MAC regimen, type of donor (maximum risk for a haploidentical donor), year of HSCT and the presence of severe acute GVHD (aGVHD).

In contrast to the severity of PFT disorders, none of the potential pulmonary comorbidity factors discussed above (smoking, presence of lung diseases before HSCT, pulmonary toxicity, radiation therapy), as well as the age of patients at the time of allo-HSCT, did not have independent prognostic value.

The risk of relapse after allo-HSCT as expected did not depend from the degree of pulmonary comorbidity. Despite this, due to significant differences in NRM, pulmonary comorbidity was associated with a decrease in overall survival: 71.9% (95% CI, 63.8-78.5), 61.9% (95% CI, 42.5-76.4), 54.3% (95% CI, 36.2-69.1) and 39.0 (95% CI, 14.3-63.3) at 5 years after allo-HSCT with 0, 1, 2, and 3 degrees respectively (p=0.0014) (Fig. 3).

Table 7. Multivariate analysis of characteristics affecting non-relapse mortality

Discussion

The HCT-CI is an important diagnostic tool in screening candidates for allo-HSCT [8, 9, 17]. Despite some inaccuracies with HCT-CI as prognostic indicators, a score of 3 and above always remains a sign of a high-degree risk for relapse-unrelated deaths. Currently, the assessment of the bronchopulmonary condition is one of essential components in pre-transplant examination of the patients, including PFTs with FEV1 and DLco, assessment, as well as chest CT evaluation [19].

The study by M. Sorror and colleagues has revealed that FEV1 and/or DLco reflect a correlation between causes of death and pulmonary comorbid pathology when assessing NRM rates [8]. Of the 347 patients who had moderate or severe degrees of pulmonary comorbidity, 122 died from causes unrelated to the relapse of primary disease. The causes of NRM were severe pulmonary toxicity (24%), pulmonary complications of cGVHD (11%), lower respiratory tract infections (45%) that were associated (18%), or non-associated (27%) with cGVHD, and other causes (20%) [8].

Conventional spirometry is the most common screening method in examining the function of respiratory system. Spirometry is aimed to identify and determine the type of pulmonary function disorders, primarily obstructive, with the Tiffeneau index and FEV1 [20, 21]. Spirometry makes it possible to diagnose broncho-obstructive diseases (BA, COPD, etc.), like as to predict clinical outcomes of the scheduled allo-HSCT [9, 19].

The DLco test is another functional method for assessing the state of lower respiratory tract. It is used to evaluate gas exchange via the alveolar-capillary membrane [20, 21]. The DLco test detects probable interstitial changes of pulmonary tissue in patients with a history of using pulmonary toxic drugs (cytarabine, bleomycin, carmustine, nivolumab, etc.), radiation therapy, as well as changes associated with the course of the underlying disease (specific pulmonary tissue involvement, iron overload, etc.) [20-27].

Despite its obvious diagnostic advantage in identifying “subclinical” pulmonary injuries associated with the course or therapy of oncohematological disease, the DLco study is technically difficult for real clinical practice, thus being rarely performed in routine functional diagnostics.

The main objective of this study was to perform comprehensive analysis of lung health before allo-HSCT, and its connection with development of infectious and non-infectious bronchopulmonary complications in the post-transplant period, as well as NRM rates. Our analysis included 355 adult patients with various neoplastic and benign blood diseases who received allo-HSCT from a related, unrelated, and haploidentical donors. In contrast to previously published data, the analyzed cohort was balanced in terms of conditioning regimen (MAC 40%, RIC 60%) and graft source (BM 38%, G-PBSC 62%) [8-11]. Median age of the patients at the time of allo-HSCT (33 years old) was lower compared with other observations, but the distribution of primary diagnoses did not significantly differ [8, 10, 11]. For the first time, adult patients with SAA (8%) were presented in the cohort.

The study assessed anamnestic data on pre-existing chronic respiratory diseases (COPD, BA) and previous bronchopulmonary infections (pneumonia, invasive mycosis, TBC). In addition, the presence of risk factors for the development of bronchopulmonary diseases (smoking, chemotherapy with pulmonary toxic drugs, mediastinal radiation therapy) was taken into account. In the observed cohort, COPD and BA were documented in 4.2% and 1.1% of patients, respectively, which is significantly lower than the data of the largest international and Russian population-based studies concerning general prevalence of COPD and BA (11.7% and 6.9%) [28]. According to literature data, the prevalence of COPD and BA among HSCT recipients was 2% and 12.2% [8, 29]. This fact can be explained by the negative selection of patients with severe forms of disease at earlier stages of treatment, even before their admission to the HSCT center.

A third of patients had a history of smoking, but a high smoking index was only 8% of patients from the entire cohort, which is comparable with another study, where the incidence of high smoking experience was 14% [30]. Pulmonary infections before allo-HSCT were in 44.9% of patients, among which pneumonia (35.8%), invasive mycosis (16%) and TBC (2.8%) prevailed. These data are similar to the results previously published by our group [31]. History of potential pulmonary toxic chemotherapy was documented in 72% of patients. However, no cases of drug-induced interstitial lung disease (DIILD) were detected in the analyzed cohort. According to available literature, the frequency of cytarabine-related DIILD varies from 15 to 44%, whereas for bleomycin, this condition is found in 6.8-21% of the patients [32-36]. The novel form of DIILD caused by nivolumab may be as frequent as in 11.7% of cases [37].

Pulmonary changes according to chest CT before allo-HSCT were detected in 71% of patients, including signs of local pulmonary fibrosis (58%) and focal changes (38%). An earlier study detected CT changes in 48% of patients with AML, ALL, and MDS before allo-HSCT [38]. Unlike our data, the foci in pulmonary tissue (46%) and ground-glass opacities (17%) were the most frequent CT symptoms. CT signs of terminal bronchiolitis, cavities and pleural effusion have also been detected relatively rarely.

Analysis of PFT parameters was carried out in the entire cohort of patients, as well as in groups of patients with different hematological disorders. Based on the HCT-CI criteria, we analyzed patients with mild, moderate, and severe degrees of pulmonary comorbidity [8]. The median FEV1 (106%) was higher than that shown in other multicenter studies, while the frequency of FEV1 decline was mild (14%), moderate (9%) and severe (2%), which did not significantly differ from earlier literature data [10-11].

In the present study we compared two methods of DLco adjustment for hemoglobin level: the method proposed by J.E. Cotes et al., recommended by ATS/ERS which is more commonly used in pulmonary practice, as well as the Dinakara method used by the Fred Hutchinson Cancer Research Center [15-18, 39-42]. According to our data, the Dinakara method seems to more precisely correct the impact of anemia to a decrease in DLco, which is comparable with similar results from another clinical study [42]. As a result, there was a decrease in DLco of mild (29%), moderate (28%) and severe (12%) degrees, which is comparable with the reported results of other observations [10-11].

Analysis of PFT parameters in patients with various hematological diseases revealed a decrease in the Tiffeneau index in patients with MPD and MDS, as well as a reduced DLco in patients with lymphomas. This relationship is not described in the literature, which is probably due to the previously low transplant activity in these groups of patients. It can be assumed that these disease-specific relationships are caused by the age of the patients, the history of pulmonary toxicity and radiation therapy, the length of smoking and proven COPD.

The key result of the study was a strong confirmation of the high prognostic significance of pulmonary comorbidity for allo-HSCT outcomes in the real-world practice and in context of changing transplant landscape [8, 10]. The patients with moderate and severe pulmonary comorbidity showed a 2- 3 fold increase in the cumulative incidence of MV requirements in the early post-transplant period. At the same time, the risk of NRM increased 2-4 times if compared to the patients without documented pulmonary comorbidity. Despite lacking differences in the frequency of relapses of the underlying disease, an association was found between moderate and, especially, severe degrees of pulmonary comorbidity and a decrease in overall survival.

Our study had a number of limitations, in particular, incomplete coverage of the cohort with DLco testing data in retrospective phase, which could cause underestimation of pulmonary comorbidity. However, taking into account the above-described features of a cohort based on the representation of different diagnoses, donor types, transplant sources, conditioning regimens and GVHD prophylaxis, the independent prognostic value of pulmonary comorbidity, as confirmed by multivariate analysis, is of particular importance.

Conclusion

Adult recipients of allogeneic HSCs have a wide range of potential causes and a high incidence of pulmonary comorbidity: non-infectious (5%) and infectious (45%) lung diseases, history of potential pulmonary toxicity (72%), lung changes according to CT (70%), disorders of respiratory function according to FEV1 (25%) and aDLco (69%). Pulmonary comorbidity and the frequency of violations of respiratory function have some disease-specific features.

In real practice, the use of a screening level of the PFT (spirometry) underestimates or incorrectly assesses the frequency of respiratory disorders in patients before allo-HSCT. The traditional DLco correction for hemoglobin level according to the Cotes method does not accurately reflect the contribution of anemia to impaired pulmonary diffusion capacity in adult patients with blood diseases and leads to an overestimated frequency of detecting severe violations of respiratory function before allo-HSCT. The Dinakara method provides more accurate DLco correction for hemoglobin levels.

In the modern landscape of allo-HSCT with a changing spectrum of indications, age of patients, conditioning regimens, GVHD prophylaxis, the degree of pulmonary comorbidity according to HCT-CI still retains a high predictive value in terms of risk of the MV and NRM.

Conflict of interest

The authors report no conflicts of interest.

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Savchenko VG, Liubimova LS, Parovichnikova EN, Mendeleeva LP, Mamotiuk KS, Demidova IA, Gribanova EO, Gal'tseva IV, Pokrovskaia OS, Kuz'mina LA, Zhelnova EI, Kliasova GA, Glasko EN, Kaplanskaia IB, Poreshina LP, et al. Transplantations of allogenic and autologous hemopoietic stem cells in acute leukemia (results of 20-year experience). Terapevticheskiy arkhiv. 2007;79 (7):30-35. (In Russian).
Rumyantsev AG, Maschan AA Hematopoietic stem cell transplantation in children. M.: Medical Information Agency, 2003. 909 pp. (In Russian.)
Duarte RF, Labopin M, Bader P, Basak GW, Bonini C, Chabannon C, Corbacioglu S, Dreger P, Dufour C, Gennery AR, Kuball J, Lankester AC, Lanza F, Montoto S, Nagler A, de Latour RP, Snowden JA, Styczynski J, Yakoub-Agha I, Kröger N, Mohty M for the European Society for Blood and Marrow Transplantation (EBMT). Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019. Bone Marrow Transplant. 2019:1-28. Published: 05 April 2019. doi.org/10.1038/s41409-019-0516-2.
Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, Martin PJ, Sandmaier BM, Marr KA, Appelbaum FR, Storb R, McDonald GB. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363(22):2091-2101.
Horan JT, Logan BR, Agovi-Johnson M-A, Lazarus HM, Bacigalupo AA, Ballen KK, Bredeson CN, Carabasi MH, Gupta V, Hale GA, Khoury HJ, Juckett MB, Litzow MR, Martino R, McCarthy PL, Smith FO, Rizzo JD, Pasquini MC. Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J Clin Oncol. 2011;29(7):806-813.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383.
Sorror ML, Maris MB, Storb RF, Sandmaier MB, Maloney DG, Storrer B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912-2919.
Sorror ML, Storb RF, Sandmaier BM, Maziarz RT, Pulsipher MA, Maris MB, Bhatia S, Ostronoff F, Deeg MH, Syrjala KL, Estey E, Maloney DG, Appelbaum FR, Martin PJ, Storer BE. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol. 2014;32(29):3249-3256.
Parimon T, Madtes DK, Au DH, Clark JG, Chien JW. Pretransplant lung function, respiratory failure, and mortality after stem cell transplantation. Am J Respir Crit Care Med. 2005;172(3):384-390.
Piñana JL, Martino L, Barba P, Bellido-Cassado J, Valcarcel D, Sureda A, Briones J, Brunet S, Rodriguez-Arias JM, Casan P, Sierra J. Pulmonary function testing prior to reduced intensity conditioning allogeneic stem cell transplantation in an unselected patient cohort predicts posttransplantation pulmonary complications and outcome. Am J Hematol. 2012;87(1):9-14.
Dobronravov VA, Smirnov KA, Afanasiev BV, Galkina OV, Smirnov AV. Subclinical tubular epithelium damage and acute kidney injury following allogeneic hematopoietic stem cell transplantation. Cell Ther Transplant. 2016; 5(4):8-14.
Roziakova L, Mistrik M, Batorova A, Kruzliak P, Bojtarova E, Dubrava J, Gergel J, Mladosievicova B. Can we predict clinical cardiotoxicity with cardiac biomarkers in patients after haematopoietic stem cell transplantation? Cardiovasc Toxicol. 2015;15(3):210-216.
Wu AC, Kiley JP, Noel PJ, Amur S, Burghard EG, Clancy JP, Galanter J, Inada M, Jones TK, Kropski JA, Loyd JE, Nogee LM, Raby BA, Rogers AJ, Schwartz DA, Sin DD, Spira A, Weiss ST, Young LR, Himes BE. Current status and future opportunities in lung precision medicine research with a focus on biomarkers. An American Thoracic Society/National Heart, Lung, and Blood Institute Research Statement. Am J Respir Crit Care Med. 2018;198(12):116-136.
Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CPM, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre M, McKay R, Miller MR, Navajas D, Pedersen OF, Wanger J. Interpretive strategies for lung function tests. Eur Respir J. 2005;26(5):948–968.
Cotes J. E. Measurement of the transfer factor (diffusing capacity) for the lung and its subdivisions. Lung function assessment application in medicine. 4th ed. Oxford, UK: Blackwell Scientific Publications. 1979:230-250.
Dinakara P, Blumenthal WS, Johnston RF, Kauffman LA, Solnick PB. The effect of anemia on pulmonary diffusing capacity with derivation of a correction equation. Am Rev Respir Dis. 1970:102(6):965-969.
Clement RF. Fundamental and methodological foundations for the development of a unified system of proper quantities. Current problems of clinical respiratory physiology. 1987:5-19. (In Russian).
Carreras E, Dufor C, Mohty M, Kröger N. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. Springer. 2019:77-86.
Chuchalin AG. Pulmonology. National guidelines. Moscow: GEOTAR-Media. 2012: 117-135. (In Russian).
Savushkina OI, Chernyak AV. Pulmonary functional tests: from theory to practice. A guide for doctors. Moscow: Strom. 2017:11-38; 63-82. (In Russian).
Skeoch S, Weatherley N, Swift AJ, Oldroyd A, Johns C, Hayton C, Giollo A, Wild JM, Waterton JC, Buch M, Linton K, Bruce IN, Leonard C, Bianchi S, Chaudhuri N. Drug-induced interstitial lung disease: a systematic review. J Clin Med. 2018;7(10):1-30.
DeMonaco NA, McCarty Jr KS, Joyce J, Jacobs SA. Focal radiation fibrosis after radioimmunotherapy for follicular non-Hodgkin lymphoma. Clin Lymphoma Myeloma. 2007;7(5):369-372.
Guner SI, Yanmaz MT, Selvi A, Usul C. Chemotherapy and radiation induced pulmonary dysfunction in Hodgkin lymphoma patients. Indian J Hematol Blood Transfus. 2016;32(4):431-436.
Berkman N, Breuer R, Kramer MR, Polliack A. Pulmonary involvement in lymphoma. Leuk Lymphoma. 1996;20(3-4):229-237.
Mian M, Wasle I, Gritsch S, Willenbacher W, Fiegl M. B cell lymphoma with lung involvement: what is it about? Acta Haematol. 2015;133(2):221-225.
Kamble R, Rosenzweig T. Diffuse pulmonary parenchymal involvement in multiple myeloma: antemortem diagnosis. Int J Hematol. 2006;83(3):259-261.
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2017 update. 2017:13-24. Available at: http://www.ginasthma.org. Accessed June 23, 2017.
Chien SH, Liu C-J, Hong Y-C, Teng C-J, Hu Y-W, Shen C-C, Ku F-C, Chen S-C, Yeh C-M, Chiou T-J, Gau J-P, Tzeng C-H. Use of azathioprine for graft-vs-host disease is the major risk for development of secondary malignancies after haematopoietic stem cell transplantation: a nationwide population-based study. Br J Cancer. 2015;112(1):177-184.
Mehdi A, Rybicki L, Mossad S, Yurch M, Sekeres M, Gerds AT, Jagadeesh D, Hamilton B, Liu H, Dean R, Pohlman B, Sobecks R, Andresen S, Kalaycio M, Bolwell BJ, Majhail MS, Copelan E, Hill BT. Impact of cigarette smoking on survival after myeloablative allogeneic hematopoietic stem cell transplantation and contribution of invasive fungal infection. Bone Marrow Transplant. 2017;52(12);1665-1667.
Popova MO, Ekushov KA, Ayzsilnieks OV, Volkova AG, Pinegina ON, Ignatieva SM, Slesarchuk OA, Vladovskaya MD, Bondarenko SN, Zubarovskaya LS, Klimko NN, Afanasyev BV. Invasive fungal infections in recipients of allogeneic hematopoietic stem cell teens and young adults. Russian J Pediatric Hematol Oncol. 2016; (1):44-51. (In Russian).
Ilkovich MM. Interstitial and orphan lung diseases. Moscow: GEOTAR-Media. 2016:289-316 (In Russian).
Blum RH, Carter SK, Agre K. A clinical review of bleomycin – a new antineoplastic agent. Cancer. 1973;31(4):903-914.
Hubbard SP, Chabner BA, Canellos GP, Young RC, DeVita Jr. VT. High dose intravenous bleomycin in the treatment of advanced lymphomas. Eur J Cancer. 1975;11(9):623-626.
Ngeow J, Tan IB, Kanesvaran R, Tan HC, Tao M, Quek R, Lim ST. Prognostic impact of bleomycin-induced pneumonitis on the outcome of Hodgkin’s lymphoma. Ann Hematol. 2011;90(1):67-72.
Stamatoullas A, Brice P, Bouabdallah R, Mareschal S, Camus V, Rahal I, Franchi P, Lanic H, Tilly H. Outcome of patients older than 60 years with classical Hodgkin lymphoma treated with front line ABVD chemotherapy: frequent pulmonary events suggest limiting the use of bleomycin in the elderly. Br J Haematol. 2015;170(2):179-184.
Nishino M, Ramaiya NH, Awad MM, Sholl LM, Maattala JA, Taibi M, Hatabu H, Ott PA, Armand PF, Hodi FS. PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res. 2016;22(24):6051-6060.
El Boghdadly Z, Oran B, Rondon JG, Champlin R, Kontoiyannis DP. Pretransplant chest computed tomography screening in asymptomatic patients with leukemia and myelodysplastic syndrome. Bone Marrow Transplant. 2017;52(3):476-479.
Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood. 2013;121(15):2854-2863.
Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, Maziarz RT, Antin JH, Soiffer RJ, Weisdorf DJ, Rizzo D, Horowitz MM, Saber W. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123(23):3664-3671.
Shouval R, Labopin M, Bondi O, Mishan Shamay H, Shimoni A, Ciceri F, Esteve Reiner J, Giebel S, Gorin NC, Schmid C, Polge E, Aljurf M, Kroger N, Craddock CF, Bacigalupo A, Cornelissen JJ, Baron F, Under R, Nagler A, Mohty M. Prediction of allogeneic hematopoietic stem-cell transplantation mortality 100 days after transplantation using a machine learning algorithm: a European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Retrospective Data Mining Study. J Clin Oncol. 2015;33(28):3144-3151.
Coffey DG, Pollyea DA, Myint H, Smith C, Gutman JA. Adjusting DLCO for Hb and its effects on the Hematopoietic Cell Transplantation-specific Comorbidity Index. Bone Marrow Transplant. 2013;48(9):1253-1256.

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Introduction

Patients and methods

Results

Clinical characteristics

Table 1. The basic demographic and clinical characteristics of patient cohort

Baseline factors of pulmonary comorbidity

At the first stage of the study, we analyzed the baseline potential risk factors and causes of pulmonary comorbidity in the entire patient cohort, as listed in Table 2.

Table 2. Risk factors for pulmonary comorbidity

Table 3. Frequency of individual pulmonary CT symptoms before allo-HSCT (n=270)

Pulmonary function tests (PFT)

Table 4. Pulmonary function tests characteristics before allo-HSCT

Table 5. Pulmonary function tests before allo-HSCT according to the diagnosis

Table 6. Severity of pulmonary function abnormalities before allo-HSCT

Figure 1. NRM with stratification of patients according to the severity of pulmonary comorbidity

Figure 2. Cumulative incidence of mechanical ventilation with stratification of patients according to the severity of pulmonary comorbidity

Figure 3. Overall survival after allo-HSCT with stratification of patients according to the severity of pulmonary comorbidity

Prognostic value of pulmonary comorbidity for the outcome of allo-HSCT

Table 7. Multivariate analysis of characteristics affecting non-relapse mortality

Discussion

Conclusion

Conflict of interest

The authors report no conflicts of interest.

References

Afanasyev BV, Zubarovskaya LS, Moiseev IS. Allogeneic hematopoietic stem cell transplantation in children: now, problems and prospects. Russian J Pediatric Hematol Oncol. 2015;2(2):28-42. (In Russian).
Savchenko VG, Liubimova LS, Parovichnikova EN, Mendeleeva LP, Mamotiuk KS, Demidova IA, Gribanova EO, Gal'tseva IV, Pokrovskaia OS, Kuz'mina LA, Zhelnova EI, Kliasova GA, Glasko EN, Kaplanskaia IB, Poreshina LP, et al. Transplantations of allogenic and autologous hemopoietic stem cells in acute leukemia (results of 20-year experience). Terapevticheskiy arkhiv. 2007;79 (7):30-35. (In Russian).
Rumyantsev AG, Maschan AA Hematopoietic stem cell transplantation in children. M.: Medical Information Agency, 2003. 909 pp. (In Russian.)
Duarte RF, Labopin M, Bader P, Basak GW, Bonini C, Chabannon C, Corbacioglu S, Dreger P, Dufour C, Gennery AR, Kuball J, Lankester AC, Lanza F, Montoto S, Nagler A, de Latour RP, Snowden JA, Styczynski J, Yakoub-Agha I, Kröger N, Mohty M for the European Society for Blood and Marrow Transplantation (EBMT). Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019. Bone Marrow Transplant. 2019:1-28. Published: 05 April 2019. doi.org/10.1038/s41409-019-0516-2.
Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, Martin PJ, Sandmaier BM, Marr KA, Appelbaum FR, Storb R, McDonald GB. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363(22):2091-2101.
Horan JT, Logan BR, Agovi-Johnson M-A, Lazarus HM, Bacigalupo AA, Ballen KK, Bredeson CN, Carabasi MH, Gupta V, Hale GA, Khoury HJ, Juckett MB, Litzow MR, Martino R, McCarthy PL, Smith FO, Rizzo JD, Pasquini MC. Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J Clin Oncol. 2011;29(7):806-813.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383.
Sorror ML, Maris MB, Storb RF, Sandmaier MB, Maloney DG, Storrer B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912-2919.
Sorror ML, Storb RF, Sandmaier BM, Maziarz RT, Pulsipher MA, Maris MB, Bhatia S, Ostronoff F, Deeg MH, Syrjala KL, Estey E, Maloney DG, Appelbaum FR, Martin PJ, Storer BE. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol. 2014;32(29):3249-3256.
Parimon T, Madtes DK, Au DH, Clark JG, Chien JW. Pretransplant lung function, respiratory failure, and mortality after stem cell transplantation. Am J Respir Crit Care Med. 2005;172(3):384-390.
Piñana JL, Martino L, Barba P, Bellido-Cassado J, Valcarcel D, Sureda A, Briones J, Brunet S, Rodriguez-Arias JM, Casan P, Sierra J. Pulmonary function testing prior to reduced intensity conditioning allogeneic stem cell transplantation in an unselected patient cohort predicts posttransplantation pulmonary complications and outcome. Am J Hematol. 2012;87(1):9-14.
Dobronravov VA, Smirnov KA, Afanasiev BV, Galkina OV, Smirnov AV. Subclinical tubular epithelium damage and acute kidney injury following allogeneic hematopoietic stem cell transplantation. Cell Ther Transplant. 2016; 5(4):8-14.
Roziakova L, Mistrik M, Batorova A, Kruzliak P, Bojtarova E, Dubrava J, Gergel J, Mladosievicova B. Can we predict clinical cardiotoxicity with cardiac biomarkers in patients after haematopoietic stem cell transplantation? Cardiovasc Toxicol. 2015;15(3):210-216.
Wu AC, Kiley JP, Noel PJ, Amur S, Burghard EG, Clancy JP, Galanter J, Inada M, Jones TK, Kropski JA, Loyd JE, Nogee LM, Raby BA, Rogers AJ, Schwartz DA, Sin DD, Spira A, Weiss ST, Young LR, Himes BE. Current status and future opportunities in lung precision medicine research with a focus on biomarkers. An American Thoracic Society/National Heart, Lung, and Blood Institute Research Statement. Am J Respir Crit Care Med. 2018;198(12):116-136.
Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CPM, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre M, McKay R, Miller MR, Navajas D, Pedersen OF, Wanger J. Interpretive strategies for lung function tests. Eur Respir J. 2005;26(5):948–968.
Cotes J. E. Measurement of the transfer factor (diffusing capacity) for the lung and its subdivisions. Lung function assessment application in medicine. 4th ed. Oxford, UK: Blackwell Scientific Publications. 1979:230-250.
Dinakara P, Blumenthal WS, Johnston RF, Kauffman LA, Solnick PB. The effect of anemia on pulmonary diffusing capacity with derivation of a correction equation. Am Rev Respir Dis. 1970:102(6):965-969.
Clement RF. Fundamental and methodological foundations for the development of a unified system of proper quantities. Current problems of clinical respiratory physiology. 1987:5-19. (In Russian).
Carreras E, Dufor C, Mohty M, Kröger N. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. Springer. 2019:77-86.
Chuchalin AG. Pulmonology. National guidelines. Moscow: GEOTAR-Media. 2012: 117-135. (In Russian).
Savushkina OI, Chernyak AV. Pulmonary functional tests: from theory to practice. A guide for doctors. Moscow: Strom. 2017:11-38; 63-82. (In Russian).
Skeoch S, Weatherley N, Swift AJ, Oldroyd A, Johns C, Hayton C, Giollo A, Wild JM, Waterton JC, Buch M, Linton K, Bruce IN, Leonard C, Bianchi S, Chaudhuri N. Drug-induced interstitial lung disease: a systematic review. J Clin Med. 2018;7(10):1-30.
DeMonaco NA, McCarty Jr KS, Joyce J, Jacobs SA. Focal radiation fibrosis after radioimmunotherapy for follicular non-Hodgkin lymphoma. Clin Lymphoma Myeloma. 2007;7(5):369-372.
Guner SI, Yanmaz MT, Selvi A, Usul C. Chemotherapy and radiation induced pulmonary dysfunction in Hodgkin lymphoma patients. Indian J Hematol Blood Transfus. 2016;32(4):431-436.
Berkman N, Breuer R, Kramer MR, Polliack A. Pulmonary involvement in lymphoma. Leuk Lymphoma. 1996;20(3-4):229-237.
Mian M, Wasle I, Gritsch S, Willenbacher W, Fiegl M. B cell lymphoma with lung involvement: what is it about? Acta Haematol. 2015;133(2):221-225.
Kamble R, Rosenzweig T. Diffuse pulmonary parenchymal involvement in multiple myeloma: antemortem diagnosis. Int J Hematol. 2006;83(3):259-261.
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2017 update. 2017:13-24. Available at: http://www.ginasthma.org. Accessed June 23, 2017.
Chien SH, Liu C-J, Hong Y-C, Teng C-J, Hu Y-W, Shen C-C, Ku F-C, Chen S-C, Yeh C-M, Chiou T-J, Gau J-P, Tzeng C-H. Use of azathioprine for graft-vs-host disease is the major risk for development of secondary malignancies after haematopoietic stem cell transplantation: a nationwide population-based study. Br J Cancer. 2015;112(1):177-184.
Mehdi A, Rybicki L, Mossad S, Yurch M, Sekeres M, Gerds AT, Jagadeesh D, Hamilton B, Liu H, Dean R, Pohlman B, Sobecks R, Andresen S, Kalaycio M, Bolwell BJ, Majhail MS, Copelan E, Hill BT. Impact of cigarette smoking on survival after myeloablative allogeneic hematopoietic stem cell transplantation and contribution of invasive fungal infection. Bone Marrow Transplant. 2017;52(12);1665-1667.
Popova MO, Ekushov KA, Ayzsilnieks OV, Volkova AG, Pinegina ON, Ignatieva SM, Slesarchuk OA, Vladovskaya MD, Bondarenko SN, Zubarovskaya LS, Klimko NN, Afanasyev BV. Invasive fungal infections in recipients of allogeneic hematopoietic stem cell teens and young adults. Russian J Pediatric Hematol Oncol. 2016; (1):44-51. (In Russian).
Ilkovich MM. Interstitial and orphan lung diseases. Moscow: GEOTAR-Media. 2016:289-316 (In Russian).
Blum RH, Carter SK, Agre K. A clinical review of bleomycin – a new antineoplastic agent. Cancer. 1973;31(4):903-914.
Hubbard SP, Chabner BA, Canellos GP, Young RC, DeVita Jr. VT. High dose intravenous bleomycin in the treatment of advanced lymphomas. Eur J Cancer. 1975;11(9):623-626.
Ngeow J, Tan IB, Kanesvaran R, Tan HC, Tao M, Quek R, Lim ST. Prognostic impact of bleomycin-induced pneumonitis on the outcome of Hodgkin’s lymphoma. Ann Hematol. 2011;90(1):67-72.
Stamatoullas A, Brice P, Bouabdallah R, Mareschal S, Camus V, Rahal I, Franchi P, Lanic H, Tilly H. Outcome of patients older than 60 years with classical Hodgkin lymphoma treated with front line ABVD chemotherapy: frequent pulmonary events suggest limiting the use of bleomycin in the elderly. Br J Haematol. 2015;170(2):179-184.
Nishino M, Ramaiya NH, Awad MM, Sholl LM, Maattala JA, Taibi M, Hatabu H, Ott PA, Armand PF, Hodi FS. PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res. 2016;22(24):6051-6060.
El Boghdadly Z, Oran B, Rondon JG, Champlin R, Kontoiyannis DP. Pretransplant chest computed tomography screening in asymptomatic patients with leukemia and myelodysplastic syndrome. Bone Marrow Transplant. 2017;52(3):476-479.
Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood. 2013;121(15):2854-2863.
Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, Maziarz RT, Antin JH, Soiffer RJ, Weisdorf DJ, Rizzo D, Horowitz MM, Saber W. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123(23):3664-3671.
Shouval R, Labopin M, Bondi O, Mishan Shamay H, Shimoni A, Ciceri F, Esteve Reiner J, Giebel S, Gorin NC, Schmid C, Polge E, Aljurf M, Kroger N, Craddock CF, Bacigalupo A, Cornelissen JJ, Baron F, Under R, Nagler A, Mohty M. Prediction of allogeneic hematopoietic stem-cell transplantation mortality 100 days after transplantation using a machine learning algorithm: a European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Retrospective Data Mining Study. J Clin Oncol. 2015;33(28):3144-3151.
Coffey DG, Pollyea DA, Myint H, Smith C, Gutman JA. Adjusting DLCO for Hb and its effects on the Hematopoietic Cell Transplantation-specific Comorbidity Index. Bone Marrow Transplant. 2013;48(9):1253-1256.

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Среди ключевых факторов безрецидивной летальности рассматривается коморбидность до момента алло-ТГСК. Целью настоящего исследования было охарактеризовать потенциальные предтрансплантационные факторы легочной коморбидности и интегральные показатели функции внешнего дыхания (ФВД) и оценить их прогностическое значение для исходов алло-ТГСК у взрослых пациентов. <h3>Пациенты и методы</h3> Исследование включало 355 больных, в том числе 149 (42%) в проспективной фазе исследования. Сформированная когорта включала пациентов с острыми лейкозами (60%), миелопролифератив- ными заболеваниями (10%), миелодиспластическим синдромом (5%), лимфомами (17%) и тяжелой апластической анемией (8%). Медиана возраста на момент алло-ТГСК составила 33 года (18-66). Анализировались все потенциальные предтрансплантационные факторы легочной компрометации. Степень тяжести легочной коморбидности оценивалась на основании параметров ФВД – объема форсированного выдоха за первую секунду (ОФВ1) и диффузионной способности лёгких для оксида углерода (CO) (DLco) в соответствии с критериями индекса коморбидности Hematopoietic cell transplantation specific comorbidity index (HCT-CI). Прогностическое значение степени легочной коморбидности исследовано в отношении кумулятивной частоты перевода на искусственную вентиляцию легких (ИВЛ) и безрецидивной летальности. <h3>Результаты</h3> Среди наиболее частых факторов легочной компрометации до алло-ТГСК идентифицированы курение (32%), анамнез хронической обструктивной болезни легких (ХОБЛ) и бронхиальной астмы (БА) (5%), инфекции легких (45%), потенциально пульмонотоксичная химиотерапия (79%), аутологичная ТГСК (8%), ингибиторы иммунных контрольных точек (5%), лучевая терапия на область средостения (6%) и др. Критериальное снижение ОФВ1 от должного имело место у 90 (25%) больных, включая 14%, 9% и 2% легкой, средней и тяжелой степени соответственно. Нарушение DLco было выявлено у 69% обследованных пациентов, включая 29%, 28% и 12% легкой, средней и тяжелой степени соответственно. Кумулятивная частота перевода на ИВЛ в течение 100 дней после алло-ТГСК составила 7,2%, 10,9%, 16,7% и 22,1% у пациентов с легочной коморбидностью 0, 1, 2, 3 степени соответственно. Степень легочной коморбидности была независимым фактором риска безрецидивной летальности (отношение рисков 1,39, ДИ 95%, 1.03-1.89, p=0.033) и ассоциировалась со снижением общей выживаемости. <h3>Выводы</h3> Взрослые пациенты имеют широкий спектр факторов легочной коморбидности до алло-ТГСК. Легочная коморбидность по HCT-CI является фактором риска перевода на ИВЛ в течение первых 100 дней после алло-ТГСК и безрецидивной летальности. <h2>Ключевые слова</h2> Аллогенная трансплантация гемопоэтических стволовых клеток, взрослые, коморбидная патология легких, функция внешнего дыхания, клинический прогноз. 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Кулагин 1, Алиса Г. Волкова 2, Илья Ю. Николаев 2, Олег В. Голощапов 2, Анна Г. Смирнова 2, Татьяна А. Рудакова 2, Елена И. Дарская 2, Елена В. Морозова 2, Наталья Б. Михайлова 2, Юлия Д. Рабик 3, Виктория Г. Тимчик 3, Татьяна И. Щемелинина 3, Руфь Д. Скворцова 3, Татьяна С. Разумовская 3, Сергей Н. Бондаренко 2, Иван С. Моисеев 2, Валерий Н. Марченко 1, Василий И. Трофимов 1, Борис В. Афанасьев 2" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(903) "

Егор А. Кулагин ¹, Алиса Г. Волкова ², Илья Ю. Николаев ², Олег В. Голощапов ², Анна Г. Смирнова ², Татьяна А. Рудакова ², Елена И. Дарская ², Елена В. Морозова ², Наталья Б. Михайлова ², Юлия Д. Рабик ³, Виктория Г. Тимчик ³, Татьяна И. Щемелинина ³, Руфь Д. Скворцова ³, Татьяна С. Разумовская ³, Сергей Н. Бондаренко ², Иван С. Моисеев ², Валерий Н. Марченко ¹, Василий И. Трофимов ¹, Борис В. Афанасьев ²

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¹ Кафедра госпитальной терапии с курсом аллергологии и иммунологии имени академика М.В. Черноруцкого, Санкт-Петербург, Россия
² НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Санкт-Петербург, Россия
³ Отделение функциональной диагностики №2 Научно-клинического исследовательского центра, ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова» Минздрава России, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "22619" ["VALUE"]=> array(2) { ["TEXT"]=> string(5923) "Высокая эффективность аллогенной трансплантации гемопоэтических стволовых клеток (алло- ТГСК) при широком спектре злокачественных и незлокачественных заболеваний системы крови ограничивается риском тяжелых осложнений и летального исхода без признаков рецидива или прогрессирования основного заболевания (безрецидивная летальность). Среди ключевых факторов безрецидивной летальности рассматривается коморбидность до момента алло-ТГСК. Целью настоящего исследования было охарактеризовать потенциальные предтрансплантационные факторы легочной коморбидности и интегральные показатели функции внешнего дыхания (ФВД) и оценить их прогностическое значение для исходов алло-ТГСК у взрослых пациентов. <h3>Пациенты и методы</h3> Исследование включало 355 больных, в том числе 149 (42%) в проспективной фазе исследования. Сформированная когорта включала пациентов с острыми лейкозами (60%), миелопролифератив- ными заболеваниями (10%), миелодиспластическим синдромом (5%), лимфомами (17%) и тяжелой апластической анемией (8%). Медиана возраста на момент алло-ТГСК составила 33 года (18-66). Анализировались все потенциальные предтрансплантационные факторы легочной компрометации. Степень тяжести легочной коморбидности оценивалась на основании параметров ФВД – объема форсированного выдоха за первую секунду (ОФВ1) и диффузионной способности лёгких для оксида углерода (CO) (DLco) в соответствии с критериями индекса коморбидности Hematopoietic cell transplantation specific comorbidity index (HCT-CI). Прогностическое значение степени легочной коморбидности исследовано в отношении кумулятивной частоты перевода на искусственную вентиляцию легких (ИВЛ) и безрецидивной летальности. <h3>Результаты</h3> Среди наиболее частых факторов легочной компрометации до алло-ТГСК идентифицированы курение (32%), анамнез хронической обструктивной болезни легких (ХОБЛ) и бронхиальной астмы (БА) (5%), инфекции легких (45%), потенциально пульмонотоксичная химиотерапия (79%), аутологичная ТГСК (8%), ингибиторы иммунных контрольных точек (5%), лучевая терапия на область средостения (6%) и др. Критериальное снижение ОФВ1 от должного имело место у 90 (25%) больных, включая 14%, 9% и 2% легкой, средней и тяжелой степени соответственно. Нарушение DLco было выявлено у 69% обследованных пациентов, включая 29%, 28% и 12% легкой, средней и тяжелой степени соответственно. Кумулятивная частота перевода на ИВЛ в течение 100 дней после алло-ТГСК составила 7,2%, 10,9%, 16,7% и 22,1% у пациентов с легочной коморбидностью 0, 1, 2, 3 степени соответственно. Степень легочной коморбидности была независимым фактором риска безрецидивной летальности (отношение рисков 1,39, ДИ 95%, 1.03-1.89, p=0.033) и ассоциировалась со снижением общей выживаемости. <h3>Выводы</h3> Взрослые пациенты имеют широкий спектр факторов легочной коморбидности до алло-ТГСК. Легочная коморбидность по HCT-CI является фактором риска перевода на ИВЛ в течение первых 100 дней после алло-ТГСК и безрецидивной летальности. <h2>Ключевые слова</h2> Аллогенная трансплантация гемопоэтических стволовых клеток, взрослые, коморбидная патология легких, функция внешнего дыхания, клинический прогноз. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5759) "

Высокая эффективность аллогенной трансплантации гемопоэтических стволовых клеток (алло- ТГСК) при широком спектре злокачественных и незлокачественных заболеваний системы крови ограничивается риском тяжелых осложнений и летального исхода без признаков рецидива или прогрессирования основного заболевания (безрецидивная летальность). Среди ключевых факторов безрецидивной летальности рассматривается коморбидность до момента алло-ТГСК. Целью настоящего исследования было охарактеризовать потенциальные предтрансплантационные факторы легочной коморбидности и интегральные показатели функции внешнего дыхания (ФВД) и оценить их прогностическое значение для исходов алло-ТГСК у взрослых пациентов.

Пациенты и методы

Исследование включало 355 больных, в том числе 149 (42%) в проспективной фазе исследования. Сформированная когорта включала пациентов с острыми лейкозами (60%), миелопролифератив-
ными заболеваниями (10%), миелодиспластическим синдромом (5%), лимфомами (17%) и тяжелой апластической анемией (8%). Медиана возраста на момент алло-ТГСК составила 33 года (18-66). Анализировались все потенциальные предтрансплантационные факторы легочной компрометации. Степень тяжести легочной коморбидности оценивалась на основании параметров ФВД – объема форсированного выдоха за первую секунду (ОФВ1) и диффузионной способности лёгких для оксида углерода (CO) (DLco) в соответствии с критериями индекса коморбидности Hematopoietic cell transplantation specific comorbidity index (HCT-CI). Прогностическое значение степени легочной коморбидности исследовано в отношении кумулятивной частоты перевода на искусственную вентиляцию легких (ИВЛ) и безрецидивной летальности.

Результаты

Среди наиболее частых факторов легочной компрометации до алло-ТГСК идентифицированы курение (32%), анамнез хронической обструктивной болезни легких (ХОБЛ) и бронхиальной астмы (БА) (5%), инфекции легких (45%), потенциально пульмонотоксичная химиотерапия (79%), аутологичная ТГСК (8%), ингибиторы иммунных контрольных точек (5%), лучевая терапия на область средостения (6%) и др. Критериальное снижение ОФВ1 от должного имело место у 90 (25%) больных, включая 14%, 9% и 2% легкой, средней и тяжелой степени соответственно. Нарушение DLco было выявлено у 69% обследованных пациентов, включая 29%, 28% и 12% легкой, средней и тяжелой степени соответственно. Кумулятивная частота перевода на ИВЛ в течение 100 дней после алло-ТГСК составила 7,2%, 10,9%, 16,7% и 22,1% у пациентов с легочной коморбидностью 0, 1, 2, 3 степени соответственно. Степень легочной коморбидности была независимым фактором риска безрецидивной летальности (отношение рисков 1,39, ДИ 95%, 1.03-1.89, p=0.033) и ассоциировалась со снижением общей выживаемости.

Выводы

Взрослые пациенты имеют широкий спектр факторов легочной коморбидности до алло-ТГСК. Легочная коморбидность по HCT-CI является фактором риска перевода на ИВЛ в течение первых 100 дней после алло-ТГСК и безрецидивной летальности.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, взрослые, коморбидная патология легких, функция внешнего дыхания, клинический прогноз.

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Egor A. Kulagin ¹, Alisa G. Volkova ², Ilya Yu. Nikolaev ², Oleg V. Goloshchapov ², Anna G. Smirnova ², Tatiana A. Rudakova ², Elena I. Darskaya ², Elena V. Morozova ², Nataliya B. Mikhaylova ², Julia D. Rabik ³, Victoria G. Timchik ³, Tatiana I. Shchemelinina ³, Ruf D. Skvortsova ³, Tatiana S. Razumovskaya ³, Sergey N. Bondarenko ², Ivan S. Moiseev ², Valeriy N. Marchenko ¹, Vasiliy I. Trofimov ¹, Boris V. Afanasyev ²

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¹ M. Chernorutskiy Department of Hospital Therapy, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
² Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
³ Department of Functional Diagnostics №2, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia

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High efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a wide range of malignant and non-malignant hematopoietic disorders system is limited to the risk of serious complications and non-relapse mortality (NRM). Pre-existing comorbidities before allo-HSCT are among key factors for NRM.

The purpose of this study was to characterize the potential pre-transplant factors of pulmonary comorbidity and integral indicators of pulmonary function tests (PFT) and to evaluate their prognostic value for the allo-HSCT outcomes in adult patients.

Patients and methods

The study included 355 patients, among them 149 (42%) in the prospective phase of the study. The cohort included patients with acute leukemia (60%), myeloproliferative diseases (10%), myelodysplastic syndrome (5%), lymphomas (17%), and severe aplastic anemia (8%). The median age at the time of allo-HSCT was 33 years old (18 to 66). We analyzed all the factors that could affect lung function before allo-HSCT. The severity of pulmonary comorbidity was assessed on the basis of forced expiratory volume in one second (FEV1) and diffusing capacity of carbon monoxide (CO) (DLco), in accordance with the criteria of the Hematopoietic Cell Transplantation Specific Comorbidity Index (HCT-CI). The prognostic value of pulmonary comorbidity was investigated with respect to the cumulative incidence of mechanical ventilation (MV) and NRM rates.

Results

Tobacco smoking (32%), history of chronic obstructive pulmonary disease (COPD) and bronchial asthma (BA) (5%), previous pulmonary infections (45%), potentially pulmonary toxic chemotherapy (79%), previous auto-HSCT (8%), usage of immune checkpoint inhibitors (5%), mediastinal radiation therapy (6%) were the most common pulmonary compromising factors before allo-HSCT. According to the HCT-CI criteria, 90 patients (25%) had low FEV1 values, with 14%, 9% and 2% of mild, moderate and severe grade respectively. DLco disorders were diagnosed in 69% of the patients examined, including 29%, 28%, and 12% of mild, moderate, and severe grade respectively. Cumulative incidence of MV within 100 days after allo-HSCT was 7.2%, 10.9%, 16.7%, and 22.1% in patients with pulmonary comorbidity of 0, 1, 2, 3 degrees, respectively. The degree of pulmonary comorbidity was an independent risk factor for NRM (hazard ratio 1.39; CI 95%; 1.03-1.89; p=0.033), being associated with a decrease in overall survival (OS).

Conclusions

Adult patients have a wide range of pulmonary comorbidity factors before allo-HSCT. HCT-CI pulmonary comorbidity is an independent risk factor for MV during the first 100 days after allo-HSCT and NRM.

Keywords

Allogeneic hematopoietic stem cell transplantation, adults, pulmonary comorbidity, pulmonary functional tests, clinical prognosis.

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Patients and methods

Results

Conclusions

Keywords

Allogeneic hematopoietic stem cell transplantation, adults, pulmonary comorbidity, pulmonary functional tests, clinical prognosis.

Patients and methods

Results

Conclusions

Keywords

Allogeneic hematopoietic stem cell transplantation, adults, pulmonary comorbidity, pulmonary functional tests, clinical prognosis.

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Степень тяжести легочной коморбидности оценивалась на основании параметров ФВД – объема форсированного выдоха за первую секунду (ОФВ1) и диффузионной способности лёгких для оксида углерода (CO) (DLco) в соответствии с критериями индекса коморбидности Hematopoietic cell transplantation specific comorbidity index (HCT-CI). Прогностическое значение степени легочной коморбидности исследовано в отношении кумулятивной частоты перевода на искусственную вентиляцию легких (ИВЛ) и безрецидивной летальности. <h3>Результаты</h3> Среди наиболее частых факторов легочной компрометации до алло-ТГСК идентифицированы курение (32%), анамнез хронической обструктивной болезни легких (ХОБЛ) и бронхиальной астмы (БА) (5%), инфекции легких (45%), потенциально пульмонотоксичная химиотерапия (79%), аутологичная ТГСК (8%), ингибиторы иммунных контрольных точек (5%), лучевая терапия на область средостения (6%) и др. Критериальное снижение ОФВ1 от должного имело место у 90 (25%) больных, включая 14%, 9% и 2% легкой, средней и тяжелой степени соответственно. Нарушение DLco было выявлено у 69% обследованных пациентов, включая 29%, 28% и 12% легкой, средней и тяжелой степени соответственно. Кумулятивная частота перевода на ИВЛ в течение 100 дней после алло-ТГСК составила 7,2%, 10,9%, 16,7% и 22,1% у пациентов с легочной коморбидностью 0, 1, 2, 3 степени соответственно. Степень легочной коморбидности была независимым фактором риска безрецидивной летальности (отношение рисков 1,39, ДИ 95%, 1.03-1.89, p=0.033) и ассоциировалась со снижением общей выживаемости. <h3>Выводы</h3> Взрослые пациенты имеют широкий спектр факторов легочной коморбидности до алло-ТГСК. Легочная коморбидность по HCT-CI является фактором риска перевода на ИВЛ в течение первых 100 дней после алло-ТГСК и безрецидивной летальности. <h2>Ключевые слова</h2> Аллогенная трансплантация гемопоэтических стволовых клеток, взрослые, коморбидная патология легких, функция внешнего дыхания, клинический прогноз. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5759) "

Пациенты и методы

Результаты

Выводы

Ключевые слова

Пациенты и методы

Результаты

Выводы

Ключевые слова

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Introduction

Modern therapy of inflammatory bowel disease takes into account the complex multifactorial pathogenetic mechanisms of development of this pathology [1, 2]. In view of the immunocorrective and immunosuppressive properties of mesenchymal stem cells, it is important to study the effectiveness of cellular therapy for patients with ulcerative colitis (UC). Immune component of pathogenesis in these immunological disorders is of sufficient importance. The inclusion of mesenchymal stromal cell transplantation in anticytokine and immunosuppressive therapy in patients with ulcerative colitis and Crohn's disease contributed to the positive dynamics of the clinical remission of these diseases [3]. However, morphological changes in large intestine mucosa (LIM) following cell therapy are still poorly understood from the standpoint of the “stem cell niche” and the mechanisms of participation of mesenchymal stem cells (MSCs) in the regulation of regenerative processes. Histological assessment of the complete remission of UC after conventional therapy considered a “golden standard for the treatment of inflammatory bowel disease” provides controversial results, due to severe destructive ulcers and reparative sclerotic changes of the colon mucosa (CM) in these diseases [4].

The purpose of our study was to evaluate the morpho-functional state of the colon mucosa in patients with ulcerative colitis after a single transplantation of autologous cultured mesenchymal bone marrow cells (MSC) against the background of standard therapy.

Patients and methods

Patients with ulcerative colitis were divided into 3 groups undergoing clinical, laboratory and morphological studies. The initial group of patients with UC before treatment included 18 subjects. Nine patients of them, received standard anti-inflammatory therapy (control group) which included 5-aminosalicylic acid (mesalazine), azathiopril, prednisone. Nine patients were treated with standard therapy supplemented by single MSC transplantation (main group) with a follow-up terms of about 10 months. Mesenchymal stem cells from bone marrow were cultured in DMEM culture medium for 14-21 days. Amounts and viability of in vitrocultured mesenchymal cells were evaluated by light microscopy, assessing activity of proliferation-associated Ki-67 antigen, production of specific biologically active substances. Transplantation of autologous mesenchymal bone marrow cells was performed once at a dose of 120-200 million cells in 200 ml of saline infused intravenously at a rate of 50 mL/h for 2.5 hours. Clinical and functional state of the patients (age from 24 to 57 years, men 11 and 7 women) with UC in the course of treatment was assessed according to the modified classifications by Truelove and Witts with updated recommendations G. Adler [5], Mayo and Rakhmilevich indices [6], extraintestinal manifestations, hemoglobin level, ESR, CRP and fecal calprotectin. 64 samples light-optical (semi-thin sections) and 320 microscopic examination of biopsy material taken endoscopically from different parts of the large intestine were subjected to histological and immunohistochemical studies. Histological sections of CM were stained with hematoxylin and eosin. Histological evaluation of the activity of inflammatory bowel disease was carried out semiquantitavely by K. Geboes et al. [7]. At the same time, structural changes, the density of inflammatory infiltration and the defects of the CM mucosa were assessed from 0 to 3 points. Immunohistochemical studies included detection of CD4, CD68, CD31, CD34, CD8, lgG, Ki-67 expression. For electron microscopy, the biopsy samples were fixed in in a 2.5% solution of glutaraldehyde with postfixation in 1% OsO₄ and then processed according to the standard technique [8]. Semi-thin and ultra-thin sections were obtained in a Leica EM UC 7 ultramicrotome (Austria). Semi-thin sections, which allow high-resolution light microscopy, were stained with Methylene Blue, Azur 2, and basic fuchsin dye, according to C. Humphrey and F. Pittman [9]. Ultrathin sections were contrasted with uranyl acetate and lead citrate according to Reynolds. Ultrathin sections were observed and captured using a Libra 120 electron microscope (K. Zeiss, Germany).

Results

Ten months after the beginning of treatment, the entire clinical and laboratory symptomatics of the patients from MCS-treated group improved or stabilized as compared to the initial condition, remaining unchanged or more severe in the control group. Significant differences in the dynamics of hemoglobin, C-reactive protein and fecal calprotein in patients of the main and control groups were not observed. Positive dynamics of normalization of the ESR level in patients of MSC-treated group were noted. In 4 patients of the main group (44.5%), normalization of the ESR level was noted, in 3 of the studied (33.3%) ESR remained at the same level, in 2 patients (22.2%) there was an increase in the level of ESR. In the control group of patients receiving only standard therapy in 9 patients (100%), the level of ESR did not change, including in patients with elevated ESR. Thus, in the main group compared with the control group, there was a positive trend in the normalization of ESR.

Meanwhile, periods of exacerbation were noted in 3 of 9 patients in the control group. The index of inflammatory activity of ulcerative colitis according to Rakhmilevich in the main group decreased from 6-9 to 4-5 points remained unchanged in the control group, and even being increased in one patient. Mayo index in the main group also slightly decreased from 7 to 5-6 points, but remained unchanged or increased in the control group. According to Truelove and Wiits scale, the degree of inflammatory activity remained unchanged in both groups, which may be explained by more generalized characteristics of this classification. When evaluating histological and immunohistochemical changes of large intestinal mucosa (LIM) in patients of the main and control groups compared with patients of the initial group, a decrease in T-lymphocytic inflammatory response was observed from severe and moderate to moderate and weak (from 2-3 to 1-2 points) with a decrease in the population of CD8+ lymphocytes. The density of the inflammatory infiltrate decreased from 2 to 3 points (Fig. 1, a). Erosive and ulcerative defects of CM (2-3 points) remained at similar level, or changed slightly. However, the number, length of crypts, number of goblet cells in epithelium and crypts were increased, flattening of the epithelium was decreased (from 2 to 1 point) and damage to the crypts (1-2 to 0-1 points) was also diminished. Interepithelial neutrophilic infiltration with decreased. Eosinophilic infiltration of the lamina propria of the mucous membrane was absent. Indicators of the positive dynamics of improving the pathological characteristics of CM in the main group of patients were observed in 5 of 6 patients, in the control in 2 of 9 patients.

Figure 1. Morphology of large intestinal mucosa after 6 months of single MSCs transplantation with standard therapy

(a) Reduction in the density of lympho-plasmacytic inflammatory infiltrate increase in the number of goblet cells in the integumentary epithelium and crypts section. Semi-thin section. Staining with Methylene Blue, Azure-2 and basic fuchsin. x400.
(b) Tight intercellular contact between the lymphocyte and the macrophage. Electron diffraction technique.
(c) Telocyte between the cells of inflammatory infiltrate. Electron diffraction technique.
(d) Cylindrical cell with microvilli, and a goblet cell with granules of mucus. Electron diffraction technique.

Discussion

Electron microscopic data revealed possible mechanisms of the positive effect of the secretion of mesenchymal stem cells on the immunocompetent, microcirculatory, neurotrophic systems, cellular and non-cellular components of the stroma of the mucous membrane of the large intestine and restoration of the epithelium. Numerous intimate contacts and small exosomes between lymphocytes, plasma cells and macrophages with high phagocytic and secretory activity were noted electronically (Fig. 1, b). Macrophages are given a key role in the presentation of the antigen and the realization of the effect of regeneration with the participation of various populations of lymphoid cells [10]. It is quite possible that the immunomodulating function of macrophages was also carried out with the help of telocytes, the long processes which were everywhere located between the cells of the inflammatory infiltrate (Fig. 1, c). First described as a new type of interstitial cells, telocytes are presumably involved in the regeneration of tissues, the formation of stem cell niches and intercellular communication through the secretion of extracellular vesicles and nanocontacts [11]. A necessary requirement for assessing the number and condition of these cells is the visualization of their double immunohistochemical staining. Although the immunohistochemical indicators of the level of angiogenesis (CD 34+ cells) were as high as before the treatment, the blood capillaries were characterized by an increased “working” area of endothelium, pronounced vesicle formation and numerous outgrowth of the luminal and basal surface. Amyelinic terminal nerve endings were numerous and contained a large number of small axons. On semi-thin sections, we observed a decrease in the degree of fibrosis of the connective tissue, due to fibroclasia of collagen fibrils. The proliferative activity of the epithelium at the neck of crypts was high, as proven by the Ki-67 antigen expression. The proliferating cells were characterized by a high degree of differentiation into goblet cells, which indicates the restoration of the secretory function of the integumentary epithelium. Cylindrical cells located on the basement membrane had different degrees of differentiation. Less differentiated cells had the appearance of vacuolation cells with poorly developed microvilli. Typical cylindrical cells had well-developed microvilli and tight intercellular contacts between long cytoplasmic processes (Fig. 1, d). Single intercellular contacts such as desmosomes in the proliferating epithelium indicated the differentiation of stem cells in the direction of the squamous epithelium, as it was phylogenetically more ancient and stable. Multivesicular endosomes were related to secretory exosomes involved in the regulation of anti-inflammatory processes [12]. Destruction of the granular endoplasmic reticulum canaliculi, and the decrease in the density of secretory granules were noted in the cytoplasm of serotonin-containing cells. A decrease in the functional activity of serotonin-containing cells is characteristic of the stage of remission of ulcerative colitis [13].

Conclusion

Inclusion of a single autologous bone marrow MSC transplant into the standard therapy of patients with ulcerative colitis 10 months after treatment generally improved the clinical and laboratory picture of the disease, as compared with the initial state and the control group. In morphological study of LIM in patients of the main and control groups, erosive and ulcerative defects persisted or slightly decreased. Indicators of positive dynamics of improving the pathological characteristics of LIM manifested mainly in patients of the MSC-treated. Group, as a decrease in local inflammatory response and restoration of crypts (“epithelial niche”) with increased number of goblet cells and a decrease in permeability of the cover epithelium. Thus, a single transplantation of autologous mesenchymal cultured bone marrow cells accompanied by standard therapy had a positive effect on the morpho-functional state of LIM in UC patients. As a part of the ongoing scientific and technical program, multiple MSC transplantation will be studied in order to achieve a more efficient histological LIM recovery in patients with ulcerative colitis.

Conflict of interest

None declared.

Acknowledgement

The work was carried out within the framework of the scientific and technical program “Transplantation of stem (mesenchymal) cells in regenerative medicine” 013 (2017-2019).

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Adler G. Crohn’s disease and ulcerative colitis. Moscow: Geotar MED, 2001 (In Russian).
Annese V, Daperno M, Rutter MD, Amiot A, Bossuyt P, East J, Ferrante M, Götz M, Katsanos KH, Kießlich R, Ordás I, Repici A, Rosa B, Sebastian S, Kucharzik T, Eliakim R; European Crohn's and Colitis Organisation. European evidence based consensus for endoscopy in inflammatory bowel disease. J Crohns Colitis. 2013; 7(12):982-1018.
Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Löfberg R. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut. 2000;47(3):404-409.
Glauert A. Fixation,dehydration and embedding of biological specimens. In: Practical Methods in Electron Microscopy (Ed. By Glauert AM). North-Holland : American Elsevier.1975.
Humphrey C, Pittman F. A simple methylene blue-azure II-basic fuchsin stain for epoxy-embedded tissue sections. Stain Technol. 1974;49(1):9-14.
Murrey PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nature Rev Immunol. 2011; 11(11): 723-737.
Popescu LM, Nicolescu MI. Telocytes and stem cells. (Inos Santos Goldenberg RC, de Carvalho ACC, eds). Resident stem cells and regenerative therapy. MA: Academic Press. 2013: 205-231.
van Niel G, Raposo G, Candalh C, Boussac M, Hershberg R, Cerf-Bensussan N, Heyman M. Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology. 2001;121(2):337-349.
Rybakova MG, Botina V, Solovyeva OI. Immunomorphological characteristic of the colon mucosal cells and endocrine structures in the patients with chronic ulcerous colitis. Arch Patol. 2005; 67(2):30-33 (In Russian).

" ["~DETAIL_TEXT"]=> string(15705) "

Introduction

Patients and methods

Results

Figure 1. Morphology of large intestinal mucosa after 6 months of single MSCs transplantation with standard therapy

Discussion

Conclusion

Conflict of interest

None declared.

Acknowledgement

The work was carried out within the framework of the scientific and technical program “Transplantation of stem (mesenchymal) cells in regenerative medicine” 013 (2017-2019).

References

Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009;330(3):864-875.
Farre R, Vicario M. Abnormal barrier function in gastrointestinal disorders, Handbook Exp Pharmacol. 2017:239:193-217.doi:10.1007/164_2016_107.
Knyazev OV, Fadeeva NA, Kagramanova AV, Lishchinskaya AA et al. Frequency of relapses in patients with ulcerative colitis and Crohn's disease, receiving cell therapy – 5 years of observation (Abstract). Materials of the III National Congress on Regenerative Medicine. Genes and Cells. 2017; 12 (3).
Villanacci V, Antonelli E, Geboes K, Casella G, Bassotti G. Histological healing in inflammatory bowel disease: a still unfulfilled promise. World J Gastroenterol. 2013; 19(7): 968-978.
Adler G. Crohn’s disease and ulcerative colitis. Moscow: Geotar MED, 2001 (In Russian).
Annese V, Daperno M, Rutter MD, Amiot A, Bossuyt P, East J, Ferrante M, Götz M, Katsanos KH, Kießlich R, Ordás I, Repici A, Rosa B, Sebastian S, Kucharzik T, Eliakim R; European Crohn's and Colitis Organisation. European evidence based consensus for endoscopy in inflammatory bowel disease. J Crohns Colitis. 2013; 7(12):982-1018.
Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Löfberg R. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut. 2000;47(3):404-409.
Glauert A. Fixation,dehydration and embedding of biological specimens. In: Practical Methods in Electron Microscopy (Ed. By Glauert AM). North-Holland : American Elsevier.1975.
Humphrey C, Pittman F. A simple methylene blue-azure II-basic fuchsin stain for epoxy-embedded tissue sections. Stain Technol. 1974;49(1):9-14.
Murrey PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nature Rev Immunol. 2011; 11(11): 723-737.
Popescu LM, Nicolescu MI. Telocytes and stem cells. (Inos Santos Goldenberg RC, de Carvalho ACC, eds). Resident stem cells and regenerative therapy. MA: Academic Press. 2013: 205-231.
van Niel G, Raposo G, Candalh C, Boussac M, Hershberg R, Cerf-Bensussan N, Heyman M. Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology. 2001;121(2):337-349.
Rybakova MG, Botina V, Solovyeva OI. Immunomorphological characteristic of the colon mucosal cells and endocrine structures in the patients with chronic ulcerous colitis. Arch Patol. 2005; 67(2):30-33 (In Russian).

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Иммуногистохимические исследования включали анализ экспрессии маркеров CD4, CD68, CD31, CD34, CD8, IgG и Ki-67. ЭМ проводили по общепринятой методике. Полутонкие срезы окрашивали по Humphrey и Pittman. Ультратонкие срезы изучали и локализовали с помощью электронного микроскопа Libra 120. <h3>Результаты</h3> Разовая трансплантация аутологичных культивированных МСК костного мозга в добавление к стандартной терапии больных с ЯК, в целом, улучшали клинические и лабораторные симптомы заболевания при исследовании через 10 мес. после лечения при сравнении с исходным клиническим статусом и контрольной группой. При морфологическом исследовании СТК в обеих группах была отмечена персистенция или некоторое уменьшение эрозивных и язвенных дефектов. Показатели позитивной динамики структуры СТК проявлялись, главным образом, у пациентов экспериментальной группы в виде снижения воспалительной реакции и восстановления кишечных крипт (“эпителиальной ниши”), с увеличением числа goblet-клеток и сниженной проницаемостью кишечного покровного эпителия. <h3>Заключение</h3> Разовая трансплантация аутологичных культивированных МСК костного мозга может быть внедрена в стандартную терапию пациентов с ЯК, что оказывает позитивный эффект на морфофунциональное состояние СТК, тем самым способствуя снижению воспалительной реакции, восстановлению крипт и покровного эпителия. <h2>Ключевые слова</h2> Язвенный колит, аутологичная трансплантация костного мозга, мезенхимные клетки, трансплантация, кишечные крипты, морфология." 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Федотовских, Галия М. Шаймарданова, Манарбек Б. Аскаров, Майя С. Жумабаева, Гульмира С. Досатаева, Айгерим К. Смагулова, Сапаргуль Марат, Татьяна Г. Ежеленко" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(305) "

Галина В. Федотовских, Галия М. Шаймарданова, Манарбек Б. Аскаров, Майя С. Жумабаева, Гульмира С. Досатаева, Айгерим К. Смагулова, Сапаргуль Марат, Татьяна Г. Ежеленко

АО «Национальный научный медицинский центр», г. Нур-Cултан (Астана), Казахстан

Применение мезенхимных стволовых клеток костного мозга (МСК) при воспалительных заболеваниях кишечника показало свою выполнимость в клинических исследованиях. Целью настоящей работы было исследование морфо-функционального состояния слизистой толстого кишечника в срок 10 мес. после единичной инфузии культивированных in vitro и размноженных МСК в дополнение к стандартной терапии больных с язвенным колитом (ЯК).

Материалы и методы

Исходная группа пациентов с ЯК включала 18 человек. Девять из них получали стандартную терапию (контрольная группа), а шесть человек проходили аналогичное лечение с добавлением разовой трансплантацией аутологичных МСК (экспериментальная группа). Клиническое и функциональное состояние пациентов оценивали по индексам Truelove и Wiits, а также Mayo и Rakhmilevich. Рутинная световая микроскопия, а также электронно-микроскопические (ЭМ) исследования проводили для 320 биоптатов слизистой толстого кишечника (СТК). Специфическое гистологическое и иммуногистохимическое обследование выполнено в 64 образцах. Гистологические признаки воспалительной активности оценивали в баллах по K.Geboes et al. Иммуногистохимические исследования включали анализ экспрессии маркеров CD4, CD68, CD31, CD34, CD8, IgG и Ki-67. ЭМ проводили по общепринятой методике. Полутонкие срезы окрашивали по Humphrey и Pittman. Ультратонкие срезы изучали и локализовали с помощью электронного микроскопа Libra 120.

Результаты

Разовая трансплантация аутологичных культивированных МСК костного мозга в добавление к стандартной терапии больных с ЯК, в целом, улучшали клинические и лабораторные симптомы заболевания при исследовании через 10 мес. после лечения при сравнении с исходным клиническим статусом и контрольной группой. При морфологическом исследовании СТК в обеих группах была отмечена персистенция или некоторое уменьшение эрозивных и язвенных дефектов. Показатели позитивной динамики структуры СТК проявлялись, главным образом, у пациентов экспериментальной группы в виде снижения воспалительной реакции и восстановления кишечных крипт (“эпителиальной ниши”), с увеличением числа goblet-клеток и сниженной проницаемостью кишечного покровного эпителия.

Заключение

Разовая трансплантация аутологичных культивированных МСК костного мозга может быть внедрена в стандартную терапию пациентов с ЯК, что оказывает позитивный эффект на морфофунциональное состояние СТК, тем самым способствуя снижению воспалительной реакции, восстановлению крипт и покровного эпителия.

Ключевые слова

Язвенный колит, аутологичная трансплантация костного мозга, мезенхимные клетки, трансплантация, кишечные крипты, морфология.

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Galina V. Fedotovskikh, Galija M. Shaymardanova, Manarbek B. Askarov, Maiya S. Zhumabayeva, Gulmira S. Dosataeva, Aigerim K. Smagulova, Sapargul Marat, Tatyana G. Ezhelenko

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National Scientific Medical Center, Nur-Sultan (Astana), Kazakhstan

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Usage of bone marrow mesenchymal stromal cells (MSCs) in human inflammatory bowel disease has proven its feasibility in clinical studies. The purpose of this work was to study morpho-functional state of large intestine mucosa (LIM) at the term of 10 months after a single infusion of cultured in vitro expanded mesenchymal bone marrow cells (MSC) added to standard therapy of patients with ulcerative colitis (UC).

Materials and methods

Initial group of the patients with UC included 18 subjects. Of those, nine patients received standard drug therapy (control group), six subjects underwent similar therapy supplied by a single transplantation of autologous MSCs (the study group). Clinical and functional state of the patients was assessed by indices, according to Truelove and Wiits, Mayo and Rakhmilevich. Routine light microscopy, as well as electron microscopic studies were performed for 320 large intestinal mucosa (LIM) biopsies. Specific histological and immunohistochemical examination was carried out in 64 samples. Histological signs of inflammatory activity were evaluated in points according to K.Geboes et al. (2000). Immunohistochemistry studies included expression of CD4, CD68, CD31, CD34, CD8, lgG, and Ki-67 markers. The electron microscopic technique was used as generally accepted. Semi-thin sections were stained by C. Humphrey and F. Pittman (1974). Ultrathin sections were observed and captured using a Libra 120 electron microscope.

Results

A single transplantation of autologous cultured bone marrow MSCs, in addition to standard therapy of patients with ulcerative colitis has generally improved clinical and laboratory signs of the disease as examined 10 months after treatment, when compared with initial clinical state and the control group. Upon morphological study of LIM in the study and control groups, erosive and ulcerative defects did persist or were slightly decreased. Indicators of positive dynamics in the LIM structure have manifested mainly in the patients of study group, as a decreased inflammatory response and restoration of intestinal crypts (“epithelial niche”), with increased number of goblet cells and decreased permeability of intestinal cover epithelium.

Conclusion

Single transplantation of autologous cultured bone marrow MSC could be implemented into the standard therapy of patients with ulcerative colitis, providing a positive effect upon morpho-functional state of LIM, thus promoting reduction of inflammatory response, recovery of crypts and cover epithelium.

Keywords

Ulcerative colitis, autologous bone marrow, mesenchymal cells, transplantation, intestinal crypts, morphology.

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Fedotovskikh, Galija M. Shaymardanova, Manarbek B. Askarov, Maiya S. Zhumabayeva, Gulmira S. Dosataeva, Aigerim K. Smagulova, Sapargul Marat, Tatyana G. Ezhelenko" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(180) "

Galina V. Fedotovskikh, Galija M. Shaymardanova, Manarbek B. Askarov, Maiya S. Zhumabayeva, Gulmira S. Dosataeva, Aigerim K. Smagulova, Sapargul Marat, Tatyana G. Ezhelenko

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Materials and methods

Results

Conclusion

Keywords

Ulcerative colitis, autologous bone marrow, mesenchymal cells, transplantation, intestinal crypts, morphology.

Materials and methods

Results

Conclusion

Keywords

Ulcerative colitis, autologous bone marrow, mesenchymal cells, transplantation, intestinal crypts, morphology.

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National Scientific Medical Center, Nur-Sultan (Astana), Kazakhstan

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Целью настоящей работы было исследование морфо-функционального состояния слизистой толстого кишечника в срок 10 мес. после единичной инфузии культивированных in vitro и размноженных МСК в дополнение к стандартной терапии больных с язвенным колитом (ЯК). <h3>Материалы и методы</h3> Исходная группа пациентов с ЯК включала 18 человек. Девять из них получали стандартную терапию (контрольная группа), а шесть человек проходили аналогичное лечение с добавлением разовой трансплантацией аутологичных МСК (экспериментальная группа). Клиническое и функциональное состояние пациентов оценивали по индексам Truelove и Wiits, а также Mayo и Rakhmilevich. Рутинная световая микроскопия, а также электронно-микроскопические (ЭМ) исследования проводили для 320 биоптатов слизистой толстого кишечника (СТК). Специфическое гистологическое и иммуногистохимическое обследование выполнено в 64 образцах. Гистологические признаки воспалительной активности оценивали в баллах по K.Geboes et al. Иммуногистохимические исследования включали анализ экспрессии маркеров CD4, CD68, CD31, CD34, CD8, IgG и Ki-67. ЭМ проводили по общепринятой методике. Полутонкие срезы окрашивали по Humphrey и Pittman. Ультратонкие срезы изучали и локализовали с помощью электронного микроскопа Libra 120. <h3>Результаты</h3> Разовая трансплантация аутологичных культивированных МСК костного мозга в добавление к стандартной терапии больных с ЯК, в целом, улучшали клинические и лабораторные симптомы заболевания при исследовании через 10 мес. после лечения при сравнении с исходным клиническим статусом и контрольной группой. При морфологическом исследовании СТК в обеих группах была отмечена персистенция или некоторое уменьшение эрозивных и язвенных дефектов. Показатели позитивной динамики структуры СТК проявлялись, главным образом, у пациентов экспериментальной группы в виде снижения воспалительной реакции и восстановления кишечных крипт (“эпителиальной ниши”), с увеличением числа goblet-клеток и сниженной проницаемостью кишечного покровного эпителия. <h3>Заключение</h3> Разовая трансплантация аутологичных культивированных МСК костного мозга может быть внедрена в стандартную терапию пациентов с ЯК, что оказывает позитивный эффект на морфофунциональное состояние СТК, тем самым способствуя снижению воспалительной реакции, восстановлению крипт и покровного эпителия. <h2>Ключевые слова</h2> Язвенный колит, аутологичная трансплантация костного мозга, мезенхимные клетки, трансплантация, кишечные крипты, морфология." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4981) "

Материалы и методы

Результаты

Заключение

Ключевые слова

Материалы и методы

Результаты

Заключение

Ключевые слова

АО «Национальный научный медицинский центр», г. Нур-Cултан (Астана), Казахстан

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Introduction

The Brain And Acute Leukemia Cytoplasmic (BAALC) gene becomes a new molecular star on the horizon of leukemia research. Its protein was initially discovered in the cytoplasm of central nervous system neuroderm cells [1]. Later on, a sufficient role of BAALC gene overexpression as a prognostic marker and pathogenetic factor of acute myeloid leukemia (AML) proved to be more obvious [2-4]. Initially, the BAALC overexpression was revealed in the patients with chromosome 8 trisomy, wherein BAALC gene maps. More recently, this abnormality has been demonstrated in 50-60% of AML patients with different morphological and cytogenetic variants [5-8]. Thus, BAALC gene overexpression proved to be rather specific for AML patients with t(8;21) translocation [5]. Meanwhile, the incidence of such phenomenon was also high in M0 and M1 AML FAB-variants [6]. On the contrary, it was observed extremely rare in AML M3 [7].

The BAALC gene expression has been recently shown to be closely associated with leukemic CD34+ but not CD34- precursor cell population which may initiate a relapse of acute leukemia that was shown in experiments with precursor cell enrichment [9-11]. Great contribution of early leukemic precursors, particularly CD34+/CD38- cells, to BAALC expression was demonstrated in other works [12], as documented by growing number of studies in the field [4, 13-18]. It is essential that the above-mentioned precursor cells with CD34+/CD38- phenotype may be responsible to regulate size of blast cell population, which, in turn, is able to express WT1 gene mRNA. Therefore, the latter gene is considered to be a basic molecular marker for AML relapses [19]. Since both these markers are functionally associated with changing levels of leukemic cells in AML patients treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT), the parallel study of their expression seems to be quite important both in clinical and tumor biology aspects [5, 20].

One of such studies [5] included a cohort of 45 adult patients with core-binding-factor-positive AML, of which 28 cases had a standard t(8;21) translocation, and 17 patients harbored the inv(16) aberration. This work revealed that the patients with elevated BAALC gene expression level at diagnosis had shorter overall survival (OS) and relapse-free survival (RFS) (p=0.031, and p=0.011, respectively) along with significantly increased cumulative incidence of relapse (CIR) post-transplant (p=0.002). In this setting, the decrease of BAALC gene expression level following induction chemotherapy had no impact on results of allo-HSCT or auto-HSCT in one-third of this group.

This study has shown for the first time that the elevated BAALC and WT1 gene expression levels over post-transplant period in the patients with core-binding-factor-positive AML may be associated with unfavorable clinical prognosis. It should be noticed here, that all the associations between BAALC and WT1 gene expression and basic clinical parameters were obtained in the cohorts with intermediate or favorable cytogenetic AML variants. At the same time, such associations are not confirmed in more heterogeneous groups of patients, including both favorable and dismal AML variants [21]. When explaining these differences in clinical and laboratory characteristics among two patient groups, we consider an important role of particular chromosomal aberrations to be responsible for the transformation of leukemic cell precursors from the sleeping condition to more active state.

Patients and methods

Our study presents the data on WT1 and BAALC gene expression levels measured in parallel, during serial assays of bone marrow samples taken from sixty-one patients with initial diagnosis of AML. All the patients were treated with allo-HSCT at R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation (St. Petersburg) from 2010 to 2016 years. The study group included 27 females and 34 males at the age of 3 to 66 years (median age 23.5 years old). Twelve patients were classified into the group with evident cytological remission (<4% in the bone marrow) at the time of HSCT, however, showing WT1 overexpression in the marrow samples [22]. Among the remaining 49 patients with different AML FAB-variants, serial BAALC and WT1 expression changes have been evaluated individually, being combined with blast cell counts in the same bone marrow aspirates.

Total mRNA extraction from fresh bone marrow samples, its reverse transcription and quantitative estimation of the BAALC gene expression level were performed as previously described [23]. Basic control time points for bone marrow sampling were as follows: at diagnosis (e.g., D-80), just before allo-HSCT, prior to the conditioning (D0) and after allo-HSCT, i.e. on D+30, D+60, D+90, D+150 and later post-transplant. The bone marrow sampling was obligatory in cases of PTR occurrence. A median follow-up time after HSCT was 7 months (range from 0.6 to 52.5). The analysis of BAALC gene expression included a total of 93 samples tested at clinical (cytologically proven) relapse, and 299 specimens were taken during clinical remission. In parallel, the WT1 gene expression levels and blast cell counts were determined in each sample at the same time points. A basal BAALC expression level of 31% to the reference gene was chosen as a common cut-off value to study clinical significance of BAALC gene overexpression before and after HSCT, in order to perform molecular monitoring of leukemic precursors and interaction of blast cell populations. This value was higher than the maximal BAALC gene expression in those patients with pre-transplant cytological remission who did not show any clinical signs of the disease progression. The copy numbers (CN) of WT1 transcripts was determined by the same quantitative real-time PCR method, according to recommendations of European LeukemiaNet group [24]. The basal WT1 expression level of 250 copies per 10⁴ copies of ABL1 reference gene was applied to designate low and high WT1 expressors.

Statistical analysis

Descriptive statistics methods for data with asymmetric distribution were used, with evaluation of the sample ranges and median values. Two-year relapse-free survival (RFS) and cumulative incidence of relapse (CIR) were calculated using Kaplan-Meier method, and the log-rank test was used to compare differences between survival curves. RFS and CIR were measured from D0 until the date of death, regardless of cause, or until terms of documented relapse, or last contact date. P <0.05 was considered a statistically significant difference level. SPSS software version 22.0 (IBM corporation, Armonk, NY, USA) was used for statistical analysis.

Results

Initially, we estimated clinical significance of the BAALC gene overexpression in AML patients with a false cytological remission at the moment of transplantation. A term of "misleading" cytological remission was used to refer to clinical state with elevated WT1 expression level (higher than 250 copies per 10⁴ copies of reference gene ABL1) combined with normal marrow blast counts (less than 5%). Among 12 such cases, nine patients (75%) did not express BAALC at the levels above the chosen cut-off of 31%, whereas increased BAALC expression was detected in three other patients. Despite limited number of tested AML cases, the RFS and CIR in the latter group appeared to be significantly worse, compared to those with low BAALC expression (р=0.019 и p=0.002, respectively), as seen from Fig. 1.

Figure 1. The difference between RFS (A) and CIR (B) depending on the BAALC gene expression level at the moment of allo-HSCT in the group of patients transplanted in a "misleading" cytological remission

Hence, one may conclude that the patients with combined WT1 and BAALC overexpression could be classified into prognostically unfavorable group, associated with high risk of early post-transplant relapse. This regulatory function seems to be retained in nine patients studied at the moment of transplantation. However, it could be lost in three other patients, in whom a combined WT1 and BAALC overexpression took place.

The BAALC and WT1 expression levels for the previously discussed AML patients [23] were assessed in the context of our recent findings. As shown in Fig. 2, the highest BAALC expression levels were observed in relapsing patients with AML classified as M1 and M2 FAB-variants, with intermediate values in M0, M4 and M5 FAB-variants of AML. The lowest BAALC expression was detected in AML M3 and M7 cases.

Figure 2. Distribution of individual values and median levels of BAALC gene expression in relapsing patients with different AML FAB-variants

In addition, we have studied the BAALC gene expression levels in patients with different cytogenetic AML variants. According to our data, the highest BAALC gene expression levels among cases with favorable cytogenetic changes were observed in the patients with t(8;21) (N=21), and in subgroups with unfavorable karyotype, i.e., aberrations in chromosomes 5 and 7 (N=23), as well as complex karyotype (N=8), and other severe abnormalities (≤2) (N=11, data not shown). In cases of relapse, no statistically significant differences of BAALC gene expression levels were noted between these subgroups.

The patient cohort with higher BAALC gene expression (>31% in relapse) consisted of 30 out of 50 cases (60%), including eight patients with both M1 and M2 FAB- variants of AML. A combined BAALC and WT1 overexpression was observed in 28 cases of 30 (93.3%). The data on two patients with M1 and M2 FAB-variants of AML are shown below (Fig. 3, 4).

Figure 3. Monitoring of BAALC and WT1 mRNA expression levels measured by QR-PCR, and bone marrow blast numbers in a patient with AML M1 (№4)

Note: The values of molecular indexes (CN_gene/10⁴_ABL1) in relapse before allo-HSCT and during 1 to 3 PTRs were 1.3; 0.15; 1.25; 1.54 for BAALC gene, and 1.05; 0.03; 0.05 and 0.03 for the WT1 gene, respectively. Abscissa, terms of observation pre- and post-transplant, Ordinate, blast numbers (left axis); gene expression (right axis).

Figure 4. Molecular monitoring of the interaction between leukemic cell precursor and blast cell masses in young patient with AML M2 (№12) measured by QR-PCR of BAALC and WT1 mRNA expression levels

Note: Values of molecular indexes (CN_gene/10⁴_ABL1) in relapse before allo-HSCT and in two PTRs were 0.04; 1.5; 0.47 for gene BAALC and 0.07; 0.24; 0.27 for gene WT1, respectively. Abscissa, terms of observation pre- and post-transplant, Ordinate, blast numbers (left axis); gene expression (right axis).

As seen from Fig. 2 and Table 2, the BAALC gene expression levels in PTR were higher in patients with AML M1 and M2, and sufficiently lower in AML M4. In order to discuss in details some special interactions between leukemic cell precursors and blast cell populations, determined by means of QR-PCR, we have demonstrated here complete clinical and laboratory characteristics from a larger group of patients with different cytological and cytogenetic AML variants according to FAB criteria. Our study cohort consisted of 22 patients (11 cases for each AML M1 and M2- variants). Twenty one of them had a fully characterized cell karyotype. Simultaneous overexpression of both BAALC and WT1 genes at PTR was detected in four and three AML M1 and M2 cases, respectively (Table 2). As based on these data, the presence of a combined gene overexpression in the patients at post-transplant period is considered an index of unfavorable prognosis.

Table 2. BAALC and WT1 gene expression levels at diagnosis, before allo-HSCT (D0) and at PTRs after hematopoietic stem cell transplantation in the patients with different AML FAB-variants

As seen from Table 2, simultaneous overexpression of BAALC and WT1 genes at relapse at any stage of the disease (at diagnosis, D0 pre-transplant, or PTR) occurred in 28/55 (56%) patients. It was observed in eight patients with AML M1 (72.7%), 8 patients with AML M2 (72.7%), as well as in 1 (33.3%), 8 (50%), 2 (40%) patients with AML M0, M4, and M5, respectively.

To illustrate this concept, several clinical cases of each AML M1, M2 and M4 FAB-variants are represented below (Fig. 3 to 5). The relative ratios of leukemic cell precursors or blast cell burdens were monitored as BAALC and WT1 gene expression levels, respectively, as shown for a patient with AML M1 (Table 2, Fig. 3). In this case No.4, a simultaneous BAALC and WT1 overexpression took place at diagnosis, and at 2^nd and 3^rd PTRs that occured despite second HSCT and high-dose chemotherapy which was unsuccessful.

In this case, cytogenetic characteristics of leukemic cells were different for the 1^st and 2^nd relapses. At the first PTR, complex karyotype changes included loss of chromosome X, deletion of 11q and additional chromosome 21 revealed in 15% of tested cells, whereas additional unbalanced translocations t(X;17), t(1;3), and t(1;17) were detected in the second PTR.

In another AML case No. 12 (M2 variant) with t(8;21) translocation (Fig. 4), a simultaneous measurement of BAALC and WT1 gene expression levels revealed overexpression of the WT1 gene at diagnosis, with bone marrow blast burden of up to 28%. Further on, a combined overexpression of both molecular markers was associated with 1^st and 2^nd relapses, thus being prognostically unfavorable. One may suggest that the disease progression and fatal outcome occurred due to resistance of tumor cells to therapy.

Similar clinical situation was observed in the next patient with AML M4 (No. 31), who received allotransplant at the age of five years. In spite of t(8;21) translocation found at diagnosis, thus classifying the patient into favorable group, an additional deletion 7q – del(7)(q32q36) before transplant allowed, however, to evaluate this case as unfavorable one. The combined BAALC and WT1 overexpression at diagnosis, as well as in first PTR, was accompanied by increased expression level of a specific RUNX1/RUNX1T1 fusion transcript (Fig. 5). Of notice, the blast burden in the bone marrow sample at relapse (D+223) was not too high, wherein hypothetic inhibition of leukemic precursor cells from side of the blast population was minimal, thus explaining higher BAALC gene expression levels observed.

Figure 5. Molecular monitoring of interactions between leukemic cell precursors and blast cells in the patient with AML M4 (№31) measured by QR-PCR of BAALC, WT1 and RUNX1/RUNX1T1 gene expression levels

Note: Values of molecular indexes (CN_gene/10⁴_ABL1) in relapse before allo-HSCT and in PTR were 0.95; 0.35 for gene BAALC and 0.1; 0.04 for gene WT1, respectively. Abscissa, terms of observation pre- and post-transplant, Ordinate, blast numbers (left axis); gene expression (right axis).

Another clinical case (No. 29) concerns a female patient 21 years old with AML M4 FAB variant (Fig. 6). The first concomitant overexpression of BAALC and WT1 genes has been observed pre-transplant, associated with complex structural chromosomal changes, i.e., monosomy 7, t(2;3) translocation, as well as 3q inversion. All these abnormalities seemed to correlate with a failure to achieve full cytological and molecular remissions. It has been combined with overexpression of both BAALC and WT1 genes during the entire posttransplant period. From this point of view, it is not surprising that the first PTR occurred early on D+80 after transplantation. Prognostically unfavorable simultaneous WT1 and BAALC overexpression, as well as the same clonal changes of karyotype were detected again at that time. The second clinical relapse was detected on the day D+232 posttransplant, when overexpression of the both genes was expressed even more, and a new additional chromosomal abnormality (monosomy 5) was detected on day D+251.

Figure 6. Molecular monitoring of the interaction between leukemic cell precursors and blast cells burdens in patient with AML M4 (№29) measured by QR-PCR of BAALC and WT1 gene expression levels

Note: Values of molecular indexes (CN_gene/10⁴_ABL1) in relapse before allo-HSCT and in two PTRs were 1.07; 3.9; 4 for gene BAALC and 0.09; 0.12; 2.6 for gene WT1, respectively. Abscissa, terms of observation pre- and post-transplant, Ordinate, blast numbers (left axis); gene expression (right axis).

Another molecular profile has been revealed during serial measurement of BAALC and WT1 gene expression levels in a 55-year old female patient (Case No. 40, Table 2) with the same AML M4 FAB-variant, but with normal karyotype (Fig. 7). As shown here, the elevated WT1 gene expression level took place not only in pre-transplant relapse, but in early PTR as well, which seems to be a result of transplantation without subsequent cytological remission. At the same time, the BAALC gene overexpression was not observed at neither of relapses. Instead of successful treatment of the first PTR at D+65 after allo-HSCT, the patient developed a new cytological relapse accompanied by the WT1 gene overexpression, and the lethal outcome was detected at D+101 after allo-HSCT.

Figure 7. Molecular monitoring of the interaction between leukemic cell precursor and blast cell masses in patient with AML M4 (№40) measured by QR-PCR of BAALC and WT1 gene expression levels

Note: Values of molecular indexes (CN_gene/10⁴_ABL1) in relapse before allo-HSCT and in PTR were 0.035; 0.0006 for gene BAALC and 1.17; 0.1 for gene WT1, respectively. Abscissa, terms of observation pre- and post-transplant, Ordinate, blast numbers (left axis); gene expression (right axis).

As regards special AML forms, characterized by the absence of BAALC overexpression we observed in 4 (8%) of 50 such cases in our cohort (three among them had AML M3 and one, M7 FAB-variant). Data of the serial parallel measurement of BAALC and WT1 gene expression levels in one of them are represented at Figure 8. Elevated BAALC gene expression level over the cut-off level in a 17-year-old female patient (№ 47) was not observed both at relapse before allo-HSCT, or in posttransplant relapse. At the same time, a significant WT1 gene overexpression took place in both relapses.

Figure 8. Molecular monitoring of the interaction between leukemic cell precursor and blast cell masses in a 17-years old female patient with AML M3 (№47) measured by QR-PCR of BAALC, WT1 and PML-RARα gene expression levels

In general, the results shown in Fig. 8 may be explained by more differentiated state of promyelocytes providing clinical development of acute promyelocytic leukemia, compared to CD34+/CD38- cell precursors of leukemic hematopoiesis. By this reason, they are unable to express BAALC gene. On the other hand, some, still unknown, immature leukemic cells in M3 FAB- variant AML must have a direct cause higher WT1 gene expression levels which should be studied at regular basis.

It is reasonable to present here some data on parallel measurement of BAALC and WT1 gene expression level in bone marrow samples from a 3-year-old female patient (№49) with AML M7 (Fig. 9). The BAALC gene expression level was under the cut-off value during the entire follow-up period. At the same time, WT1 gene overexpression closely associated with increasing blast burden in bone marrow, was detected during relapse before HSCT, as well as at the posttransplant relapse with pronounced blastosis in bone marrow (>60%).

Figure 9. Molecular monitoring of the interaction between leukemic cell precursors and blast cells in a 3-years old female patient with AML M7 (№49) measured by QR-PCR of BAALC and WT1 gene expression levels

Note: Values of molecular indexes (CN_gene/10⁴_ABL1) in relapse before allo-HSCT and in PTR were 0.0025; 0.0003 for gene BAALC and 0.03; 0.69 for gene WT1, respectively. Abscissa, terms of observation pre- and post-transplant, Ordinate, blast numbers (left axis); gene expression (right axis).

Finally, we would like to demonstrate here some special biological features of blast elements in AML patients, who did not exhibit WT1 gene overexpression. E.g., we present the graphs of molecular monitoring by WT1 and BAALC expression levels in two patients (No. 24 and 26) with M0 AML (Fig. 10) and M4 AML (Fig. 11). The first case presents a 25-year old patient (№24), who had reciprocal translocation t(3;10)(p21;p11) (without EVI1 gene overexpression), and interstitial deletion of chromosome 11 long arm (without MLL gene rearrangements, as shown by FISH technique). According to this graph, the BAALC gene expression level over the cut-off value was detected at relapse before transplantation, as well as at PTR, whereas WT1 gene expression level changes were <250 copies per 10⁴ copies of ABL1 gene during entire period of study. The lethal outcome of the disease on the D+133 after transplantation has been associated with progression.

Figure 10. Molecular monitoring of the interaction between leukemic cell precursors and blast cells in a patient with AML M0 (№24) measured by QR-PCR of BAALC and WT1 gene expression levels

Note: Values of molecular indexes (CN_gene/10⁴_ABL1) in relapse before allo-HSCT and in PTR were 1.24; 0.82 for gene BAALC and 0.0003; 0.0005 for gene WT1, respectively. Abscissa, terms of observation pre- and post-transplant, Ordinate, blast numbers (left axis); gene expression (right axis).

The data from another clinical case are demonstrated in the Figure 11. They relate to a 6-years old patient, who had permanently relapsing disease course and has undergone haploidentical hematopoietic stem cell transplantation in cytological relapse for this reason. In this case, a distinct increase in BAALC expression level has been observed upon relapse before HSCT, as well as at the first PTR on the day D+246. The WT1 expression level at relapse before transplantation and at first PTR was did not exceed the cut-off level. It is equally important that, according to cytogenetic data, this patient has undergone a clonal evolution over the period between diagnosis and first PTR karyotyping associated with its transformation from normal to complex one, including rearrangements of both chromosomes 5, as well as X, 2, 6, 9 and 19. For the first post-transplant relapse, the patient has been treated by polychemotherapy in combination with donor lymphocyte infusion and 5-azacytidin. Such supportive therapy allowed morphological remission for a sufficient period of time. However, the disease progression was detected again on the day D+734 posttransplant, as evidenced by a combined cytological relapse with myelomonocytic blast cells. Their immune profile was as follows: CD34+/CD33+/CD117+/CD13+/CD38+/CD14+ associated with complex clonal rearrangements of chromosomes 2, 5 and 19. It should be noted, that, at the second PTR, this patient had both BAALC and WT1 genes overexpression, what may be explained by hypothetical changes of negative regulation of leukemic precursors by the blast cell burden. Finally, lethal outcome has occurred in this case on the day D+779 post-transplant.

Figure 11. Molecular monitoring of the interaction between leukemic cell precursor and blast cell masses in a 6 years old patient with AML M4 (№26) measured by QR-PCR of BAALC and WT1 gene expression levels

Note: Values of molecular indexes (CN_gene/10⁴_ABL1) in relapse before allo-HSCT and in the first and second PTRs were 9.8; 71.2; 18.6 for gene BAALC and 0.02; 0.03; 0.21 for gene WT1, respectively. Abscissa, terms of observation pre- and post-transplant, Ordinate, blast numbers (left axis); gene expression (right axis).

Discussion

The data presented here show an opportunity for simultaneous BAALC and WT1 gene overexpression in a group of AML patients with increased levels of WT1 and normalized up to 4% number of blasts in bone marrow samples. Therefore, it could be considered a strong indicator of poor prognosis in these cases. On the other hand, the levels of BAALC and WT1 levels expression determined by means of PCR may reflect, in a quantitative manner, the relative sizes of precursor and blast cell burden. Of note, hypothetical correlation between these tumor compartments has not elucidated yet, and may be not obligatory for all AML cases. The study has shown that the absence of BAALC overexpression at transplantation was associated with lower CIR in 9 of 12 patients (75%) with abovementioned intermediate clinical status. On the contrary, the 3 other patients with elevated BAALC expression before transplant revealed earlier PTR development associated with shorter 2-year OS and EFS, as compared with the main group of patients. Hence, an assumption was made that simultaneous overexpression of BAALC and WT1 may be a useful indicator of dismal post-transplant AML course. Keeping this in mind, we showed a double overexpression phenomenon to be present in four patients with M1 (N=2), M2 (n=1) and M4 (n=1) AML variants associated with poor prognosis. Further on, our data showed the levels of BAALC expression to be similarly high in patients with immature and mature M1 and M2 FAB-variants, respectively. On the other hand, the lowest BAALC expression levels were noticed in patients with M3 and M7 AML FAB- variants. Today, the absence of BAALC gene expression in patients with acute promyelocytic leukemia may be explained by its origin from more “mature” cell populations than the standard CD34+CD38– precursors producing BAALC [25]. The same situation seems exist in the M7 FAB variants of AML, which also needs a similar additional study.

In our opinion, the results of BAALC gene expression measurement in patients with M2 and M4 FAB-variants are interesting in several regards. Firstly, high expression of BAALC and WT1 genes were synchronous in most cases. At the same time, the numbers of blast elements in their bone marrow aspirates increased to lower degree than expected. The simplest explanation for this discordance between findings in AML variants and cell maturity may be that these blast elements can differentiate only partially and, therefore, transform into more mature cellular populations. However, due to decreased size of blast population preserved in this kind of AML, some hypothetical regulating mechanisms can be activated for additional recruitment of new portions of CD34+CD38- precursors into leukemic hematopoiesis. Due to mentioned transition of blast elements to the more mature hematopoietic compartments, as well as their hypothetical regulator mechanism between blast burden and leukemic precursor compartment, the revealed similarity in gene BAALC overexpression for M2 and M4 FAB- variants of AML, and those in M1 and M0 FAB variants may be explained in these terms.

In conclusion, it should be like to notice, that clinical significance of our findings, concerning simultaneous overexpression of BAALC and WT1 genes in adults and children with AML treated with allo-HSCT, and/or donor lymphocyte infusions was presented for the first time and could be effectively used for clinical diagnostics and prediction of relapses in AML patients. The combined WT1 and BAALC overexpression was studied in relatively small group of patients, thus requiring further confirmation in larger groups of patients with different FAB variants of AML.

Conflict of interest

No conflict of interests is declared.

References

Tanner S, Austin J, Leone G, Rush L, Plass C, Heinonen K, Mrózek K, Still H, Knuutila S, Kolitz J, Archer K, Caligiuri M, Bloomfield C, de la Chapelle A. BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. Proc Natl Acad Sci USA. 2001;98(24):13901-13906.
Santamaría C, Chillón M, García-Sanz R, Pérez C, Caballero M, Mateos M, Ramos F, de Coca A, Alonso J, Giraldo P, Bernal T, Queizán J, Rodríguez J, Puig N, Balanzategui A, Sarasquete M, Alcoceba M, Díaz-Mediavilla J, San Miguel J, González M. BAALC is an important predictor of refractoriness to chemotherapy and poor survival in intermediate-risk acute myeloid leukemia (AML). Ann Hematol. 2010;89:453-458.
Weber S, Haferlach T, Alpermann T, Perglerová K, Schnittger S, Haferlach C, Kern W. Feasibility of BAALC gene expression for detection of minimal residual disease and risk stratification in normal karyotype acute myeloid leukemia. Br J Haematol. 2016;175(5):904-916.
Jentzsch M, Bill M, Grimm J, Schulz J, Goldmann K, Beinicke S, Häntschel J, Pönish W, Franke G-N, Vicinic V, Behre G, Lange T, Niederwiesser D, Schwind S. High BAALC copy numbers in peripheral blood prior to allogeneic transplantation predict early relapse in acute myeloid leukemia. Oncotarget. 2017;8(50):87994-97954.
Yoon J, Kim H, Shin S, Yahng S, Lee S, Cho S, Eom K, Kim Y, Lee S, Min C, Cho S, Kim D, Lee J, Min W, Park C, Lim J. BAALC and WT1 expressions from diagnosis to hematopoietic stem cell transplantation: consecutive monitoring in adult patients with core-binding–factor-positive AML. Europ J Haematol. 2013;91:112-127.
Xiao S, Shen J, Huang J, Fu H. Prognostic significance of the BAALC gene expression in adult patients with acute myeloid leukemia: A meta-analysis. Mol Clin Oncol. 2015;3(4):880-888.
Hecht A, Doll S, Altmann H, Nowak D, Lengfelder E, Röllig C, Ehninger G, Spiekermann K, Hiddemann W, Weiß C, Hofmann W, Nolte F, Platzbecker U. Validation of a molecular risk score for prognosis of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy-containing regimens. Clin Lymphoma Myeloma Leuk. 2017; 17(12):889-896.e5.
Staffas A, Kanduri M, Hovland R, Rosenquist R, Ommen HB, Abrahamsson J, Forestier E, Jahnukainen K, Jónsson ÓG, Zeller B, Palle J, Lönnerholm G, Hasle H, Palmqvist L, Ehrencrona H; Nordic Society of Pediatric Hematology and Oncology (NOPHO). Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia. Blood. 2011 Nov 24;118(22):5905-13.
Najima Y, Ohashi K, Kawamura M, Onozuka Y, Yamaguchi T, Akiyama H, et al. Molecular monitoring of BAALC expression in patients with CD34-positive acute leukemia. Int J Hematol. 2010;91:636–645.
Damiani D, Tiribelli M, Franzoni A, Michelutti A, Fabbro D, Cavallin M, Toffoletti E, Simeone E, Fanin R, Damante G. BAALC overexpression retains its negative prognostic role across all cytogenetic risk groups in acute myeloid leukemia patients. Am J Hematol. 2013;88(10):848-852.
Pogosova-Agadjanyan E, Moseley A, Othus M, Appelbaum F, Chauncey T, Chen I, Erba H, Godwin J, Fang M, Kopecky K, List A, Pogosov G, Radich J, Willman C, Wood B, Meshinchi S, Stirewalt D. Impact of specimen heterogeneity on biomarkers in repository samples from patients with acute myeloid leukemia: A SWOG report. Biopreserv Biobank. 2018;16(1):42-52.
Morita K, Masamoto Y, Kataoka K, Koya J, Kagoya Y, Yashiroda H, Sato T, Murata S, Kurokawa M. BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia. 2015;29(11):2248-2456.
Costello R, Mallet F, Gaugler B, Sainty D, Arnoulet C, Gastaut J, Olive D. Human acute myeloid leukemia CD34+/CD38- progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis? Reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res. 2000;60:4403-4411.
Gerber J, Smith B, Ngwang B, Zhang H, Vala M, Morsberger L, Galkin S, Collector M, Perkins B, Levis M, et al. A clinically relevant population of leukemic CD34+CD38- cells in acute myeloid leukemia. Blood. 2012;119(15):3571-3577.
Gerber J, Zeidner J, Morse S, Blackford A, Perkins B, Yanagisawa B, Zhang H, Morsberger L, Karp J, Ning Y, Cocke C, Rosner G, Smith D, Jones R. Association of acute myeloid leukemia’s most immature phenotype with risk groups and outcomes. Haematologica. 2016;101950;607-615.
Jentzsch M, Bill M, Nicolet D, Leiblein S, Schubert K, Pless M, Bergmann U, Wildenberger K, Schuhmann L, Cross M, et al. Prognostic impact of the CD34+/CD38- cell burden in patients with acute myeloid leukemia receiviung allogeneic stem cell transplantation. Am J Hematol. 2017;92(4):388-396.
Plesa A, Dumontet C, Mattei E, Tagoug I, Hayette S, Sujobert P, Tigaud I, Pages M, Chelghome Y, Baracco F, et al. High frequqncy of CD34+CD38-/low immature leukemia cells is correlated with unfavorable prognosis in acute leukemia. World J Stem Cells. 2017;9(12):227-234.
Thomas D, Majeti R. Biology and relevance of human acute myeloid leukemia stem cells. Blood. 2017;129(12):1577–1585.
Mamaev N, Gudozhnikova Y, Gindina T, Barkhatov I, Shakirova A, Katerina V, Gubina M, Nikolaeva E, Semenova E, Paina O, Darskaya E, Pirogova O, Porunova V, Moiseev I, Mikhailova I, Ayubova B, Kravtsova V, Bondarenko S, Zubarovskaya L, Afanasyev B. Efficacy of Chemotherapy in Acute Leukemia Patients Resistant to Previous Standard Treatment According to the Series Measurement of WT1 Gene Expression. Clinical Oncohematology. 2018;11(1):78-88 (In Russian).
Minetto P, Guolo F, Clavio M, de Astis E, Colombo N, Grasso R, Fugazza G, Sessarego M, Lemoli R, Gobbi M, Miglino M. Combined assessment of WT1 and BAALC gene expression at diagnosis may improve leukemia-free survival prediction in patients with myelodysplastic syndromes. Leukemia Res. 2015;39:866-873.
Haferlach C, Kern W, Schindela S, Kohlmann A, Alpermann T, Schnittger S, Haferlach T. Gene expression of BAALC, CDKN1B, ERG, and MN1 adds independent prognostic information to cytogenetics and molecular mutations in adult acute myeloid leukemia. Genes Chromosomes Cancer. 2012;51(3):257-265.
Gudozhnikova Y, Mamaev N, Barkhatov I, Katerina V, Gindina T, Shakirova A, Bondarenko S, Slesarchuk O, Darskaya E, Paina O, Zubarovskaya L, Afanasyev B. Results of Molecular Monitoring in Post-transplant Period by Means of Series Investigation of WT1 Gene Expression in Patients with Acute Myeloid Leukemia. Clinical Oncohematology. 2018;11(3):241-251 (In Russian).
Shakirova A, Barkhatov I, Churkina A, Moiseev I, Gindina T, Bondarenko S, Afanasyev B. Prognostic significance of BAALC overexpression in patients with AML during the post-transplant period. Cell Ther Transplant. 2018;7(2):54-63.
Cilloni D, Renneville A, Hermitte F, Hills R, Daly S, Jovanovic J, Gottardi E, Fava M, Schnittger S, Weiss T, Izzo B, Nomdedeu J, van der Heijden A, van der Reijden B, Jansen J, van der Velden V, Ommen H, Preudhomme C, Saglio G, Grimwade D. Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol. 2009;27(31):5195-5201.
Reinisch A, Thomas D, Corces MR, et al. A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells. Nat Med. 2016;22(7):812-821.

" ["~DETAIL_TEXT"]=> string(41735) "

Introduction

Patients and methods

Statistical analysis

Results

Figure 2. Distribution of individual values and median levels of BAALC gene expression in relapsing patients with different AML FAB-variants

Figure 3. Monitoring of BAALC and WT1 mRNA expression levels measured by QR-PCR, and bone marrow blast numbers in a patient with AML M1 (№4)

Table 2. BAALC and WT1 gene expression levels at diagnosis, before allo-HSCT (D0) and at PTRs after hematopoietic stem cell transplantation in the patients with different AML FAB-variants

Figure 7. Molecular monitoring of the interaction between leukemic cell precursor and blast cell masses in patient with AML M4 (№40) measured by QR-PCR of BAALC and WT1 gene expression levels

Figure 10. Molecular monitoring of the interaction between leukemic cell precursors and blast cells in a patient with AML M0 (№24) measured by QR-PCR of BAALC and WT1 gene expression levels

Discussion

Conflict of interest

No conflict of interests is declared.

References

Tanner S, Austin J, Leone G, Rush L, Plass C, Heinonen K, Mrózek K, Still H, Knuutila S, Kolitz J, Archer K, Caligiuri M, Bloomfield C, de la Chapelle A. BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. Proc Natl Acad Sci USA. 2001;98(24):13901-13906.
Santamaría C, Chillón M, García-Sanz R, Pérez C, Caballero M, Mateos M, Ramos F, de Coca A, Alonso J, Giraldo P, Bernal T, Queizán J, Rodríguez J, Puig N, Balanzategui A, Sarasquete M, Alcoceba M, Díaz-Mediavilla J, San Miguel J, González M. BAALC is an important predictor of refractoriness to chemotherapy and poor survival in intermediate-risk acute myeloid leukemia (AML). Ann Hematol. 2010;89:453-458.
Weber S, Haferlach T, Alpermann T, Perglerová K, Schnittger S, Haferlach C, Kern W. Feasibility of BAALC gene expression for detection of minimal residual disease and risk stratification in normal karyotype acute myeloid leukemia. Br J Haematol. 2016;175(5):904-916.
Jentzsch M, Bill M, Grimm J, Schulz J, Goldmann K, Beinicke S, Häntschel J, Pönish W, Franke G-N, Vicinic V, Behre G, Lange T, Niederwiesser D, Schwind S. High BAALC copy numbers in peripheral blood prior to allogeneic transplantation predict early relapse in acute myeloid leukemia. Oncotarget. 2017;8(50):87994-97954.
Yoon J, Kim H, Shin S, Yahng S, Lee S, Cho S, Eom K, Kim Y, Lee S, Min C, Cho S, Kim D, Lee J, Min W, Park C, Lim J. BAALC and WT1 expressions from diagnosis to hematopoietic stem cell transplantation: consecutive monitoring in adult patients with core-binding–factor-positive AML. Europ J Haematol. 2013;91:112-127.
Xiao S, Shen J, Huang J, Fu H. Prognostic significance of the BAALC gene expression in adult patients with acute myeloid leukemia: A meta-analysis. Mol Clin Oncol. 2015;3(4):880-888.
Hecht A, Doll S, Altmann H, Nowak D, Lengfelder E, Röllig C, Ehninger G, Spiekermann K, Hiddemann W, Weiß C, Hofmann W, Nolte F, Platzbecker U. Validation of a molecular risk score for prognosis of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy-containing regimens. Clin Lymphoma Myeloma Leuk. 2017; 17(12):889-896.e5.
Staffas A, Kanduri M, Hovland R, Rosenquist R, Ommen HB, Abrahamsson J, Forestier E, Jahnukainen K, Jónsson ÓG, Zeller B, Palle J, Lönnerholm G, Hasle H, Palmqvist L, Ehrencrona H; Nordic Society of Pediatric Hematology and Oncology (NOPHO). Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia. Blood. 2011 Nov 24;118(22):5905-13.
Najima Y, Ohashi K, Kawamura M, Onozuka Y, Yamaguchi T, Akiyama H, et al. Molecular monitoring of BAALC expression in patients with CD34-positive acute leukemia. Int J Hematol. 2010;91:636–645.
Damiani D, Tiribelli M, Franzoni A, Michelutti A, Fabbro D, Cavallin M, Toffoletti E, Simeone E, Fanin R, Damante G. BAALC overexpression retains its negative prognostic role across all cytogenetic risk groups in acute myeloid leukemia patients. Am J Hematol. 2013;88(10):848-852.
Pogosova-Agadjanyan E, Moseley A, Othus M, Appelbaum F, Chauncey T, Chen I, Erba H, Godwin J, Fang M, Kopecky K, List A, Pogosov G, Radich J, Willman C, Wood B, Meshinchi S, Stirewalt D. Impact of specimen heterogeneity on biomarkers in repository samples from patients with acute myeloid leukemia: A SWOG report. Biopreserv Biobank. 2018;16(1):42-52.
Morita K, Masamoto Y, Kataoka K, Koya J, Kagoya Y, Yashiroda H, Sato T, Murata S, Kurokawa M. BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia. 2015;29(11):2248-2456.
Costello R, Mallet F, Gaugler B, Sainty D, Arnoulet C, Gastaut J, Olive D. Human acute myeloid leukemia CD34+/CD38- progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis? Reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res. 2000;60:4403-4411.
Gerber J, Smith B, Ngwang B, Zhang H, Vala M, Morsberger L, Galkin S, Collector M, Perkins B, Levis M, et al. A clinically relevant population of leukemic CD34+CD38- cells in acute myeloid leukemia. Blood. 2012;119(15):3571-3577.
Gerber J, Zeidner J, Morse S, Blackford A, Perkins B, Yanagisawa B, Zhang H, Morsberger L, Karp J, Ning Y, Cocke C, Rosner G, Smith D, Jones R. Association of acute myeloid leukemia’s most immature phenotype with risk groups and outcomes. Haematologica. 2016;101950;607-615.
Jentzsch M, Bill M, Nicolet D, Leiblein S, Schubert K, Pless M, Bergmann U, Wildenberger K, Schuhmann L, Cross M, et al. Prognostic impact of the CD34+/CD38- cell burden in patients with acute myeloid leukemia receiviung allogeneic stem cell transplantation. Am J Hematol. 2017;92(4):388-396.
Plesa A, Dumontet C, Mattei E, Tagoug I, Hayette S, Sujobert P, Tigaud I, Pages M, Chelghome Y, Baracco F, et al. High frequqncy of CD34+CD38-/low immature leukemia cells is correlated with unfavorable prognosis in acute leukemia. World J Stem Cells. 2017;9(12):227-234.
Thomas D, Majeti R. Biology and relevance of human acute myeloid leukemia stem cells. Blood. 2017;129(12):1577–1585.
Mamaev N, Gudozhnikova Y, Gindina T, Barkhatov I, Shakirova A, Katerina V, Gubina M, Nikolaeva E, Semenova E, Paina O, Darskaya E, Pirogova O, Porunova V, Moiseev I, Mikhailova I, Ayubova B, Kravtsova V, Bondarenko S, Zubarovskaya L, Afanasyev B. Efficacy of Chemotherapy in Acute Leukemia Patients Resistant to Previous Standard Treatment According to the Series Measurement of WT1 Gene Expression. Clinical Oncohematology. 2018;11(1):78-88 (In Russian).
Minetto P, Guolo F, Clavio M, de Astis E, Colombo N, Grasso R, Fugazza G, Sessarego M, Lemoli R, Gobbi M, Miglino M. Combined assessment of WT1 and BAALC gene expression at diagnosis may improve leukemia-free survival prediction in patients with myelodysplastic syndromes. Leukemia Res. 2015;39:866-873.
Haferlach C, Kern W, Schindela S, Kohlmann A, Alpermann T, Schnittger S, Haferlach T. Gene expression of BAALC, CDKN1B, ERG, and MN1 adds independent prognostic information to cytogenetics and molecular mutations in adult acute myeloid leukemia. Genes Chromosomes Cancer. 2012;51(3):257-265.
Gudozhnikova Y, Mamaev N, Barkhatov I, Katerina V, Gindina T, Shakirova A, Bondarenko S, Slesarchuk O, Darskaya E, Paina O, Zubarovskaya L, Afanasyev B. Results of Molecular Monitoring in Post-transplant Period by Means of Series Investigation of WT1 Gene Expression in Patients with Acute Myeloid Leukemia. Clinical Oncohematology. 2018;11(3):241-251 (In Russian).
Shakirova A, Barkhatov I, Churkina A, Moiseev I, Gindina T, Bondarenko S, Afanasyev B. Prognostic significance of BAALC overexpression in patients with AML during the post-transplant period. Cell Ther Transplant. 2018;7(2):54-63.
Cilloni D, Renneville A, Hermitte F, Hills R, Daly S, Jovanovic J, Gottardi E, Fava M, Schnittger S, Weiss T, Izzo B, Nomdedeu J, van der Heijden A, van der Reijden B, Jansen J, van der Velden V, Ommen H, Preudhomme C, Saglio G, Grimwade D. Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol. 2009;27(31):5195-5201.
Reinisch A, Thomas D, Corces MR, et al. A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells. Nat Med. 2016;22(7):812-821.

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В клиническом плане, мы имели целью оценку потенциала развития рецидивов лейкоза после трансплантации гемопоэтических клеток (ТГСК). Посттрансплантационные рецидивы (ПТР), с точки зрения их биологических механизмов, могут выявляться по гиперэкспрессии определенных генов, связанных с клеточной дифференцировкой. <h3>Пациенты и методы</h3> В исследование вошло 61 больных ОМЛ, леченных с помощью алло-ТГСК, у которых осуществлено одновременное серийное измерение уровней экспрессии генов BAALC и WT1 методом количественной ПЦР в реальном времени с использованием ген-специфических праймеров. <h3>Результаты</h3> В группе из 12 больных с повышенным уровнем экспрессии гена WT1 и с нормализованным до 4 % содержанием бластных элементов в костном мозге на момент проведения аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) было показано, что подгруппа с повышенной экспрессией гена BAALC характеризуется: а) более высоким числом ПТР (р=0,002); а также б) укорочением сроков безрецидивной выживаемости (БРВ) при сопоставлении с группой сравнения (р=0,019). Дальнейшее использование этого прогностически неблагоприятного критерия, состоящего из одновременного повышения уровней экспрессии обоих генов при анализе основного массива данных, показало его более частое обнаружение у больных с М1, М2, М0, М4 и М5 ФАБ- цитологическими вариантами. При этом предварительные данные указывают на худшую общую выживаемость (228 дней) в группе больных ОМЛ, имевших сочетанную гиперэкспрессию обоих генов как непосредственно перед ТГСК, так и в посттрансплантационном периоде. <h3>Заключение</h3> Потенциальная клиническая значимость полученных данных, касающихся повышенной экспрессии гена BAALC у взрослых и детей больных ОМЛ, леченных с использованием алло-ТГСК, и особенно, наличия феномена сочетания у них гиперэкспрессии генов BAALC и WT1 несомненна, что диктует необходимость активного использования их в клинике. <h2>Ключевые слова</h2> Острый миелоидный лейкоз, аллогенная трансплантация гемопоэтических клеток, посттрансплантационные рецидивы, гены BAALC и WT1, одновременная гиперэкспрессия, клиническая значимость, прогноз." 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["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "22271" ["VALUE"]=> array(2) { ["TEXT"]=> string(255) "Алена И. Шакирова, Николай Н. Мамаев, Ильдар М. Бархатов, Яна В. Гудожникова, Татьяна Л. Гиндина, Елена В. Бабенко, Борис В. Афанасьев" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(243) "

Алена И. Шакирова, Николай Н. Мамаев, Ильдар М. Бархатов, Яна В. Гудожникова, Татьяна Л. Гиндина, Елена В. Бабенко, Борис В. Афанасьев

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "22272" ["VALUE"]=> array(2) { ["TEXT"]=> string(459) "НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой; кафедра гематологии, трансфузиологии и трансплантологии Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(447) "

НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой; кафедра гематологии, трансфузиологии и трансплантологии Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия

Цель изучения состояла в выяснении тесных связей между популяциями костномозговых бластных элементов, повышение содержания которых определяет цитологический рецидив ОМЛ, и ответственных за рецидив лейкозных клеток предшественников. В клиническом плане, мы имели целью оценку потенциала развития рецидивов лейкоза после трансплантации гемопоэтических клеток (ТГСК). Посттрансплантационные рецидивы (ПТР), с точки зрения их биологических механизмов, могут выявляться по гиперэкспрессии определенных генов, связанных с клеточной дифференцировкой.

Пациенты и методы

В исследование вошло 61 больных ОМЛ, леченных с помощью алло-ТГСК, у которых осуществлено одновременное серийное измерение уровней экспрессии генов BAALC и WT1 методом количественной ПЦР в реальном времени с использованием ген-специфических праймеров.

Результаты

В группе из 12 больных с повышенным уровнем экспрессии гена WT1 и с нормализованным до 4 % содержанием бластных элементов в костном мозге на момент проведения аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) было показано, что подгруппа с повышенной экспрессией гена BAALC характеризуется: а) более высоким числом ПТР (р=0,002); а также б) укорочением сроков безрецидивной выживаемости (БРВ) при сопоставлении с группой сравнения (р=0,019). Дальнейшее использование этого прогностически неблагоприятного критерия, состоящего из одновременного повышения уровней экспрессии обоих генов при анализе основного массива данных, показало его более частое обнаружение у больных с М1, М2, М0, М4 и М5 ФАБ- цитологическими вариантами. При этом предварительные данные указывают на худшую общую выживаемость (228 дней) в группе больных ОМЛ, имевших сочетанную гиперэкспрессию обоих генов как непосредственно перед ТГСК, так и в посттрансплантационном периоде.

Заключение

Потенциальная клиническая значимость полученных данных, касающихся повышенной экспрессии гена BAALC у взрослых и детей больных ОМЛ, леченных с использованием алло-ТГСК, и особенно, наличия феномена сочетания у них гиперэкспрессии генов BAALC и WT1 несомненна, что диктует необходимость активного использования их в клинике.

Ключевые слова

Острый миелоидный лейкоз, аллогенная трансплантация гемопоэтических клеток, посттрансплантационные рецидивы, гены BAALC и WT1, одновременная гиперэкспрессия, клиническая значимость, прогноз.

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Alena I. Shakirova, Nikolay N. Mamaev, Ildar M. Barkhatov, Yana V. Gudozhnikova, Tatiana L. Gindina, Elena V. Babenko,
Boris V. Afanasyev

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia

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The aim of this study was to clarify close associations between population of bone marrow blast elements defining cytological relapse, and that of leukemic precursor cells by means of serial quantitative measurement of WT1 and BAALC molecular markers expressed by appropriate cell types. In clinical terms, we sought to evaluate a potential for evolving leukemia relapses following hematopoietic stem cell transplantation (HSCT). The post-transplant relapses (PTR), in view of their biological mechanisms, may be detected by overexpression of distinct differentiation-related genes.

Patients and methods

We have done parallel serial measurements of BAALC and WT1 gene expression in bone marrow cells of the patients with acute myeloid leukemia, using quantitative real-time PCR (qPCR) with gene-specific primers.

Results

An initial pilot study was carried out in twelve patients with elevated WT1 expression levels and normal blast counts (<5%) in bone marrow at the time of allogeneic HSCT. It has shown that the relapse occurrence and shorter relapse-free survival (RFS) post-transplant were more common in the subgroup with higher BAALC gene expression level as compared to those without BAALC expression elevation (p=0.002, and p=0.019, respectively). Moreover, when analyzing the validating patient cohort, we have found that the simultaneous elevation of both BAALC and WT1 expression, known as unfavorable prognostic factor, was more frequently observed in the patients with AML М1, М2, and М0 FAB-variants. Preliminary results show an inferior overall survival (a mean of 228 days) in AML patients with combined overexpression of the both genes immediately before HSCT, like as in post-transplant period. In conclusion, it should be noted that our findings of simultaneous overexpressions of BAALC and WT1 genes in great cohort of adults and children patients with different FAB- variants of AML treated by means of allo-HSCT were revealed for the first time. Being associated with poor prognosis, this double test should be used actively for post-transplant monitoring of all patients with AML.

Keywords

Acute myeloblastic leukemia, hematopoietic stem cell transplantation, allogeneic, post-transplant relapses, BAALC, WT1, gene overexpression, parallel assays, relapse risk, prognostic value.

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Shakirova, Nikolay N. Mamaev, Ildar M. Barkhatov, Yana V. Gudozhnikova, Tatiana L. Gindina, Elena V. Babenko, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(153) "

Alena I. Shakirova, Nikolay N. Mamaev, Ildar M. Barkhatov, Yana V. Gudozhnikova, Tatiana L. Gindina, Elena V. Babenko,
Boris V. Afanasyev

Patients and methods

Results

Keywords

Acute myeloblastic leukemia, hematopoietic stem cell transplantation, allogeneic, post-transplant relapses, BAALC, WT1, gene overexpression, parallel assays, relapse risk, prognostic value.

Patients and methods

Results

Keywords

Acute myeloblastic leukemia, hematopoietic stem cell transplantation, allogeneic, post-transplant relapses, BAALC, WT1, gene overexpression, parallel assays, relapse risk, prognostic value.

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia

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Дальнейшее использование этого прогностически неблагоприятного критерия, состоящего из одновременного повышения уровней экспрессии обоих генов при анализе основного массива данных, показало его более частое обнаружение у больных с М1, М2, М0, М4 и М5 ФАБ- цитологическими вариантами. При этом предварительные данные указывают на худшую общую выживаемость (228 дней) в группе больных ОМЛ, имевших сочетанную гиперэкспрессию обоих генов как непосредственно перед ТГСК, так и в посттрансплантационном периоде. <h3>Заключение</h3> Потенциальная клиническая значимость полученных данных, касающихся повышенной экспрессии гена BAALC у взрослых и детей больных ОМЛ, леченных с использованием алло-ТГСК, и особенно, наличия феномена сочетания у них гиперэкспрессии генов BAALC и WT1 несомненна, что диктует необходимость активного использования их в клинике. <h2>Ключевые слова</h2> Острый миелоидный лейкоз, аллогенная трансплантация гемопоэтических клеток, посттрансплантационные рецидивы, гены BAALC и WT1, одновременная гиперэкспрессия, клиническая значимость, прогноз." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4553) "

Пациенты и методы

Результаты

Заключение

Ключевые слова

Пациенты и методы

Результаты

Заключение

Ключевые слова

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Introduction

Allogeneic stem cell transplantation (allo-HSCT) is the established option for high risk acute lymphoblastic leukemia [1]. However, allo-HSCT in refractory/resistant acute lymphoblastic leukemia (R/R ALL) has a dismal outcome [2]. Patients pretreated with high-dose chemotherapy show intolerance to further allo-HSCT, thus resulting into high transplant-related mortality and unsatisfactory overall survival. The attempts to achieve deep remission with acceptable toxicity lead to development of new immunomediated approaches, i.e., the so-called “bridge-therapy”. Initial studies report comparable CR rates when applying Blinatumomab and Inotuzumab ozogamicin with a trend for blinatumomab administration in the setting of minimal residual disease, or lower marrow blast percentages without CNS involvement. Inotuzumab ozogamicin is effective regardless of blast counts, but there is no data about the role of leukemic blasts in extramedullar lesions [4]. Extramedullary relapses are more common after allogeneic stem cell transplantation, and may occur after Blinatumomab as well, and these patients have extremely poor prognosis [5].

Case Description

Case 1.

A 31-year old woman was diagnosed with B-ALL, isolated marrow involvement, in March, 2014. Genetic abnormalities were not evaluated at the regional hospital. The patient was treated according to the National ALL-2009 Protocol, and morphological remission was reached after first induction cycle. The protocol was completed in October 2016. One year later, in September 2017, 200×10⁶ WBC/L and 45×10⁶ PLT/L of peripheral blood were found. The genetic tests revealed 46,XX,t(9;22)(q23;p22), and BCR/ABL p190. The dasatinib-containing ALL-REZ-MB-2013 protocol was then administered. Second morphologic remission was reached after the first cycle of this treatment. In January, 2018, the patient was sent to our center, and the genetic tests showed a molecular remission. HLA-typing revealed an identical sibling donor. However, allo-HSCT was delayed due to intestinal bleeding associated with dasatinib administration. Chemotherapy was interrupted for a month until allo-HSCT. Bone marrow (BM) examination has revealed 90% of blasts a month later, with CD45dim/CD19+/CD10+/CD34+/CD38+/CD22+/CD20+/CD13+/sIgM-/cytIgM-/cytCD79а+ phenotype, CD19 expression on 99.6% of the cells; conventional cytogenetics showed 46-47,XХ,?t(4;9)(q25;p24), del(6)(q23q25), t(9;22)(q34;q22),add(11)(p11), del(14)(q24),-18,-20,add(21)(q22),+mar2-3[19], mutIKAROSIKZF1. Liquor assay was normal, no extramedullar lesions were found. Blinatumomab was administered as 4-week prolonged infusion after a pre-phase of cyclophosphamide treatment (200 mg/kg). Tyrosine kinase inhibitor therapy was switched to nilotinib. The treatment was well tolerated, any non-hematologic toxicity was observed. Two weeks after Blinatumomab treatment, the patient exhibited fever, weakness, swelling of eyelids, enlargement of mandibular lymph nodes and breast. BM exam revealed 18% of blast cells, with CD19 expression (88.6%), CD22 expression (97.9%). BCR-ABL p190/ABL*100 33.5534 copies, IKAROS mut. Inotuzumab ozogamicin was administered for vital indications in the frame of extended access program 3 times weekly after pre-phase of cyclophosphamide. Inotuzumab treatment was well tolerated, non-hematologic toxicity (hepatic grade 3, ALT elevation) was reversible. Complete BM and EM was achieved, MRD was detected by RT-PCR: BCR/ABL р190 was detected at 0.0637 copies. Allogeneic stem cell transplantation from matched related donor was performed at 09.08.2018, i.e., three weeks after Inotuzumab. Conditioning regimen with reduced toxicity included Fludarabine and Busulfan (10 mg/kg). GVHD prophylaxis was performed with posttransplant cyclophosphamide. Engraftment with complete donor chimerism and MRD negativity was reached at day+24. No signs of sinusoidal occlusive syndrome were observed, and no acute GVHD occurred. Donor lymphocyte infusion CD3+ 1×10⁶/kg was carried out at day+74 as a relapse prophylaxis. Tyrosine kinase inhibitor bosutinib was administered with adverse effects, thus later switched to imatinib. Chronic GVHD of skin and mucosa has developed 4 months after allo-HSCT. Tacrolimus was implicated at D+130 in order to control GVHD. At the present time, 11 months after HSCT, the patient is in complete MRD-negative remission with mild cGVHD controlled by tacrolimus. Imatinib treatment is continued.

Case 2.

A 25-year old young woman was diagnosed in November, 2011 with B-ALL blast cells showing CD79а+/HLADR+ CD19+/CD10+/CD38+/CD22+/CD20+/CD5-/sIgM-/cytIgM-/ phenotype, isolated BM involvement. Conventional cytogenetics showed normal karyotype. The patient received the National ALL-2009 Protocol with rituximab. Morphological remission was achieved after first induction cycle. The protocol was completed in April, 2014. BM relapse occurred in May, 2015. Blasts characteristics didn’t differ from initial levels. The second remission was achieved after first cycle of HyperCVAD protocol. A search for unrelated matched donor was launched. Second BM and CNS relapse accomplished by the breast lesions was diagnosed after the 3rd HyperCVAD cycle. Morphological remission with incomplete hematologic recovery was achieved after salvage therapy according to FLAG-Ida protocol. The chemotherapy was complicated by severe non-hematologic toxicity and sistem systemic inflammatory responce syndrome (SIRS). Allogeneic stem cell transplantation from matched unrelated donor was performed at 25.11.2015. The reduced-toxicity conditioning regimen included Fludarabine and Busulfan (12 mg/kg), GVHD prophylaxis was performed with tacrolimus, mycophenolate mofetil (MMF), and posttransplant cyclophosphamide. Stem cell engraftment with complete donor chimerism and MRD negativity was reached at day+20. However, on the day+50, BM and liquor assays revealed 3rd bone marrow relapse. The patient received Blinatumomab as a 4-week continuous infusion. The cytokine release syndrome occurred on day 2, being successfully treated with Tocilizumab, an anti-IL-6 receptor antagonist. The patient achieved 4^th remission with complete donor chimerism. However, MRD was detected by flow cytometry. Next two cycles of Blinatumomab were applied with a dose reduction followed by donor lymphocyte infusion (DLI). No significant toxicity was observed, and no GVHD has developed. MRD negativity was reached after 2^nd cycle. One year after transplantation patient developed an isolated left ocular extramedullary relapse. A remission was achieved after high-dose methotrexate and cytarabine followed by local radiotherapy. 1.5 years later, an isolated nasal extramedullary relapse was successfully treated in similar way. Six months later, a 7^th isolated breast relapse was confirmed by the biopsy. BM and liquor assays revealed MRD-negative remission and complete donor chimerism. Immunohistochemistry showed CD22 positivity, thus allowing us to use Inotuzumab in the frame of extended access program for vital indications. The patients received four cycles of Inotuzumab in the outpatient regimen. Complete metabolic response was documented by PET-CT (Fig. 1).

Figure 1. PET-CT scan before Inotuzumab treatment, SULmax 11.93 (A) and after the forth cycle of Inotuzumab (B)

Discussion

Extramedullary lesions are often revealed in cases of ALL relapse. Incidence of extramedullary relapses after allo-HSCT is higher than those in BM. So far, best results were demonstrated after high-dose chemotherapy followed by local radiotherapy [6]. Clinical prognosis in these patients remains very poor despite of different treatment options.

Blinotumomab is highly effective in R/R ALL patients with 69% of complete remission or complete remission with incomplete hematologic recovery achieved even after allo- HSCT [7-9]. In TOWER study the 1-year, the overall survival (OS) rate was 36% (median OS, 7.7 months), and the duration of remission was 7.3 months. Several studies including limited number of patients demonstrate similar results in Philadelphia chromosome-positive R/R ALL – up to 36% CR/CRi with median OS of 7.1 months [10]. The outcomes of Blinotumomab treatment in the patients relapsing after allo-HSCT were comparable: 45% CR/CRi and the median OS value was 8.5 months.

The Inotuzumab ozogamicin INO-VATE study included wider range of patients, e.g. Philadelphia chromosome positive R/R ALL, and the CR/CRi rate was 73.8% [4]. For patients achieving CR/CRi, the duration of remission was 5.2 months with 3-year OS rates of 20.3% (median 7.7 months). CR/CRi rate in patients who received previous allo-HSCT was similar, i.e., 69%.

Despite versatile analysis of these innovative drugs, no study has assessed their efficacy in the cases of extramedullary lesions. Some data about Blinotumomab and Inotuzumab ozogamicin impact on soft tissue tumors in limited studies are obtained in relapsed or refractory B-cell non-Hodgkin lymphoma. Viardot et al. report 43% overall response, including 19% of complete remissions after Blinotumomab treatment[11]. The results of Phase I study from Goebeler et al. showed 55% of overall response with complete remission in 36% of the cases [12].

Inotuzumab ozogamicin demonstrates better results only in combination with rituximab and chemotherapy: the overall response rate of 84% was reported, with CR values of 24%, but only 57% overall response in the patients with histologically aggressive lymphoma [13]. These results from NHL trials are not encouraging, with respect to high efficacy of Blinotumomab and Inotuzumab ozogamicin in R/R ALL with extramedullar involvement.

Conclusion

Inotuzumab ozogamicin is feasible and effective for highly pre-treated patients with R/R ALL before and after allo- HSCT. Despite moderate efficacy of immunotherapy in treatment of extramedullar R/R ALL, it may be further enhanced with additional immune strategies such as anti-PD-1 immunotherapy agents.

Conflict of Interest

No conflict of interest is declared.

References

Giebel S, Marks DI, Boissel N , Baron F, Chiaretti S, Ciceri F, Cornelissen JJ, Doubek M, Esteve J, Fielding A et al. Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2019; 54(6):798-809.
Gökbuget N, Dombret H, Ribera JM, Fielding AK, Advani A, Bassan R, Chia V, Doubek M, Giebel S, Hoelzer D et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016;101(12):1524-1533.
Rafei H, Kantarjian HM, Jabbour EJ. Recent advances in the treatment of acute lymphoblastic leukemia. Leuk Lymphoma. 2019; 16:1-16.
Kantarjian HM, De Angelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATEstudy. Cancer. 2019;125(14): 2474-2487.
Gunes G, Goker H, Demiroglu H, Malkan UY, Buyukasik Y. Extramedullary relapses of acute leukemias after allogeneic hematopoietic stem cell transplantation: clinical features, cumulative incidence, and risk factors. Bone Marrow Transplant. 2019; 54(4):595-600.
Shi JM, Meng XJ, Luo Y, Tan YM, Zhu XL, Zheng GF, He JS, Zheng WY, Xie WZ, Li L et al. Clinical characteristics and outcome of isolated extramedullary relapse in acute leukemia after allogeneic stem cell transplantation: a single-center analysis. Leuk Res. 2013; 37(4):372-377.
Kantarjian H, Stein A, Gökbuget N et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017; 376(9): 836-847.
Stein AS, Kantarjian H, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R et al. Blinatumomab for acute lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019 Apr 17.
Bondarenko SN, Parovichnikova EN, Maschan AA, Baranova OYu, Shelekhovas TV, Doronin VA, Mel'nichenko VYa, Kaplanov KD, Uspenskaya OS, Sokolov AN et al. Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Russian Multicenter Clinical Trial. Clinical Oncohematology. 2019;12(2):145-153 (In Russ).
Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, Fielding AK, Rambaldi A, Ritchie EK, Papayannidis C et al. Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. J Clin Oncol. 2017;35(16):1795-1802.
Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N, Zettl F, Libicher M, Sayehli C, Stieglmaier J et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016;127(11):1410-1416.
Goebeler ME, Knop S, Viardot A, Kufer P, Topp MS, Einsele H, Noppeney R, Hess G, Kallert S, Mackensen A et al. Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma: Final Results From a Phase I Study. J Clin Oncol. 2016; 34(10):1104-1111.
Dang NH, Ogura M, Castaigne S, Fayad LE, Jerkeman M, Radford J, Pezzutto A, Bondarenko I, Stewart DA, Shnaidman M et al. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2018; 182(4):583-586.

" ["~DETAIL_TEXT"]=> string(14843) "

Introduction

Case Description

Case 1.

Case 2.

Figure 1. PET-CT scan before Inotuzumab treatment, SULmax 11.93 (A) and after the forth cycle of Inotuzumab (B)

Discussion

Conclusion

Conflict of Interest

No conflict of interest is declared.

References

Giebel S, Marks DI, Boissel N , Baron F, Chiaretti S, Ciceri F, Cornelissen JJ, Doubek M, Esteve J, Fielding A et al. Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2019; 54(6):798-809.
Gökbuget N, Dombret H, Ribera JM, Fielding AK, Advani A, Bassan R, Chia V, Doubek M, Giebel S, Hoelzer D et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016;101(12):1524-1533.
Rafei H, Kantarjian HM, Jabbour EJ. Recent advances in the treatment of acute lymphoblastic leukemia. Leuk Lymphoma. 2019; 16:1-16.
Kantarjian HM, De Angelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATEstudy. Cancer. 2019;125(14): 2474-2487.
Gunes G, Goker H, Demiroglu H, Malkan UY, Buyukasik Y. Extramedullary relapses of acute leukemias after allogeneic hematopoietic stem cell transplantation: clinical features, cumulative incidence, and risk factors. Bone Marrow Transplant. 2019; 54(4):595-600.
Shi JM, Meng XJ, Luo Y, Tan YM, Zhu XL, Zheng GF, He JS, Zheng WY, Xie WZ, Li L et al. Clinical characteristics and outcome of isolated extramedullary relapse in acute leukemia after allogeneic stem cell transplantation: a single-center analysis. Leuk Res. 2013; 37(4):372-377.
Kantarjian H, Stein A, Gökbuget N et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017; 376(9): 836-847.
Stein AS, Kantarjian H, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R et al. Blinatumomab for acute lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019 Apr 17.
Bondarenko SN, Parovichnikova EN, Maschan AA, Baranova OYu, Shelekhovas TV, Doronin VA, Mel'nichenko VYa, Kaplanov KD, Uspenskaya OS, Sokolov AN et al. Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Russian Multicenter Clinical Trial. Clinical Oncohematology. 2019;12(2):145-153 (In Russ).
Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, Fielding AK, Rambaldi A, Ritchie EK, Papayannidis C et al. Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. J Clin Oncol. 2017;35(16):1795-1802.
Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N, Zettl F, Libicher M, Sayehli C, Stieglmaier J et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016;127(11):1410-1416.
Goebeler ME, Knop S, Viardot A, Kufer P, Topp MS, Einsele H, Noppeney R, Hess G, Kallert S, Mackensen A et al. Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma: Final Results From a Phase I Study. J Clin Oncol. 2016; 34(10):1104-1111.
Dang NH, Ogura M, Castaigne S, Fayad LE, Jerkeman M, Radford J, Pezzutto A, Bondarenko I, Stewart DA, Shnaidman M et al. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2018; 182(4):583-586.

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Несколько клинических исследований демонстрируют более высокую частоту полных ремиссии и реализаций алло-ТГСК после терапии Блинатумомабом и Инотузумабом по сравнению со стандартной химиотерапией при разном профиле токсичности. Но проблема лечения пациентов с наличием экстрамедуллярных поражений не отражена в этих исследованиях. <h3>Клинические описания</h3> В статье описаны два случая резистентного В-ОЛЛ с экстрамедуллярным поражением. Случай 1. Женщина 31 года, диагноз B-ОЛЛ, Ph-позитивный, второй рецидив, нет ответа после терапии Блинотумомабом. Прогрессия с вовлечением костного мозга, шейных и нижнечелюстных лимфатических узлов и молочной железы, полная ремиссия была достигнута после проведения терапии Инотузумабом. Впоследствии выполнена аллогенная родственная трансплантация гемопоэтических стволовых клеток. Случай 2. Женщина 25 лет, ранний изолированный костно-мозговой рецидив после аллогенной неродственной трансплантации. После терапии Блинотумомабом была достигнута ремиссия. 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стволовых клеток" ["SECTION_META_KEYWORDS"]=> string(382) "Успешная терапия резистентного B-острого лимфобластного лейкоза с экстрамедуллярным поражением с применением инотузумаба озогамицина до и после аллогенной трансплантации гемопоэтических стволовых клеток" ["SECTION_META_DESCRIPTION"]=> string(382) "Успешная терапия резистентного B-острого лимфобластного лейкоза с экстрамедуллярным поражением с применением инотузумаба озогамицина до и после аллогенной трансплантации гемопоэтических стволовых клеток" ["SECTION_PICTURE_FILE_ALT"]=> string(382) "Успешная терапия резистентного B-острого лимфобластного лейкоза с экстрамедуллярным поражением с применением инотузумаба озогамицина до и после аллогенной трансплантации гемопоэтических стволовых клеток" ["SECTION_PICTURE_FILE_TITLE"]=> string(382) "Успешная терапия резистентного B-острого лимфобластного лейкоза с экстрамедуллярным поражением с применением инотузумаба озогамицина до и после аллогенной трансплантации гемопоэтических стволовых клеток" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "uspeshnaya-terapiya-rezistentnogo-b-ostrogo-limfoblastnogo-leykoza-s-ekstramedullyarnym-porazheniem-" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(382) "Успешная терапия резистентного B-острого лимфобластного лейкоза с экстрамедуллярным поражением с применением инотузумаба озогамицина до и после аллогенной трансплантации гемопоэтических стволовых клеток" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(382) "Успешная терапия резистентного B-острого лимфобластного лейкоза с экстрамедуллярным поражением с применением инотузумаба озогамицина до и после аллогенной трансплантации гемопоэтических стволовых клеток" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "uspeshnaya-terapiya-rezistentnogo-b-ostrogo-limfoblastnogo-leykoza-s-ekstramedullyarnym-porazheniem-" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "uspeshnaya-terapiya-rezistentnogo-b-ostrogo-limfoblastnogo-leykoza-s-ekstramedullyarnym-porazheniem-" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "uspeshnaya-terapiya-rezistentnogo-b-ostrogo-limfoblastnogo-leykoza-s-ekstramedullyarnym-porazheniem-" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "127" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" 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string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "23246" ["VALUE"]=> string(10) "26.07.2019" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "26.07.2019" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "23247" ["VALUE"]=> string(3) "304" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "304" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(13) { [0]=> string(5) "23327" [1]=> string(5) "23328" [2]=> string(5) "23329" [3]=> string(5) "23330" [4]=> string(5) "23331" [5]=> string(5) "23332" [6]=> string(5) "23333" [7]=> string(5) "23334" [8]=> string(5) "23335" [9]=> string(5) "23336" [10]=> string(5) "23337" [11]=> string(5) "23338" [12]=> string(5) "23339" } ["VALUE"]=> array(13) { [0]=> string(3) "304" [1]=> string(4) "1631" [2]=> string(2) "60" [3]=> string(3) "135" [4]=> string(3) "285" [5]=> string(4) "1683" [6]=> string(4) "1684" [7]=> string(3) "500" [8]=> string(3) "695" [9]=> string(3) "498" [10]=> string(3) "177" [11]=> string(3) "503" [12]=> string(2) "34" } ["DESCRIPTION"]=> array(13) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" [5]=> string(0) "" [6]=> string(0) "" [7]=> string(0) "" [8]=> string(0) "" [9]=> string(0) "" [10]=> string(0) "" [11]=> string(0) "" [12]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(13) { [0]=> string(3) "304" [1]=> string(4) "1631" [2]=> string(2) "60" [3]=> string(3) "135" [4]=> string(3) "285" [5]=> string(4) "1683" [6]=> string(4) "1684" [7]=> string(3) "500" [8]=> string(3) "695" [9]=> string(3) "498" [10]=> string(3) "177" [11]=> string(3) "503" [12]=> string(2) "34" } ["~DESCRIPTION"]=> array(13) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" [5]=> string(0) "" [6]=> string(0) "" [7]=> string(0) "" [8]=> string(0) "" [9]=> string(0) "" [10]=> string(0) "" [11]=> string(0) "" [12]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "23261" ["VALUE"]=> array(2) { ["TEXT"]=> string(460) "Анна Г. Смирнова, Сергей Н. Бондаренко, Иван С. Моисеев, Инна В. Маркова, Елена И. Дарская, Ирина К. Голубовская, Белла И. Аюбова, Елена В. Бабенко, Ильдар М. Бархатов, Александр Л. Алянский, Татьяна Л. Гиндина, Александр Д. Кулагин, Борис В. Афанасьев" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(448) "

Анна Г. Смирнова, Сергей Н. Бондаренко, Иван С. Моисеев, Инна В. Маркова, Елена И. Дарская, Ирина К. Голубовская, Белла И. Аюбова, Елена В. Бабенко, Ильдар М. Бархатов, Александр Л. Алянский, Татьяна Л. Гиндина, Александр Д. Кулагин, Борис В. Афанасьев

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "23262" ["VALUE"]=> array(2) { ["TEXT"]=> string(367) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(355) "

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

Последние достижения в терапии резистентного B-острого лимфобластного лейкоза связаны с иммуноопосредованными методами, такими как Блинатумомаб, Инотузумаб Озогамицин и CAR-T клетки. Несколько клинических исследований демонстрируют более высокую частоту полных ремиссии и реализаций алло-ТГСК после терапии Блинатумомабом и Инотузумабом по сравнению со стандартной химиотерапией при разном профиле токсичности. Но проблема лечения пациентов с наличием экстрамедуллярных поражений не отражена в этих исследованиях.

Клинические описания

В статье описаны два случая резистентного В-ОЛЛ с экстрамедуллярным поражением. Случай 1. Женщина 31 года, диагноз B-ОЛЛ, Ph-позитивный, второй рецидив, нет ответа после терапии Блинотумомабом. Прогрессия с вовлечением костного мозга, шейных и нижнечелюстных лимфатических узлов и молочной железы, полная ремиссия была достигнута после проведения терапии Инотузумабом. Впоследствии выполнена аллогенная родственная трансплантация гемопоэтических стволовых клеток. Случай 2. Женщина 25 лет, ранний изолированный костно-мозговой рецидив после аллогенной неродственной трансплантации. После терапии Блинотумомабом была достигнута ремиссия. Инотузумаб назначен при развитии 6-ого экстрамедуллярного рецидива. Полный метаболический ответ был достигнут после 4 курсов терапии Инотузумабом.

Заключение

Описанные случаи демонстрируют возможность применения Инотузумаба при неэффективности Блинотумомаба в случае развития экстрамедуллярного рецидива до и после аллогенной трансплантации гемопоэтических стволовых клеток.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, B-острый лимфобластный лейкоз, Блинотумомаб, Инотузумаб озогамицин, экстрамедуллярный рецидив.

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Anna G. Smirnova, Sergey N. Bondarenko, Ivan S. Moiseev, Inna V. Markova, Elena I. Darskaya, Irina K. Golubovskaya, Bella I. Ayubova, Elena V. Babenko, Ildar M. Barkhatov, Alexander L. Alyanskiy, Tatiana L. Gindina, Alexander D. Kulagin, Boris V. Afanasyev

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Recent advances in treatment of relapsed/refractory B-Acute Lymphoblastic Leukemia (R/R B-ALL) are associated with targeted immune therapies, such as Blinatumomab, Inotuzumab ozogamicin and CAR-T cells. Several clinical studies demonstrate superior complete remission (CR) and allogeneic stem cell transplantation (allo-HSCT) rates after Blinatumomab or Inotuzumab treatment compared to conventional chemotherapy with different toxicity profiles. However, treatment of extramedullar lesions was not addressed in these trials.

Case presentation

We report two R/R B-ALL patients with extramedullar involvement. Case 1. A woman, 31 years old with Philadelphia positive B-ALL, being in second relapse not responding to Blinotumomab. Clinical progression was observed, with involvement of bone marrow (BM), cervical, mandibular lymph nodes and breast lesions. Complete BM and extramedullary remission was achieved after Inotuzumab followed by allogeneic stem cell transplantation from a matched related donor was performed. Case 2. A 25 years-old young woman exhibited a BM relapse after unrelated stem cell transplantation. Remission was achieved after Blinotumomab treatment. Inotuzumab was administered for 6th extramedullary relapse. A complete metabolic response was achieved after 4 cycles of Inotuzumab as shown by PET scanning.

Conclusion

The present cases demonstrate an opportunity for Inotuzumab administration after Blinotumomab failure in case of extramedullary relapse before and after allo-HSCT.

Keywords

Allogeneic hematopoietic stem cell transplantation, B-Acute Lymphoblastic Leukemia, Blinotumomab, Inotuzumab ozogamicin, extramedullary relapse.

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Case presentation

Conclusion

The present cases demonstrate an opportunity for Inotuzumab administration after Blinotumomab failure in case of extramedullary relapse before and after allo-HSCT.

Keywords

Allogeneic hematopoietic stem cell transplantation, B-Acute Lymphoblastic Leukemia, Blinotumomab, Inotuzumab ozogamicin, extramedullary relapse.

Case presentation

Conclusion

The present cases demonstrate an opportunity for Inotuzumab administration after Blinotumomab failure in case of extramedullary relapse before and after allo-HSCT.

Keywords

Allogeneic hematopoietic stem cell transplantation, B-Acute Lymphoblastic Leukemia, Blinotumomab, Inotuzumab ozogamicin, extramedullary relapse.

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Клинические описания

Заключение

Ключевые слова

Клинические описания

Заключение

Ключевые слова

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Introduction

Tissue engineering occupies the significant position among modern scientific trends. Even so, urological aspects hardly take a prominent place in the total volume of topical publications. In addition, many problems associated with the urinary bladder (UB) reconstruction remain unresolved [1]. For more than 100 years, worldwide scientists have been trying to find tissue analogues of UB wall [2]. Most of these attempts were unsuccessful due to structural and functional problems, as well as biocompatibility failure. For example, a non-resorbable synthetic reservoirs turned out to be mechanically untenable, in addition to stone formation. The use of absorbable materials led to fibroblast infiltration, cicatrization, and, as a result, a decrease in the UB capacity. Currently, when conservative methods fail, urinary tract is reconstructed using fragments of the gastrointestinal tract [3]. Such surgery always leads to various complications [4]. However, despite the high invasiveness of such intervention, they remain the golden standard in these conditions [5]. Hence, search for alternative materials able to replace the UB wall continues unabated. The tissue engineering and regenerative medicine methods can improve the treatment results of many pathological conditions in urology.

Different bioresorbable synthetic polymeric materials are widely used for the treatment of damaged organs and tissues as scaffolds for cell cultivation [1, 6]. Such scaffolds should have a number of features, such as mechanical strength and non-toxicity (including the harmlessness of their degradation products) [7]. In addition, they should promote cell growth, while the rates of the material biodegradation and recovery of damaged tissue should be comparable [8].

In 1990, Anthony Atala and his group had successfuly replaced the whole UB with an in vitro-grown neo-cyst in a series performed in 14 dogs [9], and then transplanted a similar tissue-engineered construct in human patients [10]. However, only autologous UB tissues were used here as a source of cells. This method is impossible in patients with affected urothelium and muscular wall. Such damaging conditions may be caused by a variety of diseases of the genitourinary system, often including tuberculosis [11, 12]. Moreover, in case of tuberculosis (as with a number of other infectious diseases) it is not possible to use autologous cells, because a potential hematogenic transfer of the infection cannot be excluded. Allogeneic cell transplantation could be a promising option for such patients using a lactic acid – poly-L, L-lactide, a synthetic scaffold able to serve a matrix for cell proliferation [13].

It is known that some cells of the body do not possess pronounced immunogenicity, and mesenchymal stem cells (MSCs) are even able to modulate the immune response. However, questions about the possibility of using allogeneic cells have not yet been fully investigated [14]. Many issues need to be resolved at the stage of preclinical studies. First of all, it is necessary to find the most suitable cell sources for regeneration of the bladder, to develop suitable matrices and to learn how to work with them.

The aim of present study was to perform experimental investigation of the opportunity of using an allogeneic tissue-engineering graft to replace a defect in the bladder wall.

Materials and methods

Fifteen adult Chinchilla rabbits were used for studying the results of surgical implantation into urinary bladder. The matrix for experimental implants was composed of polymer material based on lactic acid – poly-L,L-lactide, reinforced with silk fibroin at a 1:1 ratio. During preliminary series of in vivo experiments with different types of scaffolds, this composite did not exhibit toxic properties when implanted under the skin of rats for up to 3 months. Allogeneic cells of various tissue origin were isolated and cultured according to standard techniques, then being introduced in collagen gel into the prepared matrices. Three matrices of group 1 were seeded with allogeneic smooth muscle cells (SMC) and urothelium (U), three of them, with allogeneic skin fibroblasts (FB, group 2), three matrices were left cell-free (group 3) and six matrices were seeded with allogeneic MSCs of rabbit bone marrow labeled with superparamagnetic iron oxide nanoparticles (SPIONs) (group 4). The prepared multicomponent composites were implanted after partial UB resection in 15 male Chinchilla rabbits. Under intravenous anesthesia (ketamine 10-50 mg/kg and xylazine 1-3 mg/kg mixture) the bladder wall was dissected and a resection of a fragment 10×10 mm² was performed. The tissue-engineered graft was placed on the formed defect and fixed with 6.0 Vicryl stitches and then covered with a perivisceral fat. For urine outflow we installed an urethral catheter. The results were evaluated after 2.5 months observation. This time period was chosen after a series of preliminary experiment in rats, which showed resorption of this matrix implanted under the rat skin in 6-8 weeks after the experiment.

All the studies were carried out in accordance with ethical principles of laboratory animals curation "European Convention for the Protection of Vertebral Animals Used for Experimental and Other Scientific Purposes. CETS No. 123" and the Rules of Laboratory Practice (Order of the Ministry of Health and Social Development of the Russian Federation, August 23, 2010 No708n "On Approval of the Rules of Laboratory Practice").

Results

During the observation period no pathological changes in the blood and urine tests were recorded, also an adequate body weight increase was noted.

At the term of 2.5 months post-surgery, the groups 1, 2, and 3 demonstrated a decrease in bladder capacity of different severity grade, mostly manifested after implantation of FB-containing scaffolds (8% of the original values). A quantitative comparison of rabbit UB capacities at the initiation of the study and at the time of removal from the experiment is presented in Fig. 1. The diagram shows that in groups 1, 2 and 3 there is a varying degree of a decrease in the capacity of the bladder (8-48.7% of the preoperative levels, p<0.05). In group 4 animals, opposite, the capacity of the bladders practically did not change (92.6% of the pre-operative).

During macroscopic examination, no pathological changes of internal organs (except of UB) were identified in either of 15 animals: the parenchymal organs were not visually changed, there was no pathological effusion in the abdominal cavity, intra-abdominal lymph nodes were not visually enlarged. The urinary bladders of animals are investigated macro- and microscopically. Surgical implantation of structures containing allogeneic SMC and urothelium in the 1^st group caused a pronounced inflammatory reaction with a decrease in bladder capacity, development of a retracted scar at the implantation site, and displacement of the graft into the surrounding fatty tissue, its encapsulation and necrosis. In the animals from 2^nd group (FB), a marked inflammatory reaction was observed, with a significant decrease in capacity and compliance of the bladder. In one animal, it resulted into formation of hydronephrosis. In all cases, the matrix is found in the lumen of the UB, roughly cohesive with the surrounding tissues. In the 3^rd group (cell-free implant), the matrix covered with calculi was also found in the lumen of the UB. Like as in the 1^st group, a retracted scar with papillary outgrowths of the mucous membrane was formed at the implantation site. The capacity of UB was significantly reduced in all cases. Outside the zone of implantation, the bladder walls were thickened, rigid, and there was a marked adhesion process around the UB.

In the 4^th group (MSC-containing scaffold), the picture was strikingly different. 2.5 months post-surgery, the bladder capacity was comparable to the pre-operative one, the UB wall outside the implantation zone were not visually altered. At the implantation site, an area of new-formed mucosa with signs of vascularization was determined (Fig. 2).

In 5 of 6 cases (83%) of MSC-containing scaffold implants, a complete lysis of the matrix was also observed. Only in 1 case, the scaffold displacement into the UB lumen with the calculus formation did occur. On the contrary, in 100% of cases when using other scaffolds (SMC + U, FB, cell-free matrix), the matrix was displaced into the fatty tissue (with encapsulation and necrosis), or into the lumen of the UB with calculus formation.

Histologically, the initial stages of reparation and angiogenesis were revealed in the 4^th group (Fig. 3).

Figure 3. Bladder wall of a rabbit from group 4 (MSC-containing implants) at two months post-surgery. Hematoxylin-Eosin staining. 100x magnification. Newly formed layers (mucous membrane, submucosa, muscle layer and adventitia) are indicated by arrows

The mucous membrane (group 4) along its longitude was represented by transitional epithelium and the lamina propria with a high content of collagen fibers. The thickness of the transitional epithelium was not significantly changed and comprised 88.3±5.3 μm. Thickness of the mucosal layer was significantly increased (62.5±5.1 μm, p<0.05) as compared with intact rabbits (22.5±1.1). The submucous membrane was moderately swollen, its thickness compared with the control was significantly increased (to 416.7±11.8 μm, p<0.05). The number of blood vessels per 1 mm² was comparable to the control (4.0±0.0 μm). The lumen diameter of the vessels remained significantly increased (85.0±3.5 μm). The muscle membrane was also swollen, its thickness was significantly increased to 1583.3±31.3 microns, and its content of collagen fibers was increased as well. The thickness of adventitia layer with high contents of connective tissue was 83.8±8.1 μm.

Figure 4. Confocal microscopy of cryosections from Group 4. The implantation site, х40. Cell nuclei were stained with 4' ,6-diamidino-2-phenylindole (blue) and detected using a diode laser (λ=405 nm). Magnetic nanoparticles (SPION) were detected by reflected laser scanning at 488 nm (red). Scale bar, 100 μm.

The cryosections of the implantation sites were examined by confocal microscopy. Iron-containing nanoparticles were identified, and it was clear that labelled cells participated in formation of a structure similar to urotelium (Fig. 4).

Discussion

Impact of allogeneic MSCs on the immune response is of great scientific interest nowadays. In the present experiments, implantation of MSC-containing scaffold caused no significant inflammatory reaction, and also no signs of implant rejection were observed. Perhaps this is due to the MSCs unique feachures, since all implanted cell-free structures as well as matrices with allogeneic FB, SMC and urothelium induced active inflammatory reaction, that persisted even after 2,5 months of experiment. Moreover, the process spread to the surrounding tissues, which was not observed in case with MSC.

In recent years, the results of systemic treatment of MSCs for various diseases [15-17] and experimental work on the reconstruction of various urological structures including UB [18] have been published. World experience in the use of allogeneic MSCs for the UB reconstruction to date is represented by only four experimental studies [13, 18-20].

In conclusion, the current study has proved the opportunity of using a multi-component composite containing allogeneic mesenchymal stem cells for bladder defect replacement, whereas the implants without cell filling and those populated with allogeneic fibroblasts, smooth myocytes and urotelium are inevitably rejected. The technologies of creating a multicomponent graft using allogeneic cells should be further developed, because it can improve the results of treatment of such pathologies in which it is not possible to obtain autologous material. In addition, we are considering a bank of donor material as a promising idea for future pre-clinical and clinical implications. It will greatly simplify and speed up the process of obtaining the neo-organ by the recipient. We also plan long-term experiments, including the replacement of the whole bladder with a spherical reservoir. It is also planned to perform a morphological identification of cells containing SPION labels in the long-term period.

Competing interests

No conflicts of interest, financial or otherwise are declared by the authors.

Acknowledgement

This study was supported by a grant from the Russian Science Foundation (No 14-50-00068) and with financial support from the Federal Agency of Scientific Organizations (Russia).

The authors are grateful to Marina Parr, Liudmila Yakovleva, Yaroslav Marchenko, and Boris Nikolaev for synthesis of the magnetic nanoparticles, Igor Samusenko for hystologic examimation and Yuliya Idrisova for analysis of scaffold properties.

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Ho MH, Hou LT, Tu CY, Hsieh HJ, Lai JY, Chen WJ, Wang DM. Promotion of cell affinity of porous PLLA scaffolds by immobilization of RGD peptides via plasma treatment. Macromol Biosci. 2006; 6(1): 90-98.
Pattison MA, Wurster S, Webster TJ, Haberstroh KM. Three-dimensional, nano-structured PLGA scaffolds for bladder tissue replacement applications. Biomaterials. 2005; 26: 2491-2500.
Oberpenning F, Meng J, Yoo JJ, Atala A. De novo reconstitution of a functional mammalian urinary bladder by tissue engineering. Nat Biotechnol. 1999;17:149-155.
Atala A, Bauer SB, Soker S et al. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006; 367: 1241-1246.
Galkin VB, Mushkin AY, Muraviev AN, Serdobintsev MS, Belilovsky EM, Sinitsyn MV. The gender and age structure of the incidence of tuberculosis (various localizations) in the Russian Federation: changes over the XXI century Tuberculosis and Lung Diseases. 2018; 96(11):17-26. (In Russian).
Yudintceva NM, Bogolyubova IO, Muraviov AN, Sheykhov MG, Vinogradova TI, Sokolovich EG, Samusenko IA, Shevtsov MA. Application of the allogenic mesenchymal stem cells in the therapy of the bladder tuberculosis. Journal of Tissue Engineering Regener Med. 2018; 12(3): e1580-e1593.
Yudintceva NM, Nashchekina YA., Blinova MI, Orlova NV, Muraviov AN, Vinogradova TI, Sheykhov MG, Shapkova EY, Emeljannikov DV, Yablonskii PK, Samusenko IA, Mikhrina AL, Pakhomov AV, Shevtsov MA. Experimental bladder regeneration using a poly-l-lactide/
silk fibroin scaffold seeded with nanoparticle-labeled allogenic bone marrow stromal cells. Int J Nanomedicine. 2016; 11:4521-4533.
Martínez-Montiel MP, Gómez-Gómez GJ, Flores AI. Therapy with stem cells in inflammatory bowel disease. World J Gastroenterol. 2014; 20(5): 1211-1127.
Onken J, Gallup D, Hanson J, Pandak M, Custer L. Successful outpatient treatment of refractory Crohn’s disease using adult mesenchymal stem cells. ACG 2006 Final Program Book. 2006: 121.
Liang J, Zhang H, Wang D, Feng X, Wang H, Hua B, Liu B, Sun L. Allogeneic mesenchymal stem cell transplantation in seven patients with refractory inflammatory bowel disease. Gut. 2012; 61: 468-469.
Du T, Zhu YJ. The regulation of inflammatory mediators in acute kidney injury via exogenous mesenchymal stem cells. Mediat Inflam. 2014. 2014: 261697. PMID: 24839354. DOI: 10.1155/2014/261697.
Coutu DL, Mahfouz W, Loutochin O, Galipeau J, Corcos J. Tissue Engineering of Rat Bladder Using Marrow-Derived Mesenchymal Stem Cells and Bladder Acellular Matrix. PLoS One. 2014. 9(12): e111966. DOI: 10.1371.
Yuan H, Zhuang Y, Xiong J, Zhi W, Liu L, Wei Q, Han P. Human umbilical mesenchymal stem cells-seeded bladder acellular matrix grafts for reconstruction of bladder defects in a canine model. PLoS One. 2013. 8(11): e80959. PMID: 24278354. DOI: 10.1371/journal.pone.0080959.
Snow-Lisy DC, Diaz EC, Bury MI, Fuller NJ, Hannick JH, Ahmad N, Sharma AK. The role of genetically modified mesenchymal stem cells in urinary bladder regeneration. PLoS One. 2015. 10(9): e0138643. PMID: 26398705. DOI: 10.1371/journal.pone.

" ["~DETAIL_TEXT"]=> string(18914) "

Introduction

The aim of present study was to perform experimental investigation of the opportunity of using an allogeneic tissue-engineering graft to replace a defect in the bladder wall.

Materials and methods

Results

During the observation period no pathological changes in the blood and urine tests were recorded, also an adequate body weight increase was noted.

Histologically, the initial stages of reparation and angiogenesis were revealed in the 4^th group (Fig. 3).

Discussion

Competing interests

No conflicts of interest, financial or otherwise are declared by the authors.

Acknowledgement

This study was supported by a grant from the Russian Science Foundation (No 14-50-00068) and with financial support from the Federal Agency of Scientific Organizations (Russia).

References

Muravjev AN, Orlova NV, Blinova MI, Yudintseva NM. Tissue engineering in urology, new approaches for urinary bladder reconstruction. Tsitologiya. 2015; 57(1): 14-18. (In Russian).
Rohrmann D, Albrecht D, Hannappel J, Gerlach R, Schwarzkopp G, Lutzeyer W. Alloplastic replacement of the urinary bladder. J Urol. 1996; 156: 2094-2097.
Sloff, M. Simaioforidis V, de Vries R, Oosterwijk E, Feitz W. Tissue engineering of the bladder – reality or myth? A systematic review. J. Urol. 2014. 192(4): 1035-1042.
El Taji O, Khattak AQ, Hussain SA. Bladder reconstruction: The past, present and future (Review). Oncol Lett. 2015. 10(1): 3-10.
Zuban ON, Komjakov BK. Surgical correction of a minor urinary bladder. SPb:“Stiks”. 2011: 1-227 (In Russian).
Shao J, Chen C, Wang Y, Chen X, Du C. Early stage structural evolution of PLLA porous scaffolds in thermally induced phase separation process and the corresponding biodegradability and biological property. Polymer Degrad Stab. 2012; 97: 955-963.
Ho MH, Hou LT, Tu CY, Hsieh HJ, Lai JY, Chen WJ, Wang DM. Promotion of cell affinity of porous PLLA scaffolds by immobilization of RGD peptides via plasma treatment. Macromol Biosci. 2006; 6(1): 90-98.
Pattison MA, Wurster S, Webster TJ, Haberstroh KM. Three-dimensional, nano-structured PLGA scaffolds for bladder tissue replacement applications. Biomaterials. 2005; 26: 2491-2500.
Oberpenning F, Meng J, Yoo JJ, Atala A. De novo reconstitution of a functional mammalian urinary bladder by tissue engineering. Nat Biotechnol. 1999;17:149-155.
Atala A, Bauer SB, Soker S et al. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006; 367: 1241-1246.
Galkin VB, Mushkin AY, Muraviev AN, Serdobintsev MS, Belilovsky EM, Sinitsyn MV. The gender and age structure of the incidence of tuberculosis (various localizations) in the Russian Federation: changes over the XXI century Tuberculosis and Lung Diseases. 2018; 96(11):17-26. (In Russian).
Yudintceva NM, Bogolyubova IO, Muraviov AN, Sheykhov MG, Vinogradova TI, Sokolovich EG, Samusenko IA, Shevtsov MA. Application of the allogenic mesenchymal stem cells in the therapy of the bladder tuberculosis. Journal of Tissue Engineering Regener Med. 2018; 12(3): e1580-e1593.
Yudintceva NM, Nashchekina YA., Blinova MI, Orlova NV, Muraviov AN, Vinogradova TI, Sheykhov MG, Shapkova EY, Emeljannikov DV, Yablonskii PK, Samusenko IA, Mikhrina AL, Pakhomov AV, Shevtsov MA. Experimental bladder regeneration using a poly-l-lactide/
silk fibroin scaffold seeded with nanoparticle-labeled allogenic bone marrow stromal cells. Int J Nanomedicine. 2016; 11:4521-4533.
Martínez-Montiel MP, Gómez-Gómez GJ, Flores AI. Therapy with stem cells in inflammatory bowel disease. World J Gastroenterol. 2014; 20(5): 1211-1127.
Onken J, Gallup D, Hanson J, Pandak M, Custer L. Successful outpatient treatment of refractory Crohn’s disease using adult mesenchymal stem cells. ACG 2006 Final Program Book. 2006: 121.
Liang J, Zhang H, Wang D, Feng X, Wang H, Hua B, Liu B, Sun L. Allogeneic mesenchymal stem cell transplantation in seven patients with refractory inflammatory bowel disease. Gut. 2012; 61: 468-469.
Du T, Zhu YJ. The regulation of inflammatory mediators in acute kidney injury via exogenous mesenchymal stem cells. Mediat Inflam. 2014. 2014: 261697. PMID: 24839354. DOI: 10.1155/2014/261697.
Coutu DL, Mahfouz W, Loutochin O, Galipeau J, Corcos J. Tissue Engineering of Rat Bladder Using Marrow-Derived Mesenchymal Stem Cells and Bladder Acellular Matrix. PLoS One. 2014. 9(12): e111966. DOI: 10.1371.
Yuan H, Zhuang Y, Xiong J, Zhi W, Liu L, Wei Q, Han P. Human umbilical mesenchymal stem cells-seeded bladder acellular matrix grafts for reconstruction of bladder defects in a canine model. PLoS One. 2013. 8(11): e80959. PMID: 24278354. DOI: 10.1371/journal.pone.0080959.
Snow-Lisy DC, Diaz EC, Bury MI, Fuller NJ, Hannick JH, Ahmad N, Sharma AK. The role of genetically modified mesenchymal stem cells in urinary bladder regeneration. PLoS One. 2015. 10(9): e0138643. PMID: 26398705. DOI: 10.1371/journal.pone.

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Орлова1, Александр Н. Муравьев1,4, Татьяна И. Виноградова1, Наталья М. Юдинцева2, Юлия А. Нащекина2, Наталья В. Заболотных1, Александр А. Лебедев1, Магомедсадык Г. Шейхов1, Петр К. Яблонский1,3" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(458) "

Надежда В. Орлова¹, Александр Н. Муравьев^1,4, Татьяна И. Виноградова¹, Наталья М. Юдинцева², Юлия А. Нащекина², Наталья В. Заболотных¹, Александр А. Лебедев¹, Магомедсадык Г. Шейхов¹, Петр К. Яблонский^1,3

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¹ Санкт-Петербургский научно-исследовательский институт фтизиопульмонологии Минздрава России, Санкт-Петербург, Россия
² Институт цитологии РАН, Санкт-Петербург, Россия
³ Санкт-Петербургский государственный университет, Санкт-Петербург, Россия
⁴ Частное образовательное учреждение высшего образования «Санкт-Петербургский медико-социальный институт», Санкт-Петербург, Россия

В статье представлены результаты экспериментального исследования по частичной реконструкции мочевого пузыря кролика с использованием тканеинженерных конструкций на основе поли-L, L-лактида, содержащих в своем составе аллогенные клетки различного тканевого происхождения.

Цель

Экспериментальное изучение возможности применения аллогенного тканеинженерного трансплантата для замещения дефекта стенки мочевого пузыря.

Материалы и методы

15 кроликам-самцам породы «Шиншилла» выполнена парциальная резекция мочевого пузыря с имплантацией скаффолдов, содержащих гладкие миоциты с уротелием, фибробласты и мезенхимальные стволовые клетки, а также матрицей без клеток.

Результаты

В группе животных, получившей скаффолд с меченными мезенхимальными стволовыми клетками, в 5 случаях из 6 не зафиксировано признаков отторжения имплантата. Через 2,5 месяца после операции емкость мочевых пузырей была сравнима с дооперационной. В месте имплантации визуально определялся участок вновь сформированной стенки мочевого пузыря с признаками васкуляризации. Гистологически выявлены начальные стадии репарации и ангиогенеза. При конфокальной микроскопии криосрезов в месте имплантации обнаружены меченые клетки, принимающие участие в формировании структуры, сходной с уротелием. Во всех случаях имплантации бесклеточной матрицей или скаффолдов, содержащих гладкие миоциты с уротелием и фибробласты, произошло отторжение имплантата с разной степени выраженности воспалительной реакцией и уменьшением емкости мочевого пузыря.

Заключение

Проведенный эксперимент подтверждает возможность использования мезенхимальных стволовых клеток в составе тканеинженерного продукта для частичного замещения стенки мочевого пузыря. Разработка методик создания многокомпонентного трансплантата с использованием аллогенных клеток может способствовать улучшению результатов лечения патологий, при которых получение аутологичного материала не представляется возможным.

Ключевые слова

Аллогенная трансплантация, мезенхимальные стромальные клетки костного мозга, мочевой пузырь, тканевая инженерия.

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Nadezhda V. Orlova¹, Alexander N. Muraviov^1,4, Tatjana I. Vinogradova¹, Natalija M. Yudintceva², Yulia A. Nashchekina², Natalija V. Zabolotnih¹, Alexander A. Lebedev¹, Magomedsadik G. Sheykhov¹, Piotr K. Yablonsky^1,3

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¹ St. Petersburg State Research Institute of Phthisiopulmonology, St. Petersburg, Russia
² Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
³ St. Petersburg State University, St. Petersburg, Russia
⁴ Private University «St. Petersburg Medico-Social Institute», St. Petersburg, Russia

The article describes the results of an experimental study of tissue-engineering constructions based on lactic acid – poly-L, L-lactide matrix, containing allogeneic cells of various tissue origin.

Aim

Experimental investigation of the possibility of using an allogenic tissue-engineering graft to replace a defect in the bladder wall.

Materials and methods

The study was performed on 15 male Chinchilla rabbits. After partial resection of the bladder augmentation cystoplasty was performed with scaffolds containing smooth myocytes with urothelium, fibroblasts and mesenchymal stem cells.

Results

In 100% of cases of partial bladder replacement with a cell-free matrix or scaffolds containing smooth myocytes with urothelium and fibroblasts, an implant was rejected with a different severity of the inflammatory reaction and a decrease in the capacity of the bladder. In the 4^th group (mesenchymal stem cells), on the contrary, in 5 cases out of 6 lysis of the matrix occurred, the capacity of the bladders 2.5 months post-surgery was comparable to the preoperative one. At the implantation site, an area of the modified mucous membrane with signs of vascularization was determined. Histologically, the initial stages of reparation and angiogenesis were revealed. With confocal microscopy of cryosections at the implantation site, labeled cells are identified that are involved in the formation of a structure similar to the urothelium.

Conclusion

The efficiency of using mesenchymal stem cells as part of a tissue-engineered product for partial replacement of the bladder wall was shown. Development of methods of creating multi-component graft using allogeneic cells may improve the results of treatment of pathologies in which no autologous material is available.

Keywords

Allogeneic transplantation, bone marrow mesenchymal stromal cells, bladder, tissue engineering.

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Orlova1, Alexander N. Muraviov1,4, Tatjana I. Vinogradova1, Natalija M. Yudintceva2, Yulia A. Nashchekina2, Natalija V. Zabolotnih1, Alexander A. Lebedev1, Magomedsadik G. Sheykhov1, Piotr K. Yablonsky1,3" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(322) "

The article describes the results of an experimental study of tissue-engineering constructions based on lactic acid – poly-L, L-lactide matrix, containing allogeneic cells of various tissue origin.

Aim

Experimental investigation of the possibility of using an allogenic tissue-engineering graft to replace a defect in the bladder wall.

Materials and methods

Results

Conclusion

Keywords

Allogeneic transplantation, bone marrow mesenchymal stromal cells, bladder, tissue engineering.

The article describes the results of an experimental study of tissue-engineering constructions based on lactic acid – poly-L, L-lactide matrix, containing allogeneic cells of various tissue origin.

Aim

Experimental investigation of the possibility of using an allogenic tissue-engineering graft to replace a defect in the bladder wall.

Materials and methods

Results

Conclusion

Keywords

Allogeneic transplantation, bone marrow mesenchymal stromal cells, bladder, tissue engineering.

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Цель

Материалы и методы

Результаты

Заключение

Ключевые слова

Цель

Материалы и методы

Результаты

Заключение

Ключевые слова

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Introduction

Almost all cells of the human body secrete into the extracellular space a variety of vesicles, that are classified into ectosomes, apoptotic bodies, microvesicles and exosomes. The most interesting of them are exosomes, i.e., microvesicles, whose dimensions do not exceed 150 nm [1]. They are formed in the cells along the endosomal pathway with the formation of distinct endosomes, and, therefore, are of intracellular origin [2]. Exosomes are active participants in the intercellular communication system and provide for the transfer of their contents, being protected with vesicular membranes. The first evidence for the opportunity of mRNA transfer using exosomes was obtained by J. Ratajczak (2006) [3], who treated mononuclear cells from murine bone marrow with exosomes of embryonic stem cells, which harbor a lot of mRNA encoding Oct4 transcription factor in their cytoplasm, thus leading to increased Oct4 synthesis in the recipient cells. Since then, many researchers have confirmed the possibility of exosome-mediated horizontal transfer of nucleic acids.

The spectrum and significance of the fundamental biological processes in which exosomes take part, the opportunity of translating this knowledge into clinical practice determine the steadily growing interest of workers in this area of biomedicine. A promising direction of such studies is a more detailed profiling of nucleic acids carried by exosomes of blast cells, in order to search for potential markers of malignancies that could provide higher sensitivity and specificity under conditions of minimally invasive diagnostic procedures (the so-called liquid biopsy), as demonstrated for some solid tumors [4]. In the future, it would be possible to estimate the minimal residual disease based on exosome samples, but today there are a number of obstacles for clinical usage of this approach. First of all, there are difficulties with reliable purification of homogeneous exosomal fraction free of impurities, absence of standard isolation protocols, as well as lack of large studies confirming sensitivity of these techniques, and their comparison with approved methods of laboratory diagnostics.

Chronic myeloid leukemia (CML) cells are the model subject of our study. CML is a clonal myeloproliferative disease in which the cells of the myeloid lineage undergo massive clonal expansion [5]. The chimeric (fusion) BCR-ABL gene is formed as a result of reciprocal translocation between chromosome 9 and 22 [6]. Such a mutation is found in 90% of blast cells from CML patients [7] and is associated with formation of the so-called Philadelphia chromosome [t (9; 22), Ph+]. Highly active tyrosine kinase, encoded by BCR-ABL, influences the rates of DNA homologous recombination and reparation, thus promoting acquisition of additional mutations and chromosomal aberrations by the Ph+ cells, and also causes their excessive proliferation. As a rule, the activity of the BCR-ABL protein is necessary and sufficient to maintain the leukemic phenotype [8, 9]. This aberrant protein is shown to disturb the adhesion of leukemic blasts to the cells from bone marrow microenvironment [10], it changes the features of migration, and alters maturation of myelopoiesis progenitor cells. There are several different variants of proteins detectable in t(9; 22) mutation, but the most common transcripts in CML are b3a2 and b2a2, resulting in the formation of a protein with molecular mass of 210 kDa (p210, Mbcr) [11,12,13]. Thus, BCR-ABL is a typical marker of chronic myeloid leukemia.

The purpose of this work was an in vitro study of horizontal transfer of the chimeric BCR-ABL p210 transcript to the mesenchymal stromal bone marrow cells (MSCs) from healthy donors using exosomal fraction of extracellular microvesicles in model, aiming for evaluation of their potential significance for detection of minimal residual disease (MRD) in the patients with chronic myeloid leukemia.

Materials and methods

Cultural methods

K562 cells transduced with the LVT-TagGFP2 vector (Evrogen) were used as a producer and source of exosomes. The cells were positive for the BCR-ABL p210 marker and for the eGFP fluorescent protein. To expand the biomass, the cells were cultured in RPMI-1640 medium, supplied with 10% FBS, 100 μg/mL of streptomycin, 100 U/mL of penicillin (“BioloT”, St. Petersburg).

The mesenchymal stromal cells (MSCs) were isolated from the bone marrow of healthy donors according to a standard protocol in a Ficoll density gradient.

Enrichment and isolation of the K562-derived exosomes

K562 cells were cultured in serum-free nutrient medium Panexin basic, Serum Replacement with Defined Components (Pan Biotech, Germany). Twenty-four hour later, the exosomal fraction was enriched, using a protocol based on differential ultracentrifugation, according to Thery et al., [14]. In brief, the cells were separated by centrifugation at 300 g for 10 min. Further procedures were performed at 4°С. The resulting supernate was centrifuged for 20 minutes at 2000g, in order to remove cellular debris. Apoptotic bodies were harvested at 10.000 g for 45 minutes. Sedimentation regimen for the resulting supernate was dependent on the volume of centrifugation tube (70 mL), lasting for <10 hours at 100000 g. The pellet was washed in PBS, and the vesicles were precipitated at 100000 g, then dissolved in 1000 μl of serum-free medium Panexin basic and gently vortexed. The samples were stored at -80°C.

Analysis of the particles obtained

The isolated particles were analyzed using laser correlation spectroscopy approach. In the course of sample preparation, the exosomes were dissolved in 1000 μl of serum-free Panexin basic Medium. A 7-μL aliquote was then dispersed in dH₂O at a 1:100 ratio. Spectroscopic measurements were made in a Zetasizer NanoZS laser correlation spectrometer (measured particle range: 0.3 nm to 10 μm, Malvern Instruments, UK). Thus, we checked the biomaterial for presence of exosomes after plotting the particle size distribution in the sample measured by means of dynamic laser beam scattering. The diameter of particles was calculated using Zetasizer Software 7.11 software (Malvern Instruments). Zeta potential was also measured, in order to determine stability of the particles and to evaluate their ability to interact with other biological systems.

Morphological features of the particles were assessed by transmission electron microscopy with negative contrasting (JEM-100S, Jeol, Japan).

Co-cultures of MSCs and K562, contamination control

Co-cultivation of K562 and MSC was performed in a 24-well plate with semi-permeable polycarbonate membranes (pore diameter – 0.4 μm, Biofil, China) under similar culture conditions (RPMI-1640 medium, supplied with 10% FBS, 100 μg/mL of streptomycin, 100 U/mL of penicillin). The confluence of MSCs on plastic plates was 80%, the concentration of K562 cells, 1 mln/ml.

To assess the contamination with K562 cells, the MSC fraction was examined by flow cytofluorimetry (FACSCanto, BD, USA). Antibodies were used against the surface marker of CD45 leukocytes, and the detection of eGFP was also evaluated. Cell viability was assessed by means of vital 7-AAD staining. In parallel, potential contamination with K562 cells was monitored by confocal microscopy (LSM 710, Carl Zeiss, Germany).

MSC transfection with K562-derived Exosomes

The experiments with transfer of BCR/ABL transcript were carried out in a 24-well plate at the MSC concentration of 20.000 cells per well. The cells were incubated for 24 hours under standard conditions, with subsequent addition of 300 μl serum-free growth medium containing exosomes derived of 70×10⁶ K562 cells per well followed by 24-hour incubation under similar conditions.

Analysis of the BCR-ABL expression levels using real-time quantitative PCR (RT-PCR) and agarose gel electrophoresis

Total mRNA from both cells and exosomes was isolated by guanidine-phenol-chloroform extraction using TriZ Reagent (Inogene, Russia) according to the manufacturer's instructions. Eleven µL of extracted RNA were subjected to reverse transcription using the RevertAid First Stand cDNA Syntesis Kit (Thermo Fisher Scientific). For each cDNA sample, multiplex PCR was performed for the BCR-ABL p210 and ABL1 genes using primers and probes (Table 1). The relative expression level of the BCR-ABL transcript was determined by RT-PCR against the ABL1 reference gene in duplicate by means of the ICycler iQ5 device (Bio-Rad, USA), using the amplification reagent kit M-428 (Syntol, Russia). The PCR conditions were as follows: 10 μl of PCR reaction mixture containing dNTP mix 2.5 mM each, 10×PCR buffer, 5 Units of Taq-DNA polymerase and 2.5 μl of 25 mM MgCl2, supplemented with 5 pmol of Taqman probes specific for the BCR-ABL p210 and ABL1 genes. The primer and TaqMan probe sequences used for RT-PCR, and the sizes of resulting amplicons are shown in Table 1. To estimate absolute quantities of BCR-ABL and ABL1 transcripts, we used the Mbcr BCR-ABL Kit (Inogene, Russia) whose standard samples were used to plot appropriate calibration curves. The final PCR reaction volume was 25μl. The following amplification mode was used: initial incubation at 95°C for 5 minutes followed by 45 two-step cycles (95°C, 15 sec; 60°C, 1 min). Fluorescent signal was registered at 60°C at the FAM and HEX channels. The mRNA expression ratio was calculated as copies of BCR-ABL p210/copies of ABL1×100%, and the results were expressed as percentage of BCR-ABL to ABL transcripts.

Separation of the BCR-ABL and ABL1 fragments obtained by amplifying cDNA samples with the same primers was performed by horizontal electrophoresis in 2% agarose gel stained with ethidium bromide.

Table 1. Nucleotide sequences of primers and Taqman probes used for quantitative assays of chimeric BCR-ABL p210 transcripts

Results

Analysis of selected particles (exosomes)

As seen from Figure 1, the largest number of vesicles in the sample corresponded to presumed size of exosomes [1]. At the same time, the results of the study of 15 samples showed that the distribution of the average sample size by diameter is in the range of 51.8 to 107.0 nm, with a mean value of 78.96±20.03 nm. Two peaks may be discerned at the distribution curve, the largest one (82.5%) corresponds to stable subfraction with average ZP value of -29.3±7.4 mV (Fig. 2), which indirectly indicates their stability.

Figure 1. Size distribution of the K562-derived nanovesicles. The diameter for the largest number of particles is indicated

Figure 2. Zeta-potential of the isolated nanovesicles

Upon morphological studies, the particles correspond to exosomes, as confirmed by electron microscopy (Fig. 3) within the expected size range and with general exosome-like morphology, consistent with the previous studies [1].

Figure 3. Transmission electron microscopy of the vesicles detected by negative contrasting: A, general view of preparation; B, C, D – exosome-like particles (marked with circles). The length of scale lines is 200 nm

Co-cultivation of MSCs and K562 cells potential contamination issues

When assessing the possible contamination of the MSC fraction, we conducted an assessment of the presence of hematopoietic markers in the culture of adherent cells, which results in data indicating the absence of cells with the CD45+/eGFP+ phenotype (Fig. 4). In addition, the probability of MSC contamination by hematopoietic cells was assessed by confocal microscopy, which showed similar results (Fig. 5).

Figure 4. Flow cytometric phenotype of the cells under study.

A: Negative control – MSC of healthy donors, CD45-, eGFP-; B: Positive control – K562 line cells, BCR-ABL p210 +, CD45 +, eGFP +; C, D: MSCs of healthy donors and K562 cell lines following co-cultivation through a semi-permeable membrane. K562 cells are not revealed.

Figure 5. Confocal microscopy of MSC/K562 co-cultures.

A: MSC of healthy donors and K562 cell line, cocultivated through a semi-permeable membrane, K562 not detectable; B: Negative control, MSC from healthy donors, CD45-, eGFP-; C: Positive control, K562 cells: BCR-ABL p210 +, CD45 +, eGFP +.

Relative contents of BCR-ABL in K562 cells, exosomes, and transfected MSCs

According to the qPCR results, expression levels of BCR-ABL chimeric transcript in exosomes ranged from 44.42 to 863.79 copies/mL of conditioned medium, with a median value of 154.42. Nineteen K562 cell samples and six exosome preparations were included into the study. Comparable values were detected, when assessing relative expression of the BCR-ABL gene in K562 cells and exosomes (p>0.05) as seen from Fig. 6.

After cocultivation of K562 and MSCs, the relative content of BCR-ABL in recipient mesenchymal cells was 0.03 to 11.4% of ABL levels, with a median of 0.29% (N=8). High-quality verification of the target amplicon is confirmed by agarose gel electrophoresis gel (Fig. 7).

As a result of exosome-mediated transfection, the relative content of the chimeric transcript in the MSC of healthy donors (n=9) ranged from 0.01 to 15.88%, with a median value of 0.11%, which corresponds to a positive result when determining MRD in CML patients, and confirms a direct involvement of exosomes into the BCR/ABL transfer.

Discussion

In the frame of present work, we were able to demonstrate the opportunity for horizontal exosome-mediated transfer of chimeric BCR-ABL p210 transcript from malignant cell producers to the in vitro exposed human stromal bone marrow cells. Of sufficient importance, this oncogene transfer can be detected and monitored using standard molecular genetic techniques used in routine laboratory diagnostics.

We assume that the communications between stromal microenvironment and leukemic cells could be mediated, e.g., by exosomal fraction of microvesicles derived from malignant cells. Apparently, there is a wide spectrum of physiological processes modulated by exosomes, and its more detailed study is of great interest. It is still an open question about the role of exosomes in this intercellular interactions and duration of their in vivo persistence in extracellular fluids, and, in particular, in biological materials used for clinical diagnostics. Studies on the stability of circulating RNAs indicate its localization in exosomes, and also indicate to integrity of these nucleic acids within these vesicles. An opportunity of their determination in mice with xenografts was shown after 7 weeks after implantation of cancer cells, and incubation of serum samples at room temperature for 24 hours had a minimal effect on circulating RNA levels [15]. For comparison, miRNAs are stable only within several minutes [16], which makes them unsuitable candidates for assessing the risk of developing a relapse. Obviously, the vesicular membrane provides some resistance of nucleic acids to external enzymatic effects. Our in vitro results of the cocultivation experiments suggest that, at least, during co-cultures, the CML miRNA marker encapsulated in exosomes for 48-72 hours is preserved in the culture media under study.

The development of new diagnostic strategies based on vesicular nanoparticle data could be a promising research project aimed at optimizing a number of clinical laboratory diagnostic approaches.

Conclusions

In the course of differential ultracentrifugation, extracellular microvesicles were obtained, which correspond to exosomes by their morphological parameters. In exosomes derived from the K562 cell line, relative expression of the chimeric BCR-ABL gene is observed at a level comparable to the producer cells.

According to the results of cocultivation of producer cells with stromal cells, and by direct transfection of them with isolated microvesicles, it was established that the mRNA of the BCR-ABL p210 gene can be transferred into mesenchymal stromal cells of the bone marrow via exosomes.

Quantitative assessment of this transcript allows the similar order of sensitivity as the level required for obtaining positive result of the minimal residual disease detection, which indicates the potential of exosomes to contribute to the results of MRD determination.

Conflicts of interests

No potential conflicts of interests are reported.

References

Shah R, Patel T, Freedman JE. Circulating extracellular vesicles in human disease. New Engl J Med. 2018; 379(10): 958-966.
Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nature Rev Immunol. 2002; 2(8): 569-579.
Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, Ratajczak MZ. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006; 20(5): 847-856.
Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf E.A, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, Piwnica-Worms D, Kalluri R. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015; 523: 177-182.
Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037.
Melo JV. The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood. 1996;88:2375-2384.
Cortes J E, Talpaz M, Beran M, O’Brien SM, Rios MB, Stass S, Kantarjian HM. Philadelphia chromosome-negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Long-term follow-up results. Cancer. 1995; 75:464-470.
Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210 bcr/abl gene of the Philadelphia chromosome. Science. 1990;247: 824-827.
Pear WS, Miller JP, Xu L, Pui JC, Soffer B, Quackenbush RC, Pendergast AM, Bronson R, Aster JC, Scott ML, Baltimore D. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood. 1998;92: 3780-3792.
Raimondo S, Saieva L, Corrado C, Fontana S, Flugy A, Rizzo A, De Leo G, Alessandro R. Chronic myeloid leukemia-derived exosomes promote tumor growth through an autocrine mechanism. Cell Commun Signal. 2015;13:8. doi: 10.1186/s12964-015-0086-x.
Pane F, Interieri M, Quintarelli C, Izzo B, Muccioli GC, Salvatore F. Bcr-Abl genes and leukemic phenotype: from molecular mechanisms to clinical correlations. Oncogene 2002; 21: 8652-8667.
Moumen A, Dehbi H, Kottwitz D, El Amrani M, Bouchoutrouch N, El Hadi H, Quessar A, Benchekroun S, Nadifi S, Sefrioui H. Quantitative real-time polymerase chain reaction as an efficient molecular tool for detecting minimal residual disease in Moroccan chronic myeloid leukemia patients. Genet Mol Res 14.1 (2015): 1044-1055.
Thijsen, S FT, Schuurhuis G, van Oostveen J, Ossenkoppele G. Chronic myeloid leukemia from basics to bedside. Leukemia. 1999; 13(11): 1646-1674.
Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Current Protoc Cell Biol. 2006. Chapter 3. Unit 3.22. DOI: 10.1002/0471143030.cb0322s30.
Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, Chen D, Gu J, He X, Huang S. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25(8):981-984.
Taylor DD, Gercel-Taylor C. The origin, function, and diagnostic potential of RNA within extracellular vesicles present in human biological fluids. Front Genet. 2013 Jul 30;4:142. doi: 10.3389/fgene.2013.00142.

" ["~DETAIL_TEXT"]=> string(22726) "

Introduction

Materials and methods

Cultural methods

The mesenchymal stromal cells (MSCs) were isolated from the bone marrow of healthy donors according to a standard protocol in a Ficoll density gradient.

Enrichment and isolation of the K562-derived exosomes

Analysis of the particles obtained

Morphological features of the particles were assessed by transmission electron microscopy with negative contrasting (JEM-100S, Jeol, Japan).

Co-cultures of MSCs and K562, contamination control

MSC transfection with K562-derived Exosomes

Analysis of the BCR-ABL expression levels using real-time quantitative PCR (RT-PCR) and agarose gel electrophoresis

Separation of the BCR-ABL and ABL1 fragments obtained by amplifying cDNA samples with the same primers was performed by horizontal electrophoresis in 2% agarose gel stained with ethidium bromide.

Table 1. Nucleotide sequences of primers and Taqman probes used for quantitative assays of chimeric BCR-ABL p210 transcripts

Results

Analysis of selected particles (exosomes)

Figure 1. Size distribution of the K562-derived nanovesicles. The diameter for the largest number of particles is indicated

Figure 2. Zeta-potential of the isolated nanovesicles

Co-cultivation of MSCs and K562 cells potential contamination issues

Figure 4. Flow cytometric phenotype of the cells under study.

Figure 5. Confocal microscopy of MSC/K562 co-cultures.

Relative contents of BCR-ABL in K562 cells, exosomes, and transfected MSCs

Discussion

The development of new diagnostic strategies based on vesicular nanoparticle data could be a promising research project aimed at optimizing a number of clinical laboratory diagnostic approaches.

Conclusions

Conflicts of interests

No potential conflicts of interests are reported.

References

Shah R, Patel T, Freedman JE. Circulating extracellular vesicles in human disease. New Engl J Med. 2018; 379(10): 958-966.
Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nature Rev Immunol. 2002; 2(8): 569-579.
Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, Ratajczak MZ. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006; 20(5): 847-856.
Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf E.A, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, Piwnica-Worms D, Kalluri R. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015; 523: 177-182.
Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037.
Melo JV. The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood. 1996;88:2375-2384.
Cortes J E, Talpaz M, Beran M, O’Brien SM, Rios MB, Stass S, Kantarjian HM. Philadelphia chromosome-negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Long-term follow-up results. Cancer. 1995; 75:464-470.
Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210 bcr/abl gene of the Philadelphia chromosome. Science. 1990;247: 824-827.
Pear WS, Miller JP, Xu L, Pui JC, Soffer B, Quackenbush RC, Pendergast AM, Bronson R, Aster JC, Scott ML, Baltimore D. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood. 1998;92: 3780-3792.
Raimondo S, Saieva L, Corrado C, Fontana S, Flugy A, Rizzo A, De Leo G, Alessandro R. Chronic myeloid leukemia-derived exosomes promote tumor growth through an autocrine mechanism. Cell Commun Signal. 2015;13:8. doi: 10.1186/s12964-015-0086-x.
Pane F, Interieri M, Quintarelli C, Izzo B, Muccioli GC, Salvatore F. Bcr-Abl genes and leukemic phenotype: from molecular mechanisms to clinical correlations. Oncogene 2002; 21: 8652-8667.
Moumen A, Dehbi H, Kottwitz D, El Amrani M, Bouchoutrouch N, El Hadi H, Quessar A, Benchekroun S, Nadifi S, Sefrioui H. Quantitative real-time polymerase chain reaction as an efficient molecular tool for detecting minimal residual disease in Moroccan chronic myeloid leukemia patients. Genet Mol Res 14.1 (2015): 1044-1055.
Thijsen, S FT, Schuurhuis G, van Oostveen J, Ossenkoppele G. Chronic myeloid leukemia from basics to bedside. Leukemia. 1999; 13(11): 1646-1674.
Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Current Protoc Cell Biol. 2006. Chapter 3. Unit 3.22. DOI: 10.1002/0471143030.cb0322s30.
Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, Chen D, Gu J, He X, Huang S. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25(8):981-984.
Taylor DD, Gercel-Taylor C. The origin, function, and diagnostic potential of RNA within extracellular vesicles present in human biological fluids. Front Genet. 2013 Jul 30;4:142. doi: 10.3389/fgene.2013.00142.

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В рамках данной работы мы попытались выяснить, могут ли экзосомы потенциально оказывать влияние на результаты определения минимальной остаточной болезни у пациентов с хроническим миелолейкозом. Учитывая тот факт, что основная роль в регуляции кроветворения принадлежит мезенхимным стромальным клеткам (МСК) костного мозга, формирующим нишу для гемопоэтических стволовых клеток (ГСК), мы предположили, что возможным источником выявляемого транскрипта могут выступать в том числе как персистирующие в костном мозге внеклеточные везикулы, так и их миграция в клетки микроокружения. 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Парфененкова1, Ильдар М. Бархатов2, Антон А. Кремлев2, Ольга A. Епифановская2, Андрей Н. Горшков3, Вера В. Высочинская3, Михаил П. Грудинин3, Антон А. Корнев4, Борис В. Афанасьев2 " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(428) "

Анна Н. Парфененкова¹, Ильдар М. Бархатов², Антон А. Кремлев², Ольга A. Епифановская², Андрей Н. Горшков³, Вера В. Высочинская³, Михаил П. Грудинин³, Антон А. Корнев⁴, Борис В. Афанасьев²

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¹ Санкт-Петербургский Государственный Химико-фармацевтический Университет, Санкт-Петербург, Россия
² НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
³ Научно-исследовательский институт гриппа имени А. А. Смородинцева, Санкт-Петербург, Россия
⁴ Санкт-Петербургский национальный исследовательский Университет РАН, Санкт-Петербург, Россия

Ключевой задачей молекулярно-генетических исследований в онкогематологии является выявление молекулярных маркеров, характерных для трансформированных клеток с целью диагностики заболеваний, своевременной оценки их прогреcсии, а также риска развития рецидива. Одним из перспективных объектов для изучения, предположительно содержащих такие маркеры, являются экзосомы – мембранные частицы, размеры которых находятся в интервале от 30 до 150 нм. Данные везикулы являются важными участниками межклеточных взаимодействий и способны к трансферу различных биополимеров, которые также могут опосредовать репрограммирование функций клеток-реципиентов, оказать влияние на развитие резистентности к терапии. На основе экзосом может быть оптимизирована такая диагностическая методика как жидкостная биопсия, являющаяся малоинвазивной, и потому также может быть использована в качестве частного мониторинга для предикции развития рецидива.

С целью изучения характеристик экзосом мы использовали метод последовательного ультрацентрифугирования с последующим анализом морфологических и функциональных характеристик экзосом. В рамках данной работы мы попытались выяснить, могут ли экзосомы потенциально оказывать влияние на результаты определения минимальной остаточной болезни у пациентов с хроническим миелолейкозом. Учитывая тот факт, что основная роль в регуляции кроветворения принадлежит мезенхимным стромальным клеткам (МСК) костного мозга, формирующим нишу для гемопоэтических стволовых клеток (ГСК), мы предположили, что возможным источником выявляемого транскрипта могут выступать в том числе как персистирующие в костном мозге внеклеточные везикулы, так и их миграция в клетки микроокружения. Результаты нашего исследования указывают на возможность горизонтального переноса гиперэкспрессирующихся молекулярных маркеров между опухолевыми и стромальными клетками in vitro.

Ключевые слова

Внеклеточные частицы, экзосомы, генная гиперэкспрессия, молекулярные маркеры, межклеточные взаимодействия, мезенхимные стволовые клетки, транспорт мРНК, BCR-ABL, хронический миелоидный лейкоз, минимальная остаточная болезнь, «жидкая» биопсия.

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Anna N. Parfenenkova¹, Ildar M. Barkhatov², Anton A. Kremlev², Olga A. Epifanovskaya², Andrey N. Gorshkov³, Vera V. Vysochinskaya³, Mikhail P. Grudinin³, Anton A. Kornev⁴, Boris V. Afanasyev²

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¹ St. Petersburg State University of Chemical Pharmaceutics, St. Petersburg, Russia
² Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
³ A. Smorodintsev Research Institute of Influenza, St. Petersburg, Russia
⁴ St. Petersburg National Research University, Russian Academy of Sciences, St. Petersburg, Russia

Detection of molecular markers characteristic to malignant cells is the key task of molecular genetic studies in oncohematology, aiming for timely diagnosis of the diseases and evaluation of their progression, like as relapse risks. Exosomes are among the most promising objects for such studies. They represent a fraction of extracellular membrane particles ranging from 30 to 150 nm in size, presumably containing such tumor markers. These vesicles are found in blood serum and other biological fluids, being important participants in cell-cell interactions capable of transferring various biopolymers, which can also mediate the reprogramming of the functions of the recipient cells and influence the development of resistance to therapy. On the basis of exosomes, one may optimize such a novel diagnostic approach as fluid biopsy which is minimally invasive, and, therefore, can also be used as a specific monitoring tool for prediction of tumor relapse development.

As a part of this work, we aimed for finding whether exosomes can potentially influence the results of minimal residual disease determination in the patients with chronic myeloid leukemia (CML).

In order to study the characteristics of exosomes, we used the method of sequential ultracentrifugation followed by analysis of the morphological and functional characteristics of exosomes. In addition, the possibility of horizontal transfer of the chimeric BCR-ABL transcript from leukemic to stromal cells through the exosomal fraction was analyzed.

The results of our in vitro study show evidence of horizontal transfer of oncogene mRNA from malignant to normal stromal cells. In conclusion, considering the fact that bone marrow mesenchymal stromal cells (MSCs) play the main role in hematopoiesis regulation, which forms a niche for hematopoietic stem cells (HSCs), we suggested that extracellular vesicles may act as a possible source of detectable oncogene transcripts and their migration into the cells of microenvironment.

Keywords

Extracellular vesicles, exosomes, gene overexpression, molecular markers, cell-cell interactions, mesenchymal stem cells, mRNA transport, BCR-ABL, chronic myeloid leukemia, minimal residual disease, liquid biopsy.

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Parfenenkova1, Ildar M. Barkhatov2, Anton A. Kremlev2, Olga A. Epifanovskaya2, Andrey N. Gorshkov3, Vera V. Vysochinskaya3, Mikhail P. Grudinin3, Anton A. Kornev4, Boris V. Afanasyev2" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(297) "

As a part of this work, we aimed for finding whether exosomes can potentially influence the results of minimal residual disease determination in the patients with chronic myeloid leukemia (CML).

Keywords

As a part of this work, we aimed for finding whether exosomes can potentially influence the results of minimal residual disease determination in the patients with chronic myeloid leukemia (CML).

Keywords

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Ключевые слова

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Introduction

More than 12.600 hematologists had the opportunity to exchange experience during 24^th European Hematology Association (EHA) Сongress that took place in Amsterdam, the Netherlands, from 13 to 16 June 2019. That was the largest EHA Congress to date, with a growth of more than 1000 participants from 2018.

After opening of the Congress by the EHA President Pieter Sonneveld, its participants could choose between more than 360 presentations and more than 1300 poster reports that covered almost the entire spectrum of clinical and experimental hematology.

The aim of current report is to highlight the most important data as viewed by 12 participants from Raisa Gorbacheva Memorial Institute for Pediatric Oncology, Hematology and Transplantation (St. Petersburg), each representing special area of hematology and transplantation.

In total, almost 50 poster and 2 oral reports were presented by colleagues from Russian centers from St. Petersburg, Moscow, Kirov, Novosibirsk in various areas of hematology, including acute leukemia, lymphoma, myeloma and other monoclonal gammopathies, chronic myeloid leukemia, myelodysplastic syndrome and others myeloproliferative diseases, chronic lymphocytic leukemia and other non-associated malignant diseases. Among the oral reports the first was presented by our colleagues from the National Research Center for Hematology on the topic of chronic myeloid leukemia in pregnant women. The second report was demonstrated by representatives of the Russian Research Institute of hematology and transfusiology of FMBA was devoted to predictors of response to therapy in patients with immune thrombocytopenia.

Hematopoietic stem cell transplantation

Several sections were devoted to hematopoietic stem cell transplantation: 4 clinical and 1 experimental session, including a presidential symposium, which included 2 reports related to this topic. Current focus is the optimization of GVHD prophylaxis for alternative donor transplantation with post-transplant cyclophosphamide, aspects of the conditioning regimens, as well as the role of intestinal microbiota in the outcomes of allo-HSCT.

Wang Y. et al. conducted a study to compare the GVHD risk in patients transplanted from haploidentical donor who received anti-thymocyte globulin (ATG) and low-dose post-transplant cyclophosphamide (PTCy) regimen to those who received ATG only. The results of this study showed that unmanipulated haploidentical transplantation with ATG-PTCy as a GVHD prevention strategy resulted into lower rates of both acute and chronic GVHD without influence on the graft-versus-leukemia (the combined treatment resulted in lower severe acute GVHD rate (Hazard Ratio 0.18; P=0.004), chronic GVHD (HR 0.39; P=0.010), and transplant-related mortality (HR 0.24; P=0.023) but slower myeloid and platelet recovery (HR 0.27 and 0.30; both P<0.001) [1].

There were other studies devoted to modifying the conditioning regimens and GVHD prevention in patients who received haploidentical transplantation. The work of El-Cheikh J. et al. demonstrated the advantage of adding ATG to thiotepa-busulfan-fludarabine with PTCy as conditioning in this patients group. The investigators have found that ATG as part of pre-transplant conditioning led to a significant reduction in acute GVHD and non-relapse mortality (NRM) at 24 months without significant effects on progression-free survival (PFS) or overall survival (OS) [2].

Also at the alternative donor transplantation session Li C. presented results of the study showed сonditioning with busulfan following cyclophosphamide improved results in alternative donor transplantation for patients with thalassemia major (9-year OS was 95.5% in matched sibling donor HSCT vs 92.7% in alternative donor HSCT). However, this approach is accompanied by a higher acute GVHD III-IV stage than sibling donor transplantation [3].

Prof. Arnon Nagler on behalf of EBMT Acute Leukemia Working Party reported the results of study: Post-transplant cyclophosphamide (PTCy) vs ATG for graft-versus-host disease (GvHD) prophylaxis in T-replete haploidentical transplantation for acute lymphoblastic leukemia. A total of 434 ALL patients were included; 336 received PTCy-based regimen and 98 received ATG with the median follow-up was 24 months. Similar outcomes were seen for engraftment (92.7% ATG vs 93.54% PTCy), as for 100 day incidence of acute GVHD both > Gr II and severe (Gr. II+, 32.7% vs 30.5%; Gr. III+, 11.6% vs 14.1%), and chronic GvHD (27.7% vs 31.7%). In both groups, infection accounted for 32% and 30% of deaths. Relapse incidence was lower in PTCy vs ATG: 2 year RI: 33.8% vs 43%; hazard ratio [HR] 0.61 [95% CI: 0.39-0.94], p=0.03), with a trend toward lower non-relapse mortality (NRM) as well (26.7% vs 32.9%; HR 0.68 [0.42-1.11], p=0.12). Both 2 year leukemia-free (LFS) and overall survival (OS) were higher for PTCy when compared with ATG (40.3% vs 24.1%; HR 0.67 [0.46-0.96], p=0.03, and 48.4% vs 27.4%; HR 0.60 [0.42-0.84], p=0.003, respectively). Active disease and lower Karnofsky performance status were associated with lower LFS, OS, while PB grafts were associated with higher incidence of both acute and chronic GvHD [4].

The influence of intestinal microbiota and the risk of GVHD as well as potential for its correction gathered increased attention in the field of HSCT research. Han et al. performed the analysis of intestinal microbiota diversity by the 16S rRNA gene sequencing from 141 patients undergoing allogeneic hematopoietic stem cell transplantation at pre-conditioning, day 0 and day 15 post-transplantation. The microbiota diversity was lower in the aGVHD group compared with non-aGVHD group at day 0 and day 15±1 (P=0.018 and 0.009, respectively). The skewed microbial diversity was associated with conditioning (P=0.017, day 0, and P=0.045, day 15) and usage of β-lactam antibiotics (P = 0.004, day 15) and correlated with peripheral blood Treg/Th17 ratio. These findings suggest that intestinal microbiota diversity influences aGVHD risk by inflammatory factors and the Treg/Th17 balance [5]. The results of correction of intestinal microbial diversity in 15 patients with steroid-refractory gut aGVHD treated by fecal transplantation was reported by Van Lier et al. With this approach, 11 patients achieved CR defined as GvHD resolution in all cases, without other interventions to alleviate symptoms [6].

These reports encourage further investigation of this therapy in large cohorts and questioning the optimal conditioning and supportive treatment during allo-HSCT.

Lymphoma

The most important reports of this year were dedicated to the treatment of the resistant/refractory (r/r) lymphomas using new targeted drugs, immunotherapy, chimeric antigen receptor T-cell therapy (CAR-T) therapy and combinations of these approaches.

A lot of the attention was devoted to the use of new drugs in the treatment of aggressive B-cell lymphomas. Particularly, the results of the work of Senn L. and his colleagues demonstrated a significant increase in the overall response rate (ORR) (18 vs 45%), including the complete response (CR) (15 vs 40%), PFS (2 vs 6.7 months) and OS (4, against 11.8%) using the combination of rituximab/bendamustine therapy with polatuzumab vedotin in patients with r/r follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) [7].

The results of targeted therapy and immunotherapy in r/r DLBCL with the akalabrutinib/pembrolizumab regimen were presented. The latter approach showed high frequency of severe adverse events, including treatment-related mortality (6 out of 61 patients died, 17 patients stopped therapy due to adverse events), and only modest efficacy (ORR- 23%, CR- 8%) [8]. Therefore, one can conclude that the optimal treatment of r/r DLBCL is yet to be defined in further studies.

There was also promising data on a first-in-class macrophage immune checkpoint inhibitor targeting the “do-not-eat-me” CD47 (5F9) signal in patients with r/r non-Hodgkin lymphoma (NHL) presented by Roschewski M. The ORR was demonstrated in 36%, and CR in 15% patients with DLBCL, and OR in 61% with CR in 24% patients with indolent lymphoma. These results are especially promising, with regard of high potential for combination of CD47 inhibitors with other types of immunotherapy and chemotherapy [9].

The evidence gathered after introduction of CAR-T cell therapy leaves no doubt in the efficiency of this treatment in some of the r/r B-cell malignancies. Current studies are focused on the optimization of this treatment using conditional targeted and immunotherapy. The results of introduction of BTK-inhibitor ibrutinib in combination with anti-CD19 CAR-T cells for r/r mantle cell lymphoma were presented as a poster by Ruella M. et al. This preclinical model demonstrated that ibrutinib could be combined with CAR-T against the B-cell specific CD19 antigen in a rational manner to augment the anti-tumor effect and enhanced survival [10].

There were no significant findings in the treatment of Hodgkin's lymphoma (HL). The main trend is the introduction of brentuximab vedotin (BV) and immune checkpoint inhibitors (ICI) into the earlier stages of the classical HL treatment. Importantly, the efficacy and safety of nivolumab (N) and BV combination were demonstrated for pediatric population. Leblanc T. et al. presented results of study of N-BV as second-line therapy in adult and pediatric patients with primary r/r classical HL (ORR was 82% with CR in 59% of cases; in pediatric group ORR was 81% with CR of 58%) [11].

Nevertheless, the effectiveness of the first-line therapy, radiation therapy and the early use of the response-adapted approach through the use of PET-CT, remains relevant. Fuchs M. in his report brings up the question on the role of PET after 2 cycles of ABVD in patients with early-stage favorable HL treated within the phase 3 GHSG HD16 study. This study included standard treatment arm with 2×ABVD following 20 Gy involved-field radiotherapy (FR), and an arm with IF after 2xABVD only after positive PET (Deauville 3-4). Author concluded that in PET-negative patients, omission of FR resulted in poorer tumor control compared to combined-modality treatment. Also it was reported that in early-stage favorable HL, a positive PET after 2×ABVD was associated with a larger tumor volume and represented a risk factor for PFS among patients treated with standard chemotherapy. PET-guided treatment intensification in this high-risk subgroup might help to reduce the incidence of relapse [12].

The results of 3-year follow-up of the ECHELON-1 study were presented. It showed more solid improvement of 3-year PFS in the arm of BV in combination with AVD protocol compared to ABVD regimen (83 vs 76%), proving the modest but significant improvement of treatment efficacy, with introduction of BV in the first line of cHL treatment, and may change the standard for the particular population of the patients [13].

Some works presented during poster session deserve special attention, particularly, the poster report by Italian researchers who presented their data on the use of ICI before haploidentical transplantation in patients with r/r Hodgkin's lymphoma. This study included a group of patients with (n=28) or without (n=26) ICI before transplantation. The results showed that ICI as a bridge to haploidentical stem cell transplantation significantly improved the PFS in r/r Hodgkin’s lymphoma, reduced the relapse rate, however at the cost of increased rate of acute GVHD [14].

The team of researchers from Raisa Gorbacheva Memorial Istitute presented their data during poster session. The study presented by Lepik K. et al. demonstrated the 2-year follow up of 101 r/r cHL patients treated with nivolumab. With 2-year OS of 96% and PFS 40.6% (median 17.9) the dramatic improvement of quality of life was demonstrated by this report [15]. The question of possibility of CPI retreatment in patients with r/r HL is currently remains relevant. The results of analysis presented by Fedorova L. et al. demonstrate that patients with relapse of the disease after nivolumab discontinuation sustained sensitivity to nivolumab and achieved a response during retreatment with nivolumab monotherapy or in combination with chemotherapy. These results create the prerequisites for further study of this issue, as well as determining the place of allogeneic transplantation in this cohort of patients [16].

Treatment of r/r T-cell lymphoma remains an unresolved medical problem. Lepik E. reported the analysis of R. Gorbacheva Institute experience in the treatment of r/r TCL. In 34 patients with r/r TCL the 2-years OS were 82%. Patients that had underwent salvage SCT showed significantly better disease status at the moment of last follow up: 12/16 (75%) were in CR, versus 3/18 (17%) in patients who did not undergo SCT. The results of this study had again underlined the key role of SCT in the treatment of r/r TCL [17].

Myeloma and other monoclonal gammopathies

A large number of both oral and poster presentations were devoted to multiple myeloma (MM). Dr. Irene Ghobrial in her educational report tried to determine the role of genetic abnormalities, while assessing the role of the microenvironment. Also Dr. Michele Cavo discussed how to implement biological parameters of the disease in the choice of treatment.

In the report of Tacchetti P. about the role of autologous stem cell transplantation (ASCT) in the era of novel therapies, this method is still proved to be a gold standard of frontline intensification therapy of MM, even in MRD-negative patients, with the benefits of double ASCT in patients with high-risk cytogenetic abnormalities.

The issue of improving the outcome in patients with inadequate pre-ASCT response remains unresolved. Preclinical and clinical evidence suggests that the immune checkpoint programmed death-1 (PD-1) receptor/PD-1 ligand axis plays an important role in suppressing immune surveillance against MM, but monotherapy with anti-PD-1 antibody was not effective in patients with MM. The results of phase 1-2, single-arm study of nivolumab with ASCT in MM patients (NCT03292263) were presented by Pirogova O. et al. [18]. Sixteen patients who had not achieved a complete response (CR), or a very good partial response (VGPR) pre-ASCT were enrolled in the study with the median age 55 years (range, 45-62). The median follow-up was 12 months (range, 7-19). The study showed the encouraging results: at day+100 after ASCT ORR was 56% with CR in 31% pts with relative favorable therapy safety profile [18].

Prof. Philippe Moreau reviewed possible changes in future ESMO guidelines in his presentation about new treatment strategies in MM. Particularly, the combination of daratumumab with standard frontline therapy non-transplant candidates. In the case of r/r MM after immunomodulatory drug based induction the use of PomVD/Kd-Isa or Kd-Dara regimen was proposed. Therapy with Pom-Dexa-Isa regimen was suggested instead of Pom-Dexa and daratumumab monotherapy in cases of second or subsequent relapse.

The question of the efficacy of CAR-T and bispecific T-cell engagers (BiTE) therapy is being actively investigated [19]. The study by Li C. et al. demonstrated an improved efficacy with dual-target CAR-T therapy targeting BCMA and CD38 for r/r MM with a high ORR, especially a higher rate and a longer duration of stringent complete response (sCR) (ORR was 83.3%, including 5 sCR, two very good partial response (PR) and three PR; 12-week PFS is 0.77) [20].

In conclusion, it is worth to note a growing interest in the issues of monoclonal gammopathy of renal significance and MGUS with clinical significance other than renal. Emphasis was placed on the need for clone-targeted therapy, including cytotoxic therapy, as well as anti-plasma cell therapy (rituximab-based therapy, bortezomib-based therapy including ASCT) [21].

The results of treatment performed in 151 patients with monoclonal gammopathy of clinical significance (MGCS) at Raisa Gorbacheva Memorial Institute were also presented by Kudyasheva et al. [22]. Kidney, heart, liver, nervous system and gastrointestinal tract were the most commonly involved organs here. The treatment included chemotherapy in 73% and ASCT in 12.5% patients. Renal involvement and depth of the response to therapy showed a predictive value for overall survival and renal survival of patients with MGCS. The renal response was assessed in 61 patients. The overall survival in patients with CR was 100%; VGPR, 88.4%; PR,95%; the patients that did not achieve renal response comprised 58.3% (p=0.0031). The 5-year renal PFS in the patients who achieved renal response was 70.9% [22].

Acute lymphoblastic leukemia

Development and use of targeted drugs (mono- and bispecific antibodies, CAR-T) resulted in advances in treatment of the patients with refractory ALL and has became the mainstream approach.

Analysis of 5-year follow-up outcomes in a multinational "BLAST" study of adults with B-cell precursor ALL in complete hematological remission with MRD has demonstrated median OS of 36.5 months after blinatumomab treatment. The median OS was not reached among patients with a complete MRD-negative remission after first cycle of blinatumomab treatment [23].

The data presented by Markova I. have also shown the results of blinatumomab-based therapy in both children and adults with r/r В-ALL. This retrospective analysis included 120 patients with high risk B-ALL (45% patients were children; 55%, adults). The frequency of responses to blinatumomab was higher in MRD+ patients in comparison to r/r ALL cases (85% vs 62 % p=0.007). The therapy also was generally well tolerated in children and adult patients with febrile fever being the most frequent adverse event (76%) [24].

Preliminary results of the GIMEMA LAL2116 D-ALBA trial were presented by Italian group (Chiaretti S. et al.). A dasatinib-blinatumomab combination for the frontline treatment of adult Ph+ ALL patients was the first chemo-free induction-consolidation protocol which demonstrated highly promising rates of molecular responses and survival (1-year OS and PFS values were 96.2% and 91.6%, respectively) [25].

Close attention is currently paid to the study of CAR-T therapy effects in the patients with refractory ALL. According to a retrospective analysis of ELIANA and ENSIGN studies by Grupp S. et al., Tisagenlecleucel appeared effective, with high rates of durable responses, prolonged survival, and a manageable safety profile in patients with high-risk cytogenetic abnormalities with historically poor prognosis (median OS was not reached, 12-year and 24-year survival probability was 74.9% and 66.6%, respectively vs 70.7% and 58.8% in patients without high-risk cytogenetic abnormalities) [26].

The results of phase IV study "CAMPUS-ALL", which evaluated the effectiveness of nelarabine salvage therapy as a bridge to allogeneic stem cells transplantation in patients with r/r T-acute lymphoblastic leukemia/lymphoma, were presented by Candoni A. This study demonstrated the ORR and CR rate of 50 and 36% respectively. In addition, 40% of patients who received nelarabine salvage therapy underwent allogeneic stem cell transplantation with an expected OS at 2 and 5 years of 46% and 38%, respectively. Taking into account the poor prognosis of this population, nelarabine can be considered an effective option for this patient’s cohort [27].

Myeloproliferative neoplasms and acute myeloid leukemia

The question of approach to the choice of treatment in patients with resistant myeloproliferative diseases remains unresolved. A separate section was devoted to high-risk myelodysplastic syndromes (MDS) resistant to hypomethylating agents (HMA). The main diagnostic task in these patients is to reveal specific mutations for targeted therapy.

For this group of patients, allogeneic transplantation remains the standard with the "7+3" regimen as a "bridge" therapy pre-transplant. In case of non-transplant candidates, it is necessary to include them into clinical trials (IDH2 inhibitors, venethoclax, immune checkpoint inhibitors).

Search for a new drugs in the treatment of patients with r/r MDS/acute myeloid leukemia (AML) remains quite relevant. One of studies included patients with r/r MDS/AML who were treated with a first-in-class macrophage immune checkpoint inhibitor targeting CD47 with or without azacitidine. Along with good tolerability of this combination, encouraging efficacy was observed (ORR 100% for MDS, 64% for AML) [28].

The updated results from the phase I study of safety and efficacy of AMV564, a CD33/CD3 T-cell engager in patients with r/r AML demonstrated acceptable safety profile and monotherapy activity: bone marrow blast reductions were observed in 17 (63%) of 27 efficacy-evaluable patients; at the doses of 100 mcg or higher, ORR were observed in 3 of 9 evaluable patients [29].

The results of the phase III randomized study "ASTRAL" were also presented, which did not show statistically significant difference between guadecitabine and investigators choice therapy in the primary efficacy endpoints of CR and OS in treatment-naive AML patients who were not eligible for intensive chemotherapy [30].

New agents appear in the treatment of myelofibrosis resistant to ruxolitinib (e.g. sotatercept). A multi-center phase II study of luspatercept in myelofibrosis was initiated (NCT03194542). This agent has already shown its efficacy in the treatment of anemia and low risk MDA in the previous "MEDALIST" trial [31].

The search for epigenetic mutations in all patients with CML also becomes the most important issue. Based on the data of NGS analysis in this group of patients, it is possible to use a combination therapy with tyrosine kinase inhibitors and new targeted drugs as the first-line therapy [32].

Approaches to the treatment of patients with unfavorable mutations in CML were actively discussed. A team from R.Gorbacheva Institute presented the data on retrospective analysis of 79 BCR-ABLT^315I-positive CML patients. It was shown that only CML phase at the time of mutation detection could significantly affect survival in the whole group (all patients in blast crisis died within first year after T315I identification, median survival time was 1.3 month). Allo-HSCT is an effective method of treatment for this group of patients in case of good selection, with regard to transplant risk, especially for patients in chronic phase (CP) ≥2 (5-year OS after allo-HSCT was 37% with median survival time of 5 month; seven patients were alive for more than 2 years after allo-HSCT; two, for >6 years). At the same time, administration of pharmacotherapy in the first CP is an effective method of treatment, which allows to control the disease for a long time [33].

The highly debatable topic reported by Chelysheva E. et al. was the issue of pregnancy in female patients with CML. The analysis of 305 cases of the European LeukemiaNet Registry described CML patients in terms of pregnancy/conceptions management and outcome, as well as demographics, clinical features of CML, and characteristics of children. The results of this study demonstrated that the most pregnancies in females with CML resulted in normal childbirth, with no increase of birth abnormalities, in spite of TKI use at conception, even if this treatment was mostly stopped at the implant stage. The study has also shown the opportunity for different therapies during pregnancy, if required. These promising data will allow to create a unified approach to the treatment of this cohort in the future [34].

Infectious diseases in hematology patients

The issue of prevention, diagnosis and treatment of infectious complications in hematologic patients remains at central problem. A prospective multicenter study of the SEIFEM group was presented. It demonstrated improved clinical outcome in hematologic malignancies patients with lung infiltrates if BAL-driven antimicrobial treatment was implemented (120-d OS was 78% vs 64%; P=0.046, and 120-d attributable mortality comprised 11% vs 25%; P=0.018) [35].

The issue of fluoroquinolone prophylaxis during neutropenia was voiced again. According to the study of García A. B. et al. the withdrawal of quinolone prophylaxis in prolonged neutropenia associated with hematological malignancies treatment is a safe strategy with no impact on mortality [36].

The issue of infection control in patients after CAR-T therapy remains largely unstudied. French colleagues in their work call for further research of timely and accurate diagnosis of infectious complications in this group of patients, as well as the development of an algorithm for differential diagnosis between infection fever and cytokine release syndrome [37].

Infectious complications remain an actuall problem in immunocompromised patients including patients using new agents in therapy. Participants from Raisa Gorbacheva Memorial Institute presented a series of reports regarding this issue. Despite many reports about benefit of anti PD-1 antibody therapy for the treatment of Hodgkin’s lymphoma (HL), risk of infection among patients receiving nivolumab is still unknown. In this respect, 112 patients with r/r HL that were observed and treated with nivolumab (3 mg/kg) in at the R. Gorbacheva Institute between 2016 and 2018. Incidence of infectious complications in r/r HL treated with nivolumab was 10%, with onset at the median time of 98 days. Etiology of infectious complications presented by bacterial infections was 37.5%, invasive fungal diseases, 25%, and viruses, 37.5%. Primary chemoresistance was a risk factor for infection complications. Where with infections could be managed successfully and carry favorable prognosis [38].

Despite significant success of novel agents, HSCT still takes a special place in treatment of Hodgkin’s lymphoma (HL) patients. A prospective observational study by M. Popova et al. included 86 patients with classical r/r HL who underwent allo-HSCT from 2002 to 2018. reported the analysis of IFD in this cohort of patients. Incidence of pre-existing IFD in children and adults with r/r Hodgkin’s lymphoma allo-HSCT recipients was 12.8%. Incidence of IFD after allo-HSCT in naïve patients with Hodgkin’s lymphoma was 17.6%. The major etiology agent both before and after allo-HSCT were Aspergillus spp. Development of IFD after allo-HSCT was not associated with decrease of the 2-year OS rate (69.2% vs 74%, p=0.77) [39].

However, mold infections are the most frequent pathogen, but yeast infections are associated with high risk of mortality. The aim of our study was to estimate epidemiology of invasive yeast infections in large HSCT recipients’ cohort over the 10-year period of transplant activity in CIC725. Incidence of invasive yeast infections for the 10 years of observation was 1.2%: 1.4% in allo-HSCT recipients; 0.9%, in auto-HSCT setting. Candida spp. was the main etiological pathogen (87%). Overall survival at 30 days from the diagnosis of invasive yeast infections was 60%. Central venous catheter removal was the only factor which significantly improved OS at 30 days after invasive yeast infection diagnosis (91% vs 17%, p=0.001) [40].

Together with colleagues from I. I. Mechnikov North-Western State Medical University, we have analyzed clinical data from 780 patients with invasive aspergillosis [41]. Aspergillus spp. were isolated from 227 patients. The patients with "rare" pathogens accounted for 8% of patients with isolated Aspergillus spp. cultures. IA caused by "rare" pathogens, more often occured in children (22%). The features of IA caused by "rare" pathogens are as follows: long-term lymphocytopenia (67%, median, 21 days), combination of two or more pathogens (44%), high relapse rate (33%). Survival of patients with "rare" pathogens did not differ from the total cohort of patients (82%) [41].

Conclusion

In the era of new drugs, as well as the development of immune and cellular therapy, the main task is to find the optimal approach to patients with r/r hematological malignancy, as well as in patients with a high risk of an aggressive course of the disease.

Despite the emergence of a huge variety of new drugs and technologies, for most diseases, this question remains far from resolution. At the same time, hematopoietic stem cell transplantation retains its position as the curative method of treatment for a wide range of patients.

Conflict of interest

The authors report no conflicts of interest.

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Sallman D, Donnellan W, Asch A, Lee D, Malki MA, Pollyea D, Kambhampati S, Komrokji R, Elk JV, Lin M, Agoram B, Chen J, Volkmer J, Takimoto C, Chao M, Vyas P. The first-in-class anti-CD47 antibody HU5F9-G4 is active and well tolerated alone or in combination with azacitidine in AML and MDS patients: initial Phase 1B results. EHA Library. 2019; 267461; S878.
Westervelt P, Roboz GJ, Cortes JE, Altman JK, Oehler VG, Long M, Kantarjian HM, Lee S, Han TH, Guenot J, Feldman EJ, DiPersio LF. Safety and clinical activity of AMV564, a CD33/CD3 T-cell engager, in patients with relapsed/refractory acute myeloid leukemia (AML): Updated results from the Phase 1 first-in-human trial. EHA Library. 2019; 267460; S877.
Fenaux P, Gobbi M, Kropf PL, Mayer J, Roboz GJ, Döhner H, Krauter J, Döhner K, Robak T, Kantarjian H, Novak J, Jedrzejczak W.W., Thomas X, Ojeda-Uribe M, Miyazaki Y, Min YH, Yeh S-P, Brandwein J, Gercheva-Kyuchukova L, Demeter J, Griffiths E, Yee K, Azab M, IssaJ-P. Results of ASTRAL-1 study, a Phase 3 randomized trial of guadecitabine (G) vs treatment choice (TC) in treatment naïve acute myeloid leukemia (TN-AML) not eligible for intensive chemotherapy (IC). EHA Library. 2019; 267462; S879.
Fenaux P, Platzbecker U, Muft GJ, Garcia-Manero G, Buckstein R, Santini V, Díez-Campelo M, Finelli C, Cazzola M, Ilhan O, Sekeres MA, Falantes JF, Arrizabalaga B, Salvi F, Giai V, Vyas P, Bowen D, SelleslagD, DeZern AE, Jurcic JG, Germing U, Götze KS, Quesnel B, Beyne-Rauzy O, Cluzeau T, Voso MT, Mazure D, Vellenga E, Greenberg PL, Hellström-Lindberg E, Zeidan AM, Laadem A, Benzohra A, Zhang J, Rampersad A, Linde PG, Sherman ML, Komrokji RS, List AF. The MEDALIST trial: results of a Phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Blood 2018; 132:1. DOI: 10.1182/blood-2018-99-110805.
Branford S, Kim DDH, Apperley JF, Eide CA, Mustjoki S, Ong ST, Nteliopoulos G, Ernst T, Chuah C, Gambacorti-Passerini C, Mauro MJ, Druker BJ, Kim DW, Mahon FX, Cortes J, Radich JP, Hochhaus A, Hughes TP. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia. 2019. DOI: 10.1038/s41375-019-0512-y.
Vlasova J, Morozova E, Barabanshikova M, Gindina T, Alyanskiy A, Darskaya E, Afanasyev B. Characteristics and outcomes of the treatment patients with T315I mutation CML. EHA Library. 2019; 266810; PS1193.
Chelysheva E, Turkina A, Rea D, Rousselot P, Nicolini FE, Trawinska MM, Romano A, Malagola M, Cangemi D, Dyagil I, Kotlyarchuk K, Kazakbaeva K, Saliev S, Pavlovsky C, Moiraghi B, Kim D, Klamova H, Yassin M, Meliktesyan K, Mikhailov G, Ganeva P, Osorio S, Mauro M, Polushkina E, Shmakov R, Chabaeva J, Kulikov S, Abruzzese E. Pregnancy outcome in female patients with chronic myeloid leukemia worldwide: analysis of 305 cases of the European Leukemia NET Registry. EHA Library. 2019; 267464; S881.
Marchesi F, Cattaneo C, Criscuolo M, Delia M, Dargenio M, Principe MID, Spadea A, Fracchiolla NS, Melillo L, Perruccio K, Alati C, Russo D, Garzia M, Zappasodi P, Cefalo MG, Armiento D, Cesaro S, Decembrino N, Mengarelli A, Busca A, Pagano L. A BAL-driven antimicrobial treatment improves clinical outcome in hematologic malignancies patients with lung infiltrates detection: a prospective multicenter study of the SEIFEM group. EHA Library. 2019; 267391; S1637.
García AB, Calle GMDl, Sánchez CG, Gil LL, Hernández ML, López JM. Interrupting quinolone prophylaxis in hematologic patients with prolonged neutropenia: an observational study. EHA Library. 2019; 267392; S1638.
Blasi RD, Aguinaga L, Paillassa J, Darmon M, Bernard S, Azoulay E, Lafaurie M, Thieblemont C. Infectious complications in patients receiving anti-CD19 chimeric antigen receptors T-cells (CAR-T) for diffuse large B cell lymphoma (DLBCL). A monocentric preliminary experience. EHA Library. 2019; 267395; S1641.
Rogacheva Y, Popova M, Lepik K, Kondakova E, Zalyalov Y, Stelmakh L, Volkova A, Nikolaev I, Goloshchapov O, Barhatov I, Bondarenko S, Moiseev I, Baykov V, Mikhailova N, Klimko N, Afanasyev B. Infectious complications of nivolumab therapy in relapsed/refractory Hodgkin’s lymphoma. EHA Library. 2019; 266899; PS1282.
Popova M, Rogacheva Y, Volkova A, Markova I, Frolova A, Shvetcov A, Nikolaev I, Goloshchapov O, Ignatieva S, Bogomolova T, Kozlov A, Lepik K, Zalyalov Y , Stelmakh L, Kondakova E, Gevorgian A, Beynarovich A, Borzenkova E, Darskaya E, Vladovskaya M, Bondarenko S, Moiseev I, Baykov V, Mikhailova N, Zubarovskaya L, Klimko N, Afanasyev B. Invasive fungal diseases in allogeneic hematopoietic stem cell transplantation recipients with Hodgkin’s lymphoma. EHA Library. 2019; 266902; PS1285.
Popova M, Rogacheva Y, Volkova A, Markova I, Frolova A, Shvetcov A, Nikolaev I, Goloshchapov O, Bykova T, Paina O, Gevorgian A, Darskaya E, Vladovskaya M, Bondarenko S, Moiseev I, Baykov V, Zubarovskaya L, Klimko N, Afanasyev B. Invasive yeast infections in hematological patients after hematopoietic stem cell transplantation. EHA Library. 2019; 266903; PS1286.
Shadrivova O, Ryabinin I, Desyatik E, Borzova Y, Volkova A, Popova M, Bogomolova T, Zubarovskaya L, Afanasyev B, Vasilyeva N, Klimko N. Invasive aspergillosis caused by "rare" pathogens: clinical registry data analysis. EHA Library. 2019; 266892; PS1275.

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Introduction

Hematopoietic stem cell transplantation

These reports encourage further investigation of this therapy in large cohorts and questioning the optimal conditioning and supportive treatment during allo-HSCT.

Lymphoma

Myeloma and other monoclonal gammopathies

Acute lymphoblastic leukemia

Development and use of targeted drugs (mono- and bispecific antibodies, CAR-T) resulted in advances in treatment of the patients with refractory ALL and has became the mainstream approach.

Myeloproliferative neoplasms and acute myeloid leukemia

Infectious diseases in hematology patients

Conclusion

Conflict of interest

The authors report no conflicts of interest.

References

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Candoni A, Lazzarotto D, Curti A, Ferrara F, Lussana F, Papayannidis C, Principe MID, Bonifacio M, Mosna F, Delia M, Minetto P, Gottardi M, Fracchiolla N, Mancini V, Forghieri F, Zappasoldi P, Cerrano M, Vitale A, Audisio E, Trappolini S, Romani C, Defina M, Imbergamo S, Ciccone N, Santoro L, Cambò B, Iaccarino S, Dargenio M, Aprile L, Pizzolo G, Foà R. Nelarabine as salvage therapy and bridge to allogeneic stem cells transplantation in 118 adult patients with relapsed/refractory T-acute lymphoblastic leukemia/lymphoma. A CAMPUS-ALL, Phase 4, study. EHA Library. 2019; 267374; S1620.
Sallman D, Donnellan W, Asch A, Lee D, Malki MA, Pollyea D, Kambhampati S, Komrokji R, Elk JV, Lin M, Agoram B, Chen J, Volkmer J, Takimoto C, Chao M, Vyas P. The first-in-class anti-CD47 antibody HU5F9-G4 is active and well tolerated alone or in combination with azacitidine in AML and MDS patients: initial Phase 1B results. EHA Library. 2019; 267461; S878.
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Branford S, Kim DDH, Apperley JF, Eide CA, Mustjoki S, Ong ST, Nteliopoulos G, Ernst T, Chuah C, Gambacorti-Passerini C, Mauro MJ, Druker BJ, Kim DW, Mahon FX, Cortes J, Radich JP, Hochhaus A, Hughes TP. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia. 2019. DOI: 10.1038/s41375-019-0512-y.
Vlasova J, Morozova E, Barabanshikova M, Gindina T, Alyanskiy A, Darskaya E, Afanasyev B. Characteristics and outcomes of the treatment patients with T315I mutation CML. EHA Library. 2019; 266810; PS1193.
Chelysheva E, Turkina A, Rea D, Rousselot P, Nicolini FE, Trawinska MM, Romano A, Malagola M, Cangemi D, Dyagil I, Kotlyarchuk K, Kazakbaeva K, Saliev S, Pavlovsky C, Moiraghi B, Kim D, Klamova H, Yassin M, Meliktesyan K, Mikhailov G, Ganeva P, Osorio S, Mauro M, Polushkina E, Shmakov R, Chabaeva J, Kulikov S, Abruzzese E. Pregnancy outcome in female patients with chronic myeloid leukemia worldwide: analysis of 305 cases of the European Leukemia NET Registry. EHA Library. 2019; 267464; S881.
Marchesi F, Cattaneo C, Criscuolo M, Delia M, Dargenio M, Principe MID, Spadea A, Fracchiolla NS, Melillo L, Perruccio K, Alati C, Russo D, Garzia M, Zappasodi P, Cefalo MG, Armiento D, Cesaro S, Decembrino N, Mengarelli A, Busca A, Pagano L. A BAL-driven antimicrobial treatment improves clinical outcome in hematologic malignancies patients with lung infiltrates detection: a prospective multicenter study of the SEIFEM group. EHA Library. 2019; 267391; S1637.
García AB, Calle GMDl, Sánchez CG, Gil LL, Hernández ML, López JM. Interrupting quinolone prophylaxis in hematologic patients with prolonged neutropenia: an observational study. EHA Library. 2019; 267392; S1638.
Blasi RD, Aguinaga L, Paillassa J, Darmon M, Bernard S, Azoulay E, Lafaurie M, Thieblemont C. Infectious complications in patients receiving anti-CD19 chimeric antigen receptors T-cells (CAR-T) for diffuse large B cell lymphoma (DLBCL). A monocentric preliminary experience. EHA Library. 2019; 267395; S1641.
Rogacheva Y, Popova M, Lepik K, Kondakova E, Zalyalov Y, Stelmakh L, Volkova A, Nikolaev I, Goloshchapov O, Barhatov I, Bondarenko S, Moiseev I, Baykov V, Mikhailova N, Klimko N, Afanasyev B. Infectious complications of nivolumab therapy in relapsed/refractory Hodgkin’s lymphoma. EHA Library. 2019; 266899; PS1282.
Popova M, Rogacheva Y, Volkova A, Markova I, Frolova A, Shvetcov A, Nikolaev I, Goloshchapov O, Ignatieva S, Bogomolova T, Kozlov A, Lepik K, Zalyalov Y , Stelmakh L, Kondakova E, Gevorgian A, Beynarovich A, Borzenkova E, Darskaya E, Vladovskaya M, Bondarenko S, Moiseev I, Baykov V, Mikhailova N, Zubarovskaya L, Klimko N, Afanasyev B. Invasive fungal diseases in allogeneic hematopoietic stem cell transplantation recipients with Hodgkin’s lymphoma. EHA Library. 2019; 266902; PS1285.
Popova M, Rogacheva Y, Volkova A, Markova I, Frolova A, Shvetcov A, Nikolaev I, Goloshchapov O, Bykova T, Paina O, Gevorgian A, Darskaya E, Vladovskaya M, Bondarenko S, Moiseev I, Baykov V, Zubarovskaya L, Klimko N, Afanasyev B. Invasive yeast infections in hematological patients after hematopoietic stem cell transplantation. EHA Library. 2019; 266903; PS1286.
Shadrivova O, Ryabinin I, Desyatik E, Borzova Y, Volkova A, Popova M, Bogomolova T, Zubarovskaya L, Afanasyev B, Vasilyeva N, Klimko N. Invasive aspergillosis caused by "rare" pathogens: clinical registry data analysis. EHA Library. 2019; 266892; PS1275.

Людмила В. Федорова, Кирилл В. Лепик, Марина О. Попова, Юлия Ю. Власова, Ольга В. Кудяшева, Юлия А. Рогачева, Елена Е. Лепик, Валентина В. Порунова, Анна А. Осипова, Юрий Р. Залялов, Елена И. Дарская, Инна В. Маркова

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова, Санкт-Петербург, Россия

С 13 по 16 июля 2019 года в Амстердаме, Нидерланды, состоялся 24-й конгресс Европейской Ассоциации Гематологов (EHA). Объединив более 12 тысяч специалистов, он стал самым крупным конгрессом за всю историю EHA. На площадках конгресса были представлены более 360 устных и 1300 постерных докладов, которые затронули практически весь спектр вопросов клинической и экспериментальной гематологии.

Основной задачей данного обзора стало освещение наиболее актуальных вопросов, затронутых на конгрессе, в таких областях, как трансплантация гемопоэтических стволовых клеток (ТГСК), лимфомы, острые лейкозы, множественная миелома и другие плазмоклеточные дискразии, миелопролиферативные заболевания, а также инфекционные осложнения у гематологических пациентов.

В обзоре были отражены данные порядка 40 работ, которые, по мнению авторов данного сообщения, имеют наибольшую практическую и научную значимость для ТГСК. Также были выделены основные тенденции различных гематологических направлений. С данными других интересных исследований и докладов, представленных на конгрессе, можно ознакомиться, используя материалы онлайн-библиотеки EHA.

Ключевые слова

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Liudmila V. Fedorova, Kirill V. Lepik, Marina O. Popova, Yulia Yu. Vlasova, Olga V. Kudyasheva, Yulia A. Rogacheva, Elena E. Lepik, Valentina V. Porunova, Anna A. Osipova, Yury R. Zalyalov, Elena I. Darskaya, Inna V. Markova

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia

24^th Congress of European Hematology Association was held from 13th to 16th July in Amsterdam, Netherlands. Over 12000 specialists took part in the meeting and more than 360 oral and 1300 poster presentations were made, covering most of hematology fields. The main purpose of this article was to review the most important and relevant topics discussed during congress in such areas as hematopoietic stem cell transplantation, lymphomas, acute leukemia, multiple myeloma and other plasma cell disorders, myeloproliferative neoplasms and infectious complications in hematological patients.

In this review, we briefly describe results of works which, in view of the authors, are of most clinical and scientific significance for hematopoietic stem cell transplantation. Moreover, the emerging topics and trends in different fields of hematology were discussed. Other interesting studies and presentations can be accessed through the EHA online-library.

Keywords

EHA congress, hematopoietic stem cell transplantation, lymphoma, acute leukemia, multiple myeloma, myeloproliferative neoplasms, infectious complications.

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Keywords

EHA congress, hematopoietic stem cell transplantation, lymphoma, acute leukemia, multiple myeloma, myeloproliferative neoplasms, infectious complications.

Keywords

EHA congress, hematopoietic stem cell transplantation, lymphoma, acute leukemia, multiple myeloma, myeloproliferative neoplasms, infectious complications.

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia

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Ключевые слова

Конгресс ЕНА, аллогенная трансплантация гемопоэтических стволовых клеток, лимфома, множественная миелома, миелопролиферативные заболевания, острые лейкозы, инфекционные осложнения." } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "23727" ["VALUE"]=> array(2) { ["TEXT"]=> string(381) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(369) "

" } } } }

Том 8, Номер 2
28.06.2019

Главный редактор
Афанасьев Б. В. (Санкт-Петербург, Россия)

Со-редакторы
Вагемакер Г. (Роттердам, Нидерланды)
Цандер А. Р. (Гамбург, Германия)

Заместитель главного редактора
Фезе Б. (Гамбург, Германия)

Ответственный редактор
Чухловин А. Б. (Санкт-Петербург, Россия)

Редакционная коллегия
Алейникова О. В. (Минск, Республика Беларусь)
Борсет М. (Трондхейм, Норвегия)
Галибин О. В. (Санкт-Петербург, Россия)
Зубаровская Л. С. (Санкт-Петербург, Россия)
Климко Н. Н. (Санкт-Петербург, Россия)
Кольб Х. (Мюнхен, Германия)
Крегер Н. (Гамбург, Германия)
Кулагин А. Д. (Санкт-Петербург, Россия)
Ланге К. (Гамбург, Германия)
Мамаев Н. Н. (Санкт-Петербург, Россия)
Михайлова Н. Б. (Санкт-Петербург, Россия)
Моисеев И. С. (Санкт-Петербург, Россия)
Наглер А. (Тель-Авив, Израиль)
Немков А. С. (Санкт-Петербург, Россия)
Парамонов И. В. (Киров, Россия)
Румянцев А. Г. (Москва, Россия)
Савченко В. Г. (Москва, Россия)
Смирнов А. В. (Санкт-Петербург, Россия)
Усс А. Л. (Минск, Республика Беларусь)
Фиббе В. (Лейден, Нидерланды)
Хельтцер Д. (Франкфурт-на-Майне, Германия)
Чечеткин А. В. (Санкт-Петербург, Россия)

Обзор выпуска

Данный номер СТТ начинается обзорной статьей Д. Елезова и И. Кудрявцева, которая касается современных знаний об экспрессии и регуляции рецептора PD-1 и его лиганда PLD-1, а также их значения в диагностике и прогнозе лечения раковых заболеваний посредством ингибиторов иммунных контрольных точек.

Оригинальное исследование М. О. Поповой и соавт. описывает репрезентативную выборку пациентов, которым выполнялась аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК). Авторы диагностировали грибковые инфекции до трансплантации и обнаружили, что предшествующие грибковые заболевания не оказывают существенного влияния на частоту посттрансплантационных осложнений и общей выживаемости.

Клиническое исследование д-ра Т. Рудаковой и соавт. содержит оригинальные данные об их опыте применения агонистов рецепторов тромбопоэтина (ТПО) у пациентов с низкой функцией гемопоэтического трансплантата после ТГСК. Авторы наблюдали хороший клинический ответ у большой части этой группы, а также отмечают безопасность длительного введения агонистов ТПО.

Междисциплинарное исследование E. Кулагина и соавт. касалось предшествующей ТГСК респираторной патологии в качестве возможного фактора негативных эффектов в плане посттрансплантационных осложнений и выживаемости пациентов после ТГСК. Коморбидность со стороны легочной системы у детей и взрослых, выявленная до ТГСК, оказалась достоверным и независимым фактором риска различных осложнений после трансплантации.

Обстоятельная статья проф. Н. Н. Мамаева и соавт. предоставляет дополнительные аргументы в плане диагностической ценности гиперэкспрессии гена BAALC при острой миелобластном лейкозе. Одновременная гиперэкспрессия генов BAALC и WT1 может быть использована для регулярного посттрансплантационного мониторинга рецидивов при данном заболевании.

Пилотное исследование результатов инфузий мезенхимных стволовых клеток (МСК) для лечения язвенного колита, представленное проф. Федотовской и соавт., сосредоточено на морфологических коррелятах повреждения кишечника через несколько месяцев после терапии, как стандартной, так и усиленной введением МСК. Данная статья может вызвать дискуссии, ввиду малого числа клинических случаев и использованных морфологических критериев.

Два интересных клинических случая публикуются Смирновой и соавт. Они показывают выраженный клинический эффект от лечения Инотузумабом после неудачной терапии Блинотумомабом при экстрамедуллярной рефрактерной форме острого В-клеточного лейкоза, что может указывать на различия целевых эффектов при использовании этих антител.

Экспериментальный раздел открывается статьей Орловой и соавт., касающейся применения поли-L, L-лактидных матриц, которые при их имплантации с аллогенными МСК способствуют усилению регенерации дефектов такней мочевого пузыря в опытах на животных. Статья Парфененковой и соавт. рассматривает функции экзосом – наночастиц, производные от опухолевых клеток, которые, по данным экспериментов in vitro, могут переносить онкогенные РНК-транскрипты в культивированные нормальные мезенхимные клетки, которые являются компонентом гемопоэтического микроокружения у человека.

Выпуск завершается обзором ряда интересных исследований, о которых сообщалось на XXIV конгрессе Европейской ассоциации гематологов. Статья описывает новые результаты и разработки в области трансплантации гемопоэтических стволовых клеток, применения новых таргетных препаратов, в т.ч. – ингибиторов иммунных контрольных точек, при лечении лимфом, CAR-T-клеточной терапии при остром лимфобластном лейкозе, новых подходов к лечению миелоидных неоплазий, а также возникающих инфекционных осложнений и антибактериального лечения при этих состояниях.