ISSN 1866-8836
Клеточная терапия и трансплантация
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Introduction

It is widely believed that the recovery of bone marrow function after haematopoietic cell transplantation arises from pluripotent haematopoietic stem cells (HSCs). It is also generally assumed that the contents of CD34-positive cells in a graft are an accurate proxy for numbers of HSCs, that the dose of CD34-positive cells should be quantified by body weight and that there is a threshold dose of CD34-positive cells required for successful bone marrow recovery post-transplant. We argue that several or all of these beliefs are wrong. We consider biological plausibility and clinical data from persons receiving umbilical cord blood cells transplants and advanced statistical analyses of this dataset. Our conclusions have important implications for transplant practices.

Biology

HSCs and CD34-positive cells are not the same

There is no accurate way to identify human haematopoietic stem cells (HSCs) [1-3]. Although many people assume human HSCs to be CD34-positive but this is conjecture lacking a human HSC assay [4-6]. Quiescent HSCs in mice are CD34-negative acquiring CD34 expression only after they begin dividing and, thus, are no longer stem cells [7]. Some data suggest an ever-changing phenotype of human HSCs [1, 2].

Most CD34-positive cells in blood, bone marrow and umbilical cord blood cell grafts in humans are not HSCs [4]. Data from transplanting human haematopoietic cells into immune-deficient mice suggest that 10E-6 to 10E-7 CD34-positive mononuclear cells might be HSCs, a frequency which could be relatively higher in human umbilical cord blood grafts and lower in bone marrow grafts, and still lower in quiescent and mobilised blood cell grafts [8].

Since almost all CD34-positive cells in a graft are not HSCs the estimated contents of HSCs based on numbers of CD34-positive cells must be imprecise. If we assume that the ratio of HSCs to CD34-postive cells is 1 to 5000 in umbilical cord blood, a graft containing 40×10E+5 CD34-positive cells could have variation of +10 percent in numbers of HSCs due to Poisson noise.

Posttransplant bone marrow recovery is not only from HSCs

Another complexity is that we lack knowledge of which haematopoietic cell(s) underly posttransplant recovery of bone marrow function. Data in mice indicate that a number of different cells in a graft including many which are not HSCs contribute to short- and long-term bone marrow recovery [9-11]. Data obtained in humans are largely consistent with animal data [12-14]. Even within the phenotypically most primitive HSCs, the pool of individual stem cells can have very different self-renewal potentials and different contribution to bone marrow recovery [15-21]. Namely, not all HSCs contribute equally to sustained multi-lineage haematopoiesis and most of them show biased differentiation towards specific haematopoietic lineages.

Clinical considerations

We are left with an insoluble challenge. First, we don’t know which cells in a graft are responsible for short- and long-term posttransplant bone marrow recovery. This is especially true after autotransplants and after allotransplants with less intensive pre-transplant conditioning. Second, without this knowledge, we obviously lack an accurate assay for whether a graft will restore short- and long-term post-transplant bone marrow function.

Clinicians need to address 2 questions: (1) how to derive a measure for haematopoietic potential of a graft using the number of CD34-positive cells despite the caveats we discuss above; and (2) whether there is a threshold dose needed for successful posttransplant bone marrow recovery.

Although numbers of CD34-positive cells in a graft and ability to restore posttransplant bone marrow function are dissimilar for reasons we discuss, as long as the two maintain a relatively predictable ratio, the dose of CD34-positive cells might still be a useful surrogate. This raises the question of how the numbers of CD34-positive cells may be converted to a dose. Presently, CD34-positive cell dose is quantified on body weight [22, 23]. Why this is so is unclear: In the graft we are dealing with some cells with substantial proliferative potential, not like a medical drug that is stoichiometrically metabolised by the liver or excreted by the kidneys. Mammals come in various sizes: from a mouse (20 g) to humans (70 kg), and to elephants (7500 kg). A human gaining 20 kg does not suddenly have more cells (just bigger fat cells) and his or her blood volume certainly would not suddenly increase by 30 percent, since blood volume correlates better with lean body mass than with body weight, body mass index or body surface area across both sexes at all Tanner stages [24]. Such a person, obviously, does not need 30 percent more CD34-positive cells to recover posttransplant bone marrow function [25, 26].

Is there a required threshold dose for CD34-positive cells?

We suggest it is biologically implausible there is a threshold dose of CD34-positive cells for successful post-transplant bone marrow recovery. If there is a threshold dose for CD34-positive cells, the hazard function for recovery of bone marrow function is expected to be zero until the dose, however, quantified, exceeds the threshold. Conversely, if there is no threshold dose, the hazard function would continuously increase provided the dose is not zero (Fig. 1A). Previous research that interrogated the relationship between CD34-positive cell dose and posttransplant bone marrow recovery uniformly analysed dose by discretizing it into multiple classes with contradictory results [27-35]. This approach could not uncover the shape of the dose-response curve for CD34-positive cell dose versus haematopoietic function recovery and, therefore, is not suitable for answering the question whether there is a threshold dose of CD34-positive cells [36].

Consensus guidelines suggest a threshold dose of CD34-positive cell dose ranging from ≥1.5×10E+5/kg for umbilical cord blood cell grafts to ≥5×10E+6/kg for mobilized peripheral blood cell grafts [23, 37]. Applying this recommendation, only 4 percent of the US cord blood inventory is suitable for single-unit transplants to adults [38]. Theoretically, however, even one HSC is capable of restoring post-transplant bone marrow function given sufficient time and provided we can keep the recipient alive for this interval [8, 26]. Data in mice indicate that some HSC clones are highly efficient in restoring long-term bone marrow function [39]. Moreover, we reported recovery of bone marrow function in a person exposed to acute extremely high-dose and dose-rate total body radiation doses without a transplant [40]. Because radiation killing of cells is stochastic it is impossible any dose of ionising radiations could kill every HSC without killing the person. These data indicate the concept of so-called myelo-ablative pretransplant conditioning regimens to be a misnomer.

Clinical data

To help resolve these controversies we interrogated data from 619 consecutive subjects with acute leukaemia receiving a single-unit umbilical cord blood cell transplant 2015-2020. Mean age was 13.6 (0.7-62.3) years. Most had acute leukemia. The absolute dose of CD34-positive cells was 72.15×10+5 (Range, 3.85-502×10E+5/kg) with median dose of 1.90×10+5/kg (Range, 0.17-10.90×10E+5/kg). Median CD34+ cell dose was 1.9 0×10E+5/L recipient blood volume (Range, 0.02-2.40)×10E+5/L. We choose umbilical cord blood cell transplants because an insufficient CD34-positive cell dose is often referred as the reason to exclude potential adult recipients and because umbilical cord blood is likely to have the highest fraction of HSCs amongst different CD34-positive cell populations [8].

We considered 3 expression modes of CD34-positive cell dose: (1) absolute numbers of CD34-positive cells (Abs CD34-positive); (2) numbers of CD34-positive cells per kg of recipient body weight (CD34-positive/BW); and (3) numbers of CD34-positive cells per estimated liter recipient blood volume (CD34-postive/BV) [24].

Our focus was on granulocyte recovery since the analyses of RBCs and platelet recovery are confounded by pre- and posttransplant transfusions and because granulocytes are the most short-lived cells. Analyses of survival and other transplant endpoints are tangential to our primary concern because of confounders such as infections and graft-versus-host disease [26]. We used a Bayesian Cox regression model with restricted cubic splines. We found the hazard function for granulocyte recovery was erratic when CD34-positive cell dose was quantified as Abs CD34-postive (Fig. 1B). In contrast, the hazard function of CD34-positive cell dose per kilogram body weight reached a plateau at ≈1.5 once CD34-postive/BW was >3×10E+5/kg and there was no threshold value below which the hazard function abruptly dropped to zero (Fig. 1C). The hazard function of CD34-positive cell dose per L of blood volume reached plateau values at >1.5 when CD34-positive/BV was >0.5×10E+7/L and the hazard remained ≈0.5 even when CD34-positive/BV dropped to 0.05×10E+7/L, the 2.5th-percentile value in the study cohort (Fig. 1D).

Next, we divided the subjects into 5 quintiles according to CD34-posive cell dose, and, for each quintile, median log2 of CD34-positive cell dose has been calculated versus time interval to granulocyte recovery. Quintile median log2(dose) and quintile median recovery interval correlated better when dose was quantified per blood volume (r = –0.98 (CD34-positive/BV) versus –0.65 (Abs CD34-positive) and –0.92 (CD34-postive/BW); Fig. 1E, F, G). Analysis of the linear regression coefficients of quintile median recovery interval versus quintile log2(CD34-positive/BV) suggests that the CD34-positive cell population in the blood doubled every 1.6 days (Fig. 1G).

Chen-fig01.jpg

Figure 1. Theoretical scenarios for hazard functions and estimated dose response curves of CD34-positive cells after UBC transplant

A – Hazard functions for haematopoietic function recovery under two contrasting scenarios: with or without a threshold dose.
B, C, D – Hazard functions of Abs CD34-positive (B), CD34-positive/BW (C) and CD34-positive/BV (D) for granulocyte recovery in the Anhui umbilical cord blood cell transplant data [41]. Hazard is calculated with respect to the population mean. “Hazard = 0.5” means that the instantaneous recovery rate (from day 1 posttransplant to infinity) is half-magnitude compared to the population mean. “Hazard = 0” means zero probability of granulocyte recovery.
E, F, G – Relationship between CD34-positive cell dose and interval to granulocyte recovery interval: Abs CD34-positive (E), CD34-positive/BW (F) and CD34-positive/BV (G) in the Anhui umbilical cord blood cell transplant data [41]. All the patients are divided into 5 quintiles according to the panel’s respective measure of CD34-positive cell dose. Each dot summarizes one quintile, with its x and y coordinates representing the median CD34-positive cell dose and the median interval to granulocyte recovery, respectively, of the quintile.

Discussion

We reviewed biological considerations and experimental data indicating cells responsible for posttransplant bone marrow recovery in humans cannot be accurately quantified. We also argue why numbers or dose of CD34-positive cells in a graft cannot be an accurate estimate of cells responsible for posttransplant bone marrow recovery. Nevertheless, given that many studies claiming a correlation between numbers of CD34-positive cells and posttransplant recovery of bone marrow function, we used new statistical methods to interrogate a large dataset of umbilical cord blood cell transplants to prove the non-linear CD34-positive cell dose effect and see if there is a threshold dose needed for posttransplant recovery of bone marrow function. More specifically, we used roughness penalty minimization and Markov chain Monte Carlo to estimate the CIs of smooth curves [42, 43]. We also found the best correlate with posttransplant granulocyte recovery was numbers of CD34-positive cells per blood volume, not per body weight.

We also found no threshold dose of CD34-positive cells for successful posttransplant granulocyte recovery. This observation has important clinical implications which may make more people eligible to receive haematopoietic cell transplant, especially an umbilical cord blood cell transplant, and may obviate the perceived need for repeated leukaphereses.

Our conclusions have limitations. 1st, our conclusions may not apply to other graft types. 2nd, our analyses of the clinical dataset were retrospective and possibly biased. 3rd, although we tested a range of CD34-positive cell doses none was <0.02×10E+7/L or <0.17×10E+5/kg.

In our Point-of-View we challenge current thinking and practices regarding whether CD34-positive cell dose in a graft should be used as a proxy for predicting short- and long-term posttransplant bone marrow recovery and, if there is no alternative, how CD34-positive cell dose should be quantified. Conclusions need further validation since they are potentially practice-changing.

Data Availability

Available upon reasonable request from Prof. Chen.

Funding

Supported, in part, by grants from the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2021-I2M-1-001 and 2022-I2M-2-003; JC) and Union Stem Cell & Gene Engineering Co., Ltd. (JC).

Acknowledgements

We thank Professor Zimin Sun for access to their data of umbilical cord blood cell transplants and Profs. Connie Eaves (University of British Columbia) and John Dick (University of Toronto) for valuable inputs to a prior version. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre.

Conflict of Interest

RPG is a consultant to Antengene Biotech LLC, Ascentage Pharma Group and NexImmune Inc.; Medical Director, FFF Enterprises Inc.; Board of Directors: Russian Foundation for Cancer Research Support; and Scientific Advisory Boards, Nanexa AB and StemRad Ltd.

Ethics

The study was approved by the Academic Committee (IIT2021042) of the Institute of Hematology, Chinese Academy of Medical Sciences (IHCAMS) and the Ethics Review Committees of IHCAMS and FAHUSTC (QTJC2022026-EC-1 and 2022-RE-070). Subjects gave written informed consent consistent with the precepts of the Helsinki Declaration.

Author Contributions

The authors conceived the study, reviewed the typescript, take responsibility for the content and agreed to submit for publication.

Note

This article is based on a lecture at the R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation and Cellular Therapy (St. Petersburg, 15 September 2023). An extended version was published as Chen J, Gale RP, Feng Y, Hu Y, Qi S, Liu X, Zhu H, Gong X, Zhang W, Liu H, Sun Z. Are haematopoietic stem cell transplants stem cell transplants, is there a threshold dose of CD34-positive cells and how many are needed for rapid posttransplant granulocyte recovery? Leukemia. 2023; 37(10):1963-1968. doi: 10.1038/s41375-023-01973-2.

References

  1. Quesenberry PJ, Goldberg LR, Dooner MS. Concise reviews: A stem cell apostasy: a tale of four H words. Stem Cells. 2015;33(1):15-20. doi: 10.1002/stem.1829
  2. Quesenberry PJ, Wen S, Goldberg LR, Dooner MS. The universal stem cell. Leukemia. 2022;36(12):2784-2792. doi: 10.1038/s41375-022-01715-w
  3. Goldberg LR, Dooner MS, Papa E, Pereira M, Del Tatto M, Cheng Y, et al. Differentiation Epitopes Define Hematopoietic Stem Cells and Change with Cell Cycle Passage. Stem Cell Rev Rep. 2022;18(7):2351-2364. doi: 10.1007/s12015-022-10374-4
  4. Bhatia M, Wang JC, Kapp U, Bonnet D, Dick JE. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci U S A. 1997;94(10):5320-5325. doi: 10.1073/pnas.94.10.5320
  5. Goodell MA, Rosenzweig M, Kim H, Marks DF, DeMaria M, Paradis G, Grupp SA, Sieff CA, Mulligan RC, Johnson RP. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med. 1997; 3(12):1337-1345. doi: 10.1038/nm1297-1337
  6. Bhatia M, Bonnet D, Murdoch B, Gan OI, Dick JE. A newly discovered class of human hematopoietic cells with SCID-repopulating activity. Nat Med. 1998 Sep;4(9):1038-45. doi: 10.1038/2023
  7. Sato T, Laver JH, Ogawa M. Reversible expression of CD34 by murine hematopoietic stem cells. Blood. 1999;94(8):2548-2554.
    PMID: 10515856
  8. Wang JC, Doedens M, Dick JE. Primitive human hematopoietic cells are enriched in cord blood compared with adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell assay. Blood. 1997;89(11):3919-3924.
    PMID: 9166828
  9. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science. 1996;273(5272):242-245. doi: 10.1126/science.273.5272.242
  10. Morrison SJ, Wandycz AM, Hemmati HD, Wright DE, Weissman IL. Identification of a lineage of multipotent hematopoietic progenitors. Development. 1997;124(10):1929-1939. doi: 10.1242/dev.124.10.1929
  11. Yang L, Bryder D, Adolfsson J, Nygren J, Mansson R, Sigvardsson M, et al. Identification of Lin(-)Sca1(+)kit(+)CD34(+)Flt3- short-term hematopoietic stem cells capable of rapidly reconstituting and rescuing myeloablated transplant recipients. Blood. 2005;105(7):2717-2723. doi: 10.1182/blood-2004-06-2159
  12. Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341(6148):1233151. doi: 10.1126/science.1233151
  13. Biasco L, Pellin D, Scala S, Dionisio F, Basso-Ricci L, Leonardelli L, et al. In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell. 2016;19(1):107-119. doi: 10.1016/j.stem.2016.04.016
  14. Kaufmann KB, Zeng AGX, Coyaud E, Garcia-Prat L, Papalexi E, Murison A, et al. A latent subset of human hematopoietic stem cells resists regenerative stress to preserve stemness. Nat Immunol. 2021;22(6):723-734. doi: 10.1038/s41590-021-00925-1
  15. Lemischka IR, Raulet DH, Mulligan RC. Developmental potential and dynamic behavior of hematopoietic stem cells. Cell. 1986;45(6):917-927. doi: 10.1016/0092-8674(86)90566-0
  16. Muller-Sieburg CE, Cho RH, Thoman M, Adkins B, Sieburg HB. Deterministic regulation of hematopoietic stem cell self-renewal and differentiation. Blood. 2002;100(4):1302-1309. PMID: 12149211
  17. Muller-Sieburg CE, Cho RH, Karlsson L, Huang JF, Sieburg HB. Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness. Blood. 2004;103(11):4111-4118. doi: 10.1182/blood-2003-10-3448
  18. Ema H, Sudo K, Seita J, Matsubara A, Morita Y, Osawa M, et al. Quantification of self-renewal capacity in single hematopoietic stem cells from normal and Lnk-deficient mice. Dev Cell. 2005;8(6):907-914. doi: 10.1016/j.devcel.2005.03.019
  19. Dykstra B, Kent D, Bowie M, McCaffrey L, Hamilton M, Lyons K, Lee SJ, Brinkman R, Eaves C. Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell. 2007;1(2):218-229. doi: 10.1016/j.stem.2007.05.015
  20. Morita Y, Ema H, Nakauchi H. Heterogeneity and hierarchy within the most primitive hematopoietic stem cell compartment. J Exp Med. 2010;207(6):1173-82. doi: 10.1084/jem.20091318
  21. Yamamoto R, Morita Y, Ooehara J, Hamanaka S, Onodera M, Rudolph KL, et al. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell. 2013;154(5):1112-26. doi: 10.1016/j.cell.2013.08.007
  22. Zimmerman TM, Lee WJ, Bender JG, Mick R, Williams SF. Quantitative CD34 analysis may be used to guide peripheral blood stem cell harvests. Bone Marrow Transplant. 1995;15(3):439-444. PMID: 7541269
  23. Politikos I, Davis E, Nhaissi M, Wagner JE, Brunstein CG, Cohen S, Shpall EJ, Milano F, Scaradavou A, Barker JN. Guidelines for cord blood unit selection. Biol Blood Marrow Transplant. 2020;26(12):2190-2196. doi: 10.1016/j.bbmt.2020.07.030
  24. Raes A, Van Aken S, Craen M, Donckerwolcke R, Vande Walle J. A reference frame for blood volume in children and adolescents. BMC Pediatr. 2006;6:3. doi: 10.1186/1471-2431-6-3
  25. Singhal S, Gordon LI, Tallman MS, Winter JN, Evens AM, Frankfurt O, Williams SF, Grinblatt D, Kaminer L, Meagher R, Mehta J. Ideal rather than actual body weight should be used to calculate cell dose in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2006;37(6):553-557. doi: 10.1038/sj.bmt.1705282
  26. Sanz J, Gale RP. One or two umbilical cord blood cell units? Caveat emptor. Bone Marrow Transplant. 2017;52(3):341-343.
    doi: 10.1038/bmt.2016.277
  27. Klaus J, Herrmann D, Breitkreutz I, Hegenbart U, Mazitschek U, Egerer G, Cremer FW, Lowenthal RM, Huesing J, Fruehauf S, et al. Effect of CD34 cell dose on hematopoietic reconstitution and outcome in 508 patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation. Eur J Haematol. 2007;78(1):21-28. doi: 10.1111/j.0902-4441.2006.t01-1-EJH2895.x
  28. Gorin NC, Labopin M, Reiffers J, Milpied N, Blaise D, Witz F, de Witte T, Meloni G, Attal M, Bernal T, Rocha V. Higher incidence of relapse in patients with acute myelocytic leukemia infused with higher doses of CD34+ cells from leukapheresis products autografted during the first remission. Blood. 2010; 116(17):3157-3162. doi: 10.1182/blood-2009-11-252197
  29. Martin PS, Li S, Nikiforow S, Alyea EP 3rd, Antin JH, Armand P, Cutler CS, Ho VT, Kekre N, Koreth J, Luckey CJ, Ritz J, Soiffer RJ. Infused total nucleated cell dose is a better predictor of transplant outcomes than CD34+ cell number in reduced-intensity mobilized peripheral blood allogeneic hematopoietic cell transplantation. Haematologica. 2016 Apr;101(4):499-505. doi: 10.3324/haematol.2015.134841
  30. Czerw T, Labopin M, Schmid C, Cornelissen JJ, Chevallier P, Blaise D, Kuball J, Vigouroux S, Garban F, Lioure B, et al. High CD3+ and CD34+ peripheral blood stem cell grafts content is associated with increased risk of graft-versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia – an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Oncotarget. 2016;7(19):27255-27266. doi: 10.18632/oncotarget.8463
  31. Konuma T, Kato S, Oiwa-Monna M, Tanoue S, Ogawa M, Isobe M, Tojo A, Takahashi S. Cryopreserved CD34+ Cell Dose, but Not Total Nucleated Cell Dose, Influences Hematopoietic Recovery and Extensive Chronic Graft-versus-Host Disease after Single-Unit Cord Blood Transplantation in Adult Patients. Biol Blood Marrow Transplant. 2017 Jul;23(7):1142-1150. doi: 10.1016/j.bbmt.2017.03.036
  32. Chen Y, Xu LP, Liu KY, Chen H, Chen YH, Zhang XH, Wang Y, Wang FR, Han W, Wang JZ, et al. Higher dose of CD34+ peripheral blood stem cells is associated with better survival after haploidentical stem cell transplantation in pediatric patients. Clin Transplant. 2017;31(2). e12880. doi: 10.1111/ctr.12880
  33. Yamamoto C, Ogawa H, Fukuda T, Igarashi A, Okumura H, Uchida N, Hidaka M, Nakamae H, Matsuoka KI, Eto T, et al. Impact of a low CD34(+) cell dose on allogeneic peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2018;24(4):708-716. doi: 10.1016/j.bbmt.2017.10.043
  34. Yanada M, Konuma T, Kuwatsuka Y, Kondo T, Kawata T, Takahashi S, Uchida N, Miyakoshi S, Tanaka M, Ozawa Y, et al. Unit selection for umbilical cord blood transplantation for adults with acute myeloid leukemia in complete remission: a Japanese experience. Bone Marrow Transplant. 2019; 54(11): 1789-1798. doi: 10.1038/s41409-019-0539-8
  35. Gauntner TD, Brunstein CG, Cao Q, Weisdorf DJ, Warlick ED, Jurdi NE, Maakaron JE, Arora M, Betts BC, Bachanova V, et al. Association of CD34 cell dose with 5-year overall survival after peripheral blood allogeneic hematopoietic cell transplantation in adults with hematologic malignancies. Transplant Cell Ther. 2022;28(2):88-95. doi: 10.1016/j.jtct.2021.11.004
  36. Gauthier J, Wu QV, Gooley TA. Cubic splines to model relationships between continuous variables and outcomes: a guide for clinicians. Bone Marrow Transplant. 2020;55(4):675-680. doi: 10.1038/s41409-019-0679-x
  37. Ayuk F, Balduzzi A. Donor Selection for Adults and Pediatrics. In: Carreras E, Dufour C, Mohty M, Kröger N, editors. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies [Internet]. 7th ed. Cham (CH): Springer; 2019. Chapter 12. PMID: 32091810
  38. Barker JN, Kempenich J, Kurtzberg J, Brunstein CG, Delaney C, Milano F, Politikos I, Shpall EJ, Scaradavou A, Dehn J. CD34+ cell content of 126 341 cord blood units in the US inventory: implications for transplantation and banking. Blood Adv. 2019; 3(8):1267-1271. doi: 10.1182/bloodadvances.2018029157
  39. Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011;333(6039):218-221. doi: 10.1126/science.1201219
  40. Baranov AE, Selidovkin GD, Butturini A, Gale RP. Hematopoietic recovery after 10-Gy acute total body radiation. Blood. 1994;83(2):596-599. PMID: 8286754
  41. Chen J, Gale RP, Feng Y, Hu Y, Qi S, Liu X, et al. Are haematopoietic stem cell transplants stem cell transplants, is there a threshold dose of CD34-positive cells and how many are needed for rapid posttransplant granulocyte recovery? Leukemia. 2023;37(10):1963-1968. doi: 10.1038/s41375-023-01973-2
  42. Kirkpatrick S, Gelatt CD, Jr., Vecchi MP. Optimization by simulated annealing. Science. 1983; 220(4598):671-680.
    doi: 10.1126/science.220.4598.671
  43. Green PJ, Silverman BW. Nonparametric Regression and Generalized Linear Models: A Roughness Penalty Approach. London: Chapman & Hall; 1994. doi: 10.1201/b15710
  44. Yokoyama Y, Maie K, Fukuda T, Uchida N, Mukae J, Sawa M, Kubo K, Kurokawa M, Nakamae H, Ichinohe T, Atsuta Y, Chiba S. A et al. A high CD34(+) cell dose is associated with better disease-free survival in patients with low-risk diseases undergoing peripheral blood stem cell transplantation from HLA-matched related donors. Bone Marrow Transplant. 2020;55(9):1726-1735. doi: 10.1038/s41409-020-0817-5

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Introduction

It is widely believed that the recovery of bone marrow function after haematopoietic cell transplantation arises from pluripotent haematopoietic stem cells (HSCs). It is also generally assumed that the contents of CD34-positive cells in a graft are an accurate proxy for numbers of HSCs, that the dose of CD34-positive cells should be quantified by body weight and that there is a threshold dose of CD34-positive cells required for successful bone marrow recovery post-transplant. We argue that several or all of these beliefs are wrong. We consider biological plausibility and clinical data from persons receiving umbilical cord blood cells transplants and advanced statistical analyses of this dataset. Our conclusions have important implications for transplant practices.

Biology

HSCs and CD34-positive cells are not the same

There is no accurate way to identify human haematopoietic stem cells (HSCs) [1-3]. Although many people assume human HSCs to be CD34-positive but this is conjecture lacking a human HSC assay [4-6]. Quiescent HSCs in mice are CD34-negative acquiring CD34 expression only after they begin dividing and, thus, are no longer stem cells [7]. Some data suggest an ever-changing phenotype of human HSCs [1, 2].

Most CD34-positive cells in blood, bone marrow and umbilical cord blood cell grafts in humans are not HSCs [4]. Data from transplanting human haematopoietic cells into immune-deficient mice suggest that 10E-6 to 10E-7 CD34-positive mononuclear cells might be HSCs, a frequency which could be relatively higher in human umbilical cord blood grafts and lower in bone marrow grafts, and still lower in quiescent and mobilised blood cell grafts [8].

Since almost all CD34-positive cells in a graft are not HSCs the estimated contents of HSCs based on numbers of CD34-positive cells must be imprecise. If we assume that the ratio of HSCs to CD34-postive cells is 1 to 5000 in umbilical cord blood, a graft containing 40×10E+5 CD34-positive cells could have variation of +10 percent in numbers of HSCs due to Poisson noise.

Posttransplant bone marrow recovery is not only from HSCs

Another complexity is that we lack knowledge of which haematopoietic cell(s) underly posttransplant recovery of bone marrow function. Data in mice indicate that a number of different cells in a graft including many which are not HSCs contribute to short- and long-term bone marrow recovery [9-11]. Data obtained in humans are largely consistent with animal data [12-14]. Even within the phenotypically most primitive HSCs, the pool of individual stem cells can have very different self-renewal potentials and different contribution to bone marrow recovery [15-21]. Namely, not all HSCs contribute equally to sustained multi-lineage haematopoiesis and most of them show biased differentiation towards specific haematopoietic lineages.

Clinical considerations

We are left with an insoluble challenge. First, we don’t know which cells in a graft are responsible for short- and long-term posttransplant bone marrow recovery. This is especially true after autotransplants and after allotransplants with less intensive pre-transplant conditioning. Second, without this knowledge, we obviously lack an accurate assay for whether a graft will restore short- and long-term post-transplant bone marrow function.

Clinicians need to address 2 questions: (1) how to derive a measure for haematopoietic potential of a graft using the number of CD34-positive cells despite the caveats we discuss above; and (2) whether there is a threshold dose needed for successful posttransplant bone marrow recovery.

Although numbers of CD34-positive cells in a graft and ability to restore posttransplant bone marrow function are dissimilar for reasons we discuss, as long as the two maintain a relatively predictable ratio, the dose of CD34-positive cells might still be a useful surrogate. This raises the question of how the numbers of CD34-positive cells may be converted to a dose. Presently, CD34-positive cell dose is quantified on body weight [22, 23]. Why this is so is unclear: In the graft we are dealing with some cells with substantial proliferative potential, not like a medical drug that is stoichiometrically metabolised by the liver or excreted by the kidneys. Mammals come in various sizes: from a mouse (20 g) to humans (70 kg), and to elephants (7500 kg). A human gaining 20 kg does not suddenly have more cells (just bigger fat cells) and his or her blood volume certainly would not suddenly increase by 30 percent, since blood volume correlates better with lean body mass than with body weight, body mass index or body surface area across both sexes at all Tanner stages [24]. Such a person, obviously, does not need 30 percent more CD34-positive cells to recover posttransplant bone marrow function [25, 26].

Is there a required threshold dose for CD34-positive cells?

We suggest it is biologically implausible there is a threshold dose of CD34-positive cells for successful post-transplant bone marrow recovery. If there is a threshold dose for CD34-positive cells, the hazard function for recovery of bone marrow function is expected to be zero until the dose, however, quantified, exceeds the threshold. Conversely, if there is no threshold dose, the hazard function would continuously increase provided the dose is not zero (Fig. 1A). Previous research that interrogated the relationship between CD34-positive cell dose and posttransplant bone marrow recovery uniformly analysed dose by discretizing it into multiple classes with contradictory results [27-35]. This approach could not uncover the shape of the dose-response curve for CD34-positive cell dose versus haematopoietic function recovery and, therefore, is not suitable for answering the question whether there is a threshold dose of CD34-positive cells [36].

Consensus guidelines suggest a threshold dose of CD34-positive cell dose ranging from ≥1.5×10E+5/kg for umbilical cord blood cell grafts to ≥5×10E+6/kg for mobilized peripheral blood cell grafts [23, 37]. Applying this recommendation, only 4 percent of the US cord blood inventory is suitable for single-unit transplants to adults [38]. Theoretically, however, even one HSC is capable of restoring post-transplant bone marrow function given sufficient time and provided we can keep the recipient alive for this interval [8, 26]. Data in mice indicate that some HSC clones are highly efficient in restoring long-term bone marrow function [39]. Moreover, we reported recovery of bone marrow function in a person exposed to acute extremely high-dose and dose-rate total body radiation doses without a transplant [40]. Because radiation killing of cells is stochastic it is impossible any dose of ionising radiations could kill every HSC without killing the person. These data indicate the concept of so-called myelo-ablative pretransplant conditioning regimens to be a misnomer.

Clinical data

To help resolve these controversies we interrogated data from 619 consecutive subjects with acute leukaemia receiving a single-unit umbilical cord blood cell transplant 2015-2020. Mean age was 13.6 (0.7-62.3) years. Most had acute leukemia. The absolute dose of CD34-positive cells was 72.15×10+5 (Range, 3.85-502×10E+5/kg) with median dose of 1.90×10+5/kg (Range, 0.17-10.90×10E+5/kg). Median CD34+ cell dose was 1.9 0×10E+5/L recipient blood volume (Range, 0.02-2.40)×10E+5/L. We choose umbilical cord blood cell transplants because an insufficient CD34-positive cell dose is often referred as the reason to exclude potential adult recipients and because umbilical cord blood is likely to have the highest fraction of HSCs amongst different CD34-positive cell populations [8].

We considered 3 expression modes of CD34-positive cell dose: (1) absolute numbers of CD34-positive cells (Abs CD34-positive); (2) numbers of CD34-positive cells per kg of recipient body weight (CD34-positive/BW); and (3) numbers of CD34-positive cells per estimated liter recipient blood volume (CD34-postive/BV) [24].

Our focus was on granulocyte recovery since the analyses of RBCs and platelet recovery are confounded by pre- and posttransplant transfusions and because granulocytes are the most short-lived cells. Analyses of survival and other transplant endpoints are tangential to our primary concern because of confounders such as infections and graft-versus-host disease [26]. We used a Bayesian Cox regression model with restricted cubic splines. We found the hazard function for granulocyte recovery was erratic when CD34-positive cell dose was quantified as Abs CD34-postive (Fig. 1B). In contrast, the hazard function of CD34-positive cell dose per kilogram body weight reached a plateau at ≈1.5 once CD34-postive/BW was >3×10E+5/kg and there was no threshold value below which the hazard function abruptly dropped to zero (Fig. 1C). The hazard function of CD34-positive cell dose per L of blood volume reached plateau values at >1.5 when CD34-positive/BV was >0.5×10E+7/L and the hazard remained ≈0.5 even when CD34-positive/BV dropped to 0.05×10E+7/L, the 2.5th-percentile value in the study cohort (Fig. 1D).

Next, we divided the subjects into 5 quintiles according to CD34-posive cell dose, and, for each quintile, median log2 of CD34-positive cell dose has been calculated versus time interval to granulocyte recovery. Quintile median log2(dose) and quintile median recovery interval correlated better when dose was quantified per blood volume (r = –0.98 (CD34-positive/BV) versus –0.65 (Abs CD34-positive) and –0.92 (CD34-postive/BW); Fig. 1E, F, G). Analysis of the linear regression coefficients of quintile median recovery interval versus quintile log2(CD34-positive/BV) suggests that the CD34-positive cell population in the blood doubled every 1.6 days (Fig. 1G).

Chen-fig01.jpg

Figure 1. Theoretical scenarios for hazard functions and estimated dose response curves of CD34-positive cells after UBC transplant

A – Hazard functions for haematopoietic function recovery under two contrasting scenarios: with or without a threshold dose.
B, C, D – Hazard functions of Abs CD34-positive (B), CD34-positive/BW (C) and CD34-positive/BV (D) for granulocyte recovery in the Anhui umbilical cord blood cell transplant data [41]. Hazard is calculated with respect to the population mean. “Hazard = 0.5” means that the instantaneous recovery rate (from day 1 posttransplant to infinity) is half-magnitude compared to the population mean. “Hazard = 0” means zero probability of granulocyte recovery.
E, F, G – Relationship between CD34-positive cell dose and interval to granulocyte recovery interval: Abs CD34-positive (E), CD34-positive/BW (F) and CD34-positive/BV (G) in the Anhui umbilical cord blood cell transplant data [41]. All the patients are divided into 5 quintiles according to the panel’s respective measure of CD34-positive cell dose. Each dot summarizes one quintile, with its x and y coordinates representing the median CD34-positive cell dose and the median interval to granulocyte recovery, respectively, of the quintile.

Discussion

We reviewed biological considerations and experimental data indicating cells responsible for posttransplant bone marrow recovery in humans cannot be accurately quantified. We also argue why numbers or dose of CD34-positive cells in a graft cannot be an accurate estimate of cells responsible for posttransplant bone marrow recovery. Nevertheless, given that many studies claiming a correlation between numbers of CD34-positive cells and posttransplant recovery of bone marrow function, we used new statistical methods to interrogate a large dataset of umbilical cord blood cell transplants to prove the non-linear CD34-positive cell dose effect and see if there is a threshold dose needed for posttransplant recovery of bone marrow function. More specifically, we used roughness penalty minimization and Markov chain Monte Carlo to estimate the CIs of smooth curves [42, 43]. We also found the best correlate with posttransplant granulocyte recovery was numbers of CD34-positive cells per blood volume, not per body weight.

We also found no threshold dose of CD34-positive cells for successful posttransplant granulocyte recovery. This observation has important clinical implications which may make more people eligible to receive haematopoietic cell transplant, especially an umbilical cord blood cell transplant, and may obviate the perceived need for repeated leukaphereses.

Our conclusions have limitations. 1st, our conclusions may not apply to other graft types. 2nd, our analyses of the clinical dataset were retrospective and possibly biased. 3rd, although we tested a range of CD34-positive cell doses none was <0.02×10E+7/L or <0.17×10E+5/kg.

In our Point-of-View we challenge current thinking and practices regarding whether CD34-positive cell dose in a graft should be used as a proxy for predicting short- and long-term posttransplant bone marrow recovery and, if there is no alternative, how CD34-positive cell dose should be quantified. Conclusions need further validation since they are potentially practice-changing.

Data Availability

Available upon reasonable request from Prof. Chen.

Funding

Supported, in part, by grants from the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2021-I2M-1-001 and 2022-I2M-2-003; JC) and Union Stem Cell & Gene Engineering Co., Ltd. (JC).

Acknowledgements

We thank Professor Zimin Sun for access to their data of umbilical cord blood cell transplants and Profs. Connie Eaves (University of British Columbia) and John Dick (University of Toronto) for valuable inputs to a prior version. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre.

Conflict of Interest

RPG is a consultant to Antengene Biotech LLC, Ascentage Pharma Group and NexImmune Inc.; Medical Director, FFF Enterprises Inc.; Board of Directors: Russian Foundation for Cancer Research Support; and Scientific Advisory Boards, Nanexa AB and StemRad Ltd.

Ethics

The study was approved by the Academic Committee (IIT2021042) of the Institute of Hematology, Chinese Academy of Medical Sciences (IHCAMS) and the Ethics Review Committees of IHCAMS and FAHUSTC (QTJC2022026-EC-1 and 2022-RE-070). Subjects gave written informed consent consistent with the precepts of the Helsinki Declaration.

Author Contributions

The authors conceived the study, reviewed the typescript, take responsibility for the content and agreed to submit for publication.

Note

This article is based on a lecture at the R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation and Cellular Therapy (St. Petersburg, 15 September 2023). An extended version was published as Chen J, Gale RP, Feng Y, Hu Y, Qi S, Liu X, Zhu H, Gong X, Zhang W, Liu H, Sun Z. Are haematopoietic stem cell transplants stem cell transplants, is there a threshold dose of CD34-positive cells and how many are needed for rapid posttransplant granulocyte recovery? Leukemia. 2023; 37(10):1963-1968. doi: 10.1038/s41375-023-01973-2.

References

  1. Quesenberry PJ, Goldberg LR, Dooner MS. Concise reviews: A stem cell apostasy: a tale of four H words. Stem Cells. 2015;33(1):15-20. doi: 10.1002/stem.1829
  2. Quesenberry PJ, Wen S, Goldberg LR, Dooner MS. The universal stem cell. Leukemia. 2022;36(12):2784-2792. doi: 10.1038/s41375-022-01715-w
  3. Goldberg LR, Dooner MS, Papa E, Pereira M, Del Tatto M, Cheng Y, et al. Differentiation Epitopes Define Hematopoietic Stem Cells and Change with Cell Cycle Passage. Stem Cell Rev Rep. 2022;18(7):2351-2364. doi: 10.1007/s12015-022-10374-4
  4. Bhatia M, Wang JC, Kapp U, Bonnet D, Dick JE. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci U S A. 1997;94(10):5320-5325. doi: 10.1073/pnas.94.10.5320
  5. Goodell MA, Rosenzweig M, Kim H, Marks DF, DeMaria M, Paradis G, Grupp SA, Sieff CA, Mulligan RC, Johnson RP. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med. 1997; 3(12):1337-1345. doi: 10.1038/nm1297-1337
  6. Bhatia M, Bonnet D, Murdoch B, Gan OI, Dick JE. A newly discovered class of human hematopoietic cells with SCID-repopulating activity. Nat Med. 1998 Sep;4(9):1038-45. doi: 10.1038/2023
  7. Sato T, Laver JH, Ogawa M. Reversible expression of CD34 by murine hematopoietic stem cells. Blood. 1999;94(8):2548-2554.
    PMID: 10515856
  8. Wang JC, Doedens M, Dick JE. Primitive human hematopoietic cells are enriched in cord blood compared with adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell assay. Blood. 1997;89(11):3919-3924.
    PMID: 9166828
  9. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science. 1996;273(5272):242-245. doi: 10.1126/science.273.5272.242
  10. Morrison SJ, Wandycz AM, Hemmati HD, Wright DE, Weissman IL. Identification of a lineage of multipotent hematopoietic progenitors. Development. 1997;124(10):1929-1939. doi: 10.1242/dev.124.10.1929
  11. Yang L, Bryder D, Adolfsson J, Nygren J, Mansson R, Sigvardsson M, et al. Identification of Lin(-)Sca1(+)kit(+)CD34(+)Flt3- short-term hematopoietic stem cells capable of rapidly reconstituting and rescuing myeloablated transplant recipients. Blood. 2005;105(7):2717-2723. doi: 10.1182/blood-2004-06-2159
  12. Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341(6148):1233151. doi: 10.1126/science.1233151
  13. Biasco L, Pellin D, Scala S, Dionisio F, Basso-Ricci L, Leonardelli L, et al. In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell. 2016;19(1):107-119. doi: 10.1016/j.stem.2016.04.016
  14. Kaufmann KB, Zeng AGX, Coyaud E, Garcia-Prat L, Papalexi E, Murison A, et al. A latent subset of human hematopoietic stem cells resists regenerative stress to preserve stemness. Nat Immunol. 2021;22(6):723-734. doi: 10.1038/s41590-021-00925-1
  15. Lemischka IR, Raulet DH, Mulligan RC. Developmental potential and dynamic behavior of hematopoietic stem cells. Cell. 1986;45(6):917-927. doi: 10.1016/0092-8674(86)90566-0
  16. Muller-Sieburg CE, Cho RH, Thoman M, Adkins B, Sieburg HB. Deterministic regulation of hematopoietic stem cell self-renewal and differentiation. Blood. 2002;100(4):1302-1309. PMID: 12149211
  17. Muller-Sieburg CE, Cho RH, Karlsson L, Huang JF, Sieburg HB. Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness. Blood. 2004;103(11):4111-4118. doi: 10.1182/blood-2003-10-3448
  18. Ema H, Sudo K, Seita J, Matsubara A, Morita Y, Osawa M, et al. Quantification of self-renewal capacity in single hematopoietic stem cells from normal and Lnk-deficient mice. Dev Cell. 2005;8(6):907-914. doi: 10.1016/j.devcel.2005.03.019
  19. Dykstra B, Kent D, Bowie M, McCaffrey L, Hamilton M, Lyons K, Lee SJ, Brinkman R, Eaves C. Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell. 2007;1(2):218-229. doi: 10.1016/j.stem.2007.05.015
  20. Morita Y, Ema H, Nakauchi H. Heterogeneity and hierarchy within the most primitive hematopoietic stem cell compartment. J Exp Med. 2010;207(6):1173-82. doi: 10.1084/jem.20091318
  21. Yamamoto R, Morita Y, Ooehara J, Hamanaka S, Onodera M, Rudolph KL, et al. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell. 2013;154(5):1112-26. doi: 10.1016/j.cell.2013.08.007
  22. Zimmerman TM, Lee WJ, Bender JG, Mick R, Williams SF. Quantitative CD34 analysis may be used to guide peripheral blood stem cell harvests. Bone Marrow Transplant. 1995;15(3):439-444. PMID: 7541269
  23. Politikos I, Davis E, Nhaissi M, Wagner JE, Brunstein CG, Cohen S, Shpall EJ, Milano F, Scaradavou A, Barker JN. Guidelines for cord blood unit selection. Biol Blood Marrow Transplant. 2020;26(12):2190-2196. doi: 10.1016/j.bbmt.2020.07.030
  24. Raes A, Van Aken S, Craen M, Donckerwolcke R, Vande Walle J. A reference frame for blood volume in children and adolescents. BMC Pediatr. 2006;6:3. doi: 10.1186/1471-2431-6-3
  25. Singhal S, Gordon LI, Tallman MS, Winter JN, Evens AM, Frankfurt O, Williams SF, Grinblatt D, Kaminer L, Meagher R, Mehta J. Ideal rather than actual body weight should be used to calculate cell dose in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2006;37(6):553-557. doi: 10.1038/sj.bmt.1705282
  26. Sanz J, Gale RP. One or two umbilical cord blood cell units? Caveat emptor. Bone Marrow Transplant. 2017;52(3):341-343.
    doi: 10.1038/bmt.2016.277
  27. Klaus J, Herrmann D, Breitkreutz I, Hegenbart U, Mazitschek U, Egerer G, Cremer FW, Lowenthal RM, Huesing J, Fruehauf S, et al. Effect of CD34 cell dose on hematopoietic reconstitution and outcome in 508 patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation. Eur J Haematol. 2007;78(1):21-28. doi: 10.1111/j.0902-4441.2006.t01-1-EJH2895.x
  28. Gorin NC, Labopin M, Reiffers J, Milpied N, Blaise D, Witz F, de Witte T, Meloni G, Attal M, Bernal T, Rocha V. Higher incidence of relapse in patients with acute myelocytic leukemia infused with higher doses of CD34+ cells from leukapheresis products autografted during the first remission. Blood. 2010; 116(17):3157-3162. doi: 10.1182/blood-2009-11-252197
  29. Martin PS, Li S, Nikiforow S, Alyea EP 3rd, Antin JH, Armand P, Cutler CS, Ho VT, Kekre N, Koreth J, Luckey CJ, Ritz J, Soiffer RJ. Infused total nucleated cell dose is a better predictor of transplant outcomes than CD34+ cell number in reduced-intensity mobilized peripheral blood allogeneic hematopoietic cell transplantation. Haematologica. 2016 Apr;101(4):499-505. doi: 10.3324/haematol.2015.134841
  30. Czerw T, Labopin M, Schmid C, Cornelissen JJ, Chevallier P, Blaise D, Kuball J, Vigouroux S, Garban F, Lioure B, et al. High CD3+ and CD34+ peripheral blood stem cell grafts content is associated with increased risk of graft-versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia – an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Oncotarget. 2016;7(19):27255-27266. doi: 10.18632/oncotarget.8463
  31. Konuma T, Kato S, Oiwa-Monna M, Tanoue S, Ogawa M, Isobe M, Tojo A, Takahashi S. Cryopreserved CD34+ Cell Dose, but Not Total Nucleated Cell Dose, Influences Hematopoietic Recovery and Extensive Chronic Graft-versus-Host Disease after Single-Unit Cord Blood Transplantation in Adult Patients. Biol Blood Marrow Transplant. 2017 Jul;23(7):1142-1150. doi: 10.1016/j.bbmt.2017.03.036
  32. Chen Y, Xu LP, Liu KY, Chen H, Chen YH, Zhang XH, Wang Y, Wang FR, Han W, Wang JZ, et al. Higher dose of CD34+ peripheral blood stem cells is associated with better survival after haploidentical stem cell transplantation in pediatric patients. Clin Transplant. 2017;31(2). e12880. doi: 10.1111/ctr.12880
  33. Yamamoto C, Ogawa H, Fukuda T, Igarashi A, Okumura H, Uchida N, Hidaka M, Nakamae H, Matsuoka KI, Eto T, et al. Impact of a low CD34(+) cell dose on allogeneic peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2018;24(4):708-716. doi: 10.1016/j.bbmt.2017.10.043
  34. Yanada M, Konuma T, Kuwatsuka Y, Kondo T, Kawata T, Takahashi S, Uchida N, Miyakoshi S, Tanaka M, Ozawa Y, et al. Unit selection for umbilical cord blood transplantation for adults with acute myeloid leukemia in complete remission: a Japanese experience. Bone Marrow Transplant. 2019; 54(11): 1789-1798. doi: 10.1038/s41409-019-0539-8
  35. Gauntner TD, Brunstein CG, Cao Q, Weisdorf DJ, Warlick ED, Jurdi NE, Maakaron JE, Arora M, Betts BC, Bachanova V, et al. Association of CD34 cell dose with 5-year overall survival after peripheral blood allogeneic hematopoietic cell transplantation in adults with hematologic malignancies. Transplant Cell Ther. 2022;28(2):88-95. doi: 10.1016/j.jtct.2021.11.004
  36. Gauthier J, Wu QV, Gooley TA. Cubic splines to model relationships between continuous variables and outcomes: a guide for clinicians. Bone Marrow Transplant. 2020;55(4):675-680. doi: 10.1038/s41409-019-0679-x
  37. Ayuk F, Balduzzi A. Donor Selection for Adults and Pediatrics. In: Carreras E, Dufour C, Mohty M, Kröger N, editors. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies [Internet]. 7th ed. Cham (CH): Springer; 2019. Chapter 12. PMID: 32091810
  38. Barker JN, Kempenich J, Kurtzberg J, Brunstein CG, Delaney C, Milano F, Politikos I, Shpall EJ, Scaradavou A, Dehn J. CD34+ cell content of 126 341 cord blood units in the US inventory: implications for transplantation and banking. Blood Adv. 2019; 3(8):1267-1271. doi: 10.1182/bloodadvances.2018029157
  39. Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011;333(6039):218-221. doi: 10.1126/science.1201219
  40. Baranov AE, Selidovkin GD, Butturini A, Gale RP. Hematopoietic recovery after 10-Gy acute total body radiation. Blood. 1994;83(2):596-599. PMID: 8286754
  41. Chen J, Gale RP, Feng Y, Hu Y, Qi S, Liu X, et al. Are haematopoietic stem cell transplants stem cell transplants, is there a threshold dose of CD34-positive cells and how many are needed for rapid posttransplant granulocyte recovery? Leukemia. 2023;37(10):1963-1968. doi: 10.1038/s41375-023-01973-2
  42. Kirkpatrick S, Gelatt CD, Jr., Vecchi MP. Optimization by simulated annealing. Science. 1983; 220(4598):671-680.
    doi: 10.1126/science.220.4598.671
  43. Green PJ, Silverman BW. Nonparametric Regression and Generalized Linear Models: A Roughness Penalty Approach. London: Chapman & Hall; 1994. doi: 10.1201/b15710
  44. Yokoyama Y, Maie K, Fukuda T, Uchida N, Mukae J, Sawa M, Kubo K, Kurokawa M, Nakamae H, Ichinohe T, Atsuta Y, Chiba S. A et al. A high CD34(+) cell dose is associated with better disease-free survival in patients with low-risk diseases undergoing peripheral blood stem cell transplantation from HLA-matched related donors. Bone Marrow Transplant. 2020;55(9):1726-1735. doi: 10.1038/s41409-020-0817-5

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["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(1653) "<p style="text-align: justify;">На основании различных данных мы демонстрируем, что CD34-позитивные клетки не являются точным предиктором количества гемопоэтических стволовых клеток у человека. На примере трансплантации клеток пуповинной крови при лейкозах мы также показываем, что, по-видимому, не существует пороговых значений для CD34-позитивных клеток необходимых для восстановления функций костного мозга после высокодозной претрансплантационной терапии. Наконец мы демонстрируем, что при использовании CD34-позитивных клеток в качестве суррогатного маркера гемопоэтических стволовых клеток человека, их доза должна выражаться количеством клеток на объем крови, а не на массу тела. Эти выводы, в случае их валидации, могут иметь важные клинические последствия.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> CD34-позитивные клетки, пороговая доза, трансплантация, доза трансплантата.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(196) "Поиск пороговой дозы CD34-позитивных клеток, необходимой для восстановления гемопоэза после трансплантации" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(196) "Поиск пороговой дозы CD34-позитивных клеток, необходимой для восстановления гемопоэза после трансплантации" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(196) "Поиск пороговой дозы CD34-позитивных клеток, необходимой для восстановления гемопоэза после трансплантации" ["SECTION_META_TITLE"]=> string(196) "Поиск пороговой дозы CD34-позитивных клеток, необходимой для восстановления гемопоэза после трансплантации" ["SECTION_META_KEYWORDS"]=> string(196) "Поиск пороговой дозы CD34-позитивных клеток, необходимой для восстановления гемопоэза после трансплантации" ["SECTION_META_DESCRIPTION"]=> string(196) "Поиск пороговой дозы CD34-позитивных клеток, необходимой для восстановления гемопоэза после трансплантации" ["SECTION_PICTURE_FILE_ALT"]=> string(196) "Поиск пороговой дозы CD34-позитивных клеток, необходимой для восстановления гемопоэза после трансплантации" ["SECTION_PICTURE_FILE_TITLE"]=> string(196) "Поиск пороговой дозы CD34-позитивных клеток, необходимой для восстановления гемопоэза после трансплантации" ["SECTION_PICTURE_FILE_NAME"]=> string(9) "-cd34-img" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(196) "Поиск пороговой дозы CD34-позитивных клеток, необходимой для восстановления гемопоэза после трансплантации" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(196) "Поиск пороговой дозы CD34-позитивных клеток, необходимой для восстановления гемопоэза после трансплантации" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(9) "-cd34-img" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(9) "-cd34-img" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(9) "-cd34-img" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "265" } ["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" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["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) "30748" ["VALUE"]=> string(22) "09/24/2023 12:00:00 am" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(22) "09/24/2023 12:00:00 am" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> 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) "30749" ["VALUE"]=> string(22) "10/27/2023 12:00:00 am" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(22) "10/27/2023 12:00:00 am" ["~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) { 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string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["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(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"]=> 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) "30750" ["VALUE"]=> array(2) { ["TEXT"]=> string(120) "<p>Юнрен Чен<sup>1,2</sup>, Роберт Питер Гэйл<sup>3</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(84) "

Юнрен Чен1,2, Роберт Питер Гэйл3

" ["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) "30751" ["VALUE"]=> array(2) { ["TEXT"]=> string(1019) "<p><sup>1</sup> Главная государственная лаборатория экспериментальной гематологии, Национальный клинический научный центр болезней крови; Лаборатория клеточных экосистем Хэйхэ, Институт гематологии и госпиталь болезней крови; Китайская академия медицинских наук и Пекинский объединенный медицинский колледж, Тяньцзин, Китай <br> <sup>2</sup> Tяньцзинский институт наук о здоровье, Тяньцзин, Китай<br> <sup>3</sup> Центр гематологии, Отдел иммунологии и воспаления, Имперский колледж науки, технологии и медицины, Лондон, Великобритания</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(959) "

1 Главная государственная лаборатория экспериментальной гематологии, Национальный клинический научный центр болезней крови; Лаборатория клеточных экосистем Хэйхэ, Институт гематологии и госпиталь болезней крови; Китайская академия медицинских наук и Пекинский объединенный медицинский колледж, Тяньцзин, Китай
2 Tяньцзинский институт наук о здоровье, Тяньцзин, Китай
3 Центр гематологии, Отдел иммунологии и воспаления, Имперский колледж науки, технологии и медицины, Лондон, Великобритания

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На основании различных данных мы демонстрируем, что CD34-позитивные клетки не являются точным предиктором количества гемопоэтических стволовых клеток у человека. На примере трансплантации клеток пуповинной крови при лейкозах мы также показываем, что, по-видимому, не существует пороговых значений для CD34-позитивных клеток необходимых для восстановления функций костного мозга после высокодозной претрансплантационной терапии. Наконец мы демонстрируем, что при использовании CD34-позитивных клеток в качестве суррогатного маркера гемопоэтических стволовых клеток человека, их доза должна выражаться количеством клеток на объем крови, а не на массу тела. Эти выводы, в случае их валидации, могут иметь важные клинические последствия.

Ключевые слова

CD34-позитивные клетки, пороговая доза, трансплантация, доза трансплантата.

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Junren Chen1,2, Robert Peter Gale3

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1 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
2 Tianjin Institutes of Health Science, Tianjin, China
3 Centre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK


Correspondence:
Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCP, FRCPI (hon), FRSM, Centre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK SW7 2AZ
E-mail: robertgalemd@gmail.com


Citation: Chen J, Gale RP. Is there a threshold dose of CD34-positive cells for posttransplant bone marrow recovery? Cell Ther Transplant 2023; 12(3): 4-10.

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Using diverse data we show CD34-positive cells are not an accurate estimator of numbers of haematopoietic stem cells in humans. We also show in the context of umbilical cord transplants for leukaemia there is likely no threshold of CD34-positive cells needed to restore bone marrow function after high-dose pretransplant therapy. Lastly, we show that, when CD34-positive cells are used as a surrogate marker for human haematopoietic stem cells, the dose should be expressed as numbers per blood volume and not body weight. These conclusions, if validated, may have important clinical implications.

Keywords

CD34-positive cells, threshold dose, transplant, graft dosage.

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Junren Chen1,2, Robert Peter Gale3

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Junren Chen1,2, Robert Peter Gale3

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Using diverse data we show CD34-positive cells are not an accurate estimator of numbers of haematopoietic stem cells in humans. We also show in the context of umbilical cord transplants for leukaemia there is likely no threshold of CD34-positive cells needed to restore bone marrow function after high-dose pretransplant therapy. Lastly, we show that, when CD34-positive cells are used as a surrogate marker for human haematopoietic stem cells, the dose should be expressed as numbers per blood volume and not body weight. These conclusions, if validated, may have important clinical implications.

Keywords

CD34-positive cells, threshold dose, transplant, graft dosage.

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Using diverse data we show CD34-positive cells are not an accurate estimator of numbers of haematopoietic stem cells in humans. We also show in the context of umbilical cord transplants for leukaemia there is likely no threshold of CD34-positive cells needed to restore bone marrow function after high-dose pretransplant therapy. Lastly, we show that, when CD34-positive cells are used as a surrogate marker for human haematopoietic stem cells, the dose should be expressed as numbers per blood volume and not body weight. These conclusions, if validated, may have important clinical implications.

Keywords

CD34-positive cells, threshold dose, transplant, graft dosage.

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1 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
2 Tianjin Institutes of Health Science, Tianjin, China
3 Centre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK


Correspondence:
Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCP, FRCPI (hon), FRSM, Centre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK SW7 2AZ
E-mail: robertgalemd@gmail.com


Citation: Chen J, Gale RP. Is there a threshold dose of CD34-positive cells for posttransplant bone marrow recovery? Cell Ther Transplant 2023; 12(3): 4-10.

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1 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
2 Tianjin Institutes of Health Science, Tianjin, China
3 Centre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK


Correspondence:
Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCP, FRCPI (hon), FRSM, Centre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK SW7 2AZ
E-mail: robertgalemd@gmail.com


Citation: Chen J, Gale RP. Is there a threshold dose of CD34-positive cells for posttransplant bone marrow recovery? Cell Ther Transplant 2023; 12(3): 4-10.

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Юнрен Чен1,2, Роберт Питер Гэйл3

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Юнрен Чен1,2, Роберт Питер Гэйл3

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На основании различных данных мы демонстрируем, что CD34-позитивные клетки не являются точным предиктором количества гемопоэтических стволовых клеток у человека. На примере трансплантации клеток пуповинной крови при лейкозах мы также показываем, что, по-видимому, не существует пороговых значений для CD34-позитивных клеток необходимых для восстановления функций костного мозга после высокодозной претрансплантационной терапии. Наконец мы демонстрируем, что при использовании CD34-позитивных клеток в качестве суррогатного маркера гемопоэтических стволовых клеток человека, их доза должна выражаться количеством клеток на объем крови, а не на массу тела. Эти выводы, в случае их валидации, могут иметь важные клинические последствия.

Ключевые слова

CD34-позитивные клетки, пороговая доза, трансплантация, доза трансплантата.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1597) "

На основании различных данных мы демонстрируем, что CD34-позитивные клетки не являются точным предиктором количества гемопоэтических стволовых клеток у человека. На примере трансплантации клеток пуповинной крови при лейкозах мы также показываем, что, по-видимому, не существует пороговых значений для CD34-позитивных клеток необходимых для восстановления функций костного мозга после высокодозной претрансплантационной терапии. Наконец мы демонстрируем, что при использовании CD34-позитивных клеток в качестве суррогатного маркера гемопоэтических стволовых клеток человека, их доза должна выражаться количеством клеток на объем крови, а не на массу тела. Эти выводы, в случае их валидации, могут иметь важные клинические последствия.

Ключевые слова

CD34-позитивные клетки, пороговая доза, трансплантация, доза трансплантата.

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1 Главная государственная лаборатория экспериментальной гематологии, Национальный клинический научный центр болезней крови; Лаборатория клеточных экосистем Хэйхэ, Институт гематологии и госпиталь болезней крови; Китайская академия медицинских наук и Пекинский объединенный медицинский колледж, Тяньцзин, Китай
2 Tяньцзинский институт наук о здоровье, Тяньцзин, Китай
3 Центр гематологии, Отдел иммунологии и воспаления, Имперский колледж науки, технологии и медицины, Лондон, Великобритания

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1 Главная государственная лаборатория экспериментальной гематологии, Национальный клинический научный центр болезней крови; Лаборатория клеточных экосистем Хэйхэ, Институт гематологии и госпиталь болезней крови; Китайская академия медицинских наук и Пекинский объединенный медицинский колледж, Тяньцзин, Китай
2 Tяньцзинский институт наук о здоровье, Тяньцзин, Китай
3 Центр гематологии, Отдел иммунологии и воспаления, Имперский колледж науки, технологии и медицины, Лондон, Великобритания

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Introduction

Nowadays, Hodgkin's lymphoma (HL) is a highly curable disease with estimated 5-year survival rates greater than 90% after treatment with chemotherapy alone or combined with radiotherapy (RT) in pediatric patients [1]. Nonetheless refractory disease or relapse are the therapeutic challenge for treating physicians. [2]. The standard of care for relapsed or refractory (r/r) HL in pediatrics is a risk-adapted approach using high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT). However, the treatment landscape has evolved with the advent of several novel agents, particularly with immune checkpoint inhibitors (ICIs) that have shown their efficacy in r/r pediatric cHL [3].

The mechanism of ICIs action is based on blocking PD-1 receptors on tumor cells. Structurally PD-1 is a transmembrane protein and its interaction with ligands (PD-L1 or PD-L2) results in activation of PD-1/PD-L pathway. This effect leads to downregulation of autoreactive T cells and upregulation of T regulatory cells [4]. The presence of PD-L1 on tumor cells makes them “invisible” to the immune system and thus allows the tumor to avoid an immune response. ICIs block the above-described pathways, which makes it possible for a human body to develop an immune antitumor response again.

Pembrolizumab (pembro) is approved in Russian Federation for children with r/r HL and demonstrates appropriate response rates with acceptable toxicity, but experience of other ICIs is limited in children [5]. As for nivolumab (nivo), our previous data demonstrated its efficacy and relative safety in a small group of pediatric patients with HL [6].

Although ICIs alone are effective in most patients, low progression-free survival (PFS) underlines the importance of remission consolidation. Auto-HSCT demonstrated efficiency and safety in adults for consolidation of remission after ICIs in pilot studies [7]. There are few studies on the role of the auto-HSCT after ICIs in children with r/r HL [8, 9]. Compared to allogeneic HSCT, this approach seems to be more alluring as it is associated with a lower non-relapse mortality (NRM). Overall, to avoid the double-refractory HL or relapse/progression in children with r/r HL it is important to improve the results by shifting to combination therapy, early incorporation of ICIs in treatment and consolidation with auto-HSCT. The present study demonstrates single center experience of auto-HSCT after ICIs in pediatric r/r HL.

Patients and methods

The study included 16 patients with r/r HL that received auto-HSCT after the ICIs therapy in the period of time from 2017 to 2022 (Table 1). There were 81% males and 19% females. Median age was 16 years old. All but one patient with non-classical HL were diagnosed with nodular sclerosis classical HL. Bulky disease and extranodal lesions were diagnosed in 8 (67%) and 9 (75%) children, respectively.

Table 1. Treatment regimens and clinical outcomes in the patients with r/r Hodgkin lymphoma

Kozlov-tab01.jpg

Notes: BV, brentuximab vedotin; BB, brentuximab vedotin+bendamustine; ICE, ifosfamide, etoposide, carboplatin; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone; DHAP, dexamethasone, cytarabine, cisplatin; ABVD, adriamycin, bleomycin, vinblastine and dacarbazine; COPDAC, cyclophosphamide, oncovin, prednisone, dacarbazine; COPP, cyclophosphamide, oncovin, prednisone, procarbazine; CR, complete response; PR, partial response; PD, progression of the disease. The day of auto-HSCT was admitted as the start of observation; NRM, non-relapse mortality.

To confirm the r/r status, second-look biopsies were carried out in 11 patients (69%). Refractoriness was established in 63% (n=10) of patients in case of progression of HL during first-line therapy or relapse within the first 3 months after the end of treatment. Early relapse (disease recurrence in the first 12 months after the start of therapy) was diagnosed in 5 patients (31%) and late relapse in 1 (6%).

Median number of therapy lines before auto-HSCT was 4 (3-8). ICIs were used to induce remission before auto-HSCT in all patients. Nivo was administered in 15 (94%) children at a fixed dose of 40 mg (n=9, 56%) or 3 mg/kg (n=6, 38%). Pembro (2 mg/kg triweekly) was used in four patients (25%), among them three (75%) had a history of previous nivo failure. Nivo alone was used bi- and tri-weekly in combination therapy. ICIs alone were started in all patients but later switched to combinational therapy (ICIs + other drugs) in 9 patients (56%) due to incomplete response. ICIs were combined with bendamustine 90 mg/m2 on days 1 and 2 (n=5) of 21-day cycle, gemcitabine 1000 mg on days 1 and 8 (n=2) of 21-day cycle and brentuximab vedotin 1.8 mg/kg (n=2) on day 1 of 21-day cycle. Median number of ICIs infusions was 5 (3-18) and median number of combinational therapy cycles was 3 (2-6). The response before auto-HSCT was evaluated by PET-CT using the Lugano criteria: complete remission (n=6, 38%), partial response (n=9, 56%), progression (n=1, 6%). Median interval between diagnosis and auto-HSCT was 1.6 years (0.5-3).

The conditioning regimens included BeEAM (bendamustine 320 mg/m2, etoposide 800 mg/m2, cytarabine 1600 mg/m2, melphalan 140 mg/m2) in all patients (94%, n=15) but one. This exclusive patient received FluBenda (fludarabine 90 mg/m2, bendamustine 390 mg/m2) regimen for allogeneic HSCT followed by graft failure and further reinfusion of autologous hematopoietic stem cells. Doses in conditioning regimen were reduced up to 10%-30% in 6 patients due to heavy pretreatment (n=4, >5 lines of prior therapy) and concomitant illness (n=2). The graft source was peripheral blood stem cells (PBSC) in 75% of patients (n=12) and bone marrow (BM) in 25% (n=4). Median number of infused CD34+/kg cells was 3 (2-10). Radiotherapy after auto-HSCT was administered in 8 (50%) patients (median dose 30 Gy).

Statistical analysis was performed using Easy R software. The main objectives of the study were overall survival (OS) and progression-free survival (PFS), which were calculated by Kaplan-Meier method. Survival curves were compared by means of logrank test. Non-relapse mortality (NRM) and cumulative incidence of relapse (CIR) were analyzed with regard to competing events. Adverse events (AE) were assessed according to Common Terminology Criteria for Adverse Events 5.0 (CTCAE).

Kozlov-fig01.jpg

Figure 1. Overall survival (A) and progression-free survival (B) in the r/r Hodgkin lymphoma group

Kozlov-fig02.jpg

Figure 2. Non-relapse mortality and cumulative incidence of relapse in the studied patient group

Results

With a median follow up of 1.3 years (0.3-5.3) after auto-HSCT only 1 patient died in the early posttransplant period due to infectious complications (sepsis). Among survivors 13 patients (87%) remain in complete remission. Three-year OS and PFS were 93.8% (95%Cl: 63.2-99.1) and 79.1% (95%Cl: 47.9-92.8), respectively (Fig. 1A and 1B). Median OS and PFS were not achieved. NRM and CIR were 6.3% (95%CI: 0.4-24.7) and 13.9% (95%CI: 2.3-35.9), respectively (Fig. 2).

Such factors as disease stage (early vs advanced), B symptoms, bulky disease, extranodal involvement, type of first line (EuroNet-PHL vs BEACOPP) and second line therapy (IEP/ABVD vs ICE/DHAP), disease course (refractory vs relapse), second look biopsy, number of previous therapy lines (3 vs ≥4), number of ICI lines (<5 vs ≥5), type of ICI-based therapy (mono- vs combined), disease status prior to auto-HSCT (CR vs PR), dose reduction in conditioning regimen, number of infused CD34+ cells and RT after auto-HSCT did not affect the OS and PFS rates (p>0.27). Only male gender was associated with improved OS (p=0.037).

Severe transient cytopenia was observed in all patients after auto-HSCT. Mucositis developed in the majority of patients (n=12, 75%). Among them grade 4, grade 3, grade 2 and grade 1 mucositis were diagnosed in 1 (8.3%), 5 (41.7%), 4 (33.3%) and 2 (16.7%) patients, respectively. Febrile neutropenia occurred in 9 children (75%). Bacterial infectious complications in posttransplant period included pneumonia (n=3, 25%) and catheter-associated infection (n=1, 8.3%). Three patients (25%) had clinically significant uncommon for auto-HSCT complications: pseudomembranous colitis (n=1, 8.3%), bronchiolitis (n=1, 8.3%) and vasculitis (n=1, 8.3%).

In two patients (16.7%) with relapse after auto-HSCT further antilyphoma therapy was initiated than consisted of nivolumab (n=1, 8.3%) and ICE chemotherapy (n=1, 8.3%).

Discussion

Auto-HSCT is a standard treatment for remission consolidation in pediatric r/r HL after second line chemotherapy [10]. Outcome of children with refractory and early relapsed HL is poor without auto-HSCT [11]. Meanwhile children with late relapses demonstrate relatively favorable outcome after second line chemotherapy alone. This risk-adapted treatment strategy should be used in children with r/r HL [12, 13]. The goal of such approach is to reduce incidence of long-term side effects [14]. Little is known on the role of auto-HSCT in children with r/r HL after ICIs. This approach seems attractive due to ability to achieve remission in the majority of patients with HL after ICIs while subsequent auto-HSCT has a theoretical potential to prevent relapse. ICIs are important milestone in the management of HL but still only approximately 10%-15% of patients can be cured in monotherapy [15]. Status prior to auto-HSCT is a crucial prognostic factor [16]. ICIs-based therapy increases the number of patients in CR prior to transplantation; another benefit of ICIs is a possible resensitization to chemotherapy in r/r HL [17].

Present study demonstrates retrospective single centre experience on auto-HSCT after ICIs in pediatric r/r HL. The data in children on this issue are limited to few publications with promising short-term results [8, 9]. Similar outcome was reported in adults recently [7, 18]. There is an ongoing dispute on the best treatment approach after ICIs (allo-HSCT vs auto-HSCT). To our opinion auto-HSCT is preferable due to lower NRM while allo-HSCT should be reserved for further therapy.

Overall ICIs are usually administered at least for 6 months or longer up to disease progression or unacceptable toxicity [19]. In our study we used short course of ICIs (median of 5 infusions) with the intent to proceed to auto-HSCT at the moment of best response and to reduce potential side effects of long-term ICIs exposure. The same strategy with several ICIs courses prior to auto-HSCT was adopted by other investigators as well [7, 8].

Nivo was administered at fixed dose of 40 mg in nine patients (56%) in our study. Lepik et al. used this reduced fixed dose of nivo with similar results compared to standard dose (3 mg/kg) in adults [20]. The rationale for this was an attempt to decrease possible side effects without the loss of efficacy. ICIs in combination with other antilymphoma drugs demonstrate higher efficacy compared to monotherapy [21, 22]. Our institute previously showed that combination of nivolumab and bendamustine may regain tumor control in patients with r/r HL after nivolumab monotherapy failure [20]. Nine children in our study received ICIs in combination with other drugs due to inadequate response to monotherapy. Data on combination of ICIs with other drugs in pediatric r/r HL are limited to several reports [8]. Conditioning regimen used in the study (BeEAM) is a standard approach for auto-HSCT in HL in our institute though BEAM (carmustine-based) conditioning regimen is more common approach worldwide. We demonstrated previously similar effectiveness of BeEAM and BEAM conditioning regiments for pediatric r/r HL [23].

As patients were heavily pretreated (median number of prior therapies – 4) OS (93.8%) and PFS (76.4%) obtained in our study should be regarded as satisfactory. High PFS after auto-HSCT compares favorably with historical data on ICIs alone and is in concordance with studies in children and adults on auto-HSCT after ICIs [6, 8, 9, 24]. But relatively short follow-up (median 1.3 years) as in other studies precludes valid conclusions and longer observation period is mandatory. Merryman RW et al. demonstrated similar results in heavily pretreated adults with r/r HL after ICIs and auto-HSCT (18-months OS 91%, PFS 86%) [19]. NRM (6.3%) was comparable to data published for auto-HSCT bridged with standard chemotherapy [25].

Among analyzed factors only male gender was associated with improved survival. To our opinion this fact should be regarded as random though some authors demonstrated previously possible association of gender and outcome in HL [26]. Similar survival in children with CR and PR prior to auto-HSCT and in children with different number of therapy lines (3 vs ≥4) supports the hypothesis that ICIs can resentitize to chemotherapy. The same results were previously demonstrated by investigators from USA in adults. These researchers also showed that lack of response to anti-PD-1 therapy, receipt of intervening salvage therapy, and advanced age were all significant predictors of inferior PFS on univariate analysis in a larger cohort (n=78) of adult patients after ICIs-based therapy and auto-HSCT [18]. Cytopenia, mucositis and febrile neutropenia were the three most common complications as had been expected. Unusual complications (vasculitis and bronchiolitis) could probably at least partially be driven by prior exposure to ICIs as immune component could not be ruled out. Though the largest up to date published study on auto-HSCT after ICIs-based therapy in children and young adults (n=43) did not describe any uncommon complications in posttransplant period; autoimmune adverse effects in our study probably were not associated with auto-HSCT and were related to recent ICIs exposure [8]. Complications of ICIs therapy can emerge months or years after the end of treatment [19]. Overall ICIs are well tolerated and can be administered in outpatient setting but one should be aware of rare life-threatening autoimmune complications in children [3, 5].

Conclusion

To summarize, the therapy with ICIs followed by auto-HSCT in children is a promising treatment for r/r HL with a relatively low risk of complications and high PFS rate. However, additional cases and longer follow-up are required to draw valid conclusions.

Conflict of interest

None declared.

References

  1. Smith MA, Altekruse SF, Adamson PC, Reaman GH, Seibel NL. Declining childhood and adolescent cancer mortality. Cancer. 2014;120(16):2497-2506. doi: 10.1002/cncr.28748
  2. Friedman DL, Chen L, Wolden S, Buxton A, McCarten K, FitzGerald TJ, et al. Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk Hodgkin lymphoma: a report from the Children's Oncology Group Study AHOD0031. J Clin Oncol. 2014; 32(32):3651-3658. doi: 10.1200/JCO.2013.52.5410
  3. Davis KL, Fox E, Merchant MS, Reid JM, Kudgus RA, Liu X, et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2020; 21(4):541-550.
    doi: 10.1016/S1470-2045(20)30023-1
  4. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010; 236:219-242.
    doi: 10.1111/j.1600-065X.2010.00923.x
  5. Geoerger B, Kang HJ, Yalon-Oren M, Marshall LV, Vezina C, Pappo A, et al. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2020; 21(1):121-133. doi: 10.1016/S1470-2045(19)30671-0
  6. Kozlov AV, Kazantzev IV, Iukhta TV, Tolkunova PS, Zvyagintseva DA, Gevorgian AG, et al. Nivolumab in pediatric Hodgkin's lymphoma. Cell Ther Transplant. 2019;8(4): 41-48. doi: 10.18620/ctt-1866-8836-2019-8-4-41-48
  7. Advani RH, Moskowitz AJ, Bartlett NL, Vose JM, Ramchandren R, Feldman TA, et al. Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results. Blood. 2021;138(6):427-438. doi: 10.1182/blood.2020009178. PMID: 33827139
  8. Harker-Murray P, Mauz-Körholz C, Leblanc TM, Mascarin M, Michel G, Cooper S, et al. Nivolumab, Brentuximab Vedotin, +/- Bendamustine for R/R Hodgkin lymphoma in children, adolescents, and young Adults. Blood. 2022: blood.2022017118. doi: 10.1182/blood.2022017118
  9. Patel J, Garg A, Patel K, Shah K, Shah S, Yadav R et al. Experience of nivolumab prior to autologous stem cell transplant for relapsed refractory Hodgkin lymphoma. Ind J Hematol Blood Transfus. 2022: 38: 585-590. doi: 10.1007/s12288-021-01490-1
  10. Korsantya MN, Romankova YE, Myakova NV, Pshonkin AV. The experience of using the Brentuximab vedotin in the treatment of children and young adults with primary refractory course and relapses of Hodgkin's lymphoma. Pediatric Hematology/Oncology and Immunopathology. 2020;19(1):47-52. (In Russian). doi: 10.24287/1726-1708-2020-19-1-47-52
  11. Yuen AR, Rosenberg SA, Hoppe RT, Halpern JD, Horning SJ. Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease. Blood. 1997;89(3):814-822. PMID: 9028312
  12. Schellong G, Dorffel W, Claviez A, Körholz D, Mann G, Scheel-Walter HG, et al. Salvage therapy of progressive and recurrent Hodgkin's disease: results from a multicenter study of the pediatric DAL/GPOH-HD Study Group. J Clin Oncol. 2005; 23:6181-6189.
    doi: 10.1200/JCO.2005.07.930
  13. Daw S, Hasenclever D, Mascarin M, Fernández-Teijeiro A, Balwierz W, Beishuizen A, et al. Risk and response adapted treatment guidelines for managing first relapsed and refractory classical Hodgkin lymphoma in children and young people. Recommendations from the EuroNet Pediatric Hodgkin Lymphoma Group. Hemasphere. 2020; 4(1):e329. doi: 10.1097/HS9.0000000000000329
  14. Minn AY, Riedel E, Halpern J, Johnston LJ, Horning SJ, Hoppe RT, et al. Long-term outcomes after high dose therapy and autologous haematopoietic cell rescue for refractory/relapsed Hodgkin lymphoma. Br J Haematol. 2012: 159: 329-339. doi: 10.1111/bjh.12038
  15. Manson G, Herbaux C, Schiano JM, Casasnovas O, Stamatoullas A, Deau B, et al. Lymphoma Study Association (LYSA). Can nivolumab alone cure patients with relapse or refractory Hodgkin lymphoma? A 5-year analysis of the French early access program (EPA). Br J Haematol. 2022; 198(1):203-206. doi: 10.1111/bjh.18198
  16. Kondakova EV, Mikhailova NB , Borsenkova ES, Kalashnikova OB, Medvedeva NV, Ryabchikova VV, et al. Effectiveness of high-dose chemotherapy with autologous stem cell transplantation (ASCT) in patients with relapsed and refractory course of Hodgkin’s lymphoma. Cell Ther Transplant. 2015; 5 (1): 49-50.
  17. Carreau NA, Pail O, Armand P, Advani RH, Spinner MA, Herrera A et al. Checkpoint blockade treatment may sensitize Hodgkin lymphoma to subsequent therapy. Oncologist. 2020;25(10):878-885. doi: 10.1634/theoncologist.2020-0167
  18. Merryman RW, Redd RA, Nishihori T, Chavez J, Nieto Y, Darrah JM et al. Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma. Blood Adv. 2021; 5(6):1648-1659. doi: 10.1182/bloodadvances.2020003556
  19. Marron TU, Ryan AE, Reddy SM, Kaczanowska S, Younis RH, Thakkar D et al. Considerations for treatment duration in responders to immune checkpoint inhibitors. J Immunother Cancer. 2021;9:e001901. doi: 10.1136/jitc-2020-001901
  20. Lepik KV, Mikhailova NB, Kondakova EV, Zalyalov YR, Fedorova LV, Tsvetkova LA, et al. A Study of Safety and Efficacy of Nivolumab and Bendamustine (NB) in Patients With Relapsed/Refractory Hodgkin Lymphoma After Nivolumab Monotherapy Failure. Hemasphere. 2020 Jun 8;4(3):e401. doi: 10.1097/HS9.0000000000000401
  21. Herrera AF, Moskowitz AJ, Bartlett NL, Vose JM, Ramchandren R, Feldman TA, et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018; 131(11):1183-1194.
    doi: 10.1182/blood-2017-10-811224. Epub 2017 Dec 11.
  22. Ansell SM: Beyond checkpoint inhibitors for Hodgkin lymphoma. 2018. Pan Pacific Lymphoma Conference. Invited Lecture. Presented July 19, 2018. – available https://vimeo.com/281511112
  23. Kozlov AV, Kazantsev IV, Morozova EV, Yukhta TV, Nikolayev IYu, Tolkunova PS, et al. Autologous hematopoietic stem cell transplantation in children with relapsed or refractory Hodgkin lymphoma. Pediatric Hematology/Oncology and Immunopathology. 2022;21(2):13-21. (In Russian). doi: 10.24287/1726-1708-2022-21-2-13-21
  24. Halahleh K, Al Sawajneh S, Saleh Y, Shahin O, Abufara A, Ma'koseh M, et al. Pembrolizumab for the treatment of relapsed and refractory classical Hodgkin lymphoma after autologous transplant and in transplant-naïve patients. Clin Lymphoma Myeloma Leuk. 2022; 22(8):589-595. doi: 10.1016/j.clml.2022.02.009
  25. Satwani P, Ahn KW, Carreras J, Abdel-Azim H, Cairo MS, Cashen A, et al. A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma. Bone Marrow Transplant. 2015; 50 (11): 1416-1423.
    doi: 10.1038/bmt.2015.177
  26. Provencio M, España P, Millán I, Yebra M, Sánchez AC, de la Torre A, et al. Prognostic factors in Hodgkin's disease. Leuk Lymphoma. 2004; 45(6):1133-1139. doi: 10.1080/10428190310001646022

" ["~DETAIL_TEXT"]=> string(25571) "

Introduction

Nowadays, Hodgkin's lymphoma (HL) is a highly curable disease with estimated 5-year survival rates greater than 90% after treatment with chemotherapy alone or combined with radiotherapy (RT) in pediatric patients [1]. Nonetheless refractory disease or relapse are the therapeutic challenge for treating physicians. [2]. The standard of care for relapsed or refractory (r/r) HL in pediatrics is a risk-adapted approach using high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT). However, the treatment landscape has evolved with the advent of several novel agents, particularly with immune checkpoint inhibitors (ICIs) that have shown their efficacy in r/r pediatric cHL [3].

The mechanism of ICIs action is based on blocking PD-1 receptors on tumor cells. Structurally PD-1 is a transmembrane protein and its interaction with ligands (PD-L1 or PD-L2) results in activation of PD-1/PD-L pathway. This effect leads to downregulation of autoreactive T cells and upregulation of T regulatory cells [4]. The presence of PD-L1 on tumor cells makes them “invisible” to the immune system and thus allows the tumor to avoid an immune response. ICIs block the above-described pathways, which makes it possible for a human body to develop an immune antitumor response again.

Pembrolizumab (pembro) is approved in Russian Federation for children with r/r HL and demonstrates appropriate response rates with acceptable toxicity, but experience of other ICIs is limited in children [5]. As for nivolumab (nivo), our previous data demonstrated its efficacy and relative safety in a small group of pediatric patients with HL [6].

Although ICIs alone are effective in most patients, low progression-free survival (PFS) underlines the importance of remission consolidation. Auto-HSCT demonstrated efficiency and safety in adults for consolidation of remission after ICIs in pilot studies [7]. There are few studies on the role of the auto-HSCT after ICIs in children with r/r HL [8, 9]. Compared to allogeneic HSCT, this approach seems to be more alluring as it is associated with a lower non-relapse mortality (NRM). Overall, to avoid the double-refractory HL or relapse/progression in children with r/r HL it is important to improve the results by shifting to combination therapy, early incorporation of ICIs in treatment and consolidation with auto-HSCT. The present study demonstrates single center experience of auto-HSCT after ICIs in pediatric r/r HL.

Patients and methods

The study included 16 patients with r/r HL that received auto-HSCT after the ICIs therapy in the period of time from 2017 to 2022 (Table 1). There were 81% males and 19% females. Median age was 16 years old. All but one patient with non-classical HL were diagnosed with nodular sclerosis classical HL. Bulky disease and extranodal lesions were diagnosed in 8 (67%) and 9 (75%) children, respectively.

Table 1. Treatment regimens and clinical outcomes in the patients with r/r Hodgkin lymphoma

Kozlov-tab01.jpg

Notes: BV, brentuximab vedotin; BB, brentuximab vedotin+bendamustine; ICE, ifosfamide, etoposide, carboplatin; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone; DHAP, dexamethasone, cytarabine, cisplatin; ABVD, adriamycin, bleomycin, vinblastine and dacarbazine; COPDAC, cyclophosphamide, oncovin, prednisone, dacarbazine; COPP, cyclophosphamide, oncovin, prednisone, procarbazine; CR, complete response; PR, partial response; PD, progression of the disease. The day of auto-HSCT was admitted as the start of observation; NRM, non-relapse mortality.

To confirm the r/r status, second-look biopsies were carried out in 11 patients (69%). Refractoriness was established in 63% (n=10) of patients in case of progression of HL during first-line therapy or relapse within the first 3 months after the end of treatment. Early relapse (disease recurrence in the first 12 months after the start of therapy) was diagnosed in 5 patients (31%) and late relapse in 1 (6%).

Median number of therapy lines before auto-HSCT was 4 (3-8). ICIs were used to induce remission before auto-HSCT in all patients. Nivo was administered in 15 (94%) children at a fixed dose of 40 mg (n=9, 56%) or 3 mg/kg (n=6, 38%). Pembro (2 mg/kg triweekly) was used in four patients (25%), among them three (75%) had a history of previous nivo failure. Nivo alone was used bi- and tri-weekly in combination therapy. ICIs alone were started in all patients but later switched to combinational therapy (ICIs + other drugs) in 9 patients (56%) due to incomplete response. ICIs were combined with bendamustine 90 mg/m2 on days 1 and 2 (n=5) of 21-day cycle, gemcitabine 1000 mg on days 1 and 8 (n=2) of 21-day cycle and brentuximab vedotin 1.8 mg/kg (n=2) on day 1 of 21-day cycle. Median number of ICIs infusions was 5 (3-18) and median number of combinational therapy cycles was 3 (2-6). The response before auto-HSCT was evaluated by PET-CT using the Lugano criteria: complete remission (n=6, 38%), partial response (n=9, 56%), progression (n=1, 6%). Median interval between diagnosis and auto-HSCT was 1.6 years (0.5-3).

The conditioning regimens included BeEAM (bendamustine 320 mg/m2, etoposide 800 mg/m2, cytarabine 1600 mg/m2, melphalan 140 mg/m2) in all patients (94%, n=15) but one. This exclusive patient received FluBenda (fludarabine 90 mg/m2, bendamustine 390 mg/m2) regimen for allogeneic HSCT followed by graft failure and further reinfusion of autologous hematopoietic stem cells. Doses in conditioning regimen were reduced up to 10%-30% in 6 patients due to heavy pretreatment (n=4, >5 lines of prior therapy) and concomitant illness (n=2). The graft source was peripheral blood stem cells (PBSC) in 75% of patients (n=12) and bone marrow (BM) in 25% (n=4). Median number of infused CD34+/kg cells was 3 (2-10). Radiotherapy after auto-HSCT was administered in 8 (50%) patients (median dose 30 Gy).

Statistical analysis was performed using Easy R software. The main objectives of the study were overall survival (OS) and progression-free survival (PFS), which were calculated by Kaplan-Meier method. Survival curves were compared by means of logrank test. Non-relapse mortality (NRM) and cumulative incidence of relapse (CIR) were analyzed with regard to competing events. Adverse events (AE) were assessed according to Common Terminology Criteria for Adverse Events 5.0 (CTCAE).

Kozlov-fig01.jpg

Figure 1. Overall survival (A) and progression-free survival (B) in the r/r Hodgkin lymphoma group

Kozlov-fig02.jpg

Figure 2. Non-relapse mortality and cumulative incidence of relapse in the studied patient group

Results

With a median follow up of 1.3 years (0.3-5.3) after auto-HSCT only 1 patient died in the early posttransplant period due to infectious complications (sepsis). Among survivors 13 patients (87%) remain in complete remission. Three-year OS and PFS were 93.8% (95%Cl: 63.2-99.1) and 79.1% (95%Cl: 47.9-92.8), respectively (Fig. 1A and 1B). Median OS and PFS were not achieved. NRM and CIR were 6.3% (95%CI: 0.4-24.7) and 13.9% (95%CI: 2.3-35.9), respectively (Fig. 2).

Such factors as disease stage (early vs advanced), B symptoms, bulky disease, extranodal involvement, type of first line (EuroNet-PHL vs BEACOPP) and second line therapy (IEP/ABVD vs ICE/DHAP), disease course (refractory vs relapse), second look biopsy, number of previous therapy lines (3 vs ≥4), number of ICI lines (<5 vs ≥5), type of ICI-based therapy (mono- vs combined), disease status prior to auto-HSCT (CR vs PR), dose reduction in conditioning regimen, number of infused CD34+ cells and RT after auto-HSCT did not affect the OS and PFS rates (p>0.27). Only male gender was associated with improved OS (p=0.037).

Severe transient cytopenia was observed in all patients after auto-HSCT. Mucositis developed in the majority of patients (n=12, 75%). Among them grade 4, grade 3, grade 2 and grade 1 mucositis were diagnosed in 1 (8.3%), 5 (41.7%), 4 (33.3%) and 2 (16.7%) patients, respectively. Febrile neutropenia occurred in 9 children (75%). Bacterial infectious complications in posttransplant period included pneumonia (n=3, 25%) and catheter-associated infection (n=1, 8.3%). Three patients (25%) had clinically significant uncommon for auto-HSCT complications: pseudomembranous colitis (n=1, 8.3%), bronchiolitis (n=1, 8.3%) and vasculitis (n=1, 8.3%).

In two patients (16.7%) with relapse after auto-HSCT further antilyphoma therapy was initiated than consisted of nivolumab (n=1, 8.3%) and ICE chemotherapy (n=1, 8.3%).

Discussion

Auto-HSCT is a standard treatment for remission consolidation in pediatric r/r HL after second line chemotherapy [10]. Outcome of children with refractory and early relapsed HL is poor without auto-HSCT [11]. Meanwhile children with late relapses demonstrate relatively favorable outcome after second line chemotherapy alone. This risk-adapted treatment strategy should be used in children with r/r HL [12, 13]. The goal of such approach is to reduce incidence of long-term side effects [14]. Little is known on the role of auto-HSCT in children with r/r HL after ICIs. This approach seems attractive due to ability to achieve remission in the majority of patients with HL after ICIs while subsequent auto-HSCT has a theoretical potential to prevent relapse. ICIs are important milestone in the management of HL but still only approximately 10%-15% of patients can be cured in monotherapy [15]. Status prior to auto-HSCT is a crucial prognostic factor [16]. ICIs-based therapy increases the number of patients in CR prior to transplantation; another benefit of ICIs is a possible resensitization to chemotherapy in r/r HL [17].

Present study demonstrates retrospective single centre experience on auto-HSCT after ICIs in pediatric r/r HL. The data in children on this issue are limited to few publications with promising short-term results [8, 9]. Similar outcome was reported in adults recently [7, 18]. There is an ongoing dispute on the best treatment approach after ICIs (allo-HSCT vs auto-HSCT). To our opinion auto-HSCT is preferable due to lower NRM while allo-HSCT should be reserved for further therapy.

Overall ICIs are usually administered at least for 6 months or longer up to disease progression or unacceptable toxicity [19]. In our study we used short course of ICIs (median of 5 infusions) with the intent to proceed to auto-HSCT at the moment of best response and to reduce potential side effects of long-term ICIs exposure. The same strategy with several ICIs courses prior to auto-HSCT was adopted by other investigators as well [7, 8].

Nivo was administered at fixed dose of 40 mg in nine patients (56%) in our study. Lepik et al. used this reduced fixed dose of nivo with similar results compared to standard dose (3 mg/kg) in adults [20]. The rationale for this was an attempt to decrease possible side effects without the loss of efficacy. ICIs in combination with other antilymphoma drugs demonstrate higher efficacy compared to monotherapy [21, 22]. Our institute previously showed that combination of nivolumab and bendamustine may regain tumor control in patients with r/r HL after nivolumab monotherapy failure [20]. Nine children in our study received ICIs in combination with other drugs due to inadequate response to monotherapy. Data on combination of ICIs with other drugs in pediatric r/r HL are limited to several reports [8]. Conditioning regimen used in the study (BeEAM) is a standard approach for auto-HSCT in HL in our institute though BEAM (carmustine-based) conditioning regimen is more common approach worldwide. We demonstrated previously similar effectiveness of BeEAM and BEAM conditioning regiments for pediatric r/r HL [23].

As patients were heavily pretreated (median number of prior therapies – 4) OS (93.8%) and PFS (76.4%) obtained in our study should be regarded as satisfactory. High PFS after auto-HSCT compares favorably with historical data on ICIs alone and is in concordance with studies in children and adults on auto-HSCT after ICIs [6, 8, 9, 24]. But relatively short follow-up (median 1.3 years) as in other studies precludes valid conclusions and longer observation period is mandatory. Merryman RW et al. demonstrated similar results in heavily pretreated adults with r/r HL after ICIs and auto-HSCT (18-months OS 91%, PFS 86%) [19]. NRM (6.3%) was comparable to data published for auto-HSCT bridged with standard chemotherapy [25].

Among analyzed factors only male gender was associated with improved survival. To our opinion this fact should be regarded as random though some authors demonstrated previously possible association of gender and outcome in HL [26]. Similar survival in children with CR and PR prior to auto-HSCT and in children with different number of therapy lines (3 vs ≥4) supports the hypothesis that ICIs can resentitize to chemotherapy. The same results were previously demonstrated by investigators from USA in adults. These researchers also showed that lack of response to anti-PD-1 therapy, receipt of intervening salvage therapy, and advanced age were all significant predictors of inferior PFS on univariate analysis in a larger cohort (n=78) of adult patients after ICIs-based therapy and auto-HSCT [18]. Cytopenia, mucositis and febrile neutropenia were the three most common complications as had been expected. Unusual complications (vasculitis and bronchiolitis) could probably at least partially be driven by prior exposure to ICIs as immune component could not be ruled out. Though the largest up to date published study on auto-HSCT after ICIs-based therapy in children and young adults (n=43) did not describe any uncommon complications in posttransplant period; autoimmune adverse effects in our study probably were not associated with auto-HSCT and were related to recent ICIs exposure [8]. Complications of ICIs therapy can emerge months or years after the end of treatment [19]. Overall ICIs are well tolerated and can be administered in outpatient setting but one should be aware of rare life-threatening autoimmune complications in children [3, 5].

Conclusion

To summarize, the therapy with ICIs followed by auto-HSCT in children is a promising treatment for r/r HL with a relatively low risk of complications and high PFS rate. However, additional cases and longer follow-up are required to draw valid conclusions.

Conflict of interest

None declared.

References

  1. Smith MA, Altekruse SF, Adamson PC, Reaman GH, Seibel NL. Declining childhood and adolescent cancer mortality. Cancer. 2014;120(16):2497-2506. doi: 10.1002/cncr.28748
  2. Friedman DL, Chen L, Wolden S, Buxton A, McCarten K, FitzGerald TJ, et al. Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk Hodgkin lymphoma: a report from the Children's Oncology Group Study AHOD0031. J Clin Oncol. 2014; 32(32):3651-3658. doi: 10.1200/JCO.2013.52.5410
  3. Davis KL, Fox E, Merchant MS, Reid JM, Kudgus RA, Liu X, et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2020; 21(4):541-550.
    doi: 10.1016/S1470-2045(20)30023-1
  4. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010; 236:219-242.
    doi: 10.1111/j.1600-065X.2010.00923.x
  5. Geoerger B, Kang HJ, Yalon-Oren M, Marshall LV, Vezina C, Pappo A, et al. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2020; 21(1):121-133. doi: 10.1016/S1470-2045(19)30671-0
  6. Kozlov AV, Kazantzev IV, Iukhta TV, Tolkunova PS, Zvyagintseva DA, Gevorgian AG, et al. Nivolumab in pediatric Hodgkin's lymphoma. Cell Ther Transplant. 2019;8(4): 41-48. doi: 10.18620/ctt-1866-8836-2019-8-4-41-48
  7. Advani RH, Moskowitz AJ, Bartlett NL, Vose JM, Ramchandren R, Feldman TA, et al. Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results. Blood. 2021;138(6):427-438. doi: 10.1182/blood.2020009178. PMID: 33827139
  8. Harker-Murray P, Mauz-Körholz C, Leblanc TM, Mascarin M, Michel G, Cooper S, et al. Nivolumab, Brentuximab Vedotin, +/- Bendamustine for R/R Hodgkin lymphoma in children, adolescents, and young Adults. Blood. 2022: blood.2022017118. doi: 10.1182/blood.2022017118
  9. Patel J, Garg A, Patel K, Shah K, Shah S, Yadav R et al. Experience of nivolumab prior to autologous stem cell transplant for relapsed refractory Hodgkin lymphoma. Ind J Hematol Blood Transfus. 2022: 38: 585-590. doi: 10.1007/s12288-021-01490-1
  10. Korsantya MN, Romankova YE, Myakova NV, Pshonkin AV. The experience of using the Brentuximab vedotin in the treatment of children and young adults with primary refractory course and relapses of Hodgkin's lymphoma. Pediatric Hematology/Oncology and Immunopathology. 2020;19(1):47-52. (In Russian). doi: 10.24287/1726-1708-2020-19-1-47-52
  11. Yuen AR, Rosenberg SA, Hoppe RT, Halpern JD, Horning SJ. Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease. Blood. 1997;89(3):814-822. PMID: 9028312
  12. Schellong G, Dorffel W, Claviez A, Körholz D, Mann G, Scheel-Walter HG, et al. Salvage therapy of progressive and recurrent Hodgkin's disease: results from a multicenter study of the pediatric DAL/GPOH-HD Study Group. J Clin Oncol. 2005; 23:6181-6189.
    doi: 10.1200/JCO.2005.07.930
  13. Daw S, Hasenclever D, Mascarin M, Fernández-Teijeiro A, Balwierz W, Beishuizen A, et al. Risk and response adapted treatment guidelines for managing first relapsed and refractory classical Hodgkin lymphoma in children and young people. Recommendations from the EuroNet Pediatric Hodgkin Lymphoma Group. Hemasphere. 2020; 4(1):e329. doi: 10.1097/HS9.0000000000000329
  14. Minn AY, Riedel E, Halpern J, Johnston LJ, Horning SJ, Hoppe RT, et al. Long-term outcomes after high dose therapy and autologous haematopoietic cell rescue for refractory/relapsed Hodgkin lymphoma. Br J Haematol. 2012: 159: 329-339. doi: 10.1111/bjh.12038
  15. Manson G, Herbaux C, Schiano JM, Casasnovas O, Stamatoullas A, Deau B, et al. Lymphoma Study Association (LYSA). Can nivolumab alone cure patients with relapse or refractory Hodgkin lymphoma? A 5-year analysis of the French early access program (EPA). Br J Haematol. 2022; 198(1):203-206. doi: 10.1111/bjh.18198
  16. Kondakova EV, Mikhailova NB , Borsenkova ES, Kalashnikova OB, Medvedeva NV, Ryabchikova VV, et al. Effectiveness of high-dose chemotherapy with autologous stem cell transplantation (ASCT) in patients with relapsed and refractory course of Hodgkin’s lymphoma. Cell Ther Transplant. 2015; 5 (1): 49-50.
  17. Carreau NA, Pail O, Armand P, Advani RH, Spinner MA, Herrera A et al. Checkpoint blockade treatment may sensitize Hodgkin lymphoma to subsequent therapy. Oncologist. 2020;25(10):878-885. doi: 10.1634/theoncologist.2020-0167
  18. Merryman RW, Redd RA, Nishihori T, Chavez J, Nieto Y, Darrah JM et al. Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma. Blood Adv. 2021; 5(6):1648-1659. doi: 10.1182/bloodadvances.2020003556
  19. Marron TU, Ryan AE, Reddy SM, Kaczanowska S, Younis RH, Thakkar D et al. Considerations for treatment duration in responders to immune checkpoint inhibitors. J Immunother Cancer. 2021;9:e001901. doi: 10.1136/jitc-2020-001901
  20. Lepik KV, Mikhailova NB, Kondakova EV, Zalyalov YR, Fedorova LV, Tsvetkova LA, et al. A Study of Safety and Efficacy of Nivolumab and Bendamustine (NB) in Patients With Relapsed/Refractory Hodgkin Lymphoma After Nivolumab Monotherapy Failure. Hemasphere. 2020 Jun 8;4(3):e401. doi: 10.1097/HS9.0000000000000401
  21. Herrera AF, Moskowitz AJ, Bartlett NL, Vose JM, Ramchandren R, Feldman TA, et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018; 131(11):1183-1194.
    doi: 10.1182/blood-2017-10-811224. Epub 2017 Dec 11.
  22. Ansell SM: Beyond checkpoint inhibitors for Hodgkin lymphoma. 2018. Pan Pacific Lymphoma Conference. Invited Lecture. Presented July 19, 2018. – available https://vimeo.com/281511112
  23. Kozlov AV, Kazantsev IV, Morozova EV, Yukhta TV, Nikolayev IYu, Tolkunova PS, et al. Autologous hematopoietic stem cell transplantation in children with relapsed or refractory Hodgkin lymphoma. Pediatric Hematology/Oncology and Immunopathology. 2022;21(2):13-21. (In Russian). doi: 10.24287/1726-1708-2022-21-2-13-21
  24. Halahleh K, Al Sawajneh S, Saleh Y, Shahin O, Abufara A, Ma'koseh M, et al. Pembrolizumab for the treatment of relapsed and refractory classical Hodgkin lymphoma after autologous transplant and in transplant-naïve patients. Clin Lymphoma Myeloma Leuk. 2022; 22(8):589-595. doi: 10.1016/j.clml.2022.02.009
  25. Satwani P, Ahn KW, Carreras J, Abdel-Azim H, Cairo MS, Cashen A, et al. A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma. Bone Marrow Transplant. 2015; 50 (11): 1416-1423.
    doi: 10.1038/bmt.2015.177
  26. Provencio M, España P, Millán I, Yebra M, Sánchez AC, de la Torre A, et al. Prognostic factors in Hodgkin's disease. Leuk Lymphoma. 2004; 45(6):1133-1139. doi: 10.1080/10428190310001646022

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["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" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["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) "30772" ["VALUE"]=> string(22) "06/07/2023 12:00:00 am" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(22) "06/07/2023 12:00:00 am" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> 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) "30773" ["VALUE"]=> string(22) "06/23/2023 12:00:00 am" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(22) "06/23/2023 12:00:00 am" ["~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) 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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"]=> 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(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"]=> 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) "30774" ["VALUE"]=> array(2) { ["TEXT"]=> string(669) "<p>Андрей В. Козлов, Ярослава В. Комарова, Артем А. Потанин, Александр Н. Галимов, Елена В. Морозова, Асмик Г. Геворгян, Татьяна А. Быкова, Илья В. Казанцев, Наталья Б. Михайлова, Ольга И. Богданова, Маргарита С. Халипская, Татьяна В. Юхта, Полина С. Толкунова, Анна А. Осипова, Юрий А. Пунанов, Вадим В. Байков, Анна В. Ботина, Александр Д. Кулагин, Людмила С. Зубаровская</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(657) "

Андрей В. Козлов, Ярослава В. Комарова, Артем А. Потанин, Александр Н. Галимов, Елена В. Морозова, Асмик Г. Геворгян, Татьяна А. Быкова, Илья В. Казанцев, Наталья Б. Михайлова, Ольга И. Богданова, Маргарита С. Халипская, Татьяна В. Юхта, Полина С. Толкунова, Анна А. Осипова, Юрий А. Пунанов, Вадим В. Байков, Анна В. Ботина, Александр Д. Кулагин, Людмила С. Зубаровская

" ["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) "30775" ["VALUE"]=> array(2) { ["TEXT"]=> string(373) "<p>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(361) "

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) "" ["~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) "30776" ["VALUE"]=> array(2) { ["TEXT"]=> string(1995) "<p style="text-align: justify;">Лечение рецидивирующей/рефрактерной лимфомы Ходжкина (р/р ЛХ) у детей все еще является до конца не решенной проблемой, особенно у пациентов с несколькими линиями терапии в анамнезе. В рамках данной работы была показана высокая эффективность ауто-ТГСК у предлеченных пациентов детского возраста после применения ингибиторов иммунных контрольных точек (ИКТ). Всего ауто-ТГСК после ИКТ была проведена у 16 детей с р/р ЛХ, при этом общая выживаемость и выживаемость без прогрессирования составили 93,8% и 73,1% соответственно (медиана наблюдения – 1,3 года). Был зарегистрирован один летальный случай (6,3%) из-за сепсиса в раннем посттрансплантационном периоде. Таким образом, ауто-ТГСК после терапии ИКТ представляет собой перспективный метод терапии у детей с р/р ЛХ, однако необходим более длительный период наблюдения, чтобы сделать более обоснованные выводы.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Лимфома Ходжкина, рецидивирующая/рефрактерная, ингибиторы контрольных точек, трансплантация гемопоэтических стволовых клеток, аутологичная. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1939) "

Лечение рецидивирующей/рефрактерной лимфомы Ходжкина (р/р ЛХ) у детей все еще является до конца не решенной проблемой, особенно у пациентов с несколькими линиями терапии в анамнезе. В рамках данной работы была показана высокая эффективность ауто-ТГСК у предлеченных пациентов детского возраста после применения ингибиторов иммунных контрольных точек (ИКТ). Всего ауто-ТГСК после ИКТ была проведена у 16 детей с р/р ЛХ, при этом общая выживаемость и выживаемость без прогрессирования составили 93,8% и 73,1% соответственно (медиана наблюдения – 1,3 года). Был зарегистрирован один летальный случай (6,3%) из-за сепсиса в раннем посттрансплантационном периоде. Таким образом, ауто-ТГСК после терапии ИКТ представляет собой перспективный метод терапии у детей с р/р ЛХ, однако необходим более длительный период наблюдения, чтобы сделать более обоснованные выводы.

Ключевые слова

Лимфома Ходжкина, рецидивирующая/рефрактерная, ингибиторы контрольных точек, трансплантация гемопоэтических стволовых клеток, аутологичная.

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Andrey V. Kozlov, Yaroslava V. Komarova, Artem A. Potanin, Alexander N. Galimov, Elena V. Morozova, Asmik G. Gevorgian, Tatyana A. Bykova, Ilya V. Kazantzev, Natalia B. Mikhailova, Olga I. Bogdanova, Margarita S. Halipskaya, Tatyana V. Yukhta, Polina S. Tolkunova, Anna A. Osipova, Yury A. Punanov, Vadim V. Baykov, Anna V. Botina, Alexander D. Kulagin, Ludmila S. Zubarovskaya

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Andrey V. Kozlov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
E-mail: kozlovandrew1983@ya.ru


Citation: Kozlov AV, Komarova YV, Potanin AA, et al. Autologous hematopoietic stem cell transplantation after immune checkpoint inhibitor therapy in pediatric relapsed/refractory Hodgkin lymphoma. Cell Ther Transplant 2023; 12(3): 17-22.

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Effective treatment of relapsed/refractory Hodgkin lymphoma (r/r HL) in children is still a challenge, especially in case of failure after several therapy lines. The present study demonstrates high effectiveness of auto-HSCT in heavily pretreated children with HL after immune checkpoint inhibitor (ICIs) therapy. Overall 16 children with r/r HL received auto-HSCT after ICIs with OS and PFS of 93.8% and 73.1%, respectively (median follow-up, 1.3 years). The transplantation procedure was generally well tolerated, with only one death (6.3%) due to sepsis. Thus, auto-HSCT after ICIs is a promising option in pediatric r/r HL but longer follow-up is mandatory to draw valid conclusions.

Keywords

Hodgkin lymphoma, relapsed/refractory, immune checkpoint inhibitors, hematopoietic stem cell transplantation, autologous.

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Kozlov, Yaroslava V. Komarova, Artem A. Potanin, Alexander N. Galimov, Elena V. Morozova, Asmik G. Gevorgian, Tatyana A. Bykova, Ilya V. Kazantzev, Natalia B. Mikhailova, Olga I. Bogdanova, Margarita S. Halipskaya, Tatyana V. Yukhta, Polina S. Tolkunova, Anna A. Osipova, Yury A. Punanov, Vadim V. Baykov, Anna V. Botina, Alexander D. Kulagin, Ludmila S. Zubarovskaya</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(386) "

Andrey V. Kozlov, Yaroslava V. Komarova, Artem A. Potanin, Alexander N. Galimov, Elena V. Morozova, Asmik G. Gevorgian, Tatyana A. Bykova, Ilya V. Kazantzev, Natalia B. Mikhailova, Olga I. Bogdanova, Margarita S. Halipskaya, Tatyana V. Yukhta, Polina S. Tolkunova, Anna A. Osipova, Yury A. Punanov, Vadim V. Baykov, Anna V. Botina, Alexander D. Kulagin, Ludmila S. Zubarovskaya

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Andrey V. Kozlov, Yaroslava V. Komarova, Artem A. Potanin, Alexander N. Galimov, Elena V. Morozova, Asmik G. Gevorgian, Tatyana A. Bykova, Ilya V. Kazantzev, Natalia B. Mikhailova, Olga I. Bogdanova, Margarita S. Halipskaya, Tatyana V. Yukhta, Polina S. Tolkunova, Anna A. Osipova, Yury A. Punanov, Vadim V. Baykov, Anna V. Botina, Alexander D. Kulagin, Ludmila S. Zubarovskaya

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Effective treatment of relapsed/refractory Hodgkin lymphoma (r/r HL) in children is still a challenge, especially in case of failure after several therapy lines. The present study demonstrates high effectiveness of auto-HSCT in heavily pretreated children with HL after immune checkpoint inhibitor (ICIs) therapy. Overall 16 children with r/r HL received auto-HSCT after ICIs with OS and PFS of 93.8% and 73.1%, respectively (median follow-up, 1.3 years). The transplantation procedure was generally well tolerated, with only one death (6.3%) due to sepsis. Thus, auto-HSCT after ICIs is a promising option in pediatric r/r HL but longer follow-up is mandatory to draw valid conclusions.

Keywords

Hodgkin lymphoma, relapsed/refractory, immune checkpoint inhibitors, hematopoietic stem cell transplantation, autologous.

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Effective treatment of relapsed/refractory Hodgkin lymphoma (r/r HL) in children is still a challenge, especially in case of failure after several therapy lines. The present study demonstrates high effectiveness of auto-HSCT in heavily pretreated children with HL after immune checkpoint inhibitor (ICIs) therapy. Overall 16 children with r/r HL received auto-HSCT after ICIs with OS and PFS of 93.8% and 73.1%, respectively (median follow-up, 1.3 years). The transplantation procedure was generally well tolerated, with only one death (6.3%) due to sepsis. Thus, auto-HSCT after ICIs is a promising option in pediatric r/r HL but longer follow-up is mandatory to draw valid conclusions.

Keywords

Hodgkin lymphoma, relapsed/refractory, immune checkpoint inhibitors, hematopoietic stem cell transplantation, autologous.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Andrey V. Kozlov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
E-mail: kozlovandrew1983@ya.ru


Citation: Kozlov AV, Komarova YV, Potanin AA, et al. Autologous hematopoietic stem cell transplantation after immune checkpoint inhibitor therapy in pediatric relapsed/refractory Hodgkin lymphoma. Cell Ther Transplant 2023; 12(3): 17-22.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Andrey V. Kozlov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
E-mail: kozlovandrew1983@ya.ru


Citation: Kozlov AV, Komarova YV, Potanin AA, et al. Autologous hematopoietic stem cell transplantation after immune checkpoint inhibitor therapy in pediatric relapsed/refractory Hodgkin lymphoma. Cell Ther Transplant 2023; 12(3): 17-22.

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Андрей В. Козлов, Ярослава В. Комарова, Артем А. Потанин, Александр Н. Галимов, Елена В. Морозова, Асмик Г. Геворгян, Татьяна А. Быкова, Илья В. Казанцев, Наталья Б. Михайлова, Ольга И. Богданова, Маргарита С. Халипская, Татьяна В. Юхта, Полина С. Толкунова, Анна А. Осипова, Юрий А. Пунанов, Вадим В. Байков, Анна В. Ботина, Александр Д. Кулагин, Людмила С. Зубаровская

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Андрей В. Козлов, Ярослава В. Комарова, Артем А. Потанин, Александр Н. Галимов, Елена В. Морозова, Асмик Г. Геворгян, Татьяна А. Быкова, Илья В. Казанцев, Наталья Б. Михайлова, Ольга И. Богданова, Маргарита С. Халипская, Татьяна В. Юхта, Полина С. Толкунова, Анна А. Осипова, Юрий А. Пунанов, Вадим В. Байков, Анна В. Ботина, Александр Д. Кулагин, Людмила С. Зубаровская

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Лечение рецидивирующей/рефрактерной лимфомы Ходжкина (р/р ЛХ) у детей все еще является до конца не решенной проблемой, особенно у пациентов с несколькими линиями терапии в анамнезе. В рамках данной работы была показана высокая эффективность ауто-ТГСК у предлеченных пациентов детского возраста после применения ингибиторов иммунных контрольных точек (ИКТ). Всего ауто-ТГСК после ИКТ была проведена у 16 детей с р/р ЛХ, при этом общая выживаемость и выживаемость без прогрессирования составили 93,8% и 73,1% соответственно (медиана наблюдения – 1,3 года). Был зарегистрирован один летальный случай (6,3%) из-за сепсиса в раннем посттрансплантационном периоде. Таким образом, ауто-ТГСК после терапии ИКТ представляет собой перспективный метод терапии у детей с р/р ЛХ, однако необходим более длительный период наблюдения, чтобы сделать более обоснованные выводы.

Ключевые слова

Лимфома Ходжкина, рецидивирующая/рефрактерная, ингибиторы контрольных точек, трансплантация гемопоэтических стволовых клеток, аутологичная.

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Лечение рецидивирующей/рефрактерной лимфомы Ходжкина (р/р ЛХ) у детей все еще является до конца не решенной проблемой, особенно у пациентов с несколькими линиями терапии в анамнезе. В рамках данной работы была показана высокая эффективность ауто-ТГСК у предлеченных пациентов детского возраста после применения ингибиторов иммунных контрольных точек (ИКТ). Всего ауто-ТГСК после ИКТ была проведена у 16 детей с р/р ЛХ, при этом общая выживаемость и выживаемость без прогрессирования составили 93,8% и 73,1% соответственно (медиана наблюдения – 1,3 года). Был зарегистрирован один летальный случай (6,3%) из-за сепсиса в раннем посттрансплантационном периоде. Таким образом, ауто-ТГСК после терапии ИКТ представляет собой перспективный метод терапии у детей с р/р ЛХ, однако необходим более длительный период наблюдения, чтобы сделать более обоснованные выводы.

Ключевые слова

Лимфома Ходжкина, рецидивирующая/рефрактерная, ингибиторы контрольных точек, трансплантация гемопоэтических стволовых клеток, аутологичная.

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

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

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Introduction

Successful treatment options for hematological malignancies have significantly expanded over last decades. These advances are associated with the use of targeted therapy and HSCT. However, the use of modern therapy programs is associated with higher risks of infectious complications in oncohematological patients, with systemic infections of the bloodstream being the most dangerous events [1]. Infectious processes exacerbate the severity of the patient's condition sometimes leading to reduced dosage of specific therapy, treatment interruption and, ultimately, to progression of the underlying disease. Previously, severe bacterial infections were considered mostly of exogenous origin. However, some recent studies have shown that endogenous infections of intestinal origin may be primary source for the microbes entering the bloodstream in oncohematological patients. These conditions are facilitated by immunosuppression and frequent development of mucositis in the patients [2]. Introduction of new methods for identifying microorganisms, such as real-time polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) of bacterial genome has revolutionized the approach to assessing the intestinal microbiota. Their use has allowed for a more comprehensive assessment of the species composition of the microbiota, which includes more than 1000 species of bacteria, 80% of which are unculturable microorganisms. This information has provided the basis for extensive studies of intestinal microbiota parameters as predictors of the development of bloodstream infections, particularly, in immunosuppressed oncohematological patients. In this study, we aimed to investigate the features of gut microbiome associated with development of bloodstream infections (BSI) in oncohematological patients during high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT).

Patients and methods

Table 1. Clinical baseline characteristics of multiple myeloma patients included in the study

Chebotkevich-tab01.jpg

Patients under study

The patient cohort consisted of 30 hospitalized patients with multiple myeloma, aged 48-67 years (median 60 years), who underwent autologous HSCT at the Russian Research Institute of Hematology and Transfusiology in St. Petersburg, Russia, from 2020 to 2022. The basic clinical characteristics of patients included in the study are depicted in Table 1.

Study protocol

The study protocol included collection and processing of feces obtained from patients before AHSCT and at different times from 7 to 35 days after it. All patients were treated with fluoroquinolones to prevent infections. In case of infectious complications, antibiotic treatment was performed as based on bacteriological and clinical data. The study protocol included collection and deep freezing of stool samples obtained before transplantation and at various time points ranging from D+7 to D+35 post-transplant. The patients taken into the study had at least ≥3 consecutive sequenced samples. After extraction and purification of DNA from each biological sample, PCR amplification of the V5 region of the 16S rRNA gene was performed using modified universal bacterial primers. The purified PCR products were sequenced using the MiSeq Illumina platform according to instructions from manufacturer. Phylogenetic classification from phyla to the species level was performed using the Illumina database. For the rapid identification of pathogens, automatic bacteriological systems (BacT/ALERT 3D) were used in combination with our method based on real-time PCR [3]. Clinical and demographic parameters, i.e., patient’s age, sex, underlying disease, conditioning regimen, source of hematopoietic stem cells, duration and choice of antibiotics, were included in the analysis.

Bioinformatic analysis

Primer sequences (region V3-V4) were excluded from analysis using the pre-process 16S program. Trimming of low-quality reads was performed using the Trimmomatic program [4]. Taxonomic classification to the species level was carried out using the Kraken taxonomic classification system with the Kraken standard database [5, 6]. Re-estimation of microbial abundance was conducted using the Bayesian Reestimation of Abundance with Kraken algorithm [7]. The sequences were grouped into operating taxonomic units (OTUs) based on 97% identity. The total number of 16SrRNA genes per 1 g of biological material served as a measure of bacterial density being calculated by means of quantitative PCR, based on the total DNA amount extracted from each sample.

Biodiversity indices used in this study included Shannon, Simpson, Chao 1, Simpson’s inverse index. Processing and analysis of clinical, laboratory and phylogenetic data was performed using R software (R Development Core Team, Vienna, Austria, version 4.2.1) [8, 9], along with the Phyloseq package (version 1.41.0) [10], Tidyverse (version 1.3.1) [11], rstatix package (version 0.7.0) [12] and ggstatsplot package (0.9.3) [13]. To assess the independent nature of differences in microbiome biodiversity following HSCT, we employed Bayesian nonparametric statistics, including the Dirichlet distribution (Dir (α)) from the HMP package (version 2.0.1) 14. The Bray-Curtis index was used as a measure of compositional dissimilarity between two different sites based on the counts from each site.

Results

Chebotkevich-fig01.jpg

Figure 1. Alpha diversity index of gut microbiome in myeloma patients before and after AHSCT

We have found a significant decrease in the alpha diversity indexes of intestinal microbiome in patients after AHSCT. The results of assessing changes in the alpha diversity index of MM patients examined in different periods before and after HSCT are presented in Fig. 1. Moreover, a decrease in the Shannon diversity index was detected up to 7 days after transplantation in 26 out of 30 patients. However, the extent of this decline proved to be variable. Of note, the greatest decrease in the biodiversity index (from 2.527 to 1.17) was found in one case (patient K.).

A significant decrease in the microbiota diversity index after AHSCT was shown, regardless of the stage of multiple myeloma or renal failure (p=0.0305). One should note that a significant decrease in the microbiota diversity index was established in patients over time following AHSCT, along with negative effect of antibiotics and cytostatic chemotherapy on the diversity of the microbiota. The data of individual patients has demonstrated a decrease in the Shannon index in six cases over the period of 7 to 35 days post-transplant. In three cases, this index did not change, and only in one patient an increase in the diversity index was observed after HSCT.

Furthermore, we studied the dynamics of the composition of the intestinal microbiome at the phylum level. To simplify the analysis of changes in the intestinal microbiome during AHSCT, the most common phyla of bacteria (Bacteroidetes, Firmicutes, Proteobacteria, Actinobacteria) were chosen. The time changes of intestinal microbiome composition at the level of phyla (Fig. 2) showed that the Bacteroides phylum formed the basis of the microbiota in a significant part of the patients. Firmicutes, another dominant phylum, was found somewhat less frequently.

Chebotkevich-fig02.jpg

Figure 2. Time changes of intestinal microbiome composition at the level of major bacterial phyla before AHSCT and on day +7 to D+35 post-transplant

Chebotkevich-fig03.jpg

Figure 3. Top phylum classification results (patient K. day +2 after transplantation)

In our study, the median frequency of Proteobacteria detection in gut microbiota ranged from 1% to 6%, and only in one case (patient K.), the proportion of the Proteobacteria type was 38.9%, being detected on the day +2 after transplantation (Fig. 3).

Of note, the post-transplant period in the patient K was complicated by sepsis with the development of infectious-toxic shock. It should be emphasized that no serious clinical manifestations of infectious complications were observed in other patients.

These results, in our opinion, suggest a significant diagnostic value of assessing the microbiota changes. The identification of the dominance of the Proteobacteria type made it possible to predict the occurrence of sepsis and prescribe timely antibacterial therapy, which led to the resolution of the infectious process.

Discussion

Bloodstream infections and sepsis are serious life-threatening complications in patients with hematological malignancies during high-dose chemotherapy and HSCT. Routine bacteriological analysis is often not able to predict the risk of its occurrence. It has been shown that the main route of penetration of microorganisms into the bloodstream is endogenous infection originating from intestines [2]. Extensive studies have been conducted to investigate the pathogenesis of bloodstream infections (BSI) during endogenous microbial dissemination. The opportunity of using microbiome changes as a predictor of developing systemic BSI and septicemia was suggested. It is known that endogenous infection from the intestine plays a leading role in the development of Gram-negative bloodstream infections [2]. The composition of intestinal microbiota plays an important role in this process. In addition to decreased microbial biodiversity, HSCT may result into massive replacement of normal microbiome by a single type of bacteria. A decade ago, Taur Y. et al. [15] suggested a phenomenon “domination” (replacement of more than 30% of the relative abundance of the microbiome with one taxonomic type). It was demonstrated that the dominance of the Proteobacteria type with more than 30% in gut microbiome is a reliable risk predictor of a developing Gram-negative BSI in allogeneic HSCT [15]. Recently, it was confirmed the possibility of using this criterion (Proteobacteria dominance) in clinical practice as a BSI predictor in patients with allogeneic HSCT [16]. Our present results show that this phenomenon is also observed in autologous HSCT.

Conclusions

Our results confirm the view that a significant decrease in the microbiota biological diversity index is observed in AHSCT. It has been demonstrated that endogenous infection originating intestines plays a leading role in the development of Gram-negative bloodstream infections. The composition of the intestinal microbiota plays a crucial role in this process. In addition to a decreased biodiversity during HSCT, an almost complete replacement of gut microbiome by one type of bacteria may be observed. Dominance of the Proteobacteria phylum has been shown to be an independent risk factor for the development of Gram-negative bloodstream infections. The possibility of using this phenomenon (dominance of the Proteobacteria type above 30%) in clinical practice for the diagnosis of systemic BSI in patients after AHSCT has been demonstrated. The composition of the intestinal microbiome significantly influenced the infections incidence in patients subjected to AHSCT.

A sufficiently increased proportion of Proteobacteria in the spectrum of the intestinal microbiome may be a reliable risk predictor of systemic Gram-negative BSI after high-dose therapy and AHSCT. The stool samples should be assessed by NGS both before and after HSCT, when monitoring the gut microbiota composition.

Conflict of interest

No potential conflict of interest is reported.

References

  1. Chebotkevich VN, Bessmeltsev SS, Kiseleva EE, Stizhak NP, Kaytandzhan EI, Burylev VV. Bloodstream infections and herpesvirus activation following intensive chemotherapy of adult oncohematological patients. Cell Ther Transplant. 2016; 5(4); 21-31. doi: 10.18620/ctt-1866-8836-2016-5-4-21-31
  2. Stoma I. Gut microbiota in immunocompromised patients: reappraisial of pathogenesis of bloodstream infections. Clinical Infectology and Parasitology. 2018; 7(2):224-233. (In Russian).
  3. Chebotkevich VN, Martens JA, Sidorenko SV, Kiseleva EE. Accelerated method of identification of bacteria and micromycetes in hemocultures in children using multiplex PCR in real time. Zhurnal Infektologii. 2019; 11(4):107-112 (in Russian).
    doi: 10.22625/2072-6732-2019-11-4-107-112
  4. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence reEpub 2014 Apr 1.
    doi: 10.1093/bioinformatics/btu170
  5. Wood DE, Lu J, Langmead B. Improved metagenomic analysis with Kraken 2. Genome Biol. 2020; 20, 257.
    doi: 10.1186/s13059-019-1891-0
  6. Wood DE, Salzberg SL. Kraken: ultrafast metagenomic sequence classification using exact alignments. Genome Biol. 2014. 15 (3), R46. doi: 10.1186/gb-2014-15-3-r46
  7. Lu J, Breitwieser FP, Thielen P, Salzberg S.L. Bracken: estimating species abundance in metagenomics data. PeerJ Computer Science. 2017. 3:e104. doi: 10.7717/peerj-cs.104
  8. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2022. https://www.R-project.org/
  9. RStudio Team. RStudio: Integrated Development for R. RStudio, PBC, Boston, MA. 2020. http://www.rstudio.com/
  10. McMurdie PJ, Holmes S. phyloseq: an R package for reproducible interactives analysis and graphics of microbiome census data. Plos One 2013, 8(4):e1217. doi: 10.1371/journal.pone.0061217
  11. Wickham Н, Averick М, Bryan J, Chang W, McGowan L, François R, et al. Welcome to the tidyverse. Journal of Open Source Software. 2019. 4(43), 1686. doi: 10.21105/joss.01686
  12. Kassambara A. rstatix: Pipe-Friendly Framework for Basic Statistical Tests. R package version 0.7.0. 2021.
  13. Patil I. Visualizations with statistical details: The 'ggstatsplot' approach. Journal of Open Source Software. 2021. 6(61), 3167.
    doi: 10.21105/joss.03167
  14. La Rosa PS, Deych E, Carter S, Shands B, Yang D, Shannon WD. HMP: Hypothesis Testing and Power Calculations for Comparing Metagenomic Samples from HMP. R package version 2.0.1, 2019. https://CRAN.R-project.org/package=HMP
  15. Taur Y, Xavier J, Lipuma L, Ubeda C, Goldberg J, Gobourne A. et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hemopoietic stem transplantation. Clin Infect Dis. 2012. 55(7):905-914. doi: 10.1093/cid/cis580
  16. Stoma I, Uss M, Milanova E, Iscrov I, Uss A. Biodiversity screening of gut microbiome during the allogeneic hematopoietic stem cell transplantation: data from the real-life clinical practice, All Life, 2022. Vol.15. № 1. P/547-554. doi: 10.1080/26895293.2022.2074546

" ["~DETAIL_TEXT"]=> string(17314) "

Introduction

Successful treatment options for hematological malignancies have significantly expanded over last decades. These advances are associated with the use of targeted therapy and HSCT. However, the use of modern therapy programs is associated with higher risks of infectious complications in oncohematological patients, with systemic infections of the bloodstream being the most dangerous events [1]. Infectious processes exacerbate the severity of the patient's condition sometimes leading to reduced dosage of specific therapy, treatment interruption and, ultimately, to progression of the underlying disease. Previously, severe bacterial infections were considered mostly of exogenous origin. However, some recent studies have shown that endogenous infections of intestinal origin may be primary source for the microbes entering the bloodstream in oncohematological patients. These conditions are facilitated by immunosuppression and frequent development of mucositis in the patients [2]. Introduction of new methods for identifying microorganisms, such as real-time polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) of bacterial genome has revolutionized the approach to assessing the intestinal microbiota. Their use has allowed for a more comprehensive assessment of the species composition of the microbiota, which includes more than 1000 species of bacteria, 80% of which are unculturable microorganisms. This information has provided the basis for extensive studies of intestinal microbiota parameters as predictors of the development of bloodstream infections, particularly, in immunosuppressed oncohematological patients. In this study, we aimed to investigate the features of gut microbiome associated with development of bloodstream infections (BSI) in oncohematological patients during high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT).

Patients and methods

Table 1. Clinical baseline characteristics of multiple myeloma patients included in the study

Chebotkevich-tab01.jpg

Patients under study

The patient cohort consisted of 30 hospitalized patients with multiple myeloma, aged 48-67 years (median 60 years), who underwent autologous HSCT at the Russian Research Institute of Hematology and Transfusiology in St. Petersburg, Russia, from 2020 to 2022. The basic clinical characteristics of patients included in the study are depicted in Table 1.

Study protocol

The study protocol included collection and processing of feces obtained from patients before AHSCT and at different times from 7 to 35 days after it. All patients were treated with fluoroquinolones to prevent infections. In case of infectious complications, antibiotic treatment was performed as based on bacteriological and clinical data. The study protocol included collection and deep freezing of stool samples obtained before transplantation and at various time points ranging from D+7 to D+35 post-transplant. The patients taken into the study had at least ≥3 consecutive sequenced samples. After extraction and purification of DNA from each biological sample, PCR amplification of the V5 region of the 16S rRNA gene was performed using modified universal bacterial primers. The purified PCR products were sequenced using the MiSeq Illumina platform according to instructions from manufacturer. Phylogenetic classification from phyla to the species level was performed using the Illumina database. For the rapid identification of pathogens, automatic bacteriological systems (BacT/ALERT 3D) were used in combination with our method based on real-time PCR [3]. Clinical and demographic parameters, i.e., patient’s age, sex, underlying disease, conditioning regimen, source of hematopoietic stem cells, duration and choice of antibiotics, were included in the analysis.

Bioinformatic analysis

Primer sequences (region V3-V4) were excluded from analysis using the pre-process 16S program. Trimming of low-quality reads was performed using the Trimmomatic program [4]. Taxonomic classification to the species level was carried out using the Kraken taxonomic classification system with the Kraken standard database [5, 6]. Re-estimation of microbial abundance was conducted using the Bayesian Reestimation of Abundance with Kraken algorithm [7]. The sequences were grouped into operating taxonomic units (OTUs) based on 97% identity. The total number of 16SrRNA genes per 1 g of biological material served as a measure of bacterial density being calculated by means of quantitative PCR, based on the total DNA amount extracted from each sample.

Biodiversity indices used in this study included Shannon, Simpson, Chao 1, Simpson’s inverse index. Processing and analysis of clinical, laboratory and phylogenetic data was performed using R software (R Development Core Team, Vienna, Austria, version 4.2.1) [8, 9], along with the Phyloseq package (version 1.41.0) [10], Tidyverse (version 1.3.1) [11], rstatix package (version 0.7.0) [12] and ggstatsplot package (0.9.3) [13]. To assess the independent nature of differences in microbiome biodiversity following HSCT, we employed Bayesian nonparametric statistics, including the Dirichlet distribution (Dir (α)) from the HMP package (version 2.0.1) 14. The Bray-Curtis index was used as a measure of compositional dissimilarity between two different sites based on the counts from each site.

Results

Chebotkevich-fig01.jpg

Figure 1. Alpha diversity index of gut microbiome in myeloma patients before and after AHSCT

We have found a significant decrease in the alpha diversity indexes of intestinal microbiome in patients after AHSCT. The results of assessing changes in the alpha diversity index of MM patients examined in different periods before and after HSCT are presented in Fig. 1. Moreover, a decrease in the Shannon diversity index was detected up to 7 days after transplantation in 26 out of 30 patients. However, the extent of this decline proved to be variable. Of note, the greatest decrease in the biodiversity index (from 2.527 to 1.17) was found in one case (patient K.).

A significant decrease in the microbiota diversity index after AHSCT was shown, regardless of the stage of multiple myeloma or renal failure (p=0.0305). One should note that a significant decrease in the microbiota diversity index was established in patients over time following AHSCT, along with negative effect of antibiotics and cytostatic chemotherapy on the diversity of the microbiota. The data of individual patients has demonstrated a decrease in the Shannon index in six cases over the period of 7 to 35 days post-transplant. In three cases, this index did not change, and only in one patient an increase in the diversity index was observed after HSCT.

Furthermore, we studied the dynamics of the composition of the intestinal microbiome at the phylum level. To simplify the analysis of changes in the intestinal microbiome during AHSCT, the most common phyla of bacteria (Bacteroidetes, Firmicutes, Proteobacteria, Actinobacteria) were chosen. The time changes of intestinal microbiome composition at the level of phyla (Fig. 2) showed that the Bacteroides phylum formed the basis of the microbiota in a significant part of the patients. Firmicutes, another dominant phylum, was found somewhat less frequently.

Chebotkevich-fig02.jpg

Figure 2. Time changes of intestinal microbiome composition at the level of major bacterial phyla before AHSCT and on day +7 to D+35 post-transplant

Chebotkevich-fig03.jpg

Figure 3. Top phylum classification results (patient K. day +2 after transplantation)

In our study, the median frequency of Proteobacteria detection in gut microbiota ranged from 1% to 6%, and only in one case (patient K.), the proportion of the Proteobacteria type was 38.9%, being detected on the day +2 after transplantation (Fig. 3).

Of note, the post-transplant period in the patient K was complicated by sepsis with the development of infectious-toxic shock. It should be emphasized that no serious clinical manifestations of infectious complications were observed in other patients.

These results, in our opinion, suggest a significant diagnostic value of assessing the microbiota changes. The identification of the dominance of the Proteobacteria type made it possible to predict the occurrence of sepsis and prescribe timely antibacterial therapy, which led to the resolution of the infectious process.

Discussion

Bloodstream infections and sepsis are serious life-threatening complications in patients with hematological malignancies during high-dose chemotherapy and HSCT. Routine bacteriological analysis is often not able to predict the risk of its occurrence. It has been shown that the main route of penetration of microorganisms into the bloodstream is endogenous infection originating from intestines [2]. Extensive studies have been conducted to investigate the pathogenesis of bloodstream infections (BSI) during endogenous microbial dissemination. The opportunity of using microbiome changes as a predictor of developing systemic BSI and septicemia was suggested. It is known that endogenous infection from the intestine plays a leading role in the development of Gram-negative bloodstream infections [2]. The composition of intestinal microbiota plays an important role in this process. In addition to decreased microbial biodiversity, HSCT may result into massive replacement of normal microbiome by a single type of bacteria. A decade ago, Taur Y. et al. [15] suggested a phenomenon “domination” (replacement of more than 30% of the relative abundance of the microbiome with one taxonomic type). It was demonstrated that the dominance of the Proteobacteria type with more than 30% in gut microbiome is a reliable risk predictor of a developing Gram-negative BSI in allogeneic HSCT [15]. Recently, it was confirmed the possibility of using this criterion (Proteobacteria dominance) in clinical practice as a BSI predictor in patients with allogeneic HSCT [16]. Our present results show that this phenomenon is also observed in autologous HSCT.

Conclusions

Our results confirm the view that a significant decrease in the microbiota biological diversity index is observed in AHSCT. It has been demonstrated that endogenous infection originating intestines plays a leading role in the development of Gram-negative bloodstream infections. The composition of the intestinal microbiota plays a crucial role in this process. In addition to a decreased biodiversity during HSCT, an almost complete replacement of gut microbiome by one type of bacteria may be observed. Dominance of the Proteobacteria phylum has been shown to be an independent risk factor for the development of Gram-negative bloodstream infections. The possibility of using this phenomenon (dominance of the Proteobacteria type above 30%) in clinical practice for the diagnosis of systemic BSI in patients after AHSCT has been demonstrated. The composition of the intestinal microbiome significantly influenced the infections incidence in patients subjected to AHSCT.

A sufficiently increased proportion of Proteobacteria in the spectrum of the intestinal microbiome may be a reliable risk predictor of systemic Gram-negative BSI after high-dose therapy and AHSCT. The stool samples should be assessed by NGS both before and after HSCT, when monitoring the gut microbiota composition.

Conflict of interest

No potential conflict of interest is reported.

References

  1. Chebotkevich VN, Bessmeltsev SS, Kiseleva EE, Stizhak NP, Kaytandzhan EI, Burylev VV. Bloodstream infections and herpesvirus activation following intensive chemotherapy of adult oncohematological patients. Cell Ther Transplant. 2016; 5(4); 21-31. doi: 10.18620/ctt-1866-8836-2016-5-4-21-31
  2. Stoma I. Gut microbiota in immunocompromised patients: reappraisial of pathogenesis of bloodstream infections. Clinical Infectology and Parasitology. 2018; 7(2):224-233. (In Russian).
  3. Chebotkevich VN, Martens JA, Sidorenko SV, Kiseleva EE. Accelerated method of identification of bacteria and micromycetes in hemocultures in children using multiplex PCR in real time. Zhurnal Infektologii. 2019; 11(4):107-112 (in Russian).
    doi: 10.22625/2072-6732-2019-11-4-107-112
  4. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence reEpub 2014 Apr 1.
    doi: 10.1093/bioinformatics/btu170
  5. Wood DE, Lu J, Langmead B. Improved metagenomic analysis with Kraken 2. Genome Biol. 2020; 20, 257.
    doi: 10.1186/s13059-019-1891-0
  6. Wood DE, Salzberg SL. Kraken: ultrafast metagenomic sequence classification using exact alignments. Genome Biol. 2014. 15 (3), R46. doi: 10.1186/gb-2014-15-3-r46
  7. Lu J, Breitwieser FP, Thielen P, Salzberg S.L. Bracken: estimating species abundance in metagenomics data. PeerJ Computer Science. 2017. 3:e104. doi: 10.7717/peerj-cs.104
  8. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2022. https://www.R-project.org/
  9. RStudio Team. RStudio: Integrated Development for R. RStudio, PBC, Boston, MA. 2020. http://www.rstudio.com/
  10. McMurdie PJ, Holmes S. phyloseq: an R package for reproducible interactives analysis and graphics of microbiome census data. Plos One 2013, 8(4):e1217. doi: 10.1371/journal.pone.0061217
  11. Wickham Н, Averick М, Bryan J, Chang W, McGowan L, François R, et al. Welcome to the tidyverse. Journal of Open Source Software. 2019. 4(43), 1686. doi: 10.21105/joss.01686
  12. Kassambara A. rstatix: Pipe-Friendly Framework for Basic Statistical Tests. R package version 0.7.0. 2021.
  13. Patil I. Visualizations with statistical details: The 'ggstatsplot' approach. Journal of Open Source Software. 2021. 6(61), 3167.
    doi: 10.21105/joss.03167
  14. La Rosa PS, Deych E, Carter S, Shands B, Yang D, Shannon WD. HMP: Hypothesis Testing and Power Calculations for Comparing Metagenomic Samples from HMP. R package version 2.0.1, 2019. https://CRAN.R-project.org/package=HMP
  15. Taur Y, Xavier J, Lipuma L, Ubeda C, Goldberg J, Gobourne A. et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hemopoietic stem transplantation. Clin Infect Dis. 2012. 55(7):905-914. doi: 10.1093/cid/cis580
  16. Stoma I, Uss M, Milanova E, Iscrov I, Uss A. Biodiversity screening of gut microbiome during the allogeneic hematopoietic stem cell transplantation: data from the real-life clinical practice, All Life, 2022. Vol.15. № 1. P/547-554. doi: 10.1080/26895293.2022.2074546

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Известно, что ведущую роль в их развитии играют эндогенные инфекции из кишечника. Несмотря на множество фактов, подтверждающих, что микробиом кишечника играет ключевую роль при аллогенной ТГСК, меньше известно о его роли в контексте аутологичной ТГСК. Мы исследовали 30 пациентов с множественной миеломой, перенесших аутологичную ТГСК (АТГСК). Целью нашей работы было изучение особенностей микробиома кишечника, способствующих развитию инфекций у онкогематологических больных на фоне высокодозной химиотерапии и АТГСК. Протокол включал сбор образцов стула до начала аутологичной ТГСК и в посттрансплантационном периоде. Показано, достоверное (р=0.02) снижение индекса разнообразия микробиоты после проведения аутологичной ТГСК. Доминирование типа <i>Proteobacteria </i>в спектре микробиома кишечника является независимым фактором развития грамотрицательных инфекций кровотока у пациентов. Увеличение типа <i>Proteobacteria </i>в спектре микробиома кишечника выше уровня 30% является надежным предиктором развития системных грамотрицательных инфекций кровотока у пациентов, получающих высокодозную терапию и АТГСК. Биоразнообразие кишечного микробиома необходимо контролировать как при аллогенной, так и при аутологичной ТГСК для выявления групп высокого риска развития инфекций кровотока. 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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) "30786" ["VALUE"]=> array(2) { ["TEXT"]=> string(615) "<p>Виталий Н. Чеботкевич<sup>1</sup>, Алексей А. Ковалев<sup>2</sup>, Алена В. Кулешова<sup>1</sup>, Елена И. Кайтанджан<sup>1</sup>, Наталья П. Стижак<sup>1</sup>, Иван И. Кострома<sup>1</sup>, Игорь О. Стома<sup>2</sup>, Сергей А. Чекрыгин<sup>3</sup>, Станислав С. Бессмельцев<sup>1</sup>, Сергей В. Сидоркевич<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(483) "

Виталий Н. Чеботкевич1, Алексей А. Ковалев2, Алена В. Кулешова1, Елена И. Кайтанджан1, Наталья П. Стижак1, Иван И. Кострома1, Игорь О. Стома2, Сергей А. Чекрыгин3, Станислав С. Бессмельцев1, Сергей В. Сидоркевич1

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1 Российский научно-исследовательский институт гематологии и трансфузиологии, Санкт-Петербург, Россия
2 Гомельский государственный медицинский университет, Гомель, Республика Беларусь
3 Санкт-Петербургский государственный университет, 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) "30788" ["VALUE"]=> array(2) { ["TEXT"]=> string(3172) "<p style="text-align: justify;"> Аллогенная ТГСК часто связана с тяжелыми системными инфекционными осложнениями. Известно, что ведущую роль в их развитии играют эндогенные инфекции из кишечника. Несмотря на множество фактов, подтверждающих, что микробиом кишечника играет ключевую роль при аллогенной ТГСК, меньше известно о его роли в контексте аутологичной ТГСК. Мы исследовали 30 пациентов с множественной миеломой, перенесших аутологичную ТГСК (АТГСК). Целью нашей работы было изучение особенностей микробиома кишечника, способствующих развитию инфекций у онкогематологических больных на фоне высокодозной химиотерапии и АТГСК. Протокол включал сбор образцов стула до начала аутологичной ТГСК и в посттрансплантационном периоде. Показано, достоверное (р=0.02) снижение индекса разнообразия микробиоты после проведения аутологичной ТГСК. Доминирование типа <i>Proteobacteria </i>в спектре микробиома кишечника является независимым фактором развития грамотрицательных инфекций кровотока у пациентов. Увеличение типа <i>Proteobacteria </i>в спектре микробиома кишечника выше уровня 30% является надежным предиктором развития системных грамотрицательных инфекций кровотока у пациентов, получающих высокодозную терапию и АТГСК. Биоразнообразие кишечного микробиома необходимо контролировать как при аллогенной, так и при аутологичной ТГСК для выявления групп высокого риска развития инфекций кровотока. Образцы стула для мониторинга следует оценивать как до ТГСК, так и после нее. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация аутологичных стволовых клеток, множественная миелома, микробиота кишечника, индекс разнообразия, инфекции кровотока, предикторы, онкогематологические пациенты. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3092) "

Аллогенная ТГСК часто связана с тяжелыми системными инфекционными осложнениями. Известно, что ведущую роль в их развитии играют эндогенные инфекции из кишечника. Несмотря на множество фактов, подтверждающих, что микробиом кишечника играет ключевую роль при аллогенной ТГСК, меньше известно о его роли в контексте аутологичной ТГСК. Мы исследовали 30 пациентов с множественной миеломой, перенесших аутологичную ТГСК (АТГСК). Целью нашей работы было изучение особенностей микробиома кишечника, способствующих развитию инфекций у онкогематологических больных на фоне высокодозной химиотерапии и АТГСК. Протокол включал сбор образцов стула до начала аутологичной ТГСК и в посттрансплантационном периоде. Показано, достоверное (р=0.02) снижение индекса разнообразия микробиоты после проведения аутологичной ТГСК. Доминирование типа Proteobacteria в спектре микробиома кишечника является независимым фактором развития грамотрицательных инфекций кровотока у пациентов. Увеличение типа Proteobacteria в спектре микробиома кишечника выше уровня 30% является надежным предиктором развития системных грамотрицательных инфекций кровотока у пациентов, получающих высокодозную терапию и АТГСК. Биоразнообразие кишечного микробиома необходимо контролировать как при аллогенной, так и при аутологичной ТГСК для выявления групп высокого риска развития инфекций кровотока. Образцы стула для мониторинга следует оценивать как до ТГСК, так и после нее.

Ключевые слова

Трансплантация аутологичных стволовых клеток, множественная миелома, микробиота кишечника, индекс разнообразия, инфекции кровотока, предикторы, онкогематологические пациенты.

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Vitaly N. Chebotkevich1, Alexey A. Kovalev2, Alena V. Kuleshova1, Elena I. Kaytanjan1, Natalya P. Stizhak1, Ivan I. Kostroma1, Igor O. Stoma2, Sergey A. Chekrygin3, Stanislav S. Bessmeltsev1, Sergey V. Sidorkevich1

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1 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
2 Gomel State Medical University, Gomel, Republic of Belarus
3 St. Petersburg State University, St. Petersburg, Russia


Correspondence:
Prof. Vitaly N. Chebotkevich, Russian Research Institute of Hematology and Transfusiology, 2nd Sovetskaya St 16, 191025, St. Petersburg, Russia
Phone: +7 (812) 274-56-30
E-mail: vitnikcheb@mai.ru


Citation: Chebotkevich VN, Kovalev AA, Kuleshova AV et al. Biodiversity screening of gut microbiome during autologous stem cell transplantation as a predictor of bloodstream infections in oncohematological patients. Cell Ther Transplant 2023; 12(3): 23-28.

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Allogeneic HSCT is frequently associated with severe systemic infectious complications. Endogenous infections of intestinal origin are known to play a leading role in their occurence. Despite abundant data confirming the key role of gut microbiome in allogeneic HSCT, less is known about its role in autologous HSCT (ASCT). In this study, we aimed to investigate the characteristics of the gut microbiome that contribute to the development of bloodstream infections (BSI) in oncohematological patients during high-dose chemotherapy and AHSCT. We conducted a study on the microbial diversity of the gut microbiome during AHSCT in 30 patients with multiple myeloma (MM). The protocol involved stool sampling prior to AHSCT and during the post-transplant period. Our study revealed a significant decrease of the bacterial diversity index during AHSCT (p=0.02). The dominance of Proteobacteria in the intestinal microbiome proved to be an independent factor in the development of Gram-negative bloodstream infections in the patients. An increased ratio of Proteobacteria in the spectrum of gut microbiome over 30% is a reliable predictor of systemic Gram-negative bloodstream infections in patients undergoing high-dose chemotherapy and AHSCT. Therefore, monitoring biodiversity of intestinal microbiome is crucial in both allogeneic and autologous HSCT to identify high-risk groups for developing bloodstream infections. The stool samples for such monitoring should be evaluated both prior to HSCT, and post-transplant.

Keywords

Autologous stem cell transplantation, multiple myeloma, gut microbiota, biodiversity index, bloodstream infections, predictors, oncohematological patients.

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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) "30790" ["VALUE"]=> array(2) { ["TEXT"]=> string(464) "<p>Vitaly N. Chebotkevich<sup>1</sup>, Alexey A. Kovalev<sup>2</sup>, Alena V. Kuleshova<sup>1</sup>, Elena I. Kaytanjan<sup>1</sup>, Natalya P. Stizhak<sup>1</sup>, Ivan I. Kostroma<sup>1</sup>, Igor O. Stoma<sup>2</sup>, Sergey A. Chekrygin<sup>3</sup>, Stanislav S. Bessmeltsev<sup>1</sup>, Sergey V. Sidorkevich<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(332) "

Vitaly N. Chebotkevich1, Alexey A. Kovalev2, Alena V. Kuleshova1, Elena I. Kaytanjan1, Natalya P. Stizhak1, Ivan I. Kostroma1, Igor O. Stoma2, Sergey A. Chekrygin3, Stanislav S. Bessmeltsev1, Sergey V. Sidorkevich1

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Vitaly N. Chebotkevich1, Alexey A. Kovalev2, Alena V. Kuleshova1, Elena I. Kaytanjan1, Natalya P. Stizhak1, Ivan I. Kostroma1, Igor O. Stoma2, Sergey A. Chekrygin3, Stanislav S. Bessmeltsev1, Sergey V. Sidorkevich1

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Allogeneic HSCT is frequently associated with severe systemic infectious complications. Endogenous infections of intestinal origin are known to play a leading role in their occurence. Despite abundant data confirming the key role of gut microbiome in allogeneic HSCT, less is known about its role in autologous HSCT (ASCT). In this study, we aimed to investigate the characteristics of the gut microbiome that contribute to the development of bloodstream infections (BSI) in oncohematological patients during high-dose chemotherapy and AHSCT. We conducted a study on the microbial diversity of the gut microbiome during AHSCT in 30 patients with multiple myeloma (MM). The protocol involved stool sampling prior to AHSCT and during the post-transplant period. Our study revealed a significant decrease of the bacterial diversity index during AHSCT (p=0.02). The dominance of Proteobacteria in the intestinal microbiome proved to be an independent factor in the development of Gram-negative bloodstream infections in the patients. An increased ratio of Proteobacteria in the spectrum of gut microbiome over 30% is a reliable predictor of systemic Gram-negative bloodstream infections in patients undergoing high-dose chemotherapy and AHSCT. Therefore, monitoring biodiversity of intestinal microbiome is crucial in both allogeneic and autologous HSCT to identify high-risk groups for developing bloodstream infections. The stool samples for such monitoring should be evaluated both prior to HSCT, and post-transplant.

Keywords

Autologous stem cell transplantation, multiple myeloma, gut microbiota, biodiversity index, bloodstream infections, predictors, oncohematological patients.

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Allogeneic HSCT is frequently associated with severe systemic infectious complications. Endogenous infections of intestinal origin are known to play a leading role in their occurence. Despite abundant data confirming the key role of gut microbiome in allogeneic HSCT, less is known about its role in autologous HSCT (ASCT). In this study, we aimed to investigate the characteristics of the gut microbiome that contribute to the development of bloodstream infections (BSI) in oncohematological patients during high-dose chemotherapy and AHSCT. We conducted a study on the microbial diversity of the gut microbiome during AHSCT in 30 patients with multiple myeloma (MM). The protocol involved stool sampling prior to AHSCT and during the post-transplant period. Our study revealed a significant decrease of the bacterial diversity index during AHSCT (p=0.02). The dominance of Proteobacteria in the intestinal microbiome proved to be an independent factor in the development of Gram-negative bloodstream infections in the patients. An increased ratio of Proteobacteria in the spectrum of gut microbiome over 30% is a reliable predictor of systemic Gram-negative bloodstream infections in patients undergoing high-dose chemotherapy and AHSCT. Therefore, monitoring biodiversity of intestinal microbiome is crucial in both allogeneic and autologous HSCT to identify high-risk groups for developing bloodstream infections. The stool samples for such monitoring should be evaluated both prior to HSCT, and post-transplant.

Keywords

Autologous stem cell transplantation, multiple myeloma, gut microbiota, biodiversity index, bloodstream infections, predictors, oncohematological patients.

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1 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
2 Gomel State Medical University, Gomel, Republic of Belarus
3 St. Petersburg State University, St. Petersburg, Russia


Correspondence:
Prof. Vitaly N. Chebotkevich, Russian Research Institute of Hematology and Transfusiology, 2nd Sovetskaya St 16, 191025, St. Petersburg, Russia
Phone: +7 (812) 274-56-30
E-mail: vitnikcheb@mai.ru


Citation: Chebotkevich VN, Kovalev AA, Kuleshova AV et al. Biodiversity screening of gut microbiome during autologous stem cell transplantation as a predictor of bloodstream infections in oncohematological patients. Cell Ther Transplant 2023; 12(3): 23-28.

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1 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
2 Gomel State Medical University, Gomel, Republic of Belarus
3 St. Petersburg State University, St. Petersburg, Russia


Correspondence:
Prof. Vitaly N. Chebotkevich, Russian Research Institute of Hematology and Transfusiology, 2nd Sovetskaya St 16, 191025, St. Petersburg, Russia
Phone: +7 (812) 274-56-30
E-mail: vitnikcheb@mai.ru


Citation: Chebotkevich VN, Kovalev AA, Kuleshova AV et al. Biodiversity screening of gut microbiome during autologous stem cell transplantation as a predictor of bloodstream infections in oncohematological patients. Cell Ther Transplant 2023; 12(3): 23-28.

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Виталий Н. Чеботкевич1, Алексей А. Ковалев2, Алена В. Кулешова1, Елена И. Кайтанджан1, Наталья П. Стижак1, Иван И. Кострома1, Игорь О. Стома2, Сергей А. Чекрыгин3, Станислав С. Бессмельцев1, Сергей В. Сидоркевич1

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Виталий Н. Чеботкевич1, Алексей А. Ковалев2, Алена В. Кулешова1, Елена И. Кайтанджан1, Наталья П. Стижак1, Иван И. Кострома1, Игорь О. Стома2, Сергей А. Чекрыгин3, Станислав С. Бессмельцев1, Сергей В. Сидоркевич1

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Известно, что ведущую роль в их развитии играют эндогенные инфекции из кишечника. Несмотря на множество фактов, подтверждающих, что микробиом кишечника играет ключевую роль при аллогенной ТГСК, меньше известно о его роли в контексте аутологичной ТГСК. Мы исследовали 30 пациентов с множественной миеломой, перенесших аутологичную ТГСК (АТГСК). Целью нашей работы было изучение особенностей микробиома кишечника, способствующих развитию инфекций у онкогематологических больных на фоне высокодозной химиотерапии и АТГСК. Протокол включал сбор образцов стула до начала аутологичной ТГСК и в посттрансплантационном периоде. Показано, достоверное (р=0.02) снижение индекса разнообразия микробиоты после проведения аутологичной ТГСК. Доминирование типа <i>Proteobacteria </i>в спектре микробиома кишечника является независимым фактором развития грамотрицательных инфекций кровотока у пациентов. Увеличение типа <i>Proteobacteria </i>в спектре микробиома кишечника выше уровня 30% является надежным предиктором развития системных грамотрицательных инфекций кровотока у пациентов, получающих высокодозную терапию и АТГСК. Биоразнообразие кишечного микробиома необходимо контролировать как при аллогенной, так и при аутологичной ТГСК для выявления групп высокого риска развития инфекций кровотока. Образцы стула для мониторинга следует оценивать как до ТГСК, так и после нее. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация аутологичных стволовых клеток, множественная миелома, микробиота кишечника, индекс разнообразия, инфекции кровотока, предикторы, онкогематологические пациенты. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3092) "

Аллогенная ТГСК часто связана с тяжелыми системными инфекционными осложнениями. Известно, что ведущую роль в их развитии играют эндогенные инфекции из кишечника. Несмотря на множество фактов, подтверждающих, что микробиом кишечника играет ключевую роль при аллогенной ТГСК, меньше известно о его роли в контексте аутологичной ТГСК. Мы исследовали 30 пациентов с множественной миеломой, перенесших аутологичную ТГСК (АТГСК). Целью нашей работы было изучение особенностей микробиома кишечника, способствующих развитию инфекций у онкогематологических больных на фоне высокодозной химиотерапии и АТГСК. Протокол включал сбор образцов стула до начала аутологичной ТГСК и в посттрансплантационном периоде. Показано, достоверное (р=0.02) снижение индекса разнообразия микробиоты после проведения аутологичной ТГСК. Доминирование типа Proteobacteria в спектре микробиома кишечника является независимым фактором развития грамотрицательных инфекций кровотока у пациентов. Увеличение типа Proteobacteria в спектре микробиома кишечника выше уровня 30% является надежным предиктором развития системных грамотрицательных инфекций кровотока у пациентов, получающих высокодозную терапию и АТГСК. Биоразнообразие кишечного микробиома необходимо контролировать как при аллогенной, так и при аутологичной ТГСК для выявления групп высокого риска развития инфекций кровотока. Образцы стула для мониторинга следует оценивать как до ТГСК, так и после нее.

Ключевые слова

Трансплантация аутологичных стволовых клеток, множественная миелома, микробиота кишечника, индекс разнообразия, инфекции кровотока, предикторы, онкогематологические пациенты.

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Аллогенная ТГСК часто связана с тяжелыми системными инфекционными осложнениями. Известно, что ведущую роль в их развитии играют эндогенные инфекции из кишечника. Несмотря на множество фактов, подтверждающих, что микробиом кишечника играет ключевую роль при аллогенной ТГСК, меньше известно о его роли в контексте аутологичной ТГСК. Мы исследовали 30 пациентов с множественной миеломой, перенесших аутологичную ТГСК (АТГСК). Целью нашей работы было изучение особенностей микробиома кишечника, способствующих развитию инфекций у онкогематологических больных на фоне высокодозной химиотерапии и АТГСК. Протокол включал сбор образцов стула до начала аутологичной ТГСК и в посттрансплантационном периоде. Показано, достоверное (р=0.02) снижение индекса разнообразия микробиоты после проведения аутологичной ТГСК. Доминирование типа Proteobacteria в спектре микробиома кишечника является независимым фактором развития грамотрицательных инфекций кровотока у пациентов. Увеличение типа Proteobacteria в спектре микробиома кишечника выше уровня 30% является надежным предиктором развития системных грамотрицательных инфекций кровотока у пациентов, получающих высокодозную терапию и АТГСК. Биоразнообразие кишечного микробиома необходимо контролировать как при аллогенной, так и при аутологичной ТГСК для выявления групп высокого риска развития инфекций кровотока. Образцы стула для мониторинга следует оценивать как до ТГСК, так и после нее.

Ключевые слова

Трансплантация аутологичных стволовых клеток, множественная миелома, микробиота кишечника, индекс разнообразия, инфекции кровотока, предикторы, онкогематологические пациенты.

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1 Российский научно-исследовательский институт гематологии и трансфузиологии, Санкт-Петербург, Россия
2 Гомельский государственный медицинский университет, Гомель, Республика Беларусь
3 Санкт-Петербургский государственный университет, Санкт-Петербург, Россия

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1 Российский научно-исследовательский институт гематологии и трансфузиологии, Санкт-Петербург, Россия
2 Гомельский государственный медицинский университет, Гомель, Республика Беларусь
3 Санкт-Петербургский государственный университет, Санкт-Петербург, Россия

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Introduction

Treatment of chronic myeloid leukemia (CML) has evolved from early 2000’s to the present time. Despite the excellent long-term survival for CML patients diagnosed in CP undergoing TKI treatment and a near normal life expectancy [1], allogeneic hematopoietic stem cell transplantation (allo- HSCT) remains a treatment option for the patients with CML who failed to respond to 3 and more available TKIs or being a reserved treatment option for patients who have advanced phases of CML [2]. However, the timing of the transplant has changed to the 3rd or 4th line after failure or intolerance to second-generation TKI (2GTKI) according to current recommendations [3]. Concerns regarding the feasibility and the safety of a subsequent allo-HSCT are justified due to some well-known side effects of 2GTKIs. For instance, myelotoxicity could predispose to delayed engraftment, or liver toxicity may result into sinusoidal obstructive syndrome (SOS).

Asciminib is a novel BCR::ABL1 inhibitor that works as STAMP (Specifically Targeting the ABL Myristoyl Pocket). It has shown effectiveness and a good safety profile according to the results of a phase I and III studies in patients with Ph-positive leukemia failing prior TKIs. Asciminib is potentially active against naïve and mutated BCR::ABL1 including T315I mutation and is currently approved for patients with chronic-phase CML (CP-CML) previously treated with two or more TKIs being also available for patients with mutation T315I [4, 5].

While pre-transplant use of 2nd-generation TKIs (nilotinib/ dasatinib) does not change the risk of complications associated with allo-HSCT, there are some reports on TKI therapy, in particular, with ponatinib inducing graft-versus-host disease (GvHD) [6]. There are still no similar data available for patients receiving asciminib. The Managed Access Program (MAP) ABL001A02401M was conducted to provide asciminib to patients with chronic myeloid leukemia. Three clinical centers in Russia participated in the program (RM Gorbacheva Research Institute, Pavlov University, St. Petersburg; Almazov National Medical Research Centre, St. Petersburg; National Medical Research Center for Hematology, Moscow, Russian Federation).

Therefore, our aim was to evaluate the safety and effectiveness of pre- and post-transplant asciminib in allo-HSCT candidates.

Materials and methods

Sixty eight patients with CML were enrolled in the MAP program. We reviewed clinical data of 12 patients across 2 contributing centers, who underwent allo-HSCT between August 2021 and August 2022. Inclusion Criteria were as follows:
- Adult patients in the chronic phase CML (AP and BC are acceptable in anamnesis);
- Failure of therapy with at least two TKIs in the absence of the T315I mutation;
- Failure of therapy with any TKI in the presence of the T315I mutation;
- Lack of alternative therapies and inability to participate in clinical trials with potentially effective treatment options;
- Absence of clinically significant restrictions.

Our aim was to evaluate the safety and effectiveness of pre- and post-transplant asciminib in allo-HSCT candidates. ABL1 kinase domain mutations (KDM) were analyzed by Sanger sequencing. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. The median age of this cohort was 41 years (range 28-59) and 8(58% 8/12=67%) patients were males (Table 1).

Table 1. Baseline characteristics of the CML patients treated with asciminib

Vlasova-tab01.jpg

Notes: F, Female; M, male; CP1, chronic phase 1; CP2, 2nd chronic phase; CP3, 3rd chronic phase; AP, acceleration phase; BC, blast crisis; Ima, Imatinib; Nilo, Nilotinib; Dasa, Dasatinib; BD, twice daily; CHR, complete hematological response; MMR, major molecular response; CMR, complete molecular response; Haplo, Haploidentical donor; MRD, matched related donor; MUD, matched unrelated donor; RIC, reduced-intensity conditioning; Gr, grade.

All patients had a good performance status (PS) according to Eastern Cooperative Oncology Group (ECOG 0-1) criteria. The median duration of CML before asciminib was 2.8 years (range 0.3-15).

CML status prior to asciminib administration: all patients exhibited lack (absence) of cytogenetic or molecular response to previous treatment. Six patients had complete hematological response, six patients lacked a complete hematological response (including cytopenia). Three CML patients were in the 1st chronic phase, 4 patients had a history of accelerated phase and five patients had a history of blast crisis. The median duration of asciminib before allo-HSCT was 194 days (61-377 days). Nine (75%) patients had BCR::ABL1 mutations, and seven (58%) had BCR:ABL1t315i. Four (33%) patients had additional chromosomal abnormalities. The majority of patients (84%) received ≥3 TKIs, 4 patients (33%) had a history of ponatinib treatment. In five (41%) patients, the initial dose of asciminib was 40 mg twice daily (BID), seven (59%) patients started with 200 mg BID.

Eleven patients treated with asciminib (92%) did not develop adverse events (AEs) of any grade. Only one patient (8%) exhibited AEs (grade 3 neutropenia, grade 4 thrombocytopenia), However, he was able to continue treatment at a reduced dose of 20 mg BID. The pre-transplant disease status was as follows: complete hematological response for 4 patients, complete cytogenetic response (CCyR) in one case. Major molecular response (MMR) and MR4 response have been documented in two and one case, respectively. Four patients did not exhibit hematological response (Fig. 1).

Vlasova-fig01.jpg

Figure 1. Summary graph of responses to Asciminib treatment in CML patients

Results

All patients received allo-HSCT with reduced-intensity conditioning regimen. GvHD prevention with PtCyTxMMF/PtCyCsA or monoCy/monoCsA (in case of related donor and bone marrow source) was given. Allo-HSCT was performed from related donor in 8 patients who received transplants from matched related donor and haplo donor in 5 and 3 cases respectively), and in 4 patients (33%) grafted from mismatched unrelated donors (9/10, 8/10) using PBSCs as transplant source.

Toxicity profile of the conditioning regimens is depicted in Table 1. Median day of engraftment was D+20 (range 18-24). There were 1 case of primary and 1 case of secondary graft failure observed. The 1-year overall survival was 70% (Fig. 2A).

Over the post-transplant period, 4 patients (33%) continued asciminib, due to minimal residual disease (MRD), with achievement of CMR in 3 cases (25%, Table 2). One patient developed grade 1 veno-occlusive disease (VOD) which has resolved during therapy on D+10. Two patients developed liver aGvHD (grade 2), which did not require correction of the immunosuppressive therapy. Asciminib therapy was not interrupted. Two patients developed intestinal aGvHD grade 3 requiring glucocorticosteroids and ruxolitinib treatment. In these patients, Asciminib was canceled interrupted until resolution of aGvHD. The cumulative incidence of acute GvHD (grade 1-3 until D+100) was 18% (Fig. 2B). Development of aGvHD was not associated with asciminib therapy in our group.

Eight patients (67%) are alive with median follow-up after allo-HSCT of 135 days. Causes of death were: sepsis, CML progression, secondary graft failure in 1, 2, 1 cases respectively. Non-relapse mortality was 18% at 12 months (Fig. 2C).

Table 2. Responses to asciminib administered after allo-HSCT

Vlasova-tab02.jpg

Abbreviations: MRD, matched related donor; BD, twice daily; CMR, complete molecular response.

Vlasova-fig02.jpg

Figure 2. 1-year overall survival (A); cumulative incidence of aGvHD (B), and non-relapse mortality (C) following Asciminib treatment in CML patients

Discussion

While imatinib seems to have no adverse impact on outcomes after transplant, little is known about its effects of prior use of second-generation TKI (2GTKI). Stavroula Masouridi-Levrat et al. [7] presented the results of a prospective non-interventional study performed by EBMT in 383 CML patients previously treated with dasatinib or nilotinib undergoing allo-HSCT from 2009 to 2013. The choice of 2GTKI was as follows: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. No differences were found for the incidence of post-transplant complications and clinical outcomes between the different 2GTKI subgroups. This prospective study demonstrates feasibility of allo-HCT in patients previously treated with 2GTKI, with rates of post-transplant complications comparable to that among TKI-naive or imatinib-treated patients [7]. This results confirm prior observations: during the first 5 years of 2GTKI use, three retrospective studies [8-10] analyzing the outcome in a total of 43 patients who underwent allo-HCT following dasatinib or nilotinib treatment after imatinib failure provided no evidence for increased risk of graft failure or delayed engraftment, treatment-related organ toxicity, or GvHD. Y. Chalandon et al. (2023) reported that neither a number of TKIs, nor the choice of TKIs given prior to allo-HSCT for CML impacts upon survival outcome of those patients, thus also suggesting that the biology of the disease most likely determines the overall outcome [11].

TKIs also are used to treat molecular relapse after allo-HSCT and may be administered as maintenance post-HSCT in high risk patients. Fiona Fernando et al. (2023) presented that post-transplant asciminib was well tolerated and induced improvement in molecular response in heavily pre-treated cohort of patients, leading to acceptable control of disease. The majority of patients attained MMR or better quality of remission, improving their molecular response from asciminib initiation, despite previous resistance to multiple TKIs. Within this patient group, the patients with pre-transplant ponatinib resistance also achieved a deep molecular response [12].

Conclusions

In summary, asciminib showed promising results for the therapy of heavily pre-treated CML patients from the Phase 1 data and ASCEMBL study. In our observation (limited with small dataset) asciminib was effective as a bridge therapy before allo-HSCT in highly pretreated patients with low rate of severe toxicity and acceptable rate of aGvHD. It seems that in patients with advanced CML phases, asciminib is a promising drug to improve the status of the disease before allo-HSCT without an increase of aGvHD rate after allo-HSCT.

In summary, asciminib showed promising results for the therapy of heavily pre-treated CML patients from the Phase 1 data and ASCEMBL study. In our observation (limited with small dataset) asciminib was effective as a bridge therapy before allo-HSCT in highly pretreated patients with low rate of severe toxicity and acceptable rate of aGvHD. It seems that in patients with advanced CML phases, asciminib is a promising drug to improve the status of the disease before allo-HSCT without an increase of aGvHD rate after allo-HSCT.

Acknowledgements

To Novartis Pharma for the support Managed Access Program ABL001A02401M to provide asciminib to patients with chronic myeloid leukemia.

Contributions

All authors reviewed and edited the manuscript and figures. All authors approved the final manuscript version.

Conflict of interest

None declared.

References

  1. Hoffmann VS, Baccarani M, Hasford J, Castagnetti F, Di Raimondo F, Casado LF, et al. Treatment and outcome of 2904 CML patients from the EUTOS population-based registry. Leukemia. 2017;31(3):593-601. doi: 10.1038/leu.2016.246
  2. Barrett AJ, Ito S. The role of stem cell transplantation for chronic myelogenous leukemia in the 21st century. Blood. 2015;125(21):3230-3235. doi: 10.1182/blood-2014-10-567784
  3. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-884. doi: 10.1182/blood-2013-05-501569
  4. Réa D, Mauro MJ, Boquimpani C, Minami Y, Lomaia E, Voloshin S, Turkina A, et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021;138(21):2031-2041. doi: 10.1182/blood.2020009984
  5. Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med. 2019; 381(24):2315-2326. doi: 10.1056/NEJMoa1902328
  6. Petrungaro A, Gentile M, Mazzone C, Greco R, Uccello G, Recchia A, et al. Ponatinib-induced graft-versus-host disease/graft-versus-leukemia effect in a patient with philadelphia-positive acute lymphoblastic leukemia without the T315I mutation relapsing after allogeneic transplant. Chemotherapy. 2017; 62(6): 353-356. doi: 10.1159/000477714
  7. Masouridi-Levrat S, Olavarria E, Iacobelli S, Aljurf M, Morozova E, Niittyvuopio R, et al. Outcomes and toxicity of allogeneic hematopoietic cell transplantation in chronic myeloid leukemia patients previously treated with second-generation tyrosine kinase inhibitors: a prospective non-interventional study from the Chronic Malignancy Working Party of the EBMT. Bone Marrow Transplant. 2022; 57(1):23-30. doi: 10.1038/s41409-021-01472-x
  8. Jabbour E, Cortes J, Kantarjian H, Giralt S, Andersson BS, Giles F, et al. Novel tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with chronic myeloid leukemia: no evidence for increased transplant-related toxicity. Cancer. 2007;110(2):340-344. doi: 10.1002/cncr.22778
  9. Shimoni A, Leiba M, Schleuning M, Martineau G, Renaud M, Koren-Michowitz M, et al. Prior treatment with the tyrosine kinase inhibitors dasatinib and nilotinib allows stem cell transplantation (SCT) in a less advanced disease phase and does not increase SCT in patients with chronic myelogenous leukemia and Philadelphia-positive acute lymphoblastic leukemia. Leukemia. 2009; 23(1):190-194. doi: 10.1038/leu.2008.160
  10. Breccia M, Palandri F, Iori AP, Colaci E, Latagliata R, Castagnetti F, et al. Second-generation tyrosine kinase inhibitors before allogeneic stem cell transplantation in patients with chronic myeloid leukemia resistant to imatinib. Leuk Res. 2010; 34(2):143-147. doi: 10.1016/j.leukres.2009.04.036
  11. Chalandon Y, Sbianchi G, Gras L, Koster L, Apperley J, Byrne J, et al. Allogeneic hematopoietic cell transplantation in patients with chronic phase chronic myeloid leukemia in the era of third generation tyrosine kinase inhibitors: A retrospective study by the chronic malignancies working party of the EBMT. Am J Hematol. 2023; 98(1):112-121. doi: 10.1002/ajh.26764
  12. Fernando F, Innes AJ, Claudiani S, Pryce A, Hayden C, Byrne J, et al. The outcome of post-transplant asciminib in patients with chronic myeloid leukaemia. Bone Marrow Transplant. 2023; 58(7):826-828. doi: 10.1038/s41409-023-01975-9

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Introduction

Treatment of chronic myeloid leukemia (CML) has evolved from early 2000’s to the present time. Despite the excellent long-term survival for CML patients diagnosed in CP undergoing TKI treatment and a near normal life expectancy [1], allogeneic hematopoietic stem cell transplantation (allo- HSCT) remains a treatment option for the patients with CML who failed to respond to 3 and more available TKIs or being a reserved treatment option for patients who have advanced phases of CML [2]. However, the timing of the transplant has changed to the 3rd or 4th line after failure or intolerance to second-generation TKI (2GTKI) according to current recommendations [3]. Concerns regarding the feasibility and the safety of a subsequent allo-HSCT are justified due to some well-known side effects of 2GTKIs. For instance, myelotoxicity could predispose to delayed engraftment, or liver toxicity may result into sinusoidal obstructive syndrome (SOS).

Asciminib is a novel BCR::ABL1 inhibitor that works as STAMP (Specifically Targeting the ABL Myristoyl Pocket). It has shown effectiveness and a good safety profile according to the results of a phase I and III studies in patients with Ph-positive leukemia failing prior TKIs. Asciminib is potentially active against naïve and mutated BCR::ABL1 including T315I mutation and is currently approved for patients with chronic-phase CML (CP-CML) previously treated with two or more TKIs being also available for patients with mutation T315I [4, 5].

While pre-transplant use of 2nd-generation TKIs (nilotinib/ dasatinib) does not change the risk of complications associated with allo-HSCT, there are some reports on TKI therapy, in particular, with ponatinib inducing graft-versus-host disease (GvHD) [6]. There are still no similar data available for patients receiving asciminib. The Managed Access Program (MAP) ABL001A02401M was conducted to provide asciminib to patients with chronic myeloid leukemia. Three clinical centers in Russia participated in the program (RM Gorbacheva Research Institute, Pavlov University, St. Petersburg; Almazov National Medical Research Centre, St. Petersburg; National Medical Research Center for Hematology, Moscow, Russian Federation).

Therefore, our aim was to evaluate the safety and effectiveness of pre- and post-transplant asciminib in allo-HSCT candidates.

Materials and methods

Sixty eight patients with CML were enrolled in the MAP program. We reviewed clinical data of 12 patients across 2 contributing centers, who underwent allo-HSCT between August 2021 and August 2022. Inclusion Criteria were as follows:
- Adult patients in the chronic phase CML (AP and BC are acceptable in anamnesis);
- Failure of therapy with at least two TKIs in the absence of the T315I mutation;
- Failure of therapy with any TKI in the presence of the T315I mutation;
- Lack of alternative therapies and inability to participate in clinical trials with potentially effective treatment options;
- Absence of clinically significant restrictions.

Our aim was to evaluate the safety and effectiveness of pre- and post-transplant asciminib in allo-HSCT candidates. ABL1 kinase domain mutations (KDM) were analyzed by Sanger sequencing. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. The median age of this cohort was 41 years (range 28-59) and 8(58% 8/12=67%) patients were males (Table 1).

Table 1. Baseline characteristics of the CML patients treated with asciminib

Vlasova-tab01.jpg

Notes: F, Female; M, male; CP1, chronic phase 1; CP2, 2nd chronic phase; CP3, 3rd chronic phase; AP, acceleration phase; BC, blast crisis; Ima, Imatinib; Nilo, Nilotinib; Dasa, Dasatinib; BD, twice daily; CHR, complete hematological response; MMR, major molecular response; CMR, complete molecular response; Haplo, Haploidentical donor; MRD, matched related donor; MUD, matched unrelated donor; RIC, reduced-intensity conditioning; Gr, grade.

All patients had a good performance status (PS) according to Eastern Cooperative Oncology Group (ECOG 0-1) criteria. The median duration of CML before asciminib was 2.8 years (range 0.3-15).

CML status prior to asciminib administration: all patients exhibited lack (absence) of cytogenetic or molecular response to previous treatment. Six patients had complete hematological response, six patients lacked a complete hematological response (including cytopenia). Three CML patients were in the 1st chronic phase, 4 patients had a history of accelerated phase and five patients had a history of blast crisis. The median duration of asciminib before allo-HSCT was 194 days (61-377 days). Nine (75%) patients had BCR::ABL1 mutations, and seven (58%) had BCR:ABL1t315i. Four (33%) patients had additional chromosomal abnormalities. The majority of patients (84%) received ≥3 TKIs, 4 patients (33%) had a history of ponatinib treatment. In five (41%) patients, the initial dose of asciminib was 40 mg twice daily (BID), seven (59%) patients started with 200 mg BID.

Eleven patients treated with asciminib (92%) did not develop adverse events (AEs) of any grade. Only one patient (8%) exhibited AEs (grade 3 neutropenia, grade 4 thrombocytopenia), However, he was able to continue treatment at a reduced dose of 20 mg BID. The pre-transplant disease status was as follows: complete hematological response for 4 patients, complete cytogenetic response (CCyR) in one case. Major molecular response (MMR) and MR4 response have been documented in two and one case, respectively. Four patients did not exhibit hematological response (Fig. 1).

Vlasova-fig01.jpg

Figure 1. Summary graph of responses to Asciminib treatment in CML patients

Results

All patients received allo-HSCT with reduced-intensity conditioning regimen. GvHD prevention with PtCyTxMMF/PtCyCsA or monoCy/monoCsA (in case of related donor and bone marrow source) was given. Allo-HSCT was performed from related donor in 8 patients who received transplants from matched related donor and haplo donor in 5 and 3 cases respectively), and in 4 patients (33%) grafted from mismatched unrelated donors (9/10, 8/10) using PBSCs as transplant source.

Toxicity profile of the conditioning regimens is depicted in Table 1. Median day of engraftment was D+20 (range 18-24). There were 1 case of primary and 1 case of secondary graft failure observed. The 1-year overall survival was 70% (Fig. 2A).

Over the post-transplant period, 4 patients (33%) continued asciminib, due to minimal residual disease (MRD), with achievement of CMR in 3 cases (25%, Table 2). One patient developed grade 1 veno-occlusive disease (VOD) which has resolved during therapy on D+10. Two patients developed liver aGvHD (grade 2), which did not require correction of the immunosuppressive therapy. Asciminib therapy was not interrupted. Two patients developed intestinal aGvHD grade 3 requiring glucocorticosteroids and ruxolitinib treatment. In these patients, Asciminib was canceled interrupted until resolution of aGvHD. The cumulative incidence of acute GvHD (grade 1-3 until D+100) was 18% (Fig. 2B). Development of aGvHD was not associated with asciminib therapy in our group.

Eight patients (67%) are alive with median follow-up after allo-HSCT of 135 days. Causes of death were: sepsis, CML progression, secondary graft failure in 1, 2, 1 cases respectively. Non-relapse mortality was 18% at 12 months (Fig. 2C).

Table 2. Responses to asciminib administered after allo-HSCT

Vlasova-tab02.jpg

Abbreviations: MRD, matched related donor; BD, twice daily; CMR, complete molecular response.

Vlasova-fig02.jpg

Figure 2. 1-year overall survival (A); cumulative incidence of aGvHD (B), and non-relapse mortality (C) following Asciminib treatment in CML patients

Discussion

While imatinib seems to have no adverse impact on outcomes after transplant, little is known about its effects of prior use of second-generation TKI (2GTKI). Stavroula Masouridi-Levrat et al. [7] presented the results of a prospective non-interventional study performed by EBMT in 383 CML patients previously treated with dasatinib or nilotinib undergoing allo-HSCT from 2009 to 2013. The choice of 2GTKI was as follows: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. No differences were found for the incidence of post-transplant complications and clinical outcomes between the different 2GTKI subgroups. This prospective study demonstrates feasibility of allo-HCT in patients previously treated with 2GTKI, with rates of post-transplant complications comparable to that among TKI-naive or imatinib-treated patients [7]. This results confirm prior observations: during the first 5 years of 2GTKI use, three retrospective studies [8-10] analyzing the outcome in a total of 43 patients who underwent allo-HCT following dasatinib or nilotinib treatment after imatinib failure provided no evidence for increased risk of graft failure or delayed engraftment, treatment-related organ toxicity, or GvHD. Y. Chalandon et al. (2023) reported that neither a number of TKIs, nor the choice of TKIs given prior to allo-HSCT for CML impacts upon survival outcome of those patients, thus also suggesting that the biology of the disease most likely determines the overall outcome [11].

TKIs also are used to treat molecular relapse after allo-HSCT and may be administered as maintenance post-HSCT in high risk patients. Fiona Fernando et al. (2023) presented that post-transplant asciminib was well tolerated and induced improvement in molecular response in heavily pre-treated cohort of patients, leading to acceptable control of disease. The majority of patients attained MMR or better quality of remission, improving their molecular response from asciminib initiation, despite previous resistance to multiple TKIs. Within this patient group, the patients with pre-transplant ponatinib resistance also achieved a deep molecular response [12].

Conclusions

In summary, asciminib showed promising results for the therapy of heavily pre-treated CML patients from the Phase 1 data and ASCEMBL study. In our observation (limited with small dataset) asciminib was effective as a bridge therapy before allo-HSCT in highly pretreated patients with low rate of severe toxicity and acceptable rate of aGvHD. It seems that in patients with advanced CML phases, asciminib is a promising drug to improve the status of the disease before allo-HSCT without an increase of aGvHD rate after allo-HSCT.

In summary, asciminib showed promising results for the therapy of heavily pre-treated CML patients from the Phase 1 data and ASCEMBL study. In our observation (limited with small dataset) asciminib was effective as a bridge therapy before allo-HSCT in highly pretreated patients with low rate of severe toxicity and acceptable rate of aGvHD. It seems that in patients with advanced CML phases, asciminib is a promising drug to improve the status of the disease before allo-HSCT without an increase of aGvHD rate after allo-HSCT.

Acknowledgements

To Novartis Pharma for the support Managed Access Program ABL001A02401M to provide asciminib to patients with chronic myeloid leukemia.

Contributions

All authors reviewed and edited the manuscript and figures. All authors approved the final manuscript version.

Conflict of interest

None declared.

References

  1. Hoffmann VS, Baccarani M, Hasford J, Castagnetti F, Di Raimondo F, Casado LF, et al. Treatment and outcome of 2904 CML patients from the EUTOS population-based registry. Leukemia. 2017;31(3):593-601. doi: 10.1038/leu.2016.246
  2. Barrett AJ, Ito S. The role of stem cell transplantation for chronic myelogenous leukemia in the 21st century. Blood. 2015;125(21):3230-3235. doi: 10.1182/blood-2014-10-567784
  3. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-884. doi: 10.1182/blood-2013-05-501569
  4. Réa D, Mauro MJ, Boquimpani C, Minami Y, Lomaia E, Voloshin S, Turkina A, et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021;138(21):2031-2041. doi: 10.1182/blood.2020009984
  5. Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med. 2019; 381(24):2315-2326. doi: 10.1056/NEJMoa1902328
  6. Petrungaro A, Gentile M, Mazzone C, Greco R, Uccello G, Recchia A, et al. Ponatinib-induced graft-versus-host disease/graft-versus-leukemia effect in a patient with philadelphia-positive acute lymphoblastic leukemia without the T315I mutation relapsing after allogeneic transplant. Chemotherapy. 2017; 62(6): 353-356. doi: 10.1159/000477714
  7. Masouridi-Levrat S, Olavarria E, Iacobelli S, Aljurf M, Morozova E, Niittyvuopio R, et al. Outcomes and toxicity of allogeneic hematopoietic cell transplantation in chronic myeloid leukemia patients previously treated with second-generation tyrosine kinase inhibitors: a prospective non-interventional study from the Chronic Malignancy Working Party of the EBMT. Bone Marrow Transplant. 2022; 57(1):23-30. doi: 10.1038/s41409-021-01472-x
  8. Jabbour E, Cortes J, Kantarjian H, Giralt S, Andersson BS, Giles F, et al. Novel tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with chronic myeloid leukemia: no evidence for increased transplant-related toxicity. Cancer. 2007;110(2):340-344. doi: 10.1002/cncr.22778
  9. Shimoni A, Leiba M, Schleuning M, Martineau G, Renaud M, Koren-Michowitz M, et al. Prior treatment with the tyrosine kinase inhibitors dasatinib and nilotinib allows stem cell transplantation (SCT) in a less advanced disease phase and does not increase SCT in patients with chronic myelogenous leukemia and Philadelphia-positive acute lymphoblastic leukemia. Leukemia. 2009; 23(1):190-194. doi: 10.1038/leu.2008.160
  10. Breccia M, Palandri F, Iori AP, Colaci E, Latagliata R, Castagnetti F, et al. Second-generation tyrosine kinase inhibitors before allogeneic stem cell transplantation in patients with chronic myeloid leukemia resistant to imatinib. Leuk Res. 2010; 34(2):143-147. doi: 10.1016/j.leukres.2009.04.036
  11. Chalandon Y, Sbianchi G, Gras L, Koster L, Apperley J, Byrne J, et al. Allogeneic hematopoietic cell transplantation in patients with chronic phase chronic myeloid leukemia in the era of third generation tyrosine kinase inhibitors: A retrospective study by the chronic malignancies working party of the EBMT. Am J Hematol. 2023; 98(1):112-121. doi: 10.1002/ajh.26764
  12. Fernando F, Innes AJ, Claudiani S, Pryce A, Hayden C, Byrne J, et al. The outcome of post-transplant asciminib in patients with chronic myeloid leukaemia. Bone Marrow Transplant. 2023; 58(7):826-828. doi: 10.1038/s41409-023-01975-9

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Препарат продемонстрировал эффективность и благоприятный профиль безопасности, согласно результатам исследования I и III фазы у пациентов с Ph+ ХМЛ, резистентным к предыдущей терапии ИТК. В то время как предтрансплантационное использование ИТК 2-го поколения (нилотиниб/дазатиниб) не изменяет риски, связанные с аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК), пока нет подобных данных о пациентах, получающих перед алло-ТГСК асциминиб. В России асциминиб был доступен в рамках Программы управляемого доступа (MAP), одобренной Novartis. В программу MAP было включено 68 пациентов с ХМЛ. Мы проанализировали данные 12 пациентов из 2-х трансплантационных центров, которым была проведена алло-ТГСК в период с августа 2021 г. по август 2022 г. Наша цель заключалась в том, чтобы оценить безопасность и эффективность асциминиба до и после алло-ТГСК. Медиана продолжительности лечения асциминибом до алло-ТГСК составила 194 дня (61-377 дней). У 92% пациентов не развилось нежелательных явлений (НЯ) любой степени тяжести. Медиана приживления составила 20 дней (диапазон 18-24). Общая выживаемость в течение 1 года составила 70%. Кумулятивная частота острой РТПХ (от 1 до 3 степени до D+100) составила 18%. В нашей группе развитие оРТПХ не было обусловлено приемом асциминиба. Безрецидивная смертность составила 18% через 12 месяцев. Восемь пациентов (67%) живы, средняя продолжительность наблюдения после алло-ТГСК составила 135 дней. У всех пациентов достигнут глубокий молекулярный ответ. В нашем наблюдении (ограниченном небольшим набором данных) асциминиб был эффективен в качестве bridge-терапии перед алло-ТГСК у пациентов с несколькими линиями ИТК. Предтрансплантационное лечение асциминибом не оказывало негативного влияния на результаты трансплантации. 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["SECTION_META_KEYWORDS"]=> string(260) "Асциминиб в качестве «бридж»-терапии перед аллогенной трансплантацией гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_META_DESCRIPTION"]=> string(260) "Асциминиб в качестве «бридж»-терапии перед аллогенной трансплантацией гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_PICTURE_FILE_ALT"]=> string(260) "Асциминиб в качестве «бридж»-терапии перед аллогенной трансплантацией гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_PICTURE_FILE_TITLE"]=> string(260) "Асциминиб в качестве «бридж»-терапии перед аллогенной трансплантацией гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_PICTURE_FILE_NAME"]=> string(4) "-img" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(260) "Асциминиб в качестве «бридж»-терапии перед аллогенной трансплантацией гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" 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string(5) "30762" ["VALUE"]=> array(2) { ["TEXT"]=> string(767) "<p>Юлия Ю. Власова<sup>1</sup>, Елена В. Морозова<sup>1</sup>, Эльза Г. Ломайя<sup>2</sup>, Тамара В. Читанава<sup>2</sup>, Никита П. Волков<sup>1</sup>, Ксения С. Юровская<sup>1</sup>, Татьяна А. Рудакова<sup>1</sup>, Татьяна Л. Гиндина<sup>1</sup>, Дмитрий В. Моторин<sup>3</sup>, Юлия А. Алексеева<sup>2</sup>, Валерия А. Катерина<sup>1</sup>, Иван С. Моисеев<sup>1</sup>, Александр Д. Кулагин<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(599) "

Юлия Ю. Власова1, Елена В. Морозова1, Эльза Г. Ломайя2, Тамара В. Читанава2, Никита П. Волков1, Ксения С. Юровская1, Татьяна А. Рудакова1, Татьяна Л. Гиндина1, Дмитрий В. Моторин3, Юлия А. Алексеева2, Валерия А. Катерина1, Иван С. Моисеев1, Александр Д. Кулагин1

" ["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) "30763" ["VALUE"]=> array(2) { ["TEXT"]=> string(857) "<p><sup>1</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия<br> <sup>2</sup> Национальный медицинский исследовательский центр имени В. А. Алмазова, Санкт-Петербург, Россия<br> <sup>3</sup> Российский научно-исследовательский институт гематологии и трансфузиологии ФМБА России, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(797) "

1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Национальный медицинский исследовательский центр имени В. А. Алмазова, Санкт-Петербург, Россия
3 Российский научно-исследовательский институт гематологии и трансфузиологии ФМБА России, Санкт-Петербург, Россия

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Асциминиб является новым ингибитором BCR::ABL, который действует посредством STAMP(Specifically Targeting the ABL Myristoyl Pocket), блокируя BCR::ABL1 киназу за счет взаимодействия с миристоиловым карманом. Препарат продемонстрировал эффективность и благоприятный профиль безопасности, согласно результатам исследования I и III фазы у пациентов с Ph+ ХМЛ, резистентным к предыдущей терапии ИТК. В то время как предтрансплантационное использование ИТК 2-го поколения (нилотиниб/дазатиниб) не изменяет риски, связанные с аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК), пока нет подобных данных о пациентах, получающих перед алло-ТГСК асциминиб. В России асциминиб был доступен в рамках Программы управляемого доступа (MAP), одобренной Novartis. В программу MAP было включено 68 пациентов с ХМЛ. Мы проанализировали данные 12 пациентов из 2-х трансплантационных центров, которым была проведена алло-ТГСК в период с августа 2021 г. по август 2022 г. Наша цель заключалась в том, чтобы оценить безопасность и эффективность асциминиба до и после алло-ТГСК. Медиана продолжительности лечения асциминибом до алло-ТГСК составила 194 дня (61-377 дней). У 92% пациентов не развилось нежелательных явлений (НЯ) любой степени тяжести. Медиана приживления составила 20 дней (диапазон 18-24). Общая выживаемость в течение 1 года составила 70%. Кумулятивная частота острой РТПХ (от 1 до 3 степени до D+100) составила 18%. В нашей группе развитие оРТПХ не было обусловлено приемом асциминиба. Безрецидивная смертность составила 18% через 12 месяцев. Восемь пациентов (67%) живы, средняя продолжительность наблюдения после алло-ТГСК составила 135 дней. У всех пациентов достигнут глубокий молекулярный ответ. В нашем наблюдении (ограниченном небольшим набором данных) асциминиб был эффективен в качестве bridge-терапии перед алло-ТГСК у пациентов с несколькими линиями ИТК. Предтрансплантационное лечение асциминибом не оказывало негативного влияния на результаты трансплантации. Необходимо больше данных, полученных по более крупной когорте, чтобы оценить влияние препарата на долгосрочную выживаемость.

Ключевые слова

Хронический миелоидный лейкоз, алло-ТГСК, асциминиб.

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Yulia Yu. Vlasova1, Elena V. Morozova1, Elza G. Lomaia2, Tamara V. Chitanava2, Nikita P. Volkov1, Ksenia S. Yurovskaya1, Tatiana A. Rudakova1, Tatiana L. Gindina1, Dmitriy V. Motorin3, Yulia A. Alexeeva1, Valeria A. Katerina1, Ivan S. Moiseev1, Alexander D. Kulagin1

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Almazov National Medical Research Centre, St. Petersburg, Russia
3 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia


Correspondence:
Dr. Yulia Yu. Vlasova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L.Tolstoy St 6-8, St. Petersburg, Russia, 197022
Phone: +7 (965) 041-55-05
E-mail: jj_vlasova@mail.ru


Citation: Vlasova YuY, Morozova EV, Lomaia EG, et al. Asciminib as a bridge therapy prior to allogeneic hematopoietic stem cell transplantation and in post-transplant period for chronic myeloid leukemia. Cell Ther Transplant 2023; 12(3): 11-16.

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Asciminib is a novel BCR::ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP) showing effectiveness and good safety profile according to the results of a phase I and III studies in patients with Ph-positive chronic myeloid leukemia (CML) failing prior tyrosine kinase inhibitors (TKIs). Pre-transplant use of 2nd generation TKIs (nilotinib/dasatinib) does not change the risk of complications associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there are no appropriate data for the patients who received asciminib prior to transplant. In Russia, asciminib is available under the Managed Access Program (MAP) approved by Novartis. In the MAP program 68 patients with CML were enrolled. We reviewed data of 12 patients across 2 contributing centers, who underwent allo-HSCT between August 2021 and August 2022. Our aim was to evaluate the safety and effectiveness of pre- and post-transplant asciminib in allo-HSCT candidates. The median duration of asciminib before allo-HSCT was 194 days (61-377 days). 92% of patients did not develop adverse events (AEs) of any grade. Median day of engraftment was D+20 (range 18-24). The 1-year overall survival was 70%. The cumulative incidence of acute GvHD (grade 1-3 until D+100) was 18%.

Non-relapse mortality was 18% at 12 months. Eight patients (67%) are alive with median follow-up after allo-HSCT of 135 days and achieved deep molecular response. In our observation (limited with small dataset) asciminib was effective as a bridge therapy before allo-HSCT in highly pretreated patients with low rate of severe toxicity and acceptable rate of aGvHD.

Keywords

Chronic myeloid leukemia, allo-HSCT, asciminib.

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["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) "30766" ["VALUE"]=> array(2) { ["TEXT"]=> string(584) "<p>Yulia Yu. Vlasova<sup>1</sup>, Elena V. Morozova<sup>1</sup>, Elza G. Lomaia<sup>2</sup>, Tamara V. Chitanava<sup>2</sup>, Nikita P. Volkov<sup>1</sup>, Ksenia S. Yurovskaya<sup>1</sup>, Tatiana A. Rudakova<sup>1</sup>, Tatiana L. Gindina<sup>1</sup>, Dmitriy V. Motorin<sup>3</sup>, Yulia A. Alexeeva<sup>1</sup>, Valeria A. Katerina<sup>1</sup>, Ivan S. Moiseev<sup>1</sup>, Alexander D. Kulagin<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(416) "

Yulia Yu. Vlasova1, Elena V. Morozova1, Elza G. Lomaia2, Tamara V. Chitanava2, Nikita P. Volkov1, Ksenia S. Yurovskaya1, Tatiana A. Rudakova1, Tatiana L. Gindina1, Dmitriy V. Motorin3, Yulia A. Alexeeva1, Valeria A. Katerina1, Ivan S. Moiseev1, Alexander D. Kulagin1

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Yulia Yu. Vlasova1, Elena V. Morozova1, Elza G. Lomaia2, Tamara V. Chitanava2, Nikita P. Volkov1, Ksenia S. Yurovskaya1, Tatiana A. Rudakova1, Tatiana L. Gindina1, Dmitriy V. Motorin3, Yulia A. Alexeeva1, Valeria A. Katerina1, Ivan S. Moiseev1, Alexander D. Kulagin1

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Asciminib is a novel BCR::ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP) showing effectiveness and good safety profile according to the results of a phase I and III studies in patients with Ph-positive chronic myeloid leukemia (CML) failing prior tyrosine kinase inhibitors (TKIs). Pre-transplant use of 2nd generation TKIs (nilotinib/dasatinib) does not change the risk of complications associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there are no appropriate data for the patients who received asciminib prior to transplant. In Russia, asciminib is available under the Managed Access Program (MAP) approved by Novartis. In the MAP program 68 patients with CML were enrolled. We reviewed data of 12 patients across 2 contributing centers, who underwent allo-HSCT between August 2021 and August 2022. Our aim was to evaluate the safety and effectiveness of pre- and post-transplant asciminib in allo-HSCT candidates. The median duration of asciminib before allo-HSCT was 194 days (61-377 days). 92% of patients did not develop adverse events (AEs) of any grade. Median day of engraftment was D+20 (range 18-24). The 1-year overall survival was 70%. The cumulative incidence of acute GvHD (grade 1-3 until D+100) was 18%.

Non-relapse mortality was 18% at 12 months. Eight patients (67%) are alive with median follow-up after allo-HSCT of 135 days and achieved deep molecular response. In our observation (limited with small dataset) asciminib was effective as a bridge therapy before allo-HSCT in highly pretreated patients with low rate of severe toxicity and acceptable rate of aGvHD.

Keywords

Chronic myeloid leukemia, allo-HSCT, asciminib.

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Asciminib is a novel BCR::ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP) showing effectiveness and good safety profile according to the results of a phase I and III studies in patients with Ph-positive chronic myeloid leukemia (CML) failing prior tyrosine kinase inhibitors (TKIs). Pre-transplant use of 2nd generation TKIs (nilotinib/dasatinib) does not change the risk of complications associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there are no appropriate data for the patients who received asciminib prior to transplant. In Russia, asciminib is available under the Managed Access Program (MAP) approved by Novartis. In the MAP program 68 patients with CML were enrolled. We reviewed data of 12 patients across 2 contributing centers, who underwent allo-HSCT between August 2021 and August 2022. Our aim was to evaluate the safety and effectiveness of pre- and post-transplant asciminib in allo-HSCT candidates. The median duration of asciminib before allo-HSCT was 194 days (61-377 days). 92% of patients did not develop adverse events (AEs) of any grade. Median day of engraftment was D+20 (range 18-24). The 1-year overall survival was 70%. The cumulative incidence of acute GvHD (grade 1-3 until D+100) was 18%.

Non-relapse mortality was 18% at 12 months. Eight patients (67%) are alive with median follow-up after allo-HSCT of 135 days and achieved deep molecular response. In our observation (limited with small dataset) asciminib was effective as a bridge therapy before allo-HSCT in highly pretreated patients with low rate of severe toxicity and acceptable rate of aGvHD.

Keywords

Chronic myeloid leukemia, allo-HSCT, asciminib.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Almazov National Medical Research Centre, St. Petersburg, Russia
3 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia


Correspondence:
Dr. Yulia Yu. Vlasova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L.Tolstoy St 6-8, St. Petersburg, Russia, 197022
Phone: +7 (965) 041-55-05
E-mail: jj_vlasova@mail.ru


Citation: Vlasova YuY, Morozova EV, Lomaia EG, et al. Asciminib as a bridge therapy prior to allogeneic hematopoietic stem cell transplantation and in post-transplant period for chronic myeloid leukemia. Cell Ther Transplant 2023; 12(3): 11-16.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Almazov National Medical Research Centre, St. Petersburg, Russia
3 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia


Correspondence:
Dr. Yulia Yu. Vlasova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L.Tolstoy St 6-8, St. Petersburg, Russia, 197022
Phone: +7 (965) 041-55-05
E-mail: jj_vlasova@mail.ru


Citation: Vlasova YuY, Morozova EV, Lomaia EG, et al. Asciminib as a bridge therapy prior to allogeneic hematopoietic stem cell transplantation and in post-transplant period for chronic myeloid leukemia. Cell Ther Transplant 2023; 12(3): 11-16.

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Юлия Ю. Власова1, Елена В. Морозова1, Эльза Г. Ломайя2, Тамара В. Читанава2, Никита П. Волков1, Ксения С. Юровская1, Татьяна А. Рудакова1, Татьяна Л. Гиндина1, Дмитрий В. Моторин3, Юлия А. Алексеева2, Валерия А. Катерина1, Иван С. Моисеев1, Александр Д. Кулагин1

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Препарат продемонстрировал эффективность и благоприятный профиль безопасности, согласно результатам исследования I и III фазы у пациентов с Ph+ ХМЛ, резистентным к предыдущей терапии ИТК. В то время как предтрансплантационное использование ИТК 2-го поколения (нилотиниб/дазатиниб) не изменяет риски, связанные с аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК), пока нет подобных данных о пациентах, получающих перед алло-ТГСК асциминиб. В России асциминиб был доступен в рамках Программы управляемого доступа (MAP), одобренной Novartis. В программу MAP было включено 68 пациентов с ХМЛ. Мы проанализировали данные 12 пациентов из 2-х трансплантационных центров, которым была проведена алло-ТГСК в период с августа 2021 г. по август 2022 г. Наша цель заключалась в том, чтобы оценить безопасность и эффективность асциминиба до и после алло-ТГСК. Медиана продолжительности лечения асциминибом до алло-ТГСК составила 194 дня (61-377 дней). У 92% пациентов не развилось нежелательных явлений (НЯ) любой степени тяжести. Медиана приживления составила 20 дней (диапазон 18-24). Общая выживаемость в течение 1 года составила 70%. Кумулятивная частота острой РТПХ (от 1 до 3 степени до D+100) составила 18%. В нашей группе развитие оРТПХ не было обусловлено приемом асциминиба. Безрецидивная смертность составила 18% через 12 месяцев. Восемь пациентов (67%) живы, средняя продолжительность наблюдения после алло-ТГСК составила 135 дней. У всех пациентов достигнут глубокий молекулярный ответ. В нашем наблюдении (ограниченном небольшим набором данных) асциминиб был эффективен в качестве bridge-терапии перед алло-ТГСК у пациентов с несколькими линиями ИТК. Предтрансплантационное лечение асциминибом не оказывало негативного влияния на результаты трансплантации. Необходимо больше данных, полученных по более крупной когорте, чтобы оценить влияние препарата на долгосрочную выживаемость. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Хронический миелоидный лейкоз, алло-ТГСК, асциминиб.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3956) "

Асциминиб является новым ингибитором BCR::ABL, который действует посредством STAMP(Specifically Targeting the ABL Myristoyl Pocket), блокируя BCR::ABL1 киназу за счет взаимодействия с миристоиловым карманом. Препарат продемонстрировал эффективность и благоприятный профиль безопасности, согласно результатам исследования I и III фазы у пациентов с Ph+ ХМЛ, резистентным к предыдущей терапии ИТК. В то время как предтрансплантационное использование ИТК 2-го поколения (нилотиниб/дазатиниб) не изменяет риски, связанные с аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК), пока нет подобных данных о пациентах, получающих перед алло-ТГСК асциминиб. В России асциминиб был доступен в рамках Программы управляемого доступа (MAP), одобренной Novartis. В программу MAP было включено 68 пациентов с ХМЛ. Мы проанализировали данные 12 пациентов из 2-х трансплантационных центров, которым была проведена алло-ТГСК в период с августа 2021 г. по август 2022 г. Наша цель заключалась в том, чтобы оценить безопасность и эффективность асциминиба до и после алло-ТГСК. Медиана продолжительности лечения асциминибом до алло-ТГСК составила 194 дня (61-377 дней). У 92% пациентов не развилось нежелательных явлений (НЯ) любой степени тяжести. Медиана приживления составила 20 дней (диапазон 18-24). Общая выживаемость в течение 1 года составила 70%. Кумулятивная частота острой РТПХ (от 1 до 3 степени до D+100) составила 18%. В нашей группе развитие оРТПХ не было обусловлено приемом асциминиба. Безрецидивная смертность составила 18% через 12 месяцев. Восемь пациентов (67%) живы, средняя продолжительность наблюдения после алло-ТГСК составила 135 дней. У всех пациентов достигнут глубокий молекулярный ответ. В нашем наблюдении (ограниченном небольшим набором данных) асциминиб был эффективен в качестве bridge-терапии перед алло-ТГСК у пациентов с несколькими линиями ИТК. Предтрансплантационное лечение асциминибом не оказывало негативного влияния на результаты трансплантации. Необходимо больше данных, полученных по более крупной когорте, чтобы оценить влияние препарата на долгосрочную выживаемость.

Ключевые слова

Хронический миелоидный лейкоз, алло-ТГСК, асциминиб.

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Асциминиб является новым ингибитором BCR::ABL, который действует посредством STAMP(Specifically Targeting the ABL Myristoyl Pocket), блокируя BCR::ABL1 киназу за счет взаимодействия с миристоиловым карманом. Препарат продемонстрировал эффективность и благоприятный профиль безопасности, согласно результатам исследования I и III фазы у пациентов с Ph+ ХМЛ, резистентным к предыдущей терапии ИТК. В то время как предтрансплантационное использование ИТК 2-го поколения (нилотиниб/дазатиниб) не изменяет риски, связанные с аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК), пока нет подобных данных о пациентах, получающих перед алло-ТГСК асциминиб. В России асциминиб был доступен в рамках Программы управляемого доступа (MAP), одобренной Novartis. В программу MAP было включено 68 пациентов с ХМЛ. Мы проанализировали данные 12 пациентов из 2-х трансплантационных центров, которым была проведена алло-ТГСК в период с августа 2021 г. по август 2022 г. Наша цель заключалась в том, чтобы оценить безопасность и эффективность асциминиба до и после алло-ТГСК. Медиана продолжительности лечения асциминибом до алло-ТГСК составила 194 дня (61-377 дней). У 92% пациентов не развилось нежелательных явлений (НЯ) любой степени тяжести. Медиана приживления составила 20 дней (диапазон 18-24). Общая выживаемость в течение 1 года составила 70%. Кумулятивная частота острой РТПХ (от 1 до 3 степени до D+100) составила 18%. В нашей группе развитие оРТПХ не было обусловлено приемом асциминиба. Безрецидивная смертность составила 18% через 12 месяцев. Восемь пациентов (67%) живы, средняя продолжительность наблюдения после алло-ТГСК составила 135 дней. У всех пациентов достигнут глубокий молекулярный ответ. В нашем наблюдении (ограниченном небольшим набором данных) асциминиб был эффективен в качестве bridge-терапии перед алло-ТГСК у пациентов с несколькими линиями ИТК. Предтрансплантационное лечение асциминибом не оказывало негативного влияния на результаты трансплантации. Необходимо больше данных, полученных по более крупной когорте, чтобы оценить влияние препарата на долгосрочную выживаемость.

Ключевые слова

Хронический миелоидный лейкоз, алло-ТГСК, асциминиб.

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Национальный медицинский исследовательский центр имени В. А. Алмазова, Санкт-Петербург, Россия
3 Российский научно-исследовательский институт гематологии и трансфузиологии ФМБА России, Санкт-Петербург, Россия

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Национальный медицинский исследовательский центр имени В. А. Алмазова, Санкт-Петербург, Россия
3 Российский научно-исследовательский институт гематологии и трансфузиологии ФМБА России, Санкт-Петербург, Россия

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Introduction

Non-Hodgkin lymphomas (NHL) represent a heterogeneous group of malignancies which, in the current WHO classification, includes more than 80 disease types arising from B, T lymphocytes and NK cells at distinct stages of differentiation [1].

B-cell lymphomas comprise about 85-90% of all lymphomas [2]. The two most common types of NHL are diffuse large B-cell lymphomas (DLBCL) and follicular lymphomas which account for approximately 35% and 20% of all lymphomas, respectively [3]. Primary mediastinal B-cell lymphoma (PMBCL) is a rare type B-cell lymphoma sharing clinical features with DLBCL constituting approximately 2% to 4% of all NHL. Despite advances of the induction treatment, relapses and refractory (r/r) course of B-NHL remains a common problem [4]. Being the most common forms, mature B-cell lymphomas, are usually highly treatable at initial presentation, whereas other rarer variants are more difficult to treat, and almost all of them have dismal outcomes in cases of relapsed or refractory (r/r) disease. High-dose chemotherapy followed by autologous hematopoietic stem cells transplantation (ASCT) is an important clinical option for consolidation of remission in second and third line treatment of relapsed and refractory lymphomas [5].

The addition of targeted immunotherapy has contributed significantly to the treatment strategy of B-NHL. Anti-CD20 monoclonal antibody rituximab is currently a basic component of treatment for most B-NHL types in primary and r/r setting [6]. Immunotherapy with immune checkpoint inhibitors (ICI), namely programmed death 1 (PD-1) inhibitors may be efficiently used in B-NHL subtypes with high expression of PD-L1/PD-L2, such as PMBCL [7-9].

Among common side effects of r/r NHL treatment, severe colitis is a serious gastrointestinal tract-related complication reported for the therapy with anti-CD20, anti-PD-1 drugs, and following SCT [10-14].

The treatment for therapy-associated colitis depends on its pathogenetic mechanisms and includes antibacterial treatment [15], anti-inflammatory and immunosuppressive therapy [16]. Despite these measures, certain cases of colitis are refractory to standard treatments, and there is a need for additional therapeutic approaches.

Pathogenesis of inflammatory disorders involves various pathways, including the disorders of epithelial barrier, symbiotic flora, antigen recognition, immune dysregulation, leukocyte recruitment and genetic factors [17]. Damage to the colonic epithelial barrier causes its increased permeability for bacteria and their toxins, thus leading to alterations in innate and acquired host immune responses. Some studies explore the significance of fecal microbiota composition in inflammatory diseases, as well as for lymphoma development [18].

Lymphocytes play a key role in responding to microbial colonization, with the majority of immunologically active cells belonging to mucosa-associated lymphoid tissue, permanently exposed to signals from antigen-presenting cells [19]. Dysregulation of this complex mechanisms may lead to inflammatory bowel diseases as well as malignant transformation. Lymphocytes and microbes are, generally, separated by epithelial barrier, whereas mucosal barrier is crossed by the bacteria, antigens, or metabolites via dendritic cells or M cells that constantly interact with luminal space and significantly affect the host organism by a set of direct and indirect mechanisms [20].

Fecal microbiota transplantation (FMT) refers to the therapeutic procedure of transplanting fecal bacteria from healthy persons into the patients, thus leading to correction and recovery of colonic microbiota due to introduction of appropriate bacterial populations. This method has been proven to be successful for the treatment of recurrent C.difficile infection (CDI) [21]. In addition, there are some studies that have demonstrated that FMT could be a productive method for treatment of inflammatory bowel disease (IBD) [22]. Many investigations are underway to test the utility of FMT in other conditions including colitis associated with immune checkpoint inhibitors [23, 24]. Therefore, FMT seems to be a potentially universal therapy for inflammatory bowel diseases of different origin. However, clinical evidence for safety and efficiency of this approach is limited.

Cell-free bacterial DNAs (cfbDNAs) are known to circulate in human bloodstream [25]. Furthermore, some studies have shown that the patients with immune-related diseases, e.g. inflammatory bowel disease, Kawasaki disease and HIV, exhibit higher amounts of cfbDNAs at lower microbial biodiversity if compared to healthy subjects [26]. However, little is known about the origin and existence of cfbDNAs and their effects upon immune response and diseases, e.g., changes of cfbDNAs following FMT.

Here we report two cases of patients with refractory B cell lymphomas, treated with FMT due to resistant colitis which affected the salvage treatment with ASCT and immune checkpoint inhibitors. We have observed a clinical effect after fecal transplantation, along with changing spectrum of circulating bacterial DNAs in bloodstream, which correlated with other laboratory markers and clinical effect.

Materials and methods

We observed two patients after immunotherapy with rituximab or ICI and ASCT who developed prolonged therapy-resistant colitis. The diagnosis of inflammatory colitis was confirmed by morphological and histological features. Blood cell counts and serum biochemistry were made by routine methods at local clinical laboratory. To assess potential pathogens in biological samples, routine bacterological cultures were also performed, and antibiotic susceptibility of clinical isolates was assessed by disk-diffusion test. Clostridium difficile toxin A/B was assesed with immunochromatographic test (VEDALAB, France). Fecal calprotectin levels were also determined by ELISA test.

To perform the therapeutic FMT, we used a standard protocol including dosage and timing and observation terms corresponding to the protocol described elsewhere [27]. FMT was performed from unrelated healthy donors tested for common viral and bacterial infections, including toxigenic C.difficile and E.coli. The gelatin capsules with fecal donor microbiota were administered per os at a dose of 10 (3-15) capsules for 2 or 3 subsequent days. The total dose per single TFM course was 22 g (30 capsules). Clinical evaluation and laboratory analyses were conducted on day 0, and on D +3, D +8, D +16, D +30, D +60, D +90, D +120 after FMT. To assess efficacy of FMT, clinical condition and routine laboratory parameters of patients was monitored. Special attention was drawn to qualitative changes in taxonomic composition of gut and blood microbiota.

The stool samples were collected in sterile plastic containers and immediately frozen at -80ºC until DNA studies. Blood specimens were taken by puncture of the peripheral cubital vein under aseptic conditions. DNA from stool samples was extracted as described elsewhere [27]. Composition of microbial community and its dynamics were assessed by means of next-generation sequencing (NGS) of 16S rRNA gene as previously reported [28]. To this purpose, the samples of stool and EDTA-preserved blood plasma were immediately frozen at -80ºC. The NGS procedures were performed as follows: the nucleic acids were isolated using a QIAsymphony DSP circulating DNA kit (Qiagen, Hilden, Germany), then being quantified with the Qubit dsDNA HS Assay Kit (Life Technologies, Carlsbad, Calif.). NGS libraries were prepared from 0.5 to 1 ng of cfbDNAs using the Nextera XT Library Prep Kit (Illumina, San Diego, CA) or the NEXTflex Cell- Free DNA-Seq Kit (Bio Scientific, Austin, TX) and then were sequenced by HiSeq2500 (Illumina, San Diego, CA). The 16S rDNA data analysis was performed by the QIIME framework and R software. The forward and reverse reads were aligned and attributed to distinct samples as based on barcoding and truncated by cutting off the barcode and primer sequence. Differences in microbiome diversity were determined using Shannon index. To compare patient gut samples with donor specimens, multidimensional scaling analysis (MDSA) was performed using Euclidean distance approach.

Clinical data was evaluated retrospectively from medical records. The patients were informed about the features of FMT procedure and possible complications. Written informed consent was obtained from the patients. The present study was approved by the Local Review Board at the Pavlov University (№192 of 30.01.2017). The study was conducted in accordance with standard operating procedures (SOPs) to ensure that all parties involved adhere to the principles of Good Clinical Practice (GCP) and the Declaration of Helsinki.

Case reports

Case 1

The first patient (Ba) is a 53 y.o. male diagnosed with stage IVB follicular lymphoma (grade 3A) in Oct 2016. The initial treatment included 8 cycles of R-CHOP chemotherapy with only transient partial response and progression of disease in Feb 2017. He was treated with 3 cycles of R-DHAP, followed by peripheral blood stem cells harvest. Further on, he underwent high-dose BeEAM conditioning and ASCT in November 2018. Obinutuzumab was infused as part of conditioning regimen and early after transplant which resulted in complete remission of lymphoma. The patient further received rituximab maintenance therapy from February 2018 to January 2019.

Meanwhile, on day +5 after ASCT, the patient presented with grade 4 diarrhea at the stool volume of up to 2 liters, and an episode of intestinal bleeding. Consecutive analyses for C. difficile toxins A and B were negative. Routine bacteriology of stool was non-specific, with E. faecalis and E.coli as predominant bacterial types. Colonoscopy showed signs of ulcerative colitis and revealed friability, erosion, complete loss of vascular pattern, significant erythema, and mild mucosal hemorrhage. The biopsy detected diffuse and severe mononuclear cell infiltration, distal Paneth cell metaplasia, and basal plasmacytosis. Treatment with metronidazole (500 mg q12h) and vancomycin (500 mg q6h) was inefficient. The stool volume decreased after hematological recovery, but still did not normalize, and diarrhea persisted for next 10 months. Therefore, fecal microbiota transplantation (FMT) was performed for this patient followed by pronounced clinical effect, i.e., normalization of stool and decreased abdominal pain severity, whereas satisfactory bowel habits and quality of life improved 1 month after FMT. At these terms, colonoscopic and histopathologic examinations showed amelioration of the mucosal damage.

To date, more than 2 years after FMT, the patient has a PET-negative complete remission of follicular lymphoma, and no relapses of ulcerative colitis have been noted.

Case 2

The second patient (Er) is a 22 y.o. male diagnosed in with stage IVB PMBCL manifesting with enlarged mediastinal lymph nodes, involvement of lungs and kidneys in Mar 2018. Initial therapy included R-EPOCH/MACOP-B protocol and radiation therapy to the residual mediastinal tumor volume, with complete remission documented in Aug 2018. The patient relapsed with isolated CNS involvement in Oct 2018. The second-line treatment consisted of 1 cycle of HD MTX and Ara-C combined with rituximab without clinical response. The salvage treatment was continued with 2 cycles of CALGB 50202 resulting into stabilization of disease. Due to a dismal prognosis, the patient was treated with 2 cycles of R-ICE regimen along with infusions of nivolumab (№8), thus achieving partial response in February 2019. After the consolidation treatment with high-dose chemotherapy (BuCy) and ASCT in Apr 2019 followed by radiotherapy, a complete response has been achieved in June 2019.

Maintenance treatment with nivolumab had been continued in the posttransplant period, from May 2019 to Sep 2019 and was stopped due to persistent diarrhea. Colonoscopic examination showed edema, erythema, exudate, and sequential loss of vascular pattern in the colon, including rectal segment. Histopathologic examination of biopsy specimens showed active colitis involving infiltration with neutrophils, eosinophils, plasma cells, crypt abscesses. The patient was diagnosed with ICI therapy-related colitis and arthritis being treated without corticosteroids.

Antibacterial treatment was immediately started with metronidazole but had no effect as well as treatment with vancomycin. Treatment with probiotics did not relieve the diarrhea. Each feeding was associated with diarrhea, factoring for progradient weight loss. FMT procedure was performed in September 2019. During the first month, the diarrhea was gradually reduced, and adequate nutrition was restarted. Within 2 months after FMT, the complete resolution of colitis was achieved. The follow-up observations did not reveal any signs of colitis and PMBCL progression.

Time dynamics of clinical parameters in the patients following FMA is shown in Fig. 1 (A-D).

Goloshchapov-fig01.jpg

Figure 1. Time-dependent trends in clinical and laboratory parameters in two cases of post-treatment colitis (patients Ba and Er) following FMT

Abscissa, terms posttransplant, days. Ordinate, values of distinct parameters. A-D: Hb, Leukocytes, Platelets, Calprotectin; E-H, Daily stool frequency, Abdominal pain, points, Stool, Bristol scale, Weight, kg.

Main characteristics of intestinal microbiota after FMT

The 16S rDNA data analysis was performed by the QIIME framework and R software. The forward and reverse reads were aligned and attributed to distinct samples as based on barcoding and truncated by cutting off the barcode and primer sequence.

Before transplant, the gut microbiome was presented mostly by Bacteroides and Firmicutes, with sufficient admixture of Proteobacteria in patient Er (Fig. 2.) After FMT (since day +30), a drastic and continuous decrease in Enterobacteria ratio was registered during the entire observation period. Of note, normalization of stool by Bristol scale and other signs of colitis as well as fecal calprotectin were just diminished by the day +30 in the both patients.

Goloshchapov-fig02.jpg

Figure 2. The dynamics of gut microbiota structure in presented cases. A. Representation of common bacterial genera in stool and peripheral blood of the lymphoma patients (Ba and Er) following fecal microbiota transplantation. B. Shannon indices for stool and blood microbiota at different terms after FMT

Gut microbiome of both colitis patients before FMT showed some similarities, i.e., some predominance of Proteobacteria. along with absence of Acinetobacter in gut samples from both patients. Meanwhile, the post-FMT diversity of gut microbiome decreased in both patients and becomes close to donor indexes. E.g., in patient Ba, the ratio of Bacteroides increased to 51% (donor microbiota, 58%); relative contents of Firmicutes, to 36% (donor, 34%).

Microbiota in blood plasma

Microbiome analysis of circulating blood DNA after FMT demonstrated a significant time-dependent decrease of Shannon diversity index in both patients (pat. Ba, 0.93 versus 0.57 on the day +120, pat. E, 1.39 and 0.45 at day +120). In blood samples, we have revealed predominance of Proteobacteria at day +60 to +120 after FMT as well as Deinococcus thermos, and some presence of Firmicutes. In patient Er, we found absence of Actinobacteria at 120 day after FMT.

Discussion

Immune-checkpoint inhibitors (ICI), as well as anti-CD20 antibodies, have been shown to extend the survival rate of lymphomas patients (6-9), and their clinical usage has increased rapidly. However, inflammatory colitis is a well-known adverse effect induced by these therapies [10, 11, 12, 29]. E.g., typical endoscopic findings of immune-induced colitis such as exudates, tissue granulations, loss of vascular pattern, and significant erythema, can be observed during colonoscopy in patients treated with ICI. These findings are similar to those in inflammatory bowel disease, particularly ulcerative colitis [30]. Pathogenesis of immune-mediated colitis is not well understood, however, these disorders are characterized by immune dysregulation and alterations in gut microbiota [31]. Most recent therapeutic strategies including corticosteroids and/or TNF-α targeting agents may directly affect the immune response, but these therapies are associated with significant risk of adverse events [32]. Modification of the microbial environment by fecal microbiota transplant offers an alternative approach which could indirectly influence the host immune system in a safe and less costly way [22].

FMT is highly efficient for treating recurrent and refractory infections associated with Clostridium difficile [21]. In recently published trials, FMT has shown a curative effect in ulcerative colitis thus being a safe, cost effective treatment option in a subset of patients with inflammatory bowel disease [22]. However, clinical data regarding safety and efficiency of this method for treatment of ICI-induced colitis are quite limited, and appropriate clinical indications for optimal management are still evolving. Some studies have demonstrated that targeting specific bacterial taxa by FMT may eliminate the ICI-related toxicity [23-24].

In this study we presented two cases of patients with colitis associated with nivolumab or rituximab treatment. Both patients had complete resolution of clinical symptoms after FMT with intestinal motility, nutrition habits and life quality being returned to normal. We have also found a decreased diversity of gut microbiome after FMT, thus becoming close to the donor’s biodiversity. Along with clinical improvement, endoscopic evaluation after FMT did also show an improvement, with reduced inflammation and resolution of ulcerations.

Intestinal bacteria play a crucial role in maintaining immune homeostasis due to their ability to regulate the innate and adaptive immune systems [33]. E.g., when studying experimental uveitis in R161H mice, it was shown that activated T cells were present in gut tissues before local manifestations of retinal disease [34]. It was demonstrated that T cells activated by intestinal stimuli in R161H animals could induce uveitis in naive recipient mice, suggesting that these stimuli are sufficient to make them pathogenic. Previously, it has been demonstrated that modulation of the gut microbiome of germ-free mice by FMT could change antitumor immunity and response to ICI therapy in gnotobiotic mice [35]. Recent reports suggest that such regulation seems to also be exerted epigenetically, directly by gut microbes, capable of regulating the expression of specific immune-modulating miRNAs [36]. Hence, the potentially healthy gut microbiota could modulate antitumor immunity by activating the T-cell link, thereby contributing to the maintenance of durable remission of the disease. Thus, we suggest that FMT may be an effective treatment option for autoimmune colitis and also facilitates to improve results of therapy in patients with refractory of malignant blood diseases.

It is known that the cell-free bacterial DNAs (cfbDNAs) originate from colonizing or invasive microbes that, along with bacterial endotoxins, may be released into the bloodstream [25]. Early studies did not focus on cfbDNAs of microbial origin in bloodstream because of limited knowledge on these items [37], but the development of cfbDNAs-based tests for infectious diseases were proposed in clinical practice since early 2000’s. Blauwkamp and colleagues validated a plasma cfbDNAs sequencing assay, and proposed that this technique is now relevant and actionable and offers distinct advantages over traditional diagnostic methods [38]. An increasing number of studies have demonstrated that the cfbDNAs detection offers the potential to reliably identify a wide variety of infections, such as invasive fungal infection [39], tuberculosis [37] and sepsis [40]. Some studies have shown that the patients with immune-related diseases exhibit higher amounts of cfbDNAs with lower microbial biodiversity compared with healthy individuals [26].

Evaluation of the cell-free bacterial DNAs is suggested to be among important cancer biomarkers. A recent study by Poore et al. [41] was able to validate distinct cancer-type specific cfmDNA signatures identified by analyzing a large collection of tissue and blood samples. This report highlights a potential of cfbDNAs based diagnostics in cancer. So far, however, there are no reliable controls for false-positive results due to exogenous bacterial contamination. Moreover, there are no further information on changes of cfbDNAs after FMT.

In our study, we first described the changes in the cell-free bacterial DNAs profile in the blood after FMT. Microbiome analysis demonstrated significant decrease of Shannon diversity index in blood microbiome and changing composition of microbiome in blood samples.

Conсerning the NGS techniques for 16S rDNA in our center, we assume the ubiquitous presence of microbes in clinical and laboratory environment, reagents and during the sample processing. We assume that the consistency and accuracy of NGS results may be biased at the preanalytical issues (sample processing), analytical stage (cfbDNAs isolation, and sequencing procedure) and postanalytical phase (bioinformatics and interpretation of results).

Conclusion

Hence, we can be unambiguously conclude that both intestinal and blood microbiome undergo sufficient changes following FMT when compared to the background values. Restoration of gut microbiome, especially, reduction of Enterobacteria, occurred in parallel with clinical improvement of colitis symptoms. Therefore, fecal microbiota transplantation refers to a new potential option for treatment of ICI-induced colitis. The possibility of altering a patient's microbiome by FMT to improve the chances of the maintenance of durable remission and modulate antitumor immunity thus being a promising treatment option in immune-associated colitis developing after immune therapy of lymphoma patients.

Conflict of interest

None declared.

Acknowledgement

This study was supported by a research grant from Russian Science Foundation No. №22-15-00149 of 18.05.2022.

References

  1. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 19;127(20):2375-2390. doi: 10.1182/blood-2016-01-643569
  2. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program. 2009:523-31. doi: 10.1182/asheducation-2009.1.523
  3. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, et al. SEER cancer statistics review, 1975-2011. National Cancer Institute. Bethesda, MD. (2014). Available: https://seer.cancer.gov/archive/csr/1975_2011/
  4. Giulino-Roth L. How I treat primary mediastinal B-cell lymphoma. Blood. 2018; 132(8):782-790. doi: 10.1182/blood-2018-04-791566
  5. Fujita N, Kobayashi R, Atsuta Y, Iwasaki F, Suzumiya J, Sasahara Y, et al. Hematopoietic stem cell transplantation in children and adolescents with relapsed or refractory B-cell non-Hodgkin lymphoma. Int J Hematol. 2019; 109(4):483-490. doi: 10.1007/s12185-019-02608-y
  6. Barth MJ, Minard-Colin V. Novel targeted therapeutic agents for the treatment of childhood, adolescent and young adult non-Hodgkin lymphoma. Br J Haematol. 2019 Jun;185(6):1111-1124. doi: 10.1111/bjh.15783
  7. Tanaka Y, Maeshima AM, Nomoto J, Makita S, Fukuhara S, Munakata W, Maruyama D, Tobinai K, Kobayashi Y. Expression pattern of PD-L1 and PD-L2 in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and gray zone lymphoma. Eur J Haematol. 2018 May;100(5):511-517. doi: 10.1111/ejh.13033
  8. Zinzani PL, Ribrag V, Moskowitz CH, Michot JM, Kuruvilla J, Balakumaran A, Zhang Y, Chlosta S, Shipp MA, Armand P. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017 Jul 20;130(3):267-270. doi: 10.1182/blood-2016-12-758383
  9. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, Millenson MM, Cohen AD, Schuster SJ, Lebovic D, Dhodapkar M, Avigan D, Chapuy B, Ligon AH, Freeman GJ, Rodig SJ, Cattry D, Zhu L, Grosso JF, Bradley Garelik MB, Shipp MA, Borrello I, Timmerman J. Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol. 2016 Aug 10;34(23):2698-704. doi: 10.1200/JCO.2015.65.9789
  10. Mallepally N, Abu-Sbeih H, Ahmed O, Chen E, Shafi MA, Neelapu SS, Wang Y. Clinical Features of Rituximab-associated Gastrointestinal Toxicities. Am J Clin Oncol. 2019 Jun;42(6):539-545. doi: 10.1097/COC.0000000000000553
  11. Yamauchi R, Araki T, Mitsuyama K, Tokito T, Ishii H, Yoshioka S, Kuwaki K, Mori A, Yoshimura T, Tsuruta O, Torimura T. The characteristics of nivolumab-induced colitis: an evaluation of three cases and a literature review. BMC Gastroenterol. 2018 Aug 31;18(1):135. doi: 10.1186/s12876-018-0864-1
  12. Bhalme M, Hayes S, Norton A, Lal S, Chinoy H, Paine P. Rituximab-associated colitis. Inflamm Bowel Dis. 2013 Mar;19(3):E41-3.
    doi: 10.1002/ibd.22963
  13. Cañete F, Mañosa M, Lobatón T, Mesonero F, Rodríguez-Lago I, Cabré E, Cabriada JL, López-Sanromán A, Domènech E. Nivolumab-induced immune-mediated colitis: an ulcerative colitis look-alike-report of new cases and review of the literature. Int J Colorectal Dis. 2019 May;34(5):861-865. doi: 10.1007/s00384-019-03268-4
  14. Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol. 2012 Apr 28;18(16):1851-60. doi: 10.3748/wjg.v18.i16.1851
  15. Nitzan O, Elias M, Peretz A, Saliba W. Role of antibiotics for treatment of inflammatory bowel disease. World J Gastroenterol. 2016 Jan 21;22(3):1078-87. doi: 10.3748/wjg.v22.i3.1078
  16. Prieux-Klotz C, Dior M, Damotte D, Dreanic J, Brieau B, Brezault C, Abitbol V, Chaussade S, Coriat R. Immune Checkpoint Inhibitor-Induced Colitis: Diagnosis and Management. Target Oncol. 2017 Jun;12(3):301-308. doi: 10.1007/s11523-017-0495-4
  17. Guo XY, Liu XJ, Hao JY. Gut microbiota in ulcerative colitis: insights on pathogenesis and treatment. J Dig Dis. 2020 Mar;21(3):147-159. doi: 10.1111/1751-2980.12849
  18. Kaur A, Goggolidou P. Ulcerative colitis: understanding its cellular pathology could provide insights into novel therapies. J Inflamm (Lond). 2020 Apr 21;17:15. doi: 10.1186/s12950-020-00246-4
  19. Kmieć Z, Cyman M, Ślebioda TJ. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease. Adv Med Sci. 2017 Mar;62(1):1-16. doi: 10.1016/j.advms.2016.09.001
  20. Zhang S, Cao X, Huang H. Sampling Strategies for Three-Dimensional Spatial Community Structures in IBD Microbiota Research. Front Cell Infect Microbiol. 2017 Feb 24;7:51. doi: 10.3389/fcimb.2017.00051
  21. Drekonja D, Reich J, Gezahegn S, Greer N, Shaukat A, MacDonald R, Rutks I, Wilt TJ. Fecal Microbiota Transplantation for Clostridium difficile Infection: A Systematic Review. Ann Intern Med. 2015 May 5;162(9):630-8. doi: 10.7326/M14-2693
  22. Sood A, Singh A, Mahajan R, Midha V, Mehta V, Gupta YK, Narang V, Kaur K. Acceptability, tolerability, and safety of fecal microbiota transplantation in patients with active ulcerative colitis (AT&S Study). J Gastroenterol Hepatol. 2020 Mar;35(3):418-424. doi: 10.1111/jgh.14829
  23. Fasanello MK, Robillard KT, Boland PM, Bain AJ, Kanehira K. Use of Fecal Microbial Transplantation for Immune Checkpoint Inhibitor Colitis. ACG Case Rep J. 2020 Apr 10;7(4):e00360. doi: 10.14309/crj.0000000000000360
  24. Wang Y, Wiesnoski DH, Helmink BA, Gopalakrishnan V, Choi K, DuPont HL, Jiang ZD, Abu-Sbeih H, Sanchez CA, Chang CC, Parra ER, Francisco-Cruz A, Raju GS, Stroehlein JR, Campbell MT, Gao J, Subudhi SK, Maru DM, Blando JM, Lazar AJ, Allison JP, Sharma P, Tetzlaff MT, Wargo JA, Jenq RR. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis.
    Nat Med. 2018 Dec;24(12):1804-1808. doi: 10.1038/s41591-018-0238-9
  25. Nikkari S, McLaughlin IJ, Bi W, Dodge DE, Relman DA. Does blood of healthy subjects contain bacterial ribosomal DNA? J Clin Microbiol. 2001 May;39(5):1956-9. doi: 10.1128/JCM.39.5.1956-1959.2001
  26. Nishida A, Inoue R, Inatomi O, Bamba S, Naito Y, Andoh A. Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin J Gastroenterol. 2018 Feb;11(1):1-10. doi: 10.1007/s12328-017-0813-5
  27. Goloshchapov OV, Bakin EA, Kucher MA, Stanevich OV, Suvorova MA, Gostev VV, et al. Bacteroides fragilis is a potential marker of effective microbiota transplantation in acute graft-versus-host disease treatment. Cell Ther Transplant 2020; 9(2): 47-59.
    doi: 10.18620/ctt-1866-8836-2020-9-2-47-59
  28. Goloshchapov OV, Olekhnovich EI, Sidorenko SV, Moiseev IS, Kucher MA, Fedorov DE, et al. Long-term impact of fecal transplantation in healthy volunteers. BMC Microbiology. 2019; vol. 19, Article No.: 312. doi: 10.1186/s12866-019-1689-y
  29. Wang DY, Ye F, Zhao S, Johnson DB. Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: A systematic review and meta-analysis. Oncoimmunology. 2017 Jul 5;6(10):e1344805. doi: 10.1080/2162402X.2017.1344805
  30. Gupta A, De Felice KM, Loftus EV Jr, Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther. 2015 Aug;42(4):406-17. doi: 10.1111/apt.13281
  31. Cammarota G, Ianiro G, Cianci R, Bibbò S, Gasbarrini A, Currò D. The involvement of gut microbiota in inflammatory bowel disease pathogenesis: potential for therapy. Pharmacol Ther. 2015 May;149:191-212. doi: 10.1016/j.pharmthera.2014.12.006
  32. Kirchgesner J, Lemaitre M, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases. Gastroenterology. 2018 Aug;155(2):337-346.e10. doi: 10.1053/j.gastro.2018.04.012
  33. Lin L, Zhang J. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol. 2017 Jan 6;18(1):2. doi: 10.1186/s12865-016-0187-3
  34. Horai R, Silver PB, Chen J, Agarwal RK, Chong WP, Jittayasothorn Y, Mattapallil MJ, Nguyen S, Natarajan K, Villasmil R, Wang P, Karabekian Z, Lytton SD, Chan CC, Caspi RR. Breakdown of immune privilege and spontaneous autoimmunity in mice expressing a transgenic T cell receptor specific for a retinal autoantigen. J Autoimmun. 2013 Aug;44:21-33. doi: 10.1016/j.jaut.2013.06.003
  35. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103. doi: 10.1126/science.aan4236
  36. Kocic H, Damiani G, Stamenkovic B, Tirant M, Jovic A, Tiodorovic D, Peris K. Dietary compounds as potential modulators of microRNA expression in psoriasis. Ther Adv Chronic Dis. 2019 Aug 7;10:2040622319864805. doi: 10.1177/2040622319864805
  37. Fernández-Carballo BL, Broger T, Wyss R, Banaei N, Denkinger CM. Toward the Development of a Circulating Free DNA-Based In Vitro Diagnostic Test for Infectious Diseases: a Review of Evidence for Tuberculosis. J Clin Microbiol. 2019 Mar 28;57(4):e01234-18.
    doi: 10.1128/JCM.01234-18
  38. Blauwkamp TA, Thair S, Rosen MJ, Blair L, Lindner MS, Vilfan ID, Kawli T, et al. Analytical and clinical validation of a microbial cell-free DNA sequencing test for infectious disease. Nat Microbiol. 2019 Apr;4(4):663-674. doi: 10.1038/s41564-018-0349-6
  39. Hong DK, Blauwkamp TA, Kertesz M, Bercovici S, Truong C, Banaei N. Liquid biopsy for infectious diseases: sequencing of cell-free plasma to detect pathogen DNA in patients with invasive fungal disease. Diagn Microbiol Infect Dis. 2018 Nov;92(3):210-213.
    doi: 10.1016/j.diagmicrobio.2018.06.009
  40. Long Y, Zhang Y, Gong Y, Sun R, Su L, Lin X, Shen A, Zhou J, Caiji Z, Wang X, Li D, Wu H, Tan H. Diagnosis of Sepsis with Cell-free DNA by Next-Generation Sequencing Technology in ICU Patients. Arch Med Res. 2016 Jul;47(5):365-371. doi: 10.1016/j.arcmed.2016.08.004
  41. Poore GD, Kopylova E, Zhu Q, Carpenter C, Fraraccio S, Wandro S, Kosciolek T, Janssen S, Metcalf J, Song SJ, Kanbar J, Miller-Montgomery S, Heaton R, Mckay R, Patel SP, Swafford AD, Knight R. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature. 2020 Mar;579(7800):567-574. doi: 10.1038/s41586-020-2095-1

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Introduction

Non-Hodgkin lymphomas (NHL) represent a heterogeneous group of malignancies which, in the current WHO classification, includes more than 80 disease types arising from B, T lymphocytes and NK cells at distinct stages of differentiation [1].

B-cell lymphomas comprise about 85-90% of all lymphomas [2]. The two most common types of NHL are diffuse large B-cell lymphomas (DLBCL) and follicular lymphomas which account for approximately 35% and 20% of all lymphomas, respectively [3]. Primary mediastinal B-cell lymphoma (PMBCL) is a rare type B-cell lymphoma sharing clinical features with DLBCL constituting approximately 2% to 4% of all NHL. Despite advances of the induction treatment, relapses and refractory (r/r) course of B-NHL remains a common problem [4]. Being the most common forms, mature B-cell lymphomas, are usually highly treatable at initial presentation, whereas other rarer variants are more difficult to treat, and almost all of them have dismal outcomes in cases of relapsed or refractory (r/r) disease. High-dose chemotherapy followed by autologous hematopoietic stem cells transplantation (ASCT) is an important clinical option for consolidation of remission in second and third line treatment of relapsed and refractory lymphomas [5].

The addition of targeted immunotherapy has contributed significantly to the treatment strategy of B-NHL. Anti-CD20 monoclonal antibody rituximab is currently a basic component of treatment for most B-NHL types in primary and r/r setting [6]. Immunotherapy with immune checkpoint inhibitors (ICI), namely programmed death 1 (PD-1) inhibitors may be efficiently used in B-NHL subtypes with high expression of PD-L1/PD-L2, such as PMBCL [7-9].

Among common side effects of r/r NHL treatment, severe colitis is a serious gastrointestinal tract-related complication reported for the therapy with anti-CD20, anti-PD-1 drugs, and following SCT [10-14].

The treatment for therapy-associated colitis depends on its pathogenetic mechanisms and includes antibacterial treatment [15], anti-inflammatory and immunosuppressive therapy [16]. Despite these measures, certain cases of colitis are refractory to standard treatments, and there is a need for additional therapeutic approaches.

Pathogenesis of inflammatory disorders involves various pathways, including the disorders of epithelial barrier, symbiotic flora, antigen recognition, immune dysregulation, leukocyte recruitment and genetic factors [17]. Damage to the colonic epithelial barrier causes its increased permeability for bacteria and their toxins, thus leading to alterations in innate and acquired host immune responses. Some studies explore the significance of fecal microbiota composition in inflammatory diseases, as well as for lymphoma development [18].

Lymphocytes play a key role in responding to microbial colonization, with the majority of immunologically active cells belonging to mucosa-associated lymphoid tissue, permanently exposed to signals from antigen-presenting cells [19]. Dysregulation of this complex mechanisms may lead to inflammatory bowel diseases as well as malignant transformation. Lymphocytes and microbes are, generally, separated by epithelial barrier, whereas mucosal barrier is crossed by the bacteria, antigens, or metabolites via dendritic cells or M cells that constantly interact with luminal space and significantly affect the host organism by a set of direct and indirect mechanisms [20].

Fecal microbiota transplantation (FMT) refers to the therapeutic procedure of transplanting fecal bacteria from healthy persons into the patients, thus leading to correction and recovery of colonic microbiota due to introduction of appropriate bacterial populations. This method has been proven to be successful for the treatment of recurrent C.difficile infection (CDI) [21]. In addition, there are some studies that have demonstrated that FMT could be a productive method for treatment of inflammatory bowel disease (IBD) [22]. Many investigations are underway to test the utility of FMT in other conditions including colitis associated with immune checkpoint inhibitors [23, 24]. Therefore, FMT seems to be a potentially universal therapy for inflammatory bowel diseases of different origin. However, clinical evidence for safety and efficiency of this approach is limited.

Cell-free bacterial DNAs (cfbDNAs) are known to circulate in human bloodstream [25]. Furthermore, some studies have shown that the patients with immune-related diseases, e.g. inflammatory bowel disease, Kawasaki disease and HIV, exhibit higher amounts of cfbDNAs at lower microbial biodiversity if compared to healthy subjects [26]. However, little is known about the origin and existence of cfbDNAs and their effects upon immune response and diseases, e.g., changes of cfbDNAs following FMT.

Here we report two cases of patients with refractory B cell lymphomas, treated with FMT due to resistant colitis which affected the salvage treatment with ASCT and immune checkpoint inhibitors. We have observed a clinical effect after fecal transplantation, along with changing spectrum of circulating bacterial DNAs in bloodstream, which correlated with other laboratory markers and clinical effect.

Materials and methods

We observed two patients after immunotherapy with rituximab or ICI and ASCT who developed prolonged therapy-resistant colitis. The diagnosis of inflammatory colitis was confirmed by morphological and histological features. Blood cell counts and serum biochemistry were made by routine methods at local clinical laboratory. To assess potential pathogens in biological samples, routine bacterological cultures were also performed, and antibiotic susceptibility of clinical isolates was assessed by disk-diffusion test. Clostridium difficile toxin A/B was assesed with immunochromatographic test (VEDALAB, France). Fecal calprotectin levels were also determined by ELISA test.

To perform the therapeutic FMT, we used a standard protocol including dosage and timing and observation terms corresponding to the protocol described elsewhere [27]. FMT was performed from unrelated healthy donors tested for common viral and bacterial infections, including toxigenic C.difficile and E.coli. The gelatin capsules with fecal donor microbiota were administered per os at a dose of 10 (3-15) capsules for 2 or 3 subsequent days. The total dose per single TFM course was 22 g (30 capsules). Clinical evaluation and laboratory analyses were conducted on day 0, and on D +3, D +8, D +16, D +30, D +60, D +90, D +120 after FMT. To assess efficacy of FMT, clinical condition and routine laboratory parameters of patients was monitored. Special attention was drawn to qualitative changes in taxonomic composition of gut and blood microbiota.

The stool samples were collected in sterile plastic containers and immediately frozen at -80ºC until DNA studies. Blood specimens were taken by puncture of the peripheral cubital vein under aseptic conditions. DNA from stool samples was extracted as described elsewhere [27]. Composition of microbial community and its dynamics were assessed by means of next-generation sequencing (NGS) of 16S rRNA gene as previously reported [28]. To this purpose, the samples of stool and EDTA-preserved blood plasma were immediately frozen at -80ºC. The NGS procedures were performed as follows: the nucleic acids were isolated using a QIAsymphony DSP circulating DNA kit (Qiagen, Hilden, Germany), then being quantified with the Qubit dsDNA HS Assay Kit (Life Technologies, Carlsbad, Calif.). NGS libraries were prepared from 0.5 to 1 ng of cfbDNAs using the Nextera XT Library Prep Kit (Illumina, San Diego, CA) or the NEXTflex Cell- Free DNA-Seq Kit (Bio Scientific, Austin, TX) and then were sequenced by HiSeq2500 (Illumina, San Diego, CA). The 16S rDNA data analysis was performed by the QIIME framework and R software. The forward and reverse reads were aligned and attributed to distinct samples as based on barcoding and truncated by cutting off the barcode and primer sequence. Differences in microbiome diversity were determined using Shannon index. To compare patient gut samples with donor specimens, multidimensional scaling analysis (MDSA) was performed using Euclidean distance approach.

Clinical data was evaluated retrospectively from medical records. The patients were informed about the features of FMT procedure and possible complications. Written informed consent was obtained from the patients. The present study was approved by the Local Review Board at the Pavlov University (№192 of 30.01.2017). The study was conducted in accordance with standard operating procedures (SOPs) to ensure that all parties involved adhere to the principles of Good Clinical Practice (GCP) and the Declaration of Helsinki.

Case reports

Case 1

The first patient (Ba) is a 53 y.o. male diagnosed with stage IVB follicular lymphoma (grade 3A) in Oct 2016. The initial treatment included 8 cycles of R-CHOP chemotherapy with only transient partial response and progression of disease in Feb 2017. He was treated with 3 cycles of R-DHAP, followed by peripheral blood stem cells harvest. Further on, he underwent high-dose BeEAM conditioning and ASCT in November 2018. Obinutuzumab was infused as part of conditioning regimen and early after transplant which resulted in complete remission of lymphoma. The patient further received rituximab maintenance therapy from February 2018 to January 2019.

Meanwhile, on day +5 after ASCT, the patient presented with grade 4 diarrhea at the stool volume of up to 2 liters, and an episode of intestinal bleeding. Consecutive analyses for C. difficile toxins A and B were negative. Routine bacteriology of stool was non-specific, with E. faecalis and E.coli as predominant bacterial types. Colonoscopy showed signs of ulcerative colitis and revealed friability, erosion, complete loss of vascular pattern, significant erythema, and mild mucosal hemorrhage. The biopsy detected diffuse and severe mononuclear cell infiltration, distal Paneth cell metaplasia, and basal plasmacytosis. Treatment with metronidazole (500 mg q12h) and vancomycin (500 mg q6h) was inefficient. The stool volume decreased after hematological recovery, but still did not normalize, and diarrhea persisted for next 10 months. Therefore, fecal microbiota transplantation (FMT) was performed for this patient followed by pronounced clinical effect, i.e., normalization of stool and decreased abdominal pain severity, whereas satisfactory bowel habits and quality of life improved 1 month after FMT. At these terms, colonoscopic and histopathologic examinations showed amelioration of the mucosal damage.

To date, more than 2 years after FMT, the patient has a PET-negative complete remission of follicular lymphoma, and no relapses of ulcerative colitis have been noted.

Case 2

The second patient (Er) is a 22 y.o. male diagnosed in with stage IVB PMBCL manifesting with enlarged mediastinal lymph nodes, involvement of lungs and kidneys in Mar 2018. Initial therapy included R-EPOCH/MACOP-B protocol and radiation therapy to the residual mediastinal tumor volume, with complete remission documented in Aug 2018. The patient relapsed with isolated CNS involvement in Oct 2018. The second-line treatment consisted of 1 cycle of HD MTX and Ara-C combined with rituximab without clinical response. The salvage treatment was continued with 2 cycles of CALGB 50202 resulting into stabilization of disease. Due to a dismal prognosis, the patient was treated with 2 cycles of R-ICE regimen along with infusions of nivolumab (№8), thus achieving partial response in February 2019. After the consolidation treatment with high-dose chemotherapy (BuCy) and ASCT in Apr 2019 followed by radiotherapy, a complete response has been achieved in June 2019.

Maintenance treatment with nivolumab had been continued in the posttransplant period, from May 2019 to Sep 2019 and was stopped due to persistent diarrhea. Colonoscopic examination showed edema, erythema, exudate, and sequential loss of vascular pattern in the colon, including rectal segment. Histopathologic examination of biopsy specimens showed active colitis involving infiltration with neutrophils, eosinophils, plasma cells, crypt abscesses. The patient was diagnosed with ICI therapy-related colitis and arthritis being treated without corticosteroids.

Antibacterial treatment was immediately started with metronidazole but had no effect as well as treatment with vancomycin. Treatment with probiotics did not relieve the diarrhea. Each feeding was associated with diarrhea, factoring for progradient weight loss. FMT procedure was performed in September 2019. During the first month, the diarrhea was gradually reduced, and adequate nutrition was restarted. Within 2 months after FMT, the complete resolution of colitis was achieved. The follow-up observations did not reveal any signs of colitis and PMBCL progression.

Time dynamics of clinical parameters in the patients following FMA is shown in Fig. 1 (A-D).

Goloshchapov-fig01.jpg

Figure 1. Time-dependent trends in clinical and laboratory parameters in two cases of post-treatment colitis (patients Ba and Er) following FMT

Abscissa, terms posttransplant, days. Ordinate, values of distinct parameters. A-D: Hb, Leukocytes, Platelets, Calprotectin; E-H, Daily stool frequency, Abdominal pain, points, Stool, Bristol scale, Weight, kg.

Main characteristics of intestinal microbiota after FMT

The 16S rDNA data analysis was performed by the QIIME framework and R software. The forward and reverse reads were aligned and attributed to distinct samples as based on barcoding and truncated by cutting off the barcode and primer sequence.

Before transplant, the gut microbiome was presented mostly by Bacteroides and Firmicutes, with sufficient admixture of Proteobacteria in patient Er (Fig. 2.) After FMT (since day +30), a drastic and continuous decrease in Enterobacteria ratio was registered during the entire observation period. Of note, normalization of stool by Bristol scale and other signs of colitis as well as fecal calprotectin were just diminished by the day +30 in the both patients.

Goloshchapov-fig02.jpg

Figure 2. The dynamics of gut microbiota structure in presented cases. A. Representation of common bacterial genera in stool and peripheral blood of the lymphoma patients (Ba and Er) following fecal microbiota transplantation. B. Shannon indices for stool and blood microbiota at different terms after FMT

Gut microbiome of both colitis patients before FMT showed some similarities, i.e., some predominance of Proteobacteria. along with absence of Acinetobacter in gut samples from both patients. Meanwhile, the post-FMT diversity of gut microbiome decreased in both patients and becomes close to donor indexes. E.g., in patient Ba, the ratio of Bacteroides increased to 51% (donor microbiota, 58%); relative contents of Firmicutes, to 36% (donor, 34%).

Microbiota in blood plasma

Microbiome analysis of circulating blood DNA after FMT demonstrated a significant time-dependent decrease of Shannon diversity index in both patients (pat. Ba, 0.93 versus 0.57 on the day +120, pat. E, 1.39 and 0.45 at day +120). In blood samples, we have revealed predominance of Proteobacteria at day +60 to +120 after FMT as well as Deinococcus thermos, and some presence of Firmicutes. In patient Er, we found absence of Actinobacteria at 120 day after FMT.

Discussion

Immune-checkpoint inhibitors (ICI), as well as anti-CD20 antibodies, have been shown to extend the survival rate of lymphomas patients (6-9), and their clinical usage has increased rapidly. However, inflammatory colitis is a well-known adverse effect induced by these therapies [10, 11, 12, 29]. E.g., typical endoscopic findings of immune-induced colitis such as exudates, tissue granulations, loss of vascular pattern, and significant erythema, can be observed during colonoscopy in patients treated with ICI. These findings are similar to those in inflammatory bowel disease, particularly ulcerative colitis [30]. Pathogenesis of immune-mediated colitis is not well understood, however, these disorders are characterized by immune dysregulation and alterations in gut microbiota [31]. Most recent therapeutic strategies including corticosteroids and/or TNF-α targeting agents may directly affect the immune response, but these therapies are associated with significant risk of adverse events [32]. Modification of the microbial environment by fecal microbiota transplant offers an alternative approach which could indirectly influence the host immune system in a safe and less costly way [22].

FMT is highly efficient for treating recurrent and refractory infections associated with Clostridium difficile [21]. In recently published trials, FMT has shown a curative effect in ulcerative colitis thus being a safe, cost effective treatment option in a subset of patients with inflammatory bowel disease [22]. However, clinical data regarding safety and efficiency of this method for treatment of ICI-induced colitis are quite limited, and appropriate clinical indications for optimal management are still evolving. Some studies have demonstrated that targeting specific bacterial taxa by FMT may eliminate the ICI-related toxicity [23-24].

In this study we presented two cases of patients with colitis associated with nivolumab or rituximab treatment. Both patients had complete resolution of clinical symptoms after FMT with intestinal motility, nutrition habits and life quality being returned to normal. We have also found a decreased diversity of gut microbiome after FMT, thus becoming close to the donor’s biodiversity. Along with clinical improvement, endoscopic evaluation after FMT did also show an improvement, with reduced inflammation and resolution of ulcerations.

Intestinal bacteria play a crucial role in maintaining immune homeostasis due to their ability to regulate the innate and adaptive immune systems [33]. E.g., when studying experimental uveitis in R161H mice, it was shown that activated T cells were present in gut tissues before local manifestations of retinal disease [34]. It was demonstrated that T cells activated by intestinal stimuli in R161H animals could induce uveitis in naive recipient mice, suggesting that these stimuli are sufficient to make them pathogenic. Previously, it has been demonstrated that modulation of the gut microbiome of germ-free mice by FMT could change antitumor immunity and response to ICI therapy in gnotobiotic mice [35]. Recent reports suggest that such regulation seems to also be exerted epigenetically, directly by gut microbes, capable of regulating the expression of specific immune-modulating miRNAs [36]. Hence, the potentially healthy gut microbiota could modulate antitumor immunity by activating the T-cell link, thereby contributing to the maintenance of durable remission of the disease. Thus, we suggest that FMT may be an effective treatment option for autoimmune colitis and also facilitates to improve results of therapy in patients with refractory of malignant blood diseases.

It is known that the cell-free bacterial DNAs (cfbDNAs) originate from colonizing or invasive microbes that, along with bacterial endotoxins, may be released into the bloodstream [25]. Early studies did not focus on cfbDNAs of microbial origin in bloodstream because of limited knowledge on these items [37], but the development of cfbDNAs-based tests for infectious diseases were proposed in clinical practice since early 2000’s. Blauwkamp and colleagues validated a plasma cfbDNAs sequencing assay, and proposed that this technique is now relevant and actionable and offers distinct advantages over traditional diagnostic methods [38]. An increasing number of studies have demonstrated that the cfbDNAs detection offers the potential to reliably identify a wide variety of infections, such as invasive fungal infection [39], tuberculosis [37] and sepsis [40]. Some studies have shown that the patients with immune-related diseases exhibit higher amounts of cfbDNAs with lower microbial biodiversity compared with healthy individuals [26].

Evaluation of the cell-free bacterial DNAs is suggested to be among important cancer biomarkers. A recent study by Poore et al. [41] was able to validate distinct cancer-type specific cfmDNA signatures identified by analyzing a large collection of tissue and blood samples. This report highlights a potential of cfbDNAs based diagnostics in cancer. So far, however, there are no reliable controls for false-positive results due to exogenous bacterial contamination. Moreover, there are no further information on changes of cfbDNAs after FMT.

In our study, we first described the changes in the cell-free bacterial DNAs profile in the blood after FMT. Microbiome analysis demonstrated significant decrease of Shannon diversity index in blood microbiome and changing composition of microbiome in blood samples.

Conсerning the NGS techniques for 16S rDNA in our center, we assume the ubiquitous presence of microbes in clinical and laboratory environment, reagents and during the sample processing. We assume that the consistency and accuracy of NGS results may be biased at the preanalytical issues (sample processing), analytical stage (cfbDNAs isolation, and sequencing procedure) and postanalytical phase (bioinformatics and interpretation of results).

Conclusion

Hence, we can be unambiguously conclude that both intestinal and blood microbiome undergo sufficient changes following FMT when compared to the background values. Restoration of gut microbiome, especially, reduction of Enterobacteria, occurred in parallel with clinical improvement of colitis symptoms. Therefore, fecal microbiota transplantation refers to a new potential option for treatment of ICI-induced colitis. The possibility of altering a patient's microbiome by FMT to improve the chances of the maintenance of durable remission and modulate antitumor immunity thus being a promising treatment option in immune-associated colitis developing after immune therapy of lymphoma patients.

Conflict of interest

None declared.

Acknowledgement

This study was supported by a research grant from Russian Science Foundation No. №22-15-00149 of 18.05.2022.

References

  1. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 19;127(20):2375-2390. doi: 10.1182/blood-2016-01-643569
  2. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program. 2009:523-31. doi: 10.1182/asheducation-2009.1.523
  3. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, et al. SEER cancer statistics review, 1975-2011. National Cancer Institute. Bethesda, MD. (2014). Available: https://seer.cancer.gov/archive/csr/1975_2011/
  4. Giulino-Roth L. How I treat primary mediastinal B-cell lymphoma. Blood. 2018; 132(8):782-790. doi: 10.1182/blood-2018-04-791566
  5. Fujita N, Kobayashi R, Atsuta Y, Iwasaki F, Suzumiya J, Sasahara Y, et al. Hematopoietic stem cell transplantation in children and adolescents with relapsed or refractory B-cell non-Hodgkin lymphoma. Int J Hematol. 2019; 109(4):483-490. doi: 10.1007/s12185-019-02608-y
  6. Barth MJ, Minard-Colin V. Novel targeted therapeutic agents for the treatment of childhood, adolescent and young adult non-Hodgkin lymphoma. Br J Haematol. 2019 Jun;185(6):1111-1124. doi: 10.1111/bjh.15783
  7. Tanaka Y, Maeshima AM, Nomoto J, Makita S, Fukuhara S, Munakata W, Maruyama D, Tobinai K, Kobayashi Y. Expression pattern of PD-L1 and PD-L2 in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and gray zone lymphoma. Eur J Haematol. 2018 May;100(5):511-517. doi: 10.1111/ejh.13033
  8. Zinzani PL, Ribrag V, Moskowitz CH, Michot JM, Kuruvilla J, Balakumaran A, Zhang Y, Chlosta S, Shipp MA, Armand P. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017 Jul 20;130(3):267-270. doi: 10.1182/blood-2016-12-758383
  9. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, Millenson MM, Cohen AD, Schuster SJ, Lebovic D, Dhodapkar M, Avigan D, Chapuy B, Ligon AH, Freeman GJ, Rodig SJ, Cattry D, Zhu L, Grosso JF, Bradley Garelik MB, Shipp MA, Borrello I, Timmerman J. Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol. 2016 Aug 10;34(23):2698-704. doi: 10.1200/JCO.2015.65.9789
  10. Mallepally N, Abu-Sbeih H, Ahmed O, Chen E, Shafi MA, Neelapu SS, Wang Y. Clinical Features of Rituximab-associated Gastrointestinal Toxicities. Am J Clin Oncol. 2019 Jun;42(6):539-545. doi: 10.1097/COC.0000000000000553
  11. Yamauchi R, Araki T, Mitsuyama K, Tokito T, Ishii H, Yoshioka S, Kuwaki K, Mori A, Yoshimura T, Tsuruta O, Torimura T. The characteristics of nivolumab-induced colitis: an evaluation of three cases and a literature review. BMC Gastroenterol. 2018 Aug 31;18(1):135. doi: 10.1186/s12876-018-0864-1
  12. Bhalme M, Hayes S, Norton A, Lal S, Chinoy H, Paine P. Rituximab-associated colitis. Inflamm Bowel Dis. 2013 Mar;19(3):E41-3.
    doi: 10.1002/ibd.22963
  13. Cañete F, Mañosa M, Lobatón T, Mesonero F, Rodríguez-Lago I, Cabré E, Cabriada JL, López-Sanromán A, Domènech E. Nivolumab-induced immune-mediated colitis: an ulcerative colitis look-alike-report of new cases and review of the literature. Int J Colorectal Dis. 2019 May;34(5):861-865. doi: 10.1007/s00384-019-03268-4
  14. Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol. 2012 Apr 28;18(16):1851-60. doi: 10.3748/wjg.v18.i16.1851
  15. Nitzan O, Elias M, Peretz A, Saliba W. Role of antibiotics for treatment of inflammatory bowel disease. World J Gastroenterol. 2016 Jan 21;22(3):1078-87. doi: 10.3748/wjg.v22.i3.1078
  16. Prieux-Klotz C, Dior M, Damotte D, Dreanic J, Brieau B, Brezault C, Abitbol V, Chaussade S, Coriat R. Immune Checkpoint Inhibitor-Induced Colitis: Diagnosis and Management. Target Oncol. 2017 Jun;12(3):301-308. doi: 10.1007/s11523-017-0495-4
  17. Guo XY, Liu XJ, Hao JY. Gut microbiota in ulcerative colitis: insights on pathogenesis and treatment. J Dig Dis. 2020 Mar;21(3):147-159. doi: 10.1111/1751-2980.12849
  18. Kaur A, Goggolidou P. Ulcerative colitis: understanding its cellular pathology could provide insights into novel therapies. J Inflamm (Lond). 2020 Apr 21;17:15. doi: 10.1186/s12950-020-00246-4
  19. Kmieć Z, Cyman M, Ślebioda TJ. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease. Adv Med Sci. 2017 Mar;62(1):1-16. doi: 10.1016/j.advms.2016.09.001
  20. Zhang S, Cao X, Huang H. Sampling Strategies for Three-Dimensional Spatial Community Structures in IBD Microbiota Research. Front Cell Infect Microbiol. 2017 Feb 24;7:51. doi: 10.3389/fcimb.2017.00051
  21. Drekonja D, Reich J, Gezahegn S, Greer N, Shaukat A, MacDonald R, Rutks I, Wilt TJ. Fecal Microbiota Transplantation for Clostridium difficile Infection: A Systematic Review. Ann Intern Med. 2015 May 5;162(9):630-8. doi: 10.7326/M14-2693
  22. Sood A, Singh A, Mahajan R, Midha V, Mehta V, Gupta YK, Narang V, Kaur K. Acceptability, tolerability, and safety of fecal microbiota transplantation in patients with active ulcerative colitis (AT&S Study). J Gastroenterol Hepatol. 2020 Mar;35(3):418-424. doi: 10.1111/jgh.14829
  23. Fasanello MK, Robillard KT, Boland PM, Bain AJ, Kanehira K. Use of Fecal Microbial Transplantation for Immune Checkpoint Inhibitor Colitis. ACG Case Rep J. 2020 Apr 10;7(4):e00360. doi: 10.14309/crj.0000000000000360
  24. Wang Y, Wiesnoski DH, Helmink BA, Gopalakrishnan V, Choi K, DuPont HL, Jiang ZD, Abu-Sbeih H, Sanchez CA, Chang CC, Parra ER, Francisco-Cruz A, Raju GS, Stroehlein JR, Campbell MT, Gao J, Subudhi SK, Maru DM, Blando JM, Lazar AJ, Allison JP, Sharma P, Tetzlaff MT, Wargo JA, Jenq RR. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis.
    Nat Med. 2018 Dec;24(12):1804-1808. doi: 10.1038/s41591-018-0238-9
  25. Nikkari S, McLaughlin IJ, Bi W, Dodge DE, Relman DA. Does blood of healthy subjects contain bacterial ribosomal DNA? J Clin Microbiol. 2001 May;39(5):1956-9. doi: 10.1128/JCM.39.5.1956-1959.2001
  26. Nishida A, Inoue R, Inatomi O, Bamba S, Naito Y, Andoh A. Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin J Gastroenterol. 2018 Feb;11(1):1-10. doi: 10.1007/s12328-017-0813-5
  27. Goloshchapov OV, Bakin EA, Kucher MA, Stanevich OV, Suvorova MA, Gostev VV, et al. Bacteroides fragilis is a potential marker of effective microbiota transplantation in acute graft-versus-host disease treatment. Cell Ther Transplant 2020; 9(2): 47-59.
    doi: 10.18620/ctt-1866-8836-2020-9-2-47-59
  28. Goloshchapov OV, Olekhnovich EI, Sidorenko SV, Moiseev IS, Kucher MA, Fedorov DE, et al. Long-term impact of fecal transplantation in healthy volunteers. BMC Microbiology. 2019; vol. 19, Article No.: 312. doi: 10.1186/s12866-019-1689-y
  29. Wang DY, Ye F, Zhao S, Johnson DB. Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: A systematic review and meta-analysis. Oncoimmunology. 2017 Jul 5;6(10):e1344805. doi: 10.1080/2162402X.2017.1344805
  30. Gupta A, De Felice KM, Loftus EV Jr, Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther. 2015 Aug;42(4):406-17. doi: 10.1111/apt.13281
  31. Cammarota G, Ianiro G, Cianci R, Bibbò S, Gasbarrini A, Currò D. The involvement of gut microbiota in inflammatory bowel disease pathogenesis: potential for therapy. Pharmacol Ther. 2015 May;149:191-212. doi: 10.1016/j.pharmthera.2014.12.006
  32. Kirchgesner J, Lemaitre M, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases. Gastroenterology. 2018 Aug;155(2):337-346.e10. doi: 10.1053/j.gastro.2018.04.012
  33. Lin L, Zhang J. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol. 2017 Jan 6;18(1):2. doi: 10.1186/s12865-016-0187-3
  34. Horai R, Silver PB, Chen J, Agarwal RK, Chong WP, Jittayasothorn Y, Mattapallil MJ, Nguyen S, Natarajan K, Villasmil R, Wang P, Karabekian Z, Lytton SD, Chan CC, Caspi RR. Breakdown of immune privilege and spontaneous autoimmunity in mice expressing a transgenic T cell receptor specific for a retinal autoantigen. J Autoimmun. 2013 Aug;44:21-33. doi: 10.1016/j.jaut.2013.06.003
  35. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103. doi: 10.1126/science.aan4236
  36. Kocic H, Damiani G, Stamenkovic B, Tirant M, Jovic A, Tiodorovic D, Peris K. Dietary compounds as potential modulators of microRNA expression in psoriasis. Ther Adv Chronic Dis. 2019 Aug 7;10:2040622319864805. doi: 10.1177/2040622319864805
  37. Fernández-Carballo BL, Broger T, Wyss R, Banaei N, Denkinger CM. Toward the Development of a Circulating Free DNA-Based In Vitro Diagnostic Test for Infectious Diseases: a Review of Evidence for Tuberculosis. J Clin Microbiol. 2019 Mar 28;57(4):e01234-18.
    doi: 10.1128/JCM.01234-18
  38. Blauwkamp TA, Thair S, Rosen MJ, Blair L, Lindner MS, Vilfan ID, Kawli T, et al. Analytical and clinical validation of a microbial cell-free DNA sequencing test for infectious disease. Nat Microbiol. 2019 Apr;4(4):663-674. doi: 10.1038/s41564-018-0349-6
  39. Hong DK, Blauwkamp TA, Kertesz M, Bercovici S, Truong C, Banaei N. Liquid biopsy for infectious diseases: sequencing of cell-free plasma to detect pathogen DNA in patients with invasive fungal disease. Diagn Microbiol Infect Dis. 2018 Nov;92(3):210-213.
    doi: 10.1016/j.diagmicrobio.2018.06.009
  40. Long Y, Zhang Y, Gong Y, Sun R, Su L, Lin X, Shen A, Zhou J, Caiji Z, Wang X, Li D, Wu H, Tan H. Diagnosis of Sepsis with Cell-free DNA by Next-Generation Sequencing Technology in ICU Patients. Arch Med Res. 2016 Jul;47(5):365-371. doi: 10.1016/j.arcmed.2016.08.004
  41. Poore GD, Kopylova E, Zhu Q, Carpenter C, Fraraccio S, Wandro S, Kosciolek T, Janssen S, Metcalf J, Song SJ, Kanbar J, Miller-Montgomery S, Heaton R, Mckay R, Patel SP, Swafford AD, Knight R. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature. 2020 Mar;579(7800):567-574. doi: 10.1038/s41586-020-2095-1

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Голощапов<sup>1</sup>, Алексей Б. Чухловин<sup>1</sup>, Никита П. Волков<sup>1</sup>, Анастасия В. Бейнарович<sup>1</sup>, Кирилл В. Лепик<sup>1</sup>, Андрей Н. Гавриленко<sup>1</sup>, Дмитрий Е. Полев<sup>2</sup>, Руслана В. Клементьева<sup>1</sup>, Наталья Б. Михайлова<sup>1</sup>, Иван С. Моисеев<sup>1</sup> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(482) "

Олег В. Голощапов1, Алексей Б. Чухловин1, Никита П. Волков1, Анастасия В. Бейнарович1, Кирилл В. Лепик1, Андрей Н. Гавриленко1, Дмитрий Е. Полев2, Руслана В. Клементьева1, Наталья Б. Михайлова1, Иван С. Моисеев1

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

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Исследование посвящено анализу эффективности трансплантации фекальной микробиоты (ТФМ) при лечении резистентного колита у пациентов с лимфомой, и ее влиянию на микробиом кешичника и крови. Представлено описание двух случаев пациентов с рефрактерными В-клеточными лимфомами, которым была проведена трансплантация аутологичных стволовых клеток с дальнейшей поддерживающей иммунотерапией, осложнившейся резистентным колитом, излеченным посредством ТФМ. Лечение привело к значительному клиническому улучшению, включая разрешение симптомов колита, восстановление нормальной перистальтики кишечника, питания и улучшение качества жизни. С помощью секвенирования нового поколения гена 16S рРНК продемонстрированы изменения в микробиоте стула и, впервые, изменения профиля циркулирующей бактериальной ДНК после ТФМ. Исследование подчеркивает значение ТФМ как эффективного метода лечения колита, вызванного ингибиторами иммунных контрольных точек, с потенциалом модулирования противоопухолевого иммунитета у пациентов с лимфомой, которым проводится иммунотерапия. В заключении, ТФМ представляет собой многообещающий подход к лечению воспалительного колита, ассоциированного с терапией резистентной лимфомы. С целью подтверждение данных наблюдей и определения оптимальной стратегии применения ТФМ необходимо проведение проспективных исследований.

Эта работа была поддержана из средств гранта Российского научного фонда №22-15-00149 от 18.05.2022.

Ключевые слова

Лимфома, трансплантация гемопоэтических стволовых клеток, трансплантация фекальной микробиоты, иммунотерапия, ингибиторы иммунных контрольных точек, колит, воспаление, внеклеточная ДНК, бактериальная.

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Oleg V. Goloshchapov1, Alexey B. Chukhlovin1, Nikita P. Volkov1, Anastasia V. Beynarovich1, Kirill V. Lepik1, Andrey N. Gavrilenko1, Dmitrii E. Polev2, Ruslana V. Klementieva1, Natalia B. Mikhailova1, Ivan S. Moiseev1

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 St. Petersburg Pasteur Institute, St. Petersburg, Russia


Correspondence:
Dr. Oleg V. Goloshchapov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
Phone: +7 (921) 979-29-13
E-mail: golocht@yandex.ru


Citation: Goloshchapov OV, Chukhlovin AB, Volkov NP et al. Fecal microbiota transplantation for treatment of inflammatory bowel lesions in lymphoma patients: effects on intestinal and blood microbiota. Cell Ther Transplant 2023; 12(3): 36-43.

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This study investigates the efficacy of Fecal Microbiota Transplantation (FMT) in treating inflammatory colitis in lymphoma patients, particularly focusing on the changes it induces in the intestinal and blood microbiome. Two case reports of patients with refractory B-cell lymphomas undergone autologous stem cells transplantation with immunotherapy maintenance complicated with resistant colitis, and successfully treated with FMT, are presented. The treatment led to significant clinical improvements, including the resolution of colitis symptoms, restoration of normal intestinal motility, nutrition habits, and improved quality of life. With application of next generation sequencing of 16S rRNA gene we have described the changes in microbiota of the stool, and for the first time, blood cell-free bacterial DNAs profile after FMT. The study underscore FMT's potential as a novel, effective treatment for immune checkpoint inhibitor-induced colitis, enhancing the prospects of durable remission and improved antitumor immunity in lymphoma patients undergoing immunotherapy. We conclude that FMT represents a promising approach for managing inflammatory colitis associated with resistant lymphoma treatment. Further research is advocated to corroborate these preliminary findings and establish standardized protocols for FMT application in this context.

Keywords

Lymphomas, hematopoietic stem cell transplantation, fecal microbiota transplantation, immunotherapy, immune checkpoint inhibitors, colitis, inflammation, cell-free DNA.

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Goloshchapov<sup>1</sup>, Alexey B. Chukhlovin<sup>1</sup>, Nikita P. Volkov<sup>1</sup>, Anastasia V. Beynarovich<sup>1</sup>, Kirill V. Lepik<sup>1</sup>, Andrey N. Gavrilenko<sup>1</sup>, Dmitrii E. Polev<sup>2</sup>, Ruslana V. Klementieva<sup>1</sup>, Natalia B. Mikhailova<sup>1</sup>, Ivan S. Moiseev<sup>1</sup> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(336) "

Oleg V. Goloshchapov1, Alexey B. Chukhlovin1, Nikita P. Volkov1, Anastasia V. Beynarovich1, Kirill V. Lepik1, Andrey N. Gavrilenko1, Dmitrii E. Polev2, Ruslana V. Klementieva1, Natalia B. Mikhailova1, Ivan S. Moiseev1

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Oleg V. Goloshchapov1, Alexey B. Chukhlovin1, Nikita P. Volkov1, Anastasia V. Beynarovich1, Kirill V. Lepik1, Andrey N. Gavrilenko1, Dmitrii E. Polev2, Ruslana V. Klementieva1, Natalia B. Mikhailova1, Ivan S. Moiseev1

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This study investigates the efficacy of Fecal Microbiota Transplantation (FMT) in treating inflammatory colitis in lymphoma patients, particularly focusing on the changes it induces in the intestinal and blood microbiome. Two case reports of patients with refractory B-cell lymphomas undergone autologous stem cells transplantation with immunotherapy maintenance complicated with resistant colitis, and successfully treated with FMT, are presented. The treatment led to significant clinical improvements, including the resolution of colitis symptoms, restoration of normal intestinal motility, nutrition habits, and improved quality of life. With application of next generation sequencing of 16S rRNA gene we have described the changes in microbiota of the stool, and for the first time, blood cell-free bacterial DNAs profile after FMT. The study underscore FMT's potential as a novel, effective treatment for immune checkpoint inhibitor-induced colitis, enhancing the prospects of durable remission and improved antitumor immunity in lymphoma patients undergoing immunotherapy. We conclude that FMT represents a promising approach for managing inflammatory colitis associated with resistant lymphoma treatment. Further research is advocated to corroborate these preliminary findings and establish standardized protocols for FMT application in this context.

Keywords

Lymphomas, hematopoietic stem cell transplantation, fecal microbiota transplantation, immunotherapy, immune checkpoint inhibitors, colitis, inflammation, cell-free DNA.

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This study investigates the efficacy of Fecal Microbiota Transplantation (FMT) in treating inflammatory colitis in lymphoma patients, particularly focusing on the changes it induces in the intestinal and blood microbiome. Two case reports of patients with refractory B-cell lymphomas undergone autologous stem cells transplantation with immunotherapy maintenance complicated with resistant colitis, and successfully treated with FMT, are presented. The treatment led to significant clinical improvements, including the resolution of colitis symptoms, restoration of normal intestinal motility, nutrition habits, and improved quality of life. With application of next generation sequencing of 16S rRNA gene we have described the changes in microbiota of the stool, and for the first time, blood cell-free bacterial DNAs profile after FMT. The study underscore FMT's potential as a novel, effective treatment for immune checkpoint inhibitor-induced colitis, enhancing the prospects of durable remission and improved antitumor immunity in lymphoma patients undergoing immunotherapy. We conclude that FMT represents a promising approach for managing inflammatory colitis associated with resistant lymphoma treatment. Further research is advocated to corroborate these preliminary findings and establish standardized protocols for FMT application in this context.

Keywords

Lymphomas, hematopoietic stem cell transplantation, fecal microbiota transplantation, immunotherapy, immune checkpoint inhibitors, colitis, inflammation, cell-free DNA.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 St. Petersburg Pasteur Institute, St. Petersburg, Russia


Correspondence:
Dr. Oleg V. Goloshchapov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
Phone: +7 (921) 979-29-13
E-mail: golocht@yandex.ru


Citation: Goloshchapov OV, Chukhlovin AB, Volkov NP et al. Fecal microbiota transplantation for treatment of inflammatory bowel lesions in lymphoma patients: effects on intestinal and blood microbiota. Cell Ther Transplant 2023; 12(3): 36-43.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 St. Petersburg Pasteur Institute, St. Petersburg, Russia


Correspondence:
Dr. Oleg V. Goloshchapov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
Phone: +7 (921) 979-29-13
E-mail: golocht@yandex.ru


Citation: Goloshchapov OV, Chukhlovin AB, Volkov NP et al. Fecal microbiota transplantation for treatment of inflammatory bowel lesions in lymphoma patients: effects on intestinal and blood microbiota. Cell Ther Transplant 2023; 12(3): 36-43.

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Олег В. Голощапов1, Алексей Б. Чухловин1, Никита П. Волков1, Анастасия В. Бейнарович1, Кирилл В. Лепик1, Андрей Н. Гавриленко1, Дмитрий Е. Полев2, Руслана В. Клементьева1, Наталья Б. Михайлова1, Иван С. Моисеев1

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Представлено описание двух случаев пациентов с рефрактерными В-клеточными лимфомами, которым была проведена трансплантация аутологичных стволовых клеток с дальнейшей поддерживающей иммунотерапией, осложнившейся резистентным колитом, излеченным посредством ТФМ. Лечение привело к значительному клиническому улучшению, включая разрешение симптомов колита, восстановление нормальной перистальтики кишечника, питания и улучшение качества жизни. С помощью секвенирования нового поколения гена 16S рРНК продемонстрированы изменения в микробиоте стула и, впервые, изменения профиля циркулирующей бактериальной ДНК после ТФМ. Исследование подчеркивает значение ТФМ как эффективного метода лечения колита, вызванного ингибиторами иммунных контрольных точек, с потенциалом модулирования противоопухолевого иммунитета у пациентов с лимфомой, которым проводится иммунотерапия. В заключении, ТФМ представляет собой многообещающий подход к лечению воспалительного колита, ассоциированного с терапией резистентной лимфомы. С целью подтверждение данных наблюдей и определения оптимальной стратегии применения ТФМ необходимо проведение проспективных исследований.</p> <p style="text-align: justify;"> Эта работа была поддержана из средств гранта Российского научного фонда №22-15-00149 от 18.05.2022.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Лимфома, трансплантация гемопоэтических стволовых клеток, трансплантация фекальной микробиоты, иммунотерапия, ингибиторы иммунных контрольных точек, колит, воспаление, внеклеточная ДНК, бактериальная.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3190) "

Исследование посвящено анализу эффективности трансплантации фекальной микробиоты (ТФМ) при лечении резистентного колита у пациентов с лимфомой, и ее влиянию на микробиом кешичника и крови. Представлено описание двух случаев пациентов с рефрактерными В-клеточными лимфомами, которым была проведена трансплантация аутологичных стволовых клеток с дальнейшей поддерживающей иммунотерапией, осложнившейся резистентным колитом, излеченным посредством ТФМ. Лечение привело к значительному клиническому улучшению, включая разрешение симптомов колита, восстановление нормальной перистальтики кишечника, питания и улучшение качества жизни. С помощью секвенирования нового поколения гена 16S рРНК продемонстрированы изменения в микробиоте стула и, впервые, изменения профиля циркулирующей бактериальной ДНК после ТФМ. Исследование подчеркивает значение ТФМ как эффективного метода лечения колита, вызванного ингибиторами иммунных контрольных точек, с потенциалом модулирования противоопухолевого иммунитета у пациентов с лимфомой, которым проводится иммунотерапия. В заключении, ТФМ представляет собой многообещающий подход к лечению воспалительного колита, ассоциированного с терапией резистентной лимфомы. С целью подтверждение данных наблюдей и определения оптимальной стратегии применения ТФМ необходимо проведение проспективных исследований.

Эта работа была поддержана из средств гранта Российского научного фонда №22-15-00149 от 18.05.2022.

Ключевые слова

Лимфома, трансплантация гемопоэтических стволовых клеток, трансплантация фекальной микробиоты, иммунотерапия, ингибиторы иммунных контрольных точек, колит, воспаление, внеклеточная ДНК, бактериальная.

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Исследование посвящено анализу эффективности трансплантации фекальной микробиоты (ТФМ) при лечении резистентного колита у пациентов с лимфомой, и ее влиянию на микробиом кешичника и крови. Представлено описание двух случаев пациентов с рефрактерными В-клеточными лимфомами, которым была проведена трансплантация аутологичных стволовых клеток с дальнейшей поддерживающей иммунотерапией, осложнившейся резистентным колитом, излеченным посредством ТФМ. Лечение привело к значительному клиническому улучшению, включая разрешение симптомов колита, восстановление нормальной перистальтики кишечника, питания и улучшение качества жизни. С помощью секвенирования нового поколения гена 16S рРНК продемонстрированы изменения в микробиоте стула и, впервые, изменения профиля циркулирующей бактериальной ДНК после ТФМ. Исследование подчеркивает значение ТФМ как эффективного метода лечения колита, вызванного ингибиторами иммунных контрольных точек, с потенциалом модулирования противоопухолевого иммунитета у пациентов с лимфомой, которым проводится иммунотерапия. В заключении, ТФМ представляет собой многообещающий подход к лечению воспалительного колита, ассоциированного с терапией резистентной лимфомы. С целью подтверждение данных наблюдей и определения оптимальной стратегии применения ТФМ необходимо проведение проспективных исследований.

Эта работа была поддержана из средств гранта Российского научного фонда №22-15-00149 от 18.05.2022.

Ключевые слова

Лимфома, трансплантация гемопоэтических стволовых клеток, трансплантация фекальной микробиоты, иммунотерапия, ингибиторы иммунных контрольных точек, колит, воспаление, внеклеточная ДНК, бактериальная.

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

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

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Introduction

Gindina-fig01.jpg

Figure 1. Low p53 expression in the bone marrow cells of the patient with FA – less than 1% cells with bright staining of the nuclei. Core biopsy. Immunoperoxidase, x100

Gindina-fig02.jpg

Figure 2. G-banding karyotype shows a duplication 1q21q32 (A) or a triplication 1q21q32 (B) and unbalanced translocations t(3;11) leading to various derivative chromosomes of 11th pairs

Gindina-fig03.jpg

Figure 3. Selective karyograms of 1 pairs of chromosomes from different metaphase spreads (GTG-banding and multicolor banding with XCyte 1 Human Multicolor Band probes, MetaSystems, Germany) demonstrate the duplication and triplication 1q21-1q32

Gain of chromosome 1q is considered an early and nonrandom prognostic feature in solid tumors [1], oncohematolo- gical disorders [2-6] and Fanconi anemia (FA) progression [7-12]. The 1q gain has been lately shown to associate with overexpression of MDM4 oncogene located at 1q32 which is responsible for the downregulation of the TP53 gene. Due to the clinical and experimental in-depth works with FA patients, a great progress has been recently achieved in detailing the relationships between these two genes [7, 13]. For instance, Sebert et al. studied the cohort of 335 patients with FA including 62 patients with clonal evolution [7]. Half of these patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy, thus downmodulating p53 signaling followed by secondary AML development. Hence, these results recognized a linear route towards secondary leukemogenesis with early MDM4-driven downregulation of basal p53 activation which plays a pivotal role in monitoring and therapy of the disorder. Moreover, the 1q gain can trigger an increased expression of MDM4, a negative modulator of p53 activity, thus providing the gene dose effect, as recently proven experimentally [1, 7, 14]. As a result, 1q gain/MDM4 has been shown to confer a growth advantage to human and mouse hematopoietic stem and progenitor cells (HSPCs) in FA and, therefore, rescue bone marrow failure (BMF) induced by chronic inflammatory stress. The HSPCs growth capacities are known to be deficient in FA due to accumulation of DNA damage and can be rescued by loss of p53 [15]. Of note, these clonally altered 1q gain HSPCs exhibited a number of additional nonrandom chromosome changes, e.g., 3q gain, monosomy 7 or 7q deletion. RUNX1 gene mutation were also revealed, being associated with further genomic transformation of the clone towards MDS and AML. On the other hand, а recent study shows that the bone marrow failure in FA results from dysfunctional HSPCs [13]. Based on these data, the authors concluded that MYC overexpression impairs HSPCs and exhausted bone marrow populations in FA. The aim of this article is to present unusual cytogenetic, molecular and morphologic data from an FA patient of Syrian origin at the stage of early transformation into MDS, which is consistent with earlier findings.

Case report

In our male patient, diagnosis of Fanconi anemia was recognized at the age of 21-year manifesting by mild anemia (Hb 129 g/l) and neutropenia (ANC 0.8×109/l). At that time, bone marrow (BM) trephine biopsy was hypocellular, with a predominance of adipose component over myeloid tissue. There was a reduction of erythropoiesis, whereas myelodysplastic features of hematopoietic cells were absent. No chromosomal abnormalities were found in the bone marrow cells. The pedigree analysis showed the patient to be a child from a closely related marriage, in which two siblings (younger sister and younger brother) had similar FA diagnosis. Moreover, sickle-cell anemia was diagnosed in his father and older brother. In addition, our patient had urogenital malformations (prostatic hypoplasia, micropenis, hypogonadism), and large areas of skin hyperpigmentation (café-au-lait spots). Burdened inheritance, persistent cytopenia, and organ anomalies allowed us to expect a constitutional form of bone marrow failure (BMF). The in vitro test with diepoxybutane gave a positive result, since 109 chromosomal aberrations were detected in 63 metaphases examined. A previously described pathogenic variant of the nucleotide sequence of the FANCA gene in exon 38 (chr16:89740848AG>A) in the heterozygous state was revealed by NGS technique leading to a frameshift mutation starting from codon 1262 (p.F1262Sfs*4, NM_000135.4). The general health status of the patient remained relatively stable for 10 years.

At the age of 31, the patient complained for ulcerations in oral cavity, acne on the scalp and neck, as well as periodic low-grade fever. Routine blood check revealed multilinear cytopenia with hemoglobin levels less than 92 g/L, low platelet counts (77×109/L), and severe neutropenia (min ANC, 0.21×109/L). The bone marrow aspirate showed a pronounced multilineage dysplasia; cells with blastic morphology accounted for 2.6%. The BM trephine biopsy was hypocellular with pronounced features of dysplasia in all hematopoietic lineages. The proportion of CD34+ cells was 3-5%. Immunohistochemistry showed a reduced p53 expression, with less than 1% of brightly stained cells (3+) (Fig. 1). A molecular genetics study revealed an increased EVI1 gene expression (14%, reference of 0 to 10%), and a decreased BAALC expression level (1%, reference of 10 to 30%). In addition, the mutation search performed by direct sequencing technique did not detect mutations in the RUNX1 and TP53 genes. According to chromosome banding analysis, duplications and triplications of the long arm of chromosome 1, as well as unbalanced 3q translocations on the long and short arms of chromosome 11 were detected in all studied BM metaphases (Fig. 2). To support these observations, multicolor banding of chromosomes 1 and 3 was performed (Fig. 3-4), which confirmed the presence of an increased copy number of 1q and 3q in the patient's bone marrow cells. FISH with a locus-specific DNA probe for 1p36.3 and 1q25.2 showed that in most studied cells, the number of 1q gains per a single cell varied from 3 to 4, reaching 8-9 copies in some cells (Fig. 5). In turn, the copy number of EVI1 gene varied from 3 to 4 per cell (Fig. 6). Due to the appearance of clonal cytogenetic aberrations in the karyotype, as well as available HLA-matched healthy sibling, the patient was scheduled for allogeneic hematopoietic stem cell transplantation.

Gindina-fig04.jpg

Figure 4. Selective karyograms of 3 and 11 pairs of chromosomes (GTG-banding; multicolor FISH with 24 XCyte Human Multicolor Chromosome probes, MetaSystems, Germany; multicolor banding with XCyte 3 and XCyte 11 Human Multicolor Band probes, MetaSystems, Germany) demonstrate the unbalanced translocations t(3;11) with formation the derivative chromosome 11 and the pair of normal chromosomes 3

Gindina-fig05-06.jpg

Materials and methods

Histology and immunohistochemistry for p53

Bone marrow core biopsy was delivered to the Department of Pathology in the transport medium (formalin saline), fixed and decalcified in saturated solution of EDTA in buffered neutral formalin. The specimen was processed and embedded in paraffin according to standard protocols. Conventional stains included H&E, Romanovsky and Gomori. For immunohistochemistry, we used antibodies to p53 (BOND Ready-to-Use Primary Antibody p53 (DO-7), Leica Biosystems Newcastle Ltd, UK). Immunostaining was performed with automatic immunostainer BOND-III (Leica Biosystems Melbourne Pty Ltd, Melbourne, Australia) according to recommended protocol.

Cytogenetics and molecular cytogenetics

Chromosomal analysis on bone marrow (BM) samples using GTG-banding was performed according to standard procedures [16]. A minimal number of 20 metaphase cells has been analyzed. The karyotype was described according to the International System for Human Cytogenetic Nomenclature (ISCN 2020) [17]. Fluorescence in situ hybridization (FISH) using 24 XCyte chromosome specific probes and XCyte 1, XCyte 3, XCyte 11 probes (MetaSystems, Germany), 1p32/1q21 Amplification/Deletion Probe (MetaSystems, Germany) and EVI1 Break-Apart tricolor probe (CytoCell, United Kingdom) were used according to manufacturer’s instructions. A minimum of 10 metaphase spreads (for multicolor probes), or 200 interphase nuclei (for locus-specific probe) were analyzed per a sample using a fluorescence microscope (AxioImager.M1, Carl Zeiss Ltd, Germany) equipped with appropriate filter sets to discriminate between a maximum of five fluorochromes plus counterstaining with DAPI (4’,6-diamino-2-phenylindole). Image capture and processing were performed using an ISIS imaging system (MetaSystems, Germany).

Nucleic acids extraction and gene expression analysis

Genomic DNA was extracted from bone marrow (BM) aspirates cells in patients by means of Blood DNA Column Kit (Inogene, Russia). The total RNA was extracted according the instruction of TriZ Reagent Kit (Inogene, Russia) with the following reverse transcription by using ReverZyme Kit (Inogene, Russia). The concentration and quality of gDNA and cDNA was measured with a NanoDrop spectrophotometer (Thermo Fisher Scientific, USA). The EVI1 gene expression was determined using the real-time quantitative PCR (qPCR) method. The amplification of target products was performed using oligonucleotide probes described by Mäkelä et al. [18]. The detection of EVI1 gene expression was carried out in real-time mode. The ABL gene was chosen as a reference gene [19]. Valid samples were considered to be those in which, at least,1000 copies of the ABL gene were detected. Overexpression of the EVI1 gene was registered in samples with a ratio of EVI1/ABL transcripts >10%. The levels of WT1 and BAALC gene expression were assessed as described elsewhere [20, 21].

DNA sequencing procedures

The analysis of TP53 gene coding sequence (exons 2 to 11) and adjacent intronic regions was performed by Sanger sequencing, following the IARC protocol (2010 update) [22]. The search for RUNX1 gene mutations was also carried out by Sanger, with analysis of exons 2 to 9. The oligonucleotide sequences for amplification and sequencing reactions were obtained from previously published studies [23, 24].

Whole-exome sequencing (WES) was performed on the patient’s bone marrow sample as described in the manufacturers’ instructions. The genomic DNA was fragmented, and the exons of known genes in the human genome, as well as the adjacent exon-intron boundaries, were targeted and amplified using Roche KAPA capture technology (Roche, Switzerland) and sequenced by using the NextSeq 1000/2000 P2 Reagents v3 (Illumina, USA) on NextSeq 2000 system (Illumina, USA). Raw sequencing read quality was assessed using FastQC v0.11.9. Adapter trimming and filtering of low-quality readings were carried out with Fastp v0.23.2. Next, we applied BWA v0.7.15 to align the reads to the GRCh38 reference genome. General data processing routines, such as reporting alignment statistics and marking duplicates, were performed by GATK v4.2.5.0 and SAMtools v1.3.1. DeepVariant was used for variant calling. We annotated the discovered variants with Ensembl Variant Effect Predictor and ANNOVAR, using the RefSeq database, the GnomAD population frequency database, databases of clinically discovered variants such as COSMIC and ClinVar, as well as variant effect prediction tools (PolyPhen-2 [25], SIFT [26], MutationTaster2 [27], MutationAssessor [28], PROVEAN [29]. Finally, the ACMG/AMP criteria were applied for the clinical interpretation of sequence variants [30].

Discussion

This article presents a case of FA at the initial stage of transformation to MDS which seems to be unique. In particular, his cells contained the major chromosome aberrations, e.g., 1q+ and 3q+ gains demonstrated by others [7], combined with significantly reduced expression of p53 protein. It should be noted that the number of 1q+ and 3q+ copies proved to be variable, with maximum increase to 9 and 6 copies per single cell. On the other hand, molecular biology studies revealed low expression levels of BAALC and WT1 genes, previously not reported. Unfavorable prognosis for the cases with 1q gain was expected, due to its presence in many solid tumors and oncohematological disorders which might develop in a similar way. To this point, we refer to an article concerning the above issues studied in cell lines from the patients with Burkitt’s Lymphoma (BL) [5]. The authors highlighted the critical role of p53 as a tumor suppressor in BL, and showed higher MDM4 copy numbers in a wide range of cancers, which might be therapeutically targetable. To identify molecular dependencies in BL, RNAi-based, loss-of-function screening was performed in 8 BL cell lines. Following integration of genetic data, the authors identified 76 genes essential to BL, including FLI1, BCL11A, PAX5, CDKN1B, JAK2, CARD11 etc., and found a number of context-specific dependencies including oncogene addiction in cell lines with TCF3/ID3 or MYD88 mutation. The strongest genotype-phenotype association was noted for TP53 and MDM4, a negative regulator of TP53, which is considered essential in TP53 wild-type (TP53wt) BL cell lines. MDM4 knockdown activating p53 was shown to induce cell cycle arrest and decreased tumor growth in a xenograft model which proceeded in a p53-dependent manner. Small molecule inhibition of the MDM4-p53 interaction was effective only in TP53wt BL cell lines. Moreover, primary TP53wt BL samples frequently exhibited gains of chromosome 1q which contains the MDM4 locus, and, hence, showed elevated MDM4 mRNA levels. The 1q gain was associated with TP53wt across 789 cancer cell lines, and MDM4 was essential in the TP53wt-context in 216 cell lines representing 19 cancer entities from the Achilles project [5]. Another important study [4], concerning Ph-negative chronic myeloid neoplasms, has also suggested the pivotal role of p53 expression and increased expression of its regulator MDM4 in progression of this disorder. In general, our study suggests great perspectives of in-depth study in the recently described regulatory cellular mechanism. Future investigations will show whether this subtle mechanism may be universal for tumor progression.

Conclusion

Acquisition of additional 1q/MDM4 copies is common to many solid tumors and oncohematological diseases. Therefore, it may be a reliable predictor of malignancy progression. This molecular mechanism, unrelated to known effects of fusion genes, needs further in-depth studies.

Conflict of interest

No conflicts of interests are declared.

Acknowledgements

The authors are grateful to Ekaterina Izmailova, Irina Petrova, Tatiana Gracheva and Elena Ryabikova for excellent performance of cytogenetic and molecular tests.

References

  1. Girish V, Lakhani AA, Scaduto CM, Thompson SL, Brown LM, Hagenson RA, et al. Oncogene-like addiction to aneuploidy in human cancers. Science. 2023;381(6660):eadg4521. doi: 10.1126/science.adg4521
  2. Mamaeva SE, Mamaev NN, Jartseva NM, Belyaeva LV, Scherbakova EG. Complete or partial trisomy for the long arm of chromosome 1 in patients with various hematologic malignancies. Hum Genet. 1983;63(2):107-112. doi: 10.1007/BF00291527
  3. Mamaev NN, Mamaeva SE, Pavlova VA, Patterson D. Combined trisomy 1q and monosomy 17p due to translocation t(1;17) in a patient with myelodysplastic syndrome. Cancer Genet Cytogenet. 1988;35(1):21-25. doi: 10.1016/0165-4608(88)90116-1
  4. Marcellino BK, Hoffman R, Tripodi J, Lu M, Kosiorek H, Mascarenhas J, et al. Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53. Blood Adv. 2018;2(24):3581-3589.
    doi: 10.1182/bloodadvances.2018024018
  5. Hullein J, Slabicki M, Rosolowski M, Jethwa A, Harbinger S, Tomska K, et al. MDM4 is targeted by 1q gain and drives disease in Burkitt lymphoma. Cancer Res. 2019;79(12):3125-3138. doi: 10.1158/0008-5472.CAN-18-3438
  6. Gindina TL, Baykov VV, Kozhokar PV, Ryabenko S, Gusak AA, Riumin S et al. Nonrandom extra copies of 1q and 11q in the karyotypes of the three new cases of acute myeloid leukemia associated with Down syndrome. Cell Therapy Transplant. 2023;12(1):32-40.
    doi: 10.18620/ctt-1866-8836-2023-12-1-32-40
  7. Sebert M, Gachet S, Leblanc T, Rousseau A, Bluteau O, Kim R, et al. Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia. Cell Stem Cell. 2023;30(2):153-170.e9. doi: 10.1016/j.stem.2023.01.006
  8. Mehta PA, Harris RE, Davies SM, Kim MO, Mueller R, Lampkin B, et al. Numerical chromosomal changes and risk of development of myelodysplastic syndrome – acute myeloid leukemia in patients with Fanconi anemia. Cancer Genet Cytogenet. 2010;203(20):180-186. doi: 10.1016/j.cancergencyto.2010.07.127
  9. Udayakumar AM, Nazreen-Banu K, Al-Kindi S. Duplication 1q as primary and 3q in t(3;13) as secondary aberration on Fanconi anemia: implications and literature review. Acta Haematologica Polonica. 2015;46:368-371. doi: 10.1016/j.achaem.2015.10.003
  10. Kornreich L, Soulier J, Grange B, Girard S, Ouchee-Chardin M, Ceraulo A. A paediatric myelodysplastic syndrome with 5q deletion associated with Fanconi anaemia. Pediatr Blood Cancer. 2020;67(7):e28369. doi: 10.1002/pbc.28369
  11. Merfort LW, Lisboa MDO, Cavalli LR, Bonfim CMS. Cytogenetics in Fanconi Anemia: the importance of follow-up and the search for new biomarkers of genomic instability. Int J Mol Sci. 2022;23(22):14119. doi: 10.3390/ijms232214119
  12. Rajendra N, Ramanathan S, Ashok V, Srivalli BS. Rare cytogenetic abnormalities in MDS evolving from Fanconi anemia – A case report. IP J Diagn Pathol Oncol. 2022;7(4):252-254. doi: 10.18231/j.jdpo.2022.059
  13. Rodriguez A, Zhang K, Farkkila A, Filiatrault J, Yang C, Velazquez M, et al. MYC promotes bone marrow cell dysfunction in Fanconi anemia. Cell Stem Cell. 2021;28(1):33-47.e8. doi: 10.1016/j.stem.2020.09.004
  14. Almeida GM, Castilho AC, Adamoski D, Braun-Prado K. MDM4: What do we know about the association between polymorphisms and cancer. Med Oncol. 2023;40(1):61. doi: 10.1007/s12032-022-01929-z
  15. Ceccaldi R, Parmar K, Mouly E, Delord M, Kim JM, Regairaz M, et al. Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. Cell Stem Cell. 2012; 11(1);36-49. doi: 10.1016/j.stem.2012.05.013
  16. Gindina TL, Mamaev NN, Barkhatov IM, Solomonova IS, Semenova EV, Zubarovskaia LS, et al. Complex chromosome damages in patients with recurrent acute leukemias after allogeneic hematopoietic stem cell transplantations. Terapevticheskii archiv. 2012;8;61-66. (In Russian). PMID: 22994092
  17. McGowan-Jordan J, Simons A, Schmid M. ISCN 2020: An International System for Human Cytogenomic Nomenclature; Karger: Basel, Switzerland, 2020. doi: 10.1159/isbn.978-3-318-06867-2
  18. Makela E, Loyttyniemi E, Salmenniemi U, Kauko O, Varila T, Kairisto V, et al. Arpp19 promotes Myc and Cip2a expression and associates with patient relapse in acute myeloid leukemia. Cancer (Basel). 2019;11(11):1774. doi: 10.3390/cancers11111774
  19. Beillard E, Pallisgaard N, Van der Velden VHJ, Bi W, Dee R, Van der Schoot E, et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) – a Europe against cancer program. Leukemia. 2003;17(12):2474-2486. doi: 10.1038/sj.leu.2403136
  20. Shakirova A, Barkhatov I, Chjurkina A, Moiseev I, Gindina T, Bondarenko S, et al. Prognostic significance of BAALC overexpression in patients with AML during the post transplant period. Cell Ther Transplant. 2018;7(2):00. doi: 10.18620/ctt-1866-8836-2018-7-2-54-63
  21. Mamaev NN, Shakirova AI, Gindina TL, Bondarenko SN, Ayubova BI, Barkhatov IM, et al. Quantitative study of BAALC- and WT1-expressing cell precursors in the patients with different cytogenetic and molecular AML variants treated with Gemtuzumab ozogamicin and hematopoietic stem cell transplantation. Cell Ther Transplant. 2021;10(1):55-62.
    doi: 10.18620/ctt-1866-8836-2021-10-1-55-62
  22. Malcikova J, Tausch E, Rossi D, Sutton LA, Soussi T, et al. ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia – update on methodological approaches and results interpretation. Leukemia. 2018.32(5):1070-1080.
    doi: 10.1038/s41375-017-0007-7
  23. Rocquain J, Carbuccia N, Trouplin V, Raynaud S, Murati A, Nezri M, et al. Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer. 2020.10:401. doi: 10.1186/1471-2407-10-401
  24. Harada H, Harada Y, Niimi H, Kyo T, Kimura A, Inaba T. High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood. 2004;103(6):2316-2324.
    doi: 10.1182/blood-2003-09-3074
  25. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248-249. doi: 10.1038/nmeth0410-248
  26. Sim N-L, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. Nucleic Acids Res. 2012;40(WebServer issue):W452-457.
    doi: 10.1093/nar/gks539
  27. Schwartz JM, Cooper DN, Schuelke M, Seelow D. MutationTasre2: mutation prediction for the deep-sequencin age. Nat Methods. 2014:11(4):361-362. doi: 10.1038/nmeth.2890
  28. Reva B, Antipin Y, Sander C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res. 2011;39(17):e118. doi: 10.1093/nar/gkr407
  29. Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics. 2015:31(16):2745-2747. doi: 10.1093/bioinformatics/btv195
  30. Richards S, Aziz N, Bale S, Bick D, Das S, Gaster-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi: 10.1038/gim.2015.30

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Introduction

Gindina-fig01.jpg

Figure 1. Low p53 expression in the bone marrow cells of the patient with FA – less than 1% cells with bright staining of the nuclei. Core biopsy. Immunoperoxidase, x100

Gindina-fig02.jpg

Figure 2. G-banding karyotype shows a duplication 1q21q32 (A) or a triplication 1q21q32 (B) and unbalanced translocations t(3;11) leading to various derivative chromosomes of 11th pairs

Gindina-fig03.jpg

Figure 3. Selective karyograms of 1 pairs of chromosomes from different metaphase spreads (GTG-banding and multicolor banding with XCyte 1 Human Multicolor Band probes, MetaSystems, Germany) demonstrate the duplication and triplication 1q21-1q32

Gain of chromosome 1q is considered an early and nonrandom prognostic feature in solid tumors [1], oncohematolo- gical disorders [2-6] and Fanconi anemia (FA) progression [7-12]. The 1q gain has been lately shown to associate with overexpression of MDM4 oncogene located at 1q32 which is responsible for the downregulation of the TP53 gene. Due to the clinical and experimental in-depth works with FA patients, a great progress has been recently achieved in detailing the relationships between these two genes [7, 13]. For instance, Sebert et al. studied the cohort of 335 patients with FA including 62 patients with clonal evolution [7]. Half of these patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy, thus downmodulating p53 signaling followed by secondary AML development. Hence, these results recognized a linear route towards secondary leukemogenesis with early MDM4-driven downregulation of basal p53 activation which plays a pivotal role in monitoring and therapy of the disorder. Moreover, the 1q gain can trigger an increased expression of MDM4, a negative modulator of p53 activity, thus providing the gene dose effect, as recently proven experimentally [1, 7, 14]. As a result, 1q gain/MDM4 has been shown to confer a growth advantage to human and mouse hematopoietic stem and progenitor cells (HSPCs) in FA and, therefore, rescue bone marrow failure (BMF) induced by chronic inflammatory stress. The HSPCs growth capacities are known to be deficient in FA due to accumulation of DNA damage and can be rescued by loss of p53 [15]. Of note, these clonally altered 1q gain HSPCs exhibited a number of additional nonrandom chromosome changes, e.g., 3q gain, monosomy 7 or 7q deletion. RUNX1 gene mutation were also revealed, being associated with further genomic transformation of the clone towards MDS and AML. On the other hand, а recent study shows that the bone marrow failure in FA results from dysfunctional HSPCs [13]. Based on these data, the authors concluded that MYC overexpression impairs HSPCs and exhausted bone marrow populations in FA. The aim of this article is to present unusual cytogenetic, molecular and morphologic data from an FA patient of Syrian origin at the stage of early transformation into MDS, which is consistent with earlier findings.

Case report

In our male patient, diagnosis of Fanconi anemia was recognized at the age of 21-year manifesting by mild anemia (Hb 129 g/l) and neutropenia (ANC 0.8×109/l). At that time, bone marrow (BM) trephine biopsy was hypocellular, with a predominance of adipose component over myeloid tissue. There was a reduction of erythropoiesis, whereas myelodysplastic features of hematopoietic cells were absent. No chromosomal abnormalities were found in the bone marrow cells. The pedigree analysis showed the patient to be a child from a closely related marriage, in which two siblings (younger sister and younger brother) had similar FA diagnosis. Moreover, sickle-cell anemia was diagnosed in his father and older brother. In addition, our patient had urogenital malformations (prostatic hypoplasia, micropenis, hypogonadism), and large areas of skin hyperpigmentation (café-au-lait spots). Burdened inheritance, persistent cytopenia, and organ anomalies allowed us to expect a constitutional form of bone marrow failure (BMF). The in vitro test with diepoxybutane gave a positive result, since 109 chromosomal aberrations were detected in 63 metaphases examined. A previously described pathogenic variant of the nucleotide sequence of the FANCA gene in exon 38 (chr16:89740848AG>A) in the heterozygous state was revealed by NGS technique leading to a frameshift mutation starting from codon 1262 (p.F1262Sfs*4, NM_000135.4). The general health status of the patient remained relatively stable for 10 years.

At the age of 31, the patient complained for ulcerations in oral cavity, acne on the scalp and neck, as well as periodic low-grade fever. Routine blood check revealed multilinear cytopenia with hemoglobin levels less than 92 g/L, low platelet counts (77×109/L), and severe neutropenia (min ANC, 0.21×109/L). The bone marrow aspirate showed a pronounced multilineage dysplasia; cells with blastic morphology accounted for 2.6%. The BM trephine biopsy was hypocellular with pronounced features of dysplasia in all hematopoietic lineages. The proportion of CD34+ cells was 3-5%. Immunohistochemistry showed a reduced p53 expression, with less than 1% of brightly stained cells (3+) (Fig. 1). A molecular genetics study revealed an increased EVI1 gene expression (14%, reference of 0 to 10%), and a decreased BAALC expression level (1%, reference of 10 to 30%). In addition, the mutation search performed by direct sequencing technique did not detect mutations in the RUNX1 and TP53 genes. According to chromosome banding analysis, duplications and triplications of the long arm of chromosome 1, as well as unbalanced 3q translocations on the long and short arms of chromosome 11 were detected in all studied BM metaphases (Fig. 2). To support these observations, multicolor banding of chromosomes 1 and 3 was performed (Fig. 3-4), which confirmed the presence of an increased copy number of 1q and 3q in the patient's bone marrow cells. FISH with a locus-specific DNA probe for 1p36.3 and 1q25.2 showed that in most studied cells, the number of 1q gains per a single cell varied from 3 to 4, reaching 8-9 copies in some cells (Fig. 5). In turn, the copy number of EVI1 gene varied from 3 to 4 per cell (Fig. 6). Due to the appearance of clonal cytogenetic aberrations in the karyotype, as well as available HLA-matched healthy sibling, the patient was scheduled for allogeneic hematopoietic stem cell transplantation.

Gindina-fig04.jpg

Figure 4. Selective karyograms of 3 and 11 pairs of chromosomes (GTG-banding; multicolor FISH with 24 XCyte Human Multicolor Chromosome probes, MetaSystems, Germany; multicolor banding with XCyte 3 and XCyte 11 Human Multicolor Band probes, MetaSystems, Germany) demonstrate the unbalanced translocations t(3;11) with formation the derivative chromosome 11 and the pair of normal chromosomes 3

Gindina-fig05-06.jpg

Materials and methods

Histology and immunohistochemistry for p53

Bone marrow core biopsy was delivered to the Department of Pathology in the transport medium (formalin saline), fixed and decalcified in saturated solution of EDTA in buffered neutral formalin. The specimen was processed and embedded in paraffin according to standard protocols. Conventional stains included H&E, Romanovsky and Gomori. For immunohistochemistry, we used antibodies to p53 (BOND Ready-to-Use Primary Antibody p53 (DO-7), Leica Biosystems Newcastle Ltd, UK). Immunostaining was performed with automatic immunostainer BOND-III (Leica Biosystems Melbourne Pty Ltd, Melbourne, Australia) according to recommended protocol.

Cytogenetics and molecular cytogenetics

Chromosomal analysis on bone marrow (BM) samples using GTG-banding was performed according to standard procedures [16]. A minimal number of 20 metaphase cells has been analyzed. The karyotype was described according to the International System for Human Cytogenetic Nomenclature (ISCN 2020) [17]. Fluorescence in situ hybridization (FISH) using 24 XCyte chromosome specific probes and XCyte 1, XCyte 3, XCyte 11 probes (MetaSystems, Germany), 1p32/1q21 Amplification/Deletion Probe (MetaSystems, Germany) and EVI1 Break-Apart tricolor probe (CytoCell, United Kingdom) were used according to manufacturer’s instructions. A minimum of 10 metaphase spreads (for multicolor probes), or 200 interphase nuclei (for locus-specific probe) were analyzed per a sample using a fluorescence microscope (AxioImager.M1, Carl Zeiss Ltd, Germany) equipped with appropriate filter sets to discriminate between a maximum of five fluorochromes plus counterstaining with DAPI (4’,6-diamino-2-phenylindole). Image capture and processing were performed using an ISIS imaging system (MetaSystems, Germany).

Nucleic acids extraction and gene expression analysis

Genomic DNA was extracted from bone marrow (BM) aspirates cells in patients by means of Blood DNA Column Kit (Inogene, Russia). The total RNA was extracted according the instruction of TriZ Reagent Kit (Inogene, Russia) with the following reverse transcription by using ReverZyme Kit (Inogene, Russia). The concentration and quality of gDNA and cDNA was measured with a NanoDrop spectrophotometer (Thermo Fisher Scientific, USA). The EVI1 gene expression was determined using the real-time quantitative PCR (qPCR) method. The amplification of target products was performed using oligonucleotide probes described by Mäkelä et al. [18]. The detection of EVI1 gene expression was carried out in real-time mode. The ABL gene was chosen as a reference gene [19]. Valid samples were considered to be those in which, at least,1000 copies of the ABL gene were detected. Overexpression of the EVI1 gene was registered in samples with a ratio of EVI1/ABL transcripts >10%. The levels of WT1 and BAALC gene expression were assessed as described elsewhere [20, 21].

DNA sequencing procedures

The analysis of TP53 gene coding sequence (exons 2 to 11) and adjacent intronic regions was performed by Sanger sequencing, following the IARC protocol (2010 update) [22]. The search for RUNX1 gene mutations was also carried out by Sanger, with analysis of exons 2 to 9. The oligonucleotide sequences for amplification and sequencing reactions were obtained from previously published studies [23, 24].

Whole-exome sequencing (WES) was performed on the patient’s bone marrow sample as described in the manufacturers’ instructions. The genomic DNA was fragmented, and the exons of known genes in the human genome, as well as the adjacent exon-intron boundaries, were targeted and amplified using Roche KAPA capture technology (Roche, Switzerland) and sequenced by using the NextSeq 1000/2000 P2 Reagents v3 (Illumina, USA) on NextSeq 2000 system (Illumina, USA). Raw sequencing read quality was assessed using FastQC v0.11.9. Adapter trimming and filtering of low-quality readings were carried out with Fastp v0.23.2. Next, we applied BWA v0.7.15 to align the reads to the GRCh38 reference genome. General data processing routines, such as reporting alignment statistics and marking duplicates, were performed by GATK v4.2.5.0 and SAMtools v1.3.1. DeepVariant was used for variant calling. We annotated the discovered variants with Ensembl Variant Effect Predictor and ANNOVAR, using the RefSeq database, the GnomAD population frequency database, databases of clinically discovered variants such as COSMIC and ClinVar, as well as variant effect prediction tools (PolyPhen-2 [25], SIFT [26], MutationTaster2 [27], MutationAssessor [28], PROVEAN [29]. Finally, the ACMG/AMP criteria were applied for the clinical interpretation of sequence variants [30].

Discussion

This article presents a case of FA at the initial stage of transformation to MDS which seems to be unique. In particular, his cells contained the major chromosome aberrations, e.g., 1q+ and 3q+ gains demonstrated by others [7], combined with significantly reduced expression of p53 protein. It should be noted that the number of 1q+ and 3q+ copies proved to be variable, with maximum increase to 9 and 6 copies per single cell. On the other hand, molecular biology studies revealed low expression levels of BAALC and WT1 genes, previously not reported. Unfavorable prognosis for the cases with 1q gain was expected, due to its presence in many solid tumors and oncohematological disorders which might develop in a similar way. To this point, we refer to an article concerning the above issues studied in cell lines from the patients with Burkitt’s Lymphoma (BL) [5]. The authors highlighted the critical role of p53 as a tumor suppressor in BL, and showed higher MDM4 copy numbers in a wide range of cancers, which might be therapeutically targetable. To identify molecular dependencies in BL, RNAi-based, loss-of-function screening was performed in 8 BL cell lines. Following integration of genetic data, the authors identified 76 genes essential to BL, including FLI1, BCL11A, PAX5, CDKN1B, JAK2, CARD11 etc., and found a number of context-specific dependencies including oncogene addiction in cell lines with TCF3/ID3 or MYD88 mutation. The strongest genotype-phenotype association was noted for TP53 and MDM4, a negative regulator of TP53, which is considered essential in TP53 wild-type (TP53wt) BL cell lines. MDM4 knockdown activating p53 was shown to induce cell cycle arrest and decreased tumor growth in a xenograft model which proceeded in a p53-dependent manner. Small molecule inhibition of the MDM4-p53 interaction was effective only in TP53wt BL cell lines. Moreover, primary TP53wt BL samples frequently exhibited gains of chromosome 1q which contains the MDM4 locus, and, hence, showed elevated MDM4 mRNA levels. The 1q gain was associated with TP53wt across 789 cancer cell lines, and MDM4 was essential in the TP53wt-context in 216 cell lines representing 19 cancer entities from the Achilles project [5]. Another important study [4], concerning Ph-negative chronic myeloid neoplasms, has also suggested the pivotal role of p53 expression and increased expression of its regulator MDM4 in progression of this disorder. In general, our study suggests great perspectives of in-depth study in the recently described regulatory cellular mechanism. Future investigations will show whether this subtle mechanism may be universal for tumor progression.

Conclusion

Acquisition of additional 1q/MDM4 copies is common to many solid tumors and oncohematological diseases. Therefore, it may be a reliable predictor of malignancy progression. This molecular mechanism, unrelated to known effects of fusion genes, needs further in-depth studies.

Conflict of interest

No conflicts of interests are declared.

Acknowledgements

The authors are grateful to Ekaterina Izmailova, Irina Petrova, Tatiana Gracheva and Elena Ryabikova for excellent performance of cytogenetic and molecular tests.

References

  1. Girish V, Lakhani AA, Scaduto CM, Thompson SL, Brown LM, Hagenson RA, et al. Oncogene-like addiction to aneuploidy in human cancers. Science. 2023;381(6660):eadg4521. doi: 10.1126/science.adg4521
  2. Mamaeva SE, Mamaev NN, Jartseva NM, Belyaeva LV, Scherbakova EG. Complete or partial trisomy for the long arm of chromosome 1 in patients with various hematologic malignancies. Hum Genet. 1983;63(2):107-112. doi: 10.1007/BF00291527
  3. Mamaev NN, Mamaeva SE, Pavlova VA, Patterson D. Combined trisomy 1q and monosomy 17p due to translocation t(1;17) in a patient with myelodysplastic syndrome. Cancer Genet Cytogenet. 1988;35(1):21-25. doi: 10.1016/0165-4608(88)90116-1
  4. Marcellino BK, Hoffman R, Tripodi J, Lu M, Kosiorek H, Mascarenhas J, et al. Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53. Blood Adv. 2018;2(24):3581-3589.
    doi: 10.1182/bloodadvances.2018024018
  5. Hullein J, Slabicki M, Rosolowski M, Jethwa A, Harbinger S, Tomska K, et al. MDM4 is targeted by 1q gain and drives disease in Burkitt lymphoma. Cancer Res. 2019;79(12):3125-3138. doi: 10.1158/0008-5472.CAN-18-3438
  6. Gindina TL, Baykov VV, Kozhokar PV, Ryabenko S, Gusak AA, Riumin S et al. Nonrandom extra copies of 1q and 11q in the karyotypes of the three new cases of acute myeloid leukemia associated with Down syndrome. Cell Therapy Transplant. 2023;12(1):32-40.
    doi: 10.18620/ctt-1866-8836-2023-12-1-32-40
  7. Sebert M, Gachet S, Leblanc T, Rousseau A, Bluteau O, Kim R, et al. Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia. Cell Stem Cell. 2023;30(2):153-170.e9. doi: 10.1016/j.stem.2023.01.006
  8. Mehta PA, Harris RE, Davies SM, Kim MO, Mueller R, Lampkin B, et al. Numerical chromosomal changes and risk of development of myelodysplastic syndrome – acute myeloid leukemia in patients with Fanconi anemia. Cancer Genet Cytogenet. 2010;203(20):180-186. doi: 10.1016/j.cancergencyto.2010.07.127
  9. Udayakumar AM, Nazreen-Banu K, Al-Kindi S. Duplication 1q as primary and 3q in t(3;13) as secondary aberration on Fanconi anemia: implications and literature review. Acta Haematologica Polonica. 2015;46:368-371. doi: 10.1016/j.achaem.2015.10.003
  10. Kornreich L, Soulier J, Grange B, Girard S, Ouchee-Chardin M, Ceraulo A. A paediatric myelodysplastic syndrome with 5q deletion associated with Fanconi anaemia. Pediatr Blood Cancer. 2020;67(7):e28369. doi: 10.1002/pbc.28369
  11. Merfort LW, Lisboa MDO, Cavalli LR, Bonfim CMS. Cytogenetics in Fanconi Anemia: the importance of follow-up and the search for new biomarkers of genomic instability. Int J Mol Sci. 2022;23(22):14119. doi: 10.3390/ijms232214119
  12. Rajendra N, Ramanathan S, Ashok V, Srivalli BS. Rare cytogenetic abnormalities in MDS evolving from Fanconi anemia – A case report. IP J Diagn Pathol Oncol. 2022;7(4):252-254. doi: 10.18231/j.jdpo.2022.059
  13. Rodriguez A, Zhang K, Farkkila A, Filiatrault J, Yang C, Velazquez M, et al. MYC promotes bone marrow cell dysfunction in Fanconi anemia. Cell Stem Cell. 2021;28(1):33-47.e8. doi: 10.1016/j.stem.2020.09.004
  14. Almeida GM, Castilho AC, Adamoski D, Braun-Prado K. MDM4: What do we know about the association between polymorphisms and cancer. Med Oncol. 2023;40(1):61. doi: 10.1007/s12032-022-01929-z
  15. Ceccaldi R, Parmar K, Mouly E, Delord M, Kim JM, Regairaz M, et al. Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. Cell Stem Cell. 2012; 11(1);36-49. doi: 10.1016/j.stem.2012.05.013
  16. Gindina TL, Mamaev NN, Barkhatov IM, Solomonova IS, Semenova EV, Zubarovskaia LS, et al. Complex chromosome damages in patients with recurrent acute leukemias after allogeneic hematopoietic stem cell transplantations. Terapevticheskii archiv. 2012;8;61-66. (In Russian). PMID: 22994092
  17. McGowan-Jordan J, Simons A, Schmid M. ISCN 2020: An International System for Human Cytogenomic Nomenclature; Karger: Basel, Switzerland, 2020. doi: 10.1159/isbn.978-3-318-06867-2
  18. Makela E, Loyttyniemi E, Salmenniemi U, Kauko O, Varila T, Kairisto V, et al. Arpp19 promotes Myc and Cip2a expression and associates with patient relapse in acute myeloid leukemia. Cancer (Basel). 2019;11(11):1774. doi: 10.3390/cancers11111774
  19. Beillard E, Pallisgaard N, Van der Velden VHJ, Bi W, Dee R, Van der Schoot E, et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) – a Europe against cancer program. Leukemia. 2003;17(12):2474-2486. doi: 10.1038/sj.leu.2403136
  20. Shakirova A, Barkhatov I, Chjurkina A, Moiseev I, Gindina T, Bondarenko S, et al. Prognostic significance of BAALC overexpression in patients with AML during the post transplant period. Cell Ther Transplant. 2018;7(2):00. doi: 10.18620/ctt-1866-8836-2018-7-2-54-63
  21. Mamaev NN, Shakirova AI, Gindina TL, Bondarenko SN, Ayubova BI, Barkhatov IM, et al. Quantitative study of BAALC- and WT1-expressing cell precursors in the patients with different cytogenetic and molecular AML variants treated with Gemtuzumab ozogamicin and hematopoietic stem cell transplantation. Cell Ther Transplant. 2021;10(1):55-62.
    doi: 10.18620/ctt-1866-8836-2021-10-1-55-62
  22. Malcikova J, Tausch E, Rossi D, Sutton LA, Soussi T, et al. ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia – update on methodological approaches and results interpretation. Leukemia. 2018.32(5):1070-1080.
    doi: 10.1038/s41375-017-0007-7
  23. Rocquain J, Carbuccia N, Trouplin V, Raynaud S, Murati A, Nezri M, et al. Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer. 2020.10:401. doi: 10.1186/1471-2407-10-401
  24. Harada H, Harada Y, Niimi H, Kyo T, Kimura A, Inaba T. High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood. 2004;103(6):2316-2324.
    doi: 10.1182/blood-2003-09-3074
  25. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248-249. doi: 10.1038/nmeth0410-248
  26. Sim N-L, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. Nucleic Acids Res. 2012;40(WebServer issue):W452-457.
    doi: 10.1093/nar/gks539
  27. Schwartz JM, Cooper DN, Schuelke M, Seelow D. MutationTasre2: mutation prediction for the deep-sequencin age. Nat Methods. 2014:11(4):361-362. doi: 10.1038/nmeth.2890
  28. Reva B, Antipin Y, Sander C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res. 2011;39(17):e118. doi: 10.1093/nar/gkr407
  29. Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics. 2015:31(16):2745-2747. doi: 10.1093/bioinformatics/btv195
  30. Richards S, Aziz N, Bale S, Bick D, Das S, Gaster-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi: 10.1038/gim.2015.30

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Результаты секвенирования ДНК злокачественных клеток показали, что паттерны анеуплоидий не случайны, а специфические приросты хромосом происходят довольно часто и могут играть роль, подобную онкогенам, в развитии опухоли. Хорошо известно, что определенные изменения числа копий, такие как увеличение копийности 1q, имеют прогностическую ценность при многих типах опухолей. Недавно было показано, что дополнительные копии 1q связаны с повышенной экспрессией расположенного в локусе 1q32 онкогена <i>MDM4</i>, что приводит к подавлению экспрессии гена <i>ТР53 </i>при анемии Фанкони и дальнейшему развитию клонального гемопоэза. </p> <h3>Клиническое наблюдение</h3> <p style="text-align: justify;"> Здесь представлено редкое клиническое наблюдение анемии Фанкони у 31-летнего сирийского пациента на ранней стадии трансформации гемопоэза в МДС/ОМЛ, при котором в клетках костного мозга наблюдалось увеличение количества дополнительных копий 1q и 3q и выраженное подавление экспрессии <i>ТР53 </i>в сочетании с низким уровнем экспрессии генов <i>WT1 </i>и <i>BAALC</i>. </p> <h3>Заключение</h3> <p style="text-align: justify;"> Поскольку приобретение дополнительных копий 1q/<i>MDM4</i>, характерное для многих солидных опухолей и онкогематологических заболеваний, считается надежным панраковым маркером опухолевой прогрессии, этот молекулярный механизм, не связанный со 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string(5) "30798" ["VALUE"]=> array(2) { ["TEXT"]=> string(302) "<p>Татьяна Л. Гиндина, Вадим В. Байков, Юрий Н. Кузнецов, Ильдар М. Бархатов, Сергей С. Рюмин, Дмитрий С. Буг, Артем А. Гусак, Николай Н. Мамаев, Александр Д. Кулагин</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(290) "

Татьяна Л. Гиндина, Вадим В. Байков, Юрий Н. Кузнецов, Ильдар М. Бархатов, Сергей С. Рюмин, Дмитрий С. Буг, Артем А. Гусак, Николай Н. Мамаев, Александр Д. Кулагин

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

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Вариации числа копий хромосом, также известные как анеуплоидии, являются частой особенностью опухолевых геномов. Результаты секвенирования ДНК злокачественных клеток показали, что паттерны анеуплоидий не случайны, а специфические приросты хромосом происходят довольно часто и могут играть роль, подобную онкогенам, в развитии опухоли. Хорошо известно, что определенные изменения числа копий, такие как увеличение копийности 1q, имеют прогностическую ценность при многих типах опухолей. Недавно было показано, что дополнительные копии 1q связаны с повышенной экспрессией расположенного в локусе 1q32 онкогена MDM4, что приводит к подавлению экспрессии гена ТР53 при анемии Фанкони и дальнейшему развитию клонального гемопоэза.

Клиническое наблюдение

Здесь представлено редкое клиническое наблюдение анемии Фанкони у 31-летнего сирийского пациента на ранней стадии трансформации гемопоэза в МДС/ОМЛ, при котором в клетках костного мозга наблюдалось увеличение количества дополнительных копий 1q и 3q и выраженное подавление экспрессии ТР53 в сочетании с низким уровнем экспрессии генов WT1 и BAALC.

Заключение

Поскольку приобретение дополнительных копий 1q/MDM4, характерное для многих солидных опухолей и онкогематологических заболеваний, считается надежным панраковым маркером опухолевой прогрессии, этот молекулярный механизм, не связанный со слиянием генов, требует дальнейшего углубленного изучения.

Ключевые слова

Анемия Фанкони, анеуплоидия 1q/MDM4, анеуплоидия 3q/EVI1, ТР53, миелодиспластический синдром, острый миелоидный лейкоз, клональная эволюция, цитогенетика, многоцветная FISH, BAALC, WT1.

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Tatiana L. Gindina, Vadim V. Baykov, Yurii N. Kuznetsov, Ildar M. Barkhatov, Sergey S. Riumin, Dmitrii S. Bug, Artem A. Gusak, Nikolay N. Mamaev, Alexander D. Kulagin

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Tatiana L. Gindina, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (812) 338-62-92
Fax: +7 (812) 338-62-65
E-mail: tatgindina@gmail.com


Citation: Gindina TL, Baykov VV, Kuznetsov YN et al. Сhromosome 1q and 3q gains in bone marrow of a patient with Fanconi anemia: their clinical and pathogenetic significance. Cell Ther Transplant 2023; 12(3): 29-35.

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Chromosome copy number changes, also known as aneuploidy, is a ubiquitous feature of cancer cell genome. DNA sequencing studies of the tumor cells have shown that the aneuploidy patterns are nonrandom, and specific chromosome gains occur quite frequently, thus, probably, playing an oncogene-like role in tumor development. It is well known that certain copy number changes, such as 1q gain, are of predictive value in many tumor types. It has been recently shown that the 1q gain is associated with increased expression of the MDM4 oncogene located at 1q32 which is responsible for the downregulation of TP53 gene in Fanconi anemia and clonal hematopoiesis development.

Case presentation

Here we present a rare case of Fanconi anemia in a 31-year-old Syrian male patient at the early stage of MDS/AML transformation. His bone marrow cells showed 1q and 3q gains combined with severely suppressed TP53 gene expression, along with low WT1 and BAALC gene expression.

Conclusion

Since acquisition of additional 1q/MDM4 copies is common to many solid tumors and oncohematological diseases is considered a reliable marker predictive of cancer progression, this molecular feature needs further in-depth study.

Keywords

Fanconi anemia, 1q/MDM4 gain, 3q/EVI1 gain, p53 suppression, myelodysplastic syndrome, acute myeloid leukemia, clonal evolution, cytogenetics, multicolor FISH, BAALC expression, WT1 expression.

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Gindina, Vadim V. Baykov, Yurii N. Kuznetsov, Ildar M. Barkhatov, Sergey S. Riumin, Dmitrii S. Bug, Artem A. Gusak, Nikolay N. Mamaev, Alexander D. Kulagin</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(174) "

Tatiana L. Gindina, Vadim V. Baykov, Yurii N. Kuznetsov, Ildar M. Barkhatov, Sergey S. Riumin, Dmitrii S. Bug, Artem A. Gusak, Nikolay N. Mamaev, Alexander D. Kulagin

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Tatiana L. Gindina, Vadim V. Baykov, Yurii N. Kuznetsov, Ildar M. Barkhatov, Sergey S. Riumin, Dmitrii S. Bug, Artem A. Gusak, Nikolay N. Mamaev, Alexander D. Kulagin

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Chromosome copy number changes, also known as aneuploidy, is a ubiquitous feature of cancer cell genome. DNA sequencing studies of the tumor cells have shown that the aneuploidy patterns are nonrandom, and specific chromosome gains occur quite frequently, thus, probably, playing an oncogene-like role in tumor development. It is well known that certain copy number changes, such as 1q gain, are of predictive value in many tumor types. It has been recently shown that the 1q gain is associated with increased expression of the MDM4 oncogene located at 1q32 which is responsible for the downregulation of TP53 gene in Fanconi anemia and clonal hematopoiesis development.

Case presentation

Here we present a rare case of Fanconi anemia in a 31-year-old Syrian male patient at the early stage of MDS/AML transformation. His bone marrow cells showed 1q and 3q gains combined with severely suppressed TP53 gene expression, along with low WT1 and BAALC gene expression.

Conclusion

Since acquisition of additional 1q/MDM4 copies is common to many solid tumors and oncohematological diseases is considered a reliable marker predictive of cancer progression, this molecular feature needs further in-depth study.

Keywords

Fanconi anemia, 1q/MDM4 gain, 3q/EVI1 gain, p53 suppression, myelodysplastic syndrome, acute myeloid leukemia, clonal evolution, cytogenetics, multicolor FISH, BAALC expression, WT1 expression.

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Chromosome copy number changes, also known as aneuploidy, is a ubiquitous feature of cancer cell genome. DNA sequencing studies of the tumor cells have shown that the aneuploidy patterns are nonrandom, and specific chromosome gains occur quite frequently, thus, probably, playing an oncogene-like role in tumor development. It is well known that certain copy number changes, such as 1q gain, are of predictive value in many tumor types. It has been recently shown that the 1q gain is associated with increased expression of the MDM4 oncogene located at 1q32 which is responsible for the downregulation of TP53 gene in Fanconi anemia and clonal hematopoiesis development.

Case presentation

Here we present a rare case of Fanconi anemia in a 31-year-old Syrian male patient at the early stage of MDS/AML transformation. His bone marrow cells showed 1q and 3q gains combined with severely suppressed TP53 gene expression, along with low WT1 and BAALC gene expression.

Conclusion

Since acquisition of additional 1q/MDM4 copies is common to many solid tumors and oncohematological diseases is considered a reliable marker predictive of cancer progression, this molecular feature needs further in-depth study.

Keywords

Fanconi anemia, 1q/MDM4 gain, 3q/EVI1 gain, p53 suppression, myelodysplastic syndrome, acute myeloid leukemia, clonal evolution, cytogenetics, multicolor FISH, BAALC expression, WT1 expression.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Tatiana L. Gindina, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (812) 338-62-92
Fax: +7 (812) 338-62-65
E-mail: tatgindina@gmail.com


Citation: Gindina TL, Baykov VV, Kuznetsov YN et al. Сhromosome 1q and 3q gains in bone marrow of a patient with Fanconi anemia: their clinical and pathogenetic significance. Cell Ther Transplant 2023; 12(3): 29-35.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Tatiana L. Gindina, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (812) 338-62-92
Fax: +7 (812) 338-62-65
E-mail: tatgindina@gmail.com


Citation: Gindina TL, Baykov VV, Kuznetsov YN et al. Сhromosome 1q and 3q gains in bone marrow of a patient with Fanconi anemia: their clinical and pathogenetic significance. Cell Ther Transplant 2023; 12(3): 29-35.

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Татьяна Л. Гиндина, Вадим В. Байков, Юрий Н. Кузнецов, Ильдар М. Бархатов, Сергей С. Рюмин, Дмитрий С. Буг, Артем А. Гусак, Николай Н. Мамаев, Александр Д. Кулагин

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Татьяна Л. Гиндина, Вадим В. Байков, Юрий Н. Кузнецов, Ильдар М. Бархатов, Сергей С. Рюмин, Дмитрий С. Буг, Артем А. Гусак, Николай Н. Мамаев, Александр Д. Кулагин

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Результаты секвенирования ДНК злокачественных клеток показали, что паттерны анеуплоидий не случайны, а специфические приросты хромосом происходят довольно часто и могут играть роль, подобную онкогенам, в развитии опухоли. Хорошо известно, что определенные изменения числа копий, такие как увеличение копийности 1q, имеют прогностическую ценность при многих типах опухолей. Недавно было показано, что дополнительные копии 1q связаны с повышенной экспрессией расположенного в локусе 1q32 онкогена <i>MDM4</i>, что приводит к подавлению экспрессии гена <i>ТР53 </i>при анемии Фанкони и дальнейшему развитию клонального гемопоэза. </p> <h3>Клиническое наблюдение</h3> <p style="text-align: justify;"> Здесь представлено редкое клиническое наблюдение анемии Фанкони у 31-летнего сирийского пациента на ранней стадии трансформации гемопоэза в МДС/ОМЛ, при котором в клетках костного мозга наблюдалось увеличение количества дополнительных копий 1q и 3q и выраженное подавление экспрессии <i>ТР53 </i>в сочетании с низким уровнем экспрессии генов <i>WT1 </i>и <i>BAALC</i>. </p> <h3>Заключение</h3> <p style="text-align: justify;"> Поскольку приобретение дополнительных копий 1q/<i>MDM4</i>, характерное для многих солидных опухолей и онкогематологических заболеваний, считается надежным панраковым маркером опухолевой прогрессии, этот молекулярный механизм, не связанный со слиянием генов, требует дальнейшего углубленного изучения. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Анемия Фанкони, анеуплоидия 1q/<i>MDM4</i>, анеуплоидия 3q/<i>EVI1</i>, <i>ТР53</i>, миелодиспластический синдром, острый миелоидный лейкоз, клональная эволюция, цитогенетика, многоцветная FISH, <i>BAALC</i>, <i>WT1</i>. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3190) "

Вариации числа копий хромосом, также известные как анеуплоидии, являются частой особенностью опухолевых геномов. Результаты секвенирования ДНК злокачественных клеток показали, что паттерны анеуплоидий не случайны, а специфические приросты хромосом происходят довольно часто и могут играть роль, подобную онкогенам, в развитии опухоли. Хорошо известно, что определенные изменения числа копий, такие как увеличение копийности 1q, имеют прогностическую ценность при многих типах опухолей. Недавно было показано, что дополнительные копии 1q связаны с повышенной экспрессией расположенного в локусе 1q32 онкогена MDM4, что приводит к подавлению экспрессии гена ТР53 при анемии Фанкони и дальнейшему развитию клонального гемопоэза.

Клиническое наблюдение

Здесь представлено редкое клиническое наблюдение анемии Фанкони у 31-летнего сирийского пациента на ранней стадии трансформации гемопоэза в МДС/ОМЛ, при котором в клетках костного мозга наблюдалось увеличение количества дополнительных копий 1q и 3q и выраженное подавление экспрессии ТР53 в сочетании с низким уровнем экспрессии генов WT1 и BAALC.

Заключение

Поскольку приобретение дополнительных копий 1q/MDM4, характерное для многих солидных опухолей и онкогематологических заболеваний, считается надежным панраковым маркером опухолевой прогрессии, этот молекулярный механизм, не связанный со слиянием генов, требует дальнейшего углубленного изучения.

Ключевые слова

Анемия Фанкони, анеуплоидия 1q/MDM4, анеуплоидия 3q/EVI1, ТР53, миелодиспластический синдром, острый миелоидный лейкоз, клональная эволюция, цитогенетика, многоцветная FISH, BAALC, WT1.

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Вариации числа копий хромосом, также известные как анеуплоидии, являются частой особенностью опухолевых геномов. Результаты секвенирования ДНК злокачественных клеток показали, что паттерны анеуплоидий не случайны, а специфические приросты хромосом происходят довольно часто и могут играть роль, подобную онкогенам, в развитии опухоли. Хорошо известно, что определенные изменения числа копий, такие как увеличение копийности 1q, имеют прогностическую ценность при многих типах опухолей. Недавно было показано, что дополнительные копии 1q связаны с повышенной экспрессией расположенного в локусе 1q32 онкогена MDM4, что приводит к подавлению экспрессии гена ТР53 при анемии Фанкони и дальнейшему развитию клонального гемопоэза.

Клиническое наблюдение

Здесь представлено редкое клиническое наблюдение анемии Фанкони у 31-летнего сирийского пациента на ранней стадии трансформации гемопоэза в МДС/ОМЛ, при котором в клетках костного мозга наблюдалось увеличение количества дополнительных копий 1q и 3q и выраженное подавление экспрессии ТР53 в сочетании с низким уровнем экспрессии генов WT1 и BAALC.

Заключение

Поскольку приобретение дополнительных копий 1q/MDM4, характерное для многих солидных опухолей и онкогематологических заболеваний, считается надежным панраковым маркером опухолевой прогрессии, этот молекулярный механизм, не связанный со слиянием генов, требует дальнейшего углубленного изучения.

Ключевые слова

Анемия Фанкони, анеуплоидия 1q/MDM4, анеуплоидия 3q/EVI1, ТР53, миелодиспластический синдром, острый миелоидный лейкоз, клональная эволюция, цитогенетика, многоцветная FISH, BAALC, WT1.

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

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

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Introduction

According to the WHO statistics, burn injury is a global problem of modern health care, causing 180,000 lethal cases annually in the world, steadily ranking third among the causes of death due to injuries [1]. In 2019, 111,292 people died from burns worldwide, most of them children aged 1-4 years. Global studies show a trend towards a decreased incidence of disability and death from burn injuries, while the number of new cases of burns tends to increase [2].

The development of optimal methods for restoring the integrity of skin epithelial layer, searching the means to replace the lacking donor resources for patients with extensive deep burns represent an urgent problem of modern combustiology [3, 4]. Delayed restoration of the skin integrity causes an increased incidence of purulent-septic complications of burn disease, which are the main cause of fatal outcomes [5, 6].

The opportunity for transplantation of autologous in vitro grown skin cells was initially demonstrated in 1940’s [7]. Three decades later, the Lancet published the results of first application of autologous keratinocytes grown by their co-cultivation on a feeder layer of fibroblasts [8].

Due to high regenerative ability, stem cells of nerve tissue were initially considered a universal and effective tool for the treatment of various diseases [9]. Today many developed products of tissue-engineered leather are available. Most of these products are structurally similar to human skin and provide a barrier function [10]. Stem cells in the treatment of burn wounds opened up new horizons in treatment of burned patients [11].

Application of gel structures with adipogenic mesenchymal stem cells (MSCs) reduces the duration of the period of epithelialization of borderline (dermal) burn wounds by 2 times, along with 4-fold decreased incidence of purulent inflammation. The injection of MSC suspensions into the deep burn area improves engraftment of split autografts by stimulating angiogenesis and fibroblast proliferation [12].

Preclinical studies show that therapy with pluripotent and multipotent stem cells significantly improves burn wound healing, expressed as improved marginal epithelialization, reduction in wound area, and improved tissue vascularization. The most common mode of stem cell application was intradermal injection into the wound margin or into the wound bed [13, 14]. To date, the use of stem cells in burns is still at experimental stage. The biological properties of stem cells have been well studied. However, limited data and lack of randomized trials do not allow routine clinical usage of stem cells in treatment of burn wounds. Further research in the area is required [15]. These pre-requisites suggest the relevance of further research on effectiveness of stem cell usage for treatment of burn wounds.

Therefore, the aim of our work was a comparative study of wound healing process during the injections of allogeneic dermal fibroblasts and mesenchymal adipose tissue stem cells.

Materials and methods

Cell cultures

The cell cultures were prepared and delivered from the Laboratory of Experimental Biophysics at the Center for Advanced Technologies (Ministry of Education and Science, Republic of Uzbekistan). Allogeneic fibroblasts were obtained from the skin of white outbred neonatal rats, 1-3 days old. Briefly, the skin was minced and incubated in 0.25% Trypsin/Versene solution, at 37C° for 30-60 minutes and constant shaking; the suspension was pipetted through a 100 µm filter and centrifuged at 1500 rpm for 10 minutes. The cell pellet was resuspended in DMEM/F12 (Sigma Aldrich) with 10% FBS (Capricorn Scientific) and cultured at 5% CO2 and 37°C.

Allogeneic MSCs were isolated from the adipose tissue of white outbred rats aged 3 months (230±50 g), according to previously published protocols [16, 17]. Briefly, adipose tissue isolation was performed after animals were euthanized by administering a lethal dose of barbiturates (150 mg/kg) intraperitoneally. The adipose tissue was minced and incubated in 0.5% collagenase type I in PBS with constant stirring at 37°C for 60 min. The suspension was centrifuged at 1500 rpm for 10 min; the middle fraction containing the target cells was separated, transferred to PBS and centrifuged at 1500 rpm for 10 min. The pellet was resuspended in DMEM/F12 medium with 10% FBS, and cultured at 5% CO2 and 37°C for 24 hours. After incubation, the medium was replaced by low-glucose DMEM (Sigma Aldrich) with 10% FBS, and changed every 3 days. The passage was performed after monolayer confluency reached 70-80% and proceeds up to 3-5 passages. The final concentration of 1x106 cells/mL in PBS was used for further experiments.

Animal experiments

The study was carried out in the operating room at Experimental Department of the RRCEM. For the experiments, we used twenty white, three-month-old male white rats of local breeding with body mass of 230±50 g. Four experimental groups were formed. The burns were inflicted under general anesthesia (isoflurane inhaled), the hair was removed immediately before burns by applying a depilatory cream. The thermal burns were performed by applying a glass beaker filled with boiling water and kept in a water bath, being applied to the previously depilated skin at the back of the animal. The bottom diameter of beaker was 3.5 cm, and the exposure time was 10 to 12 seconds.

Animals of the 1st group underwent active surgical intervention (ASI) with general anesthesia, carried out on the day 7 to 9 after the injury. The animals underwent sharp excision of necrotic tissues, followed by injection of the wound bed with a cell culture suspension of allogeneic dermal fibroblasts. Re-injection of cell culture suspension was performed on the 20th day. In the 2nd group subjected to conventional surgical treatment (CST) on days 12-15, after complete cleansing of the wound surface from necrotic tissues, a similar injection of a suspension of dermal allofibroblasts was carried out. Re-injection of cell culture suspension was performed on the 24th day. The animals from the 3rd group were treated with ASI on the 7-9th day after injury with general anesthesia. They underwent necrectomy, after which the wound bed was injected with a suspension of adipose tissue-derived MSC culture. Re-injection with the cell culture suspension was performed on the 20th day. In the 4th group which received CST on days 12-15, after complete cleansing of the wound surface from necrotic tissues, a similar injection of a suspension of MSCs was carried out. Re-injection of cell culture suspension was made on the day 24.

For all experimental groups, injection depth was 3-4 mm, with suspension volume of 0.3 ml, and density of 1 injection per 0.5 cm2. On average, 21 injection was performed, at total number of 6.3×106 cells applied to each wound surface.

Ethical Compliance

When working with animals, we followed the principles of the European Convention for the Protection of Vertebrate Animals used for Experimental or other Scientific Purposes (1986, Strasbourg) and Directive 2010/63/EU of the European Parliament and of the Council of the European Union (2010) on the protection of animals used in scientific purposes.

Morphological studies

In each of the groups, on the 12th, 20th and 30th days after starting the experiment, under general anesthesia, soft tissues were excised on the wound surface in the form of a square with an area of 3×3 mm. The wound surface was sharply excised in the central and peripheral zones of the injury. The excision was performed at the border between necrotic and healthy tissue, and in the central areas of the wound with partial involvement of subcutaneous adipose tissue. After fixing the tissue in 10% neutral formalin in phosphate buffer (pH 7.2-7.4), the material was passed through alcohols of increasing concentration and embedded in paraffin according to the method of Z. Loyd et al. (1982). Serial slicing at a thickness of 4-5 μm was made on a rotary microtome "HM 360" (MICROM). The resulting sections were stained with H&E using a Robot stainer HMS 760X (MICROM). The study of micropreparations to determine the qualitative changes in the microstructure was carried out on a microscope "Axiostar" (ZEISS).

Statistical evaluation

The effectiveness of the treatment was evaluated based on morphological criteria of the degree of activity of pathological processes such as dystrophy, necrosis, stages of inflammation (alteration, exudation, proliferation), and the onset of reparative regeneration by the terms of complete epithelialization of burn wounds.

Statistical calculations were performed using Microsoft Excel 2016 software, including built-in functions of statistical processing. The significance of differences between groups of quantitative parameter values was determined by the Student's criterion. Statistical statements were considered significant when p <0.05.

Results

In group 1, an active surgical intervention and early treatment with allogeneic dermal fibroblasts in the wound bed were used. Necrotic and necrobiotic processes with massive infiltration of segmented and neutrophilic leukocytes were registered in all layers on the 12th day after injury.

Foci of immature granulation tissue were found in the upper layers of the dermis. The most pronounced changes were found in the central zone. In the peripheral sections, similar changes were detected only in a small segment of the sample. The maximum damage affected the epidermis and the upper sections of the upper dermis (Fig. 1).

Khadjibayev-fig01.jpg

Figure 1. Active surgical intervention (ASI) with the injection of allofibroblasts, 12 days (H&E staining). Ocular, 10x; objective 10x. A, Central zone with epithelial necrosis and granulation tissue in the dermis. B, Peripheral zone with necrosis of the epithelium

On day 20, the elements of necrotic epidermis with massive inflammatory infiltration were still detected in the central zone, but these areas occupied a smaller area compared with day 12.

In superficial sections of dermis, we observed granulation tissue at varying maturity grades; in the deep sections, loose fibrous connective tissue with a network of capillaries. In peripheral zones, the areas of necrosis with granulation tissue were detected in the superficial parts of dermis. In the deep layers of the dermis, we found interstitial edema, growth of fibrous connective tissue, while inflammatory infiltration was practically absent (Fig. 2).

Khadjibayev-fig02.jpg

Figure 2. ASI with the injection of allofibroblasts, 20 days, H&E staining. Ocular, 10x; objective,10x. A, Central zone with epithelial necrosis and granulation tissue in the dermis. B, Peripheral zone with similar local lesions

On day 30, necrotic tissue was virtually not detectable in the central zone. In the superficial layers of the dermis, the growth of mature granulation and connective tissue was determined. In some samples, the development of a "neoepidermis" containing 1-2 layers of squamous epithelium was noted.

Samples from the peripheral portions of the wounds were represented by structure-preserving stratified squamous epithelium with signs of epidermal dystrophy, fields of loose fibrous tissue, and areas of squamous epithelium formation (Fig. 3).

Khadjibayev-fig03.jpg

Figure 3. ASI combined with the injection of allofibroblasts, 30 days. H&E staining. Ocular 10x; objective 40x. A. Central area with a focus of squamous epithelium formation arrows. B. Peripheral area with a focus of squamous epithelium formation.

In group 2, when using conventional surgical tactics (CST) and the later injection of allogeneic dermal fibroblasts, on the 12th day after injury, massive necrosis of all skin layers was noted in the samples from the central zone of the wound. In this case, there was a complete absence of inflammatory infiltration in necrotic masses, as well as colonies of microorganisms observed in the surface areas of the necrotic epidermis.

Only in some samples from the deep parts of the dermis and hypodermis there are zones with preserved structure and foci of mononuclear infiltration. The peripheral areas in the main portion of the samples exhibited similar changes (Fig. 4).

Khadjibayev-fig04.jpg

Figure 4. CST with injection of allogeneic fibroblasts, 12 days. H&E staining. Ocular, 10x; objective, 10x. A. Central area with necrosis of all skin layers with colonies of microorganisms. B. Peripheral area of the lesion with necrosis of all skin layers

On the 20th day in group 2, massive infiltration of necrotic tissue with neutrophilic cells and segmented leukocytes was found in epidermis of the central area. In adjacent sections of the dermis, we found subepithelial vacuoles that exfoliate from epidermis, fields of immature and foci of mature granulation tissue. In peripheral zones of the epidermis, we observed necrotic changes and inflammatory infiltration; in the dermis, foci of granulation tissue. In the arterial vessels of the dermis of individual samples obtained from the central and peripheral zones, thrombotic masses are detected (Fig. 5).

Khadjibayev-fig05.jpg

Figure 5. CST with the injection of allofibroblasts, 20 days. H&E staining. Ocular, 10x; lens, 10x. A. Central area with necrosis of all layers with inflammatory infiltration B. Peripheral area with necrosis of all layers with inflammatory infiltration

On day 30, in all samples of both the central and peripheral zones, fields of necrotic epithelium, diffuse inflammatory infiltration, fields of immature and mature granulation tissue are determined (Fig. 6).

Khadjibayev-fig06.jpg

Figure 6. CST combined with injection of allofibroblasts, 30 days. H&E staining. Ocular, 10x; lens 10x. A. Central zone with necrosis of all layers with inflammatory infiltration B. Peripheral zone with necrosis of the epithelium and granulation tissue in the dermis

In the 3rd group of animals, upon ASI and treatment with MSCs on the 12th day after injury, no stratified squamous epithelium was observed in the central area of the burn wound, there is a wide zone of edema with a narrow strip of moderate leukocyte infiltration.

There is a slight edema in the dermis, many dilated capillaries, and a moderate inflammatory infiltrate. In the peripheral parts of the burn wound, there was a zone of necrotic epithelium, underlied with a narrow strip of leukocyte infiltration, separating necrotic masses from the dermis. In some areas, tissue detritus was noted, with elements of exfoliated squamous epithelium and a zone of granulation tissue (Fig. 7).

Khadjibayev-fig07.jpg

Figure 7. ASI with the injection of MSCs, 12 days. H&E staining. Ocular, 10x; lens 10x. A. Central area of the lesion. Tissue edema is noted. Tissue detritus is seen on the surface of the lesion with leukocyte infiltration. There is a moderate inflammatory infiltrate in the dermis. B. Peripheral zone with tissue detritus, elements of stratified squamous epithelium and granulation tissue in the dermis

On the 20th day, a wide edematous zone with massive infiltration of neutrophilic and segmented leukocytes is determined in the central zone of the wound, forming a demarcation zone that separates the dermis from the damaged surface. In separate areas free from leukocyte infiltration, the formation of a cubic epithelium on the surface of the dermis is detected.

In the deeper parts of dermis, mature granulation tissue is determined with an abundance of full-blooded vessels, moderate leukocyte infiltration. In peripheral area, we detected foci of necrosis with leukocyte infiltration, zones of ingrowing stratified squamous epithelium onto the damaged area from the peripheral areas (Fig. 8).

Khadjibayev-fig08.jpg

Figure 8. ASI with the injection of MSCs, 20 days. H&E staining. Ocular, 10x; objective, 40x. A, Central lesion area. Formation of stratified squamous epithelium on the wound surface. B, Peripheral area. Ingrowth squamous epithelium from the peripheral zone

On the 30th day, in the central area of the burn wound, a stratified squamous epithelium of various thicknesses was noted, with formation of skin appendages located in the edematous stroma. In the cases with formation of stratified squamous epithelium in dermal areas, loose fibrous tissue is observed to the full thickness of the preparation. In adjacent sections of dermis, small areas of mature granulation tissue are detected. In peripheral areas, a moderately pronounced edema was determined, the surface was replaced by a stratified squamous epithelium. In the underlying dermis, loose fibrous tissue was observed with immersion of squamous epithelial foci (Fig. 9).

Khadjibayev-fig09.jpg

Figure 9. ASI with the injection of MSCs, 30 days. H&E staining. Ocular, 10x; lens 10x. A. Central area of the lesion. Formed stratified squamous epithelium with granulation tissue in the dermis. B. Peripheral area. Formed squamous epithelium and appendages in the edematous stroma

When using conventional surgical treatment with the injection of MSCs in the 4th group of animals on the 12th day in the central area of the burn wound, we revealed wide areas of tissue detritus with leukocyte infiltration covering the dermis, with underlying extensive areas of hemorrhages. In peripheral zones, extensive fields of necrosis of the stratified squamous epithelium with inflammatory infiltration are revealed. In the underlying dermis, the formation of granulation tissue is seen (Fig. 10).

Khadjibayev-fig10.jpg

Figure 10. CST combined with injections of MSCs, 12 days. H&E staining. Ocular, 10x; lens 10x. A, Central area of the lesion. Tissue detritus with leukocyte infiltration and areas of hemorrhage in the dermis. B, Peripheral area. Tissue detritus with leukocyte infiltration

On the 20th day, extensive areas of tissue detritus with a wide area of leukocyte infiltration, which penetrates into the underlying dermis, are determined in the central zone. In some areas, small foci of the formation of stratified squamous epithelium are noted. In the peripheral zone, extensive zones of sloughing tissue detritus with colonies of microorganisms are determined. Also, there are areas of naked dermis covered with fields of hemorrhages. Granulation tissue is visualized in the dermis (Fig. 11).

Khadjibayev-fig11.jpg

Figure 11. CST with the injection of MSCs, 20 days. H&E staining. Ocular, 10x; lens 10x. A. Central area of the lesion. Tissue detritus with leukocyte infiltration extending to the dermis. B. Peripheral area. Destroyed tissue detritus with colonies of microorganisms

On the 30th day, the dermis structures are determined in the central areas, being covered with a wide zone of tissue detritus with leukocyte infiltration of varying intensity. In some areas on the surface of the dermis, a narrow strip of the emerging squamous epithelium is determined. In the peripheral part of lesion, zones of necrosis of stratified squamous epithelium still remained, with massive leukocyte infiltration and colonies of microorganisms. There are also zones with germination of squamous epithelium from hair follicles and adjacent parts of the epidermis to the surface of the dermis (Fig. 12).

Khadjibayev-fig12.jpg

Figure 12. CST with the injection of MSCs, 30 days. H&E staining. Ocular, 10x; lens 10x. A. Central lesion area. Foci of formation of stratified squamous epithelium. B. Peripheral area. Foci of formation of stratified squamous epithelium from adjacent hair follicles and adjacent parts of the skin

Table 1. Mean epithelization terms of burn wounds in the studied animals (M±m)

Khadjibayev-tab01.jpg

Table 1 presents the time frame for complete epithelialization of burn wounds with different approaches to surgical treatment and the use of allogeneic dermal fibroblasts or mesenchymal stem cells of adipose tissue.

In a study comparing active surgical intervention with conventional surgical tactics (both, with usage of allogeneic dermal fibroblasts), the time for wound epithelialization was 30.8±0.4 days and 32.6±0.24 days, respectively. In the group of animals treated with active surgical intervention and the use of MSC, the time for complete epithelization of burn wounds was 28.0±0.32 days, while in the group treated with conventional surgical tactics and the use of MSC, this time period was 29.6±0.40 days.

Discussion

The results of the study conducted by Ahmadpour F. et al. [18] demonstrate that the use of fibroblast exosomes significantly accelerates wound healing in a rat skin ulcer model in the experiment. This proves that the use of both exosomes and fibroblasts themselves is a promising direction in wound treatment.

In the study group when using active surgical tactics and early injection of allogeneic dermal fibroblasts, early formation of immature granulation tissue (day 12), mature granulation tissue (day 20) and the formation of small neoepithelial foci (day 30) both in the central and in peripheral areas. It is noteworthy that tissue repair is more intensive in the zone of deep dermis with a decrease in the intensity of repair in superficial areas. In the group with the use of conventional surgical tactics and the later injection of allogeneic dermal fibroblasts, a pronounced slowdown in the course of the stages of inflammation is determined. On the 12th day, only tissue necrosis and colonies of microorganisms are determined. The release of inflammatory cells into the affected area begins after 12 days, reaching a pronounced degree by the 20th day. By 30 days, the burn wound is almost completely cleared of necrotic tissues. In all parts of the dermis, there is a pronounced inflammatory infiltrate and granulation tissue begins to form in the form of separate foci. Changes in the central and peripheral parts of the affected tissue have a similar microscopic picture.

A microscopic examination performed in two groups using allogeneic dermal fibroblasts revealed a significant difference in the course of the wound process in the affected area. AChT and early injection of allofibroblasts promotes earlier epithelialization of the wound surface with the onset of neoepithelial foci formation by 30 days after injury. With the use of CST with later use of allofibroblasts, the wound surface is seeded with colonies of microorganisms and the course of inflammatory and reparative processes is slowed down. And if in the ASI group on the 30th day foci of the formation of "neoepidermis" are already determined, then in the CST group by the 30th day necrotic masses with a pronounced inflammatory infiltration are still determined on the wound surface, and only in some area’s granulation tissue begins to form.

Mesenchymal stem cells (MSCs) represent a population of stem cells which may originate from various tissues other than skin. They are able to migrate and exhibit paracrine, trophic, and immunomodulatory effects, which makes them useful in clinical practice [19, 20]. In the treatment of burn wounds, MSCs obtained from adipose tissue are preferred due to their availability, simplicity of isolation procedure, and more pronounced stimulating properties of healing processes [21].

Earlier injection of MSCs with an active surgical treatment contributes to high reparative activity in the area of the wound surface. Starting from the 12th to the 20th day after the injection of the cell suspension, against the background of a pronounced inflammatory infiltration, not only the foci of granulation tissue are determined, but the zones of the formation of stratified squamous epithelium. By the 30th day, this process ends with complete epithelialization of the damaged area with well-formed stratified squamous epithelium and skin appendages. This process proceeds more actively in the peripheral zones of the wound. A conservative approach to surgical treatment, the relatively late injection of MSCs into the wound bed showed that the cleansing of the wound from necrotic tissues is delayed on the 12th and 20th days in the central zone of the wound surface, and massive inflammatory infiltration is present. Peripheral areas exhibit foci of granulation tissue formation in presence of similar inflammatory infiltration and seeding of the wound with microorganisms. By the 30th day, zones of tissue detritus with inflammatory infiltration continue to persist in the central and peripheral zones, especially in the central areas. Foci of stratified squamous epithelium are formed, mainly, in the peripheral regions.

An active approach to surgical treatment in combination with the injection of MSCs in the experiment revealed a high degree of regenerative processes with complete restoration of the stratified squamous epithelium in the damaged area by 30 days. The formation of the epithelium was detected already on the 12th day both in the central and in the peripheral areas. Regenerative processes proceeded more actively in the peripheral parts of the wound. Despite the use of MSCs with a conservative approach to surgical treatment, we revealed an increased duration of the inflammatory process with delayed wound cleansing from necrotic tissue with microbial colonization. In contrast to the animals of the 3rd group (ASI), by the 30th day, the formation of foci of stratified squamous epithelium had just begun in the affected area, mainly in peripheral areas of the wound.

Conclusion

In summary, when using allogeneic dermal fibroblasts and MSCs against the background of active surgical management, an accelerated course of reparative processes was noted. However, the use of allofibroblasts by the 30th day was associated only with development of neoepithelial foci, while the use of MSCs during this period showed a complete restoration of the structure of the skin and its appendages. The worst results were obtained when using the conventional surgical tactics of treatment, despite the injection of allofibroblasts and MSCs. In both groups, there was an increase in the timing of inflammatory and reparative processes. However, usage of allofibroblasts by 30 days only led to appearance of granulation tissue. Following injections of MSCs, not only granulation tissue was revealed, but also the foci of developing epithelial tissue. A more active formation of epithelium was detected in the peripheral areas due to growth of epithelial cells from the preserved skin and hair epithelium.

Conflict of interest

The authors declare no conflict of interest.

References

  1. Burns [Electronic resource]: World Health Organization. URL: https://www.who.int/ru/news-room/fact-sheets/detail/burns
  2. Yakupu A, Zhang J, Dong W, Song F, Dong J, Lu S. The epidemiological characteristic and trends of burns globally. BMC Public Health. 2022; 22: 1596. doi: 10.1186/s12889-022-13887-2
  3. Lumenta DB, Kamolz LP, Frey M. Adult burn patients with more than 60% TBSA involved - Meek and other techniques to overcome restricted skin harvest availability - the Viennese concept. J Burn Care Res. 2009; 30(2): 231-242. doi: 10.1097/BCR.0b013e318198a2d6
  4. Peck M, Pressman MA. The correlation between burn mortality rates from fire and flame and economic status of countries. Burns. 2013; 39(6): 1054-1059. doi: 10.1016/j.burns.2013.04.010
  5. Hayashi M, Yoshitake K, Tokunaka R, Yoshida Y, Oshima M, Tatsuta S, et al. Combination of meshed dermis graft and cultured epithelial autograft for massive burns. Medicine (Baltimore). 2018; 97(48): 13313. doi: 10.1097/MD.0000000000013313
  6. Stone RII, Natesan S, Kowalczewski CJ, Mangum LH, Clay NE, Clohessy RM, et al. Advancements in regenerative strategies through the continuum of burn care. Front Pharmacol. 2018; 9: 672. doi: 10.3389/fphar.2018.00672
  7. Medawar PR. The cultivation of adult mammalian skin epithelium in vitro. Quart J Microsc Sci. 1948; 89: 187-196.
  8. O’Connor NE, Mulliken JB, Banks-Schleger S, Kehinde O, Green H. Grafting of burns with cultured epithelium prepared from autologous epidermal cells. Lanсet. 1981; 1: 75-78. doi: 10.1016/S0140-6736(81)90006-4
  9. Karimi M, Bahrami S, Mirshekari H, Basri SMM, Nik AB, Aref AR, et al. Microfluidic systems for stem cell-based neural tissue engineering. Lab on a Chip. 2016; 16: 2551-2571. doi: 10.1039/c6lc00489j
  10. Weng T, Wu P, Zhang W, Zheng Y, Li Q, Jin R, et al. Regeneration of skin appendages and nerves: current status and further challenges. J Transl Med. 2020; 18(1): 53. doi: 10.1186/s12967-020-02248-5
  11. Jahromi MAM, Zangabad PS, Basri SMM, Zangabad KS, Ghamarypour A, Aref AR, et al. Nanomedicine and advanced technologies for burns: Preventing infection and facilitating wound healing. Adv Drug Deliv Rev. 2018; 123: 33-64. doi: 10.1016/j.addr.2017.08.001
  12. Zinoviev EV, Krainyukov PE, Asadulaev MS, Kostyakov DV, Wagner DO, Krylov PK. Clinical evaluation of the effectiveness of mesenchymal stem cells in thermal burns. Bulletin of N. I. Pirogov National Medical and Surgical Center. 2018; 13(4): 62-67 (In Russian). doi: 10.25881/BPNMSC.2018.88.91.011
  13. Li Y, Xia WD, Van der Merwe L, Dai WT, Lin C. Efficacy of stem cell therapy for burn wounds: A systematic review and meta-analysis of preclinical studies. Stem Cell Res Ther. 2020; 11: 322. doi: 10.1186/s13287-020-01839-9
  14. Yi H, Wang Y, Yang Z, Xie Z. Efficacy assessment of mesenchymal stem cell transplantation for burn wounds in animals: A systematic review. Stem Cell Res Ther. 2020; 11: 372. doi: 10.1186/s13287-020-01879-1
  15. Surowiecka A, Chrapusta A, Klimeczek-Chrapusta M, Korzeniowski T, Drukała J, Strużyna J. Mesenchymal stem cells in burn wound management. Int J Mol Sci. 2022; 23(23): 15339. doi: 10.3390/ijms232315339
  16. Francis MP, Sachs PC, Elmore LW, Holt SE. Isolating adipose-derived mesenchymal stem cells from lipoaspirate blood and saline fraction. Organogenesis. 2010; 6(1): 11-14. doi: 10.4161/org.6.1.10019
  17. Zuk PA, Min Zhu, Mizuno H. Multiline age cells from human adipose tissue: implications for cell-based therapies. Tissue Engineering. 2001; 7(2): 211-228. doi: 10.1089/107632701300062859
  18. Ahmadpour F, Rasouli HR, Talebi S, Golchin D, Esmailinejad MR, Razie A. Effects of exosomes derived from fibroblast cells on skin wound healing in Wistar rats. Burns. 2023; 49(6): 1372-1381. doi: 10.1016/j.burns.2023.02.003
  19. Ichiro MS, Ishikawa O. Mesenchymal stem cells: the roles and functions in cutaneous wound healing and tumor growth. J Dermatol Sci. 2017; 86: 83-89. doi: 10.1016/j.jdermsci.2016.11.005
  20. Malgieri A, Kantzari E, Patrizi MP, Gambardella S. Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art. Int J Clin Exp Med. 2010; 3(4): 248-269. PMCID: PMC2971538
  21. Chang YW, Wu YC, Huang SH, Wang HD, Kuo YR, Lee SS. Autologous and not allogeneic adipose-derived stem cells improve acute burn wound healing. PLoS One. 2018; 13(5): e0197744. doi: 10.1371/journal.pone.0197744

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Introduction

According to the WHO statistics, burn injury is a global problem of modern health care, causing 180,000 lethal cases annually in the world, steadily ranking third among the causes of death due to injuries [1]. In 2019, 111,292 people died from burns worldwide, most of them children aged 1-4 years. Global studies show a trend towards a decreased incidence of disability and death from burn injuries, while the number of new cases of burns tends to increase [2].

The development of optimal methods for restoring the integrity of skin epithelial layer, searching the means to replace the lacking donor resources for patients with extensive deep burns represent an urgent problem of modern combustiology [3, 4]. Delayed restoration of the skin integrity causes an increased incidence of purulent-septic complications of burn disease, which are the main cause of fatal outcomes [5, 6].

The opportunity for transplantation of autologous in vitro grown skin cells was initially demonstrated in 1940’s [7]. Three decades later, the Lancet published the results of first application of autologous keratinocytes grown by their co-cultivation on a feeder layer of fibroblasts [8].

Due to high regenerative ability, stem cells of nerve tissue were initially considered a universal and effective tool for the treatment of various diseases [9]. Today many developed products of tissue-engineered leather are available. Most of these products are structurally similar to human skin and provide a barrier function [10]. Stem cells in the treatment of burn wounds opened up new horizons in treatment of burned patients [11].

Application of gel structures with adipogenic mesenchymal stem cells (MSCs) reduces the duration of the period of epithelialization of borderline (dermal) burn wounds by 2 times, along with 4-fold decreased incidence of purulent inflammation. The injection of MSC suspensions into the deep burn area improves engraftment of split autografts by stimulating angiogenesis and fibroblast proliferation [12].

Preclinical studies show that therapy with pluripotent and multipotent stem cells significantly improves burn wound healing, expressed as improved marginal epithelialization, reduction in wound area, and improved tissue vascularization. The most common mode of stem cell application was intradermal injection into the wound margin or into the wound bed [13, 14]. To date, the use of stem cells in burns is still at experimental stage. The biological properties of stem cells have been well studied. However, limited data and lack of randomized trials do not allow routine clinical usage of stem cells in treatment of burn wounds. Further research in the area is required [15]. These pre-requisites suggest the relevance of further research on effectiveness of stem cell usage for treatment of burn wounds.

Therefore, the aim of our work was a comparative study of wound healing process during the injections of allogeneic dermal fibroblasts and mesenchymal adipose tissue stem cells.

Materials and methods

Cell cultures

The cell cultures were prepared and delivered from the Laboratory of Experimental Biophysics at the Center for Advanced Technologies (Ministry of Education and Science, Republic of Uzbekistan). Allogeneic fibroblasts were obtained from the skin of white outbred neonatal rats, 1-3 days old. Briefly, the skin was minced and incubated in 0.25% Trypsin/Versene solution, at 37C° for 30-60 minutes and constant shaking; the suspension was pipetted through a 100 µm filter and centrifuged at 1500 rpm for 10 minutes. The cell pellet was resuspended in DMEM/F12 (Sigma Aldrich) with 10% FBS (Capricorn Scientific) and cultured at 5% CO2 and 37°C.

Allogeneic MSCs were isolated from the adipose tissue of white outbred rats aged 3 months (230±50 g), according to previously published protocols [16, 17]. Briefly, adipose tissue isolation was performed after animals were euthanized by administering a lethal dose of barbiturates (150 mg/kg) intraperitoneally. The adipose tissue was minced and incubated in 0.5% collagenase type I in PBS with constant stirring at 37°C for 60 min. The suspension was centrifuged at 1500 rpm for 10 min; the middle fraction containing the target cells was separated, transferred to PBS and centrifuged at 1500 rpm for 10 min. The pellet was resuspended in DMEM/F12 medium with 10% FBS, and cultured at 5% CO2 and 37°C for 24 hours. After incubation, the medium was replaced by low-glucose DMEM (Sigma Aldrich) with 10% FBS, and changed every 3 days. The passage was performed after monolayer confluency reached 70-80% and proceeds up to 3-5 passages. The final concentration of 1x106 cells/mL in PBS was used for further experiments.

Animal experiments

The study was carried out in the operating room at Experimental Department of the RRCEM. For the experiments, we used twenty white, three-month-old male white rats of local breeding with body mass of 230±50 g. Four experimental groups were formed. The burns were inflicted under general anesthesia (isoflurane inhaled), the hair was removed immediately before burns by applying a depilatory cream. The thermal burns were performed by applying a glass beaker filled with boiling water and kept in a water bath, being applied to the previously depilated skin at the back of the animal. The bottom diameter of beaker was 3.5 cm, and the exposure time was 10 to 12 seconds.

Animals of the 1st group underwent active surgical intervention (ASI) with general anesthesia, carried out on the day 7 to 9 after the injury. The animals underwent sharp excision of necrotic tissues, followed by injection of the wound bed with a cell culture suspension of allogeneic dermal fibroblasts. Re-injection of cell culture suspension was performed on the 20th day. In the 2nd group subjected to conventional surgical treatment (CST) on days 12-15, after complete cleansing of the wound surface from necrotic tissues, a similar injection of a suspension of dermal allofibroblasts was carried out. Re-injection of cell culture suspension was performed on the 24th day. The animals from the 3rd group were treated with ASI on the 7-9th day after injury with general anesthesia. They underwent necrectomy, after which the wound bed was injected with a suspension of adipose tissue-derived MSC culture. Re-injection with the cell culture suspension was performed on the 20th day. In the 4th group which received CST on days 12-15, after complete cleansing of the wound surface from necrotic tissues, a similar injection of a suspension of MSCs was carried out. Re-injection of cell culture suspension was made on the day 24.

For all experimental groups, injection depth was 3-4 mm, with suspension volume of 0.3 ml, and density of 1 injection per 0.5 cm2. On average, 21 injection was performed, at total number of 6.3×106 cells applied to each wound surface.

Ethical Compliance

When working with animals, we followed the principles of the European Convention for the Protection of Vertebrate Animals used for Experimental or other Scientific Purposes (1986, Strasbourg) and Directive 2010/63/EU of the European Parliament and of the Council of the European Union (2010) on the protection of animals used in scientific purposes.

Morphological studies

In each of the groups, on the 12th, 20th and 30th days after starting the experiment, under general anesthesia, soft tissues were excised on the wound surface in the form of a square with an area of 3×3 mm. The wound surface was sharply excised in the central and peripheral zones of the injury. The excision was performed at the border between necrotic and healthy tissue, and in the central areas of the wound with partial involvement of subcutaneous adipose tissue. After fixing the tissue in 10% neutral formalin in phosphate buffer (pH 7.2-7.4), the material was passed through alcohols of increasing concentration and embedded in paraffin according to the method of Z. Loyd et al. (1982). Serial slicing at a thickness of 4-5 μm was made on a rotary microtome "HM 360" (MICROM). The resulting sections were stained with H&E using a Robot stainer HMS 760X (MICROM). The study of micropreparations to determine the qualitative changes in the microstructure was carried out on a microscope "Axiostar" (ZEISS).

Statistical evaluation

The effectiveness of the treatment was evaluated based on morphological criteria of the degree of activity of pathological processes such as dystrophy, necrosis, stages of inflammation (alteration, exudation, proliferation), and the onset of reparative regeneration by the terms of complete epithelialization of burn wounds.

Statistical calculations were performed using Microsoft Excel 2016 software, including built-in functions of statistical processing. The significance of differences between groups of quantitative parameter values was determined by the Student's criterion. Statistical statements were considered significant when p <0.05.

Results

In group 1, an active surgical intervention and early treatment with allogeneic dermal fibroblasts in the wound bed were used. Necrotic and necrobiotic processes with massive infiltration of segmented and neutrophilic leukocytes were registered in all layers on the 12th day after injury.

Foci of immature granulation tissue were found in the upper layers of the dermis. The most pronounced changes were found in the central zone. In the peripheral sections, similar changes were detected only in a small segment of the sample. The maximum damage affected the epidermis and the upper sections of the upper dermis (Fig. 1).

Khadjibayev-fig01.jpg

Figure 1. Active surgical intervention (ASI) with the injection of allofibroblasts, 12 days (H&E staining). Ocular, 10x; objective 10x. A, Central zone with epithelial necrosis and granulation tissue in the dermis. B, Peripheral zone with necrosis of the epithelium

On day 20, the elements of necrotic epidermis with massive inflammatory infiltration were still detected in the central zone, but these areas occupied a smaller area compared with day 12.

In superficial sections of dermis, we observed granulation tissue at varying maturity grades; in the deep sections, loose fibrous connective tissue with a network of capillaries. In peripheral zones, the areas of necrosis with granulation tissue were detected in the superficial parts of dermis. In the deep layers of the dermis, we found interstitial edema, growth of fibrous connective tissue, while inflammatory infiltration was practically absent (Fig. 2).

Khadjibayev-fig02.jpg

Figure 2. ASI with the injection of allofibroblasts, 20 days, H&E staining. Ocular, 10x; objective,10x. A, Central zone with epithelial necrosis and granulation tissue in the dermis. B, Peripheral zone with similar local lesions

On day 30, necrotic tissue was virtually not detectable in the central zone. In the superficial layers of the dermis, the growth of mature granulation and connective tissue was determined. In some samples, the development of a "neoepidermis" containing 1-2 layers of squamous epithelium was noted.

Samples from the peripheral portions of the wounds were represented by structure-preserving stratified squamous epithelium with signs of epidermal dystrophy, fields of loose fibrous tissue, and areas of squamous epithelium formation (Fig. 3).

Khadjibayev-fig03.jpg

Figure 3. ASI combined with the injection of allofibroblasts, 30 days. H&E staining. Ocular 10x; objective 40x. A. Central area with a focus of squamous epithelium formation arrows. B. Peripheral area with a focus of squamous epithelium formation.

In group 2, when using conventional surgical tactics (CST) and the later injection of allogeneic dermal fibroblasts, on the 12th day after injury, massive necrosis of all skin layers was noted in the samples from the central zone of the wound. In this case, there was a complete absence of inflammatory infiltration in necrotic masses, as well as colonies of microorganisms observed in the surface areas of the necrotic epidermis.

Only in some samples from the deep parts of the dermis and hypodermis there are zones with preserved structure and foci of mononuclear infiltration. The peripheral areas in the main portion of the samples exhibited similar changes (Fig. 4).

Khadjibayev-fig04.jpg

Figure 4. CST with injection of allogeneic fibroblasts, 12 days. H&E staining. Ocular, 10x; objective, 10x. A. Central area with necrosis of all skin layers with colonies of microorganisms. B. Peripheral area of the lesion with necrosis of all skin layers

On the 20th day in group 2, massive infiltration of necrotic tissue with neutrophilic cells and segmented leukocytes was found in epidermis of the central area. In adjacent sections of the dermis, we found subepithelial vacuoles that exfoliate from epidermis, fields of immature and foci of mature granulation tissue. In peripheral zones of the epidermis, we observed necrotic changes and inflammatory infiltration; in the dermis, foci of granulation tissue. In the arterial vessels of the dermis of individual samples obtained from the central and peripheral zones, thrombotic masses are detected (Fig. 5).

Khadjibayev-fig05.jpg

Figure 5. CST with the injection of allofibroblasts, 20 days. H&E staining. Ocular, 10x; lens, 10x. A. Central area with necrosis of all layers with inflammatory infiltration B. Peripheral area with necrosis of all layers with inflammatory infiltration

On day 30, in all samples of both the central and peripheral zones, fields of necrotic epithelium, diffuse inflammatory infiltration, fields of immature and mature granulation tissue are determined (Fig. 6).

Khadjibayev-fig06.jpg

Figure 6. CST combined with injection of allofibroblasts, 30 days. H&E staining. Ocular, 10x; lens 10x. A. Central zone with necrosis of all layers with inflammatory infiltration B. Peripheral zone with necrosis of the epithelium and granulation tissue in the dermis

In the 3rd group of animals, upon ASI and treatment with MSCs on the 12th day after injury, no stratified squamous epithelium was observed in the central area of the burn wound, there is a wide zone of edema with a narrow strip of moderate leukocyte infiltration.

There is a slight edema in the dermis, many dilated capillaries, and a moderate inflammatory infiltrate. In the peripheral parts of the burn wound, there was a zone of necrotic epithelium, underlied with a narrow strip of leukocyte infiltration, separating necrotic masses from the dermis. In some areas, tissue detritus was noted, with elements of exfoliated squamous epithelium and a zone of granulation tissue (Fig. 7).

Khadjibayev-fig07.jpg

Figure 7. ASI with the injection of MSCs, 12 days. H&E staining. Ocular, 10x; lens 10x. A. Central area of the lesion. Tissue edema is noted. Tissue detritus is seen on the surface of the lesion with leukocyte infiltration. There is a moderate inflammatory infiltrate in the dermis. B. Peripheral zone with tissue detritus, elements of stratified squamous epithelium and granulation tissue in the dermis

On the 20th day, a wide edematous zone with massive infiltration of neutrophilic and segmented leukocytes is determined in the central zone of the wound, forming a demarcation zone that separates the dermis from the damaged surface. In separate areas free from leukocyte infiltration, the formation of a cubic epithelium on the surface of the dermis is detected.

In the deeper parts of dermis, mature granulation tissue is determined with an abundance of full-blooded vessels, moderate leukocyte infiltration. In peripheral area, we detected foci of necrosis with leukocyte infiltration, zones of ingrowing stratified squamous epithelium onto the damaged area from the peripheral areas (Fig. 8).

Khadjibayev-fig08.jpg

Figure 8. ASI with the injection of MSCs, 20 days. H&E staining. Ocular, 10x; objective, 40x. A, Central lesion area. Formation of stratified squamous epithelium on the wound surface. B, Peripheral area. Ingrowth squamous epithelium from the peripheral zone

On the 30th day, in the central area of the burn wound, a stratified squamous epithelium of various thicknesses was noted, with formation of skin appendages located in the edematous stroma. In the cases with formation of stratified squamous epithelium in dermal areas, loose fibrous tissue is observed to the full thickness of the preparation. In adjacent sections of dermis, small areas of mature granulation tissue are detected. In peripheral areas, a moderately pronounced edema was determined, the surface was replaced by a stratified squamous epithelium. In the underlying dermis, loose fibrous tissue was observed with immersion of squamous epithelial foci (Fig. 9).

Khadjibayev-fig09.jpg

Figure 9. ASI with the injection of MSCs, 30 days. H&E staining. Ocular, 10x; lens 10x. A. Central area of the lesion. Formed stratified squamous epithelium with granulation tissue in the dermis. B. Peripheral area. Formed squamous epithelium and appendages in the edematous stroma

When using conventional surgical treatment with the injection of MSCs in the 4th group of animals on the 12th day in the central area of the burn wound, we revealed wide areas of tissue detritus with leukocyte infiltration covering the dermis, with underlying extensive areas of hemorrhages. In peripheral zones, extensive fields of necrosis of the stratified squamous epithelium with inflammatory infiltration are revealed. In the underlying dermis, the formation of granulation tissue is seen (Fig. 10).

Khadjibayev-fig10.jpg

Figure 10. CST combined with injections of MSCs, 12 days. H&E staining. Ocular, 10x; lens 10x. A, Central area of the lesion. Tissue detritus with leukocyte infiltration and areas of hemorrhage in the dermis. B, Peripheral area. Tissue detritus with leukocyte infiltration

On the 20th day, extensive areas of tissue detritus with a wide area of leukocyte infiltration, which penetrates into the underlying dermis, are determined in the central zone. In some areas, small foci of the formation of stratified squamous epithelium are noted. In the peripheral zone, extensive zones of sloughing tissue detritus with colonies of microorganisms are determined. Also, there are areas of naked dermis covered with fields of hemorrhages. Granulation tissue is visualized in the dermis (Fig. 11).

Khadjibayev-fig11.jpg

Figure 11. CST with the injection of MSCs, 20 days. H&E staining. Ocular, 10x; lens 10x. A. Central area of the lesion. Tissue detritus with leukocyte infiltration extending to the dermis. B. Peripheral area. Destroyed tissue detritus with colonies of microorganisms

On the 30th day, the dermis structures are determined in the central areas, being covered with a wide zone of tissue detritus with leukocyte infiltration of varying intensity. In some areas on the surface of the dermis, a narrow strip of the emerging squamous epithelium is determined. In the peripheral part of lesion, zones of necrosis of stratified squamous epithelium still remained, with massive leukocyte infiltration and colonies of microorganisms. There are also zones with germination of squamous epithelium from hair follicles and adjacent parts of the epidermis to the surface of the dermis (Fig. 12).

Khadjibayev-fig12.jpg

Figure 12. CST with the injection of MSCs, 30 days. H&E staining. Ocular, 10x; lens 10x. A. Central lesion area. Foci of formation of stratified squamous epithelium. B. Peripheral area. Foci of formation of stratified squamous epithelium from adjacent hair follicles and adjacent parts of the skin

Table 1. Mean epithelization terms of burn wounds in the studied animals (M±m)

Khadjibayev-tab01.jpg

Table 1 presents the time frame for complete epithelialization of burn wounds with different approaches to surgical treatment and the use of allogeneic dermal fibroblasts or mesenchymal stem cells of adipose tissue.

In a study comparing active surgical intervention with conventional surgical tactics (both, with usage of allogeneic dermal fibroblasts), the time for wound epithelialization was 30.8±0.4 days and 32.6±0.24 days, respectively. In the group of animals treated with active surgical intervention and the use of MSC, the time for complete epithelization of burn wounds was 28.0±0.32 days, while in the group treated with conventional surgical tactics and the use of MSC, this time period was 29.6±0.40 days.

Discussion

The results of the study conducted by Ahmadpour F. et al. [18] demonstrate that the use of fibroblast exosomes significantly accelerates wound healing in a rat skin ulcer model in the experiment. This proves that the use of both exosomes and fibroblasts themselves is a promising direction in wound treatment.

In the study group when using active surgical tactics and early injection of allogeneic dermal fibroblasts, early formation of immature granulation tissue (day 12), mature granulation tissue (day 20) and the formation of small neoepithelial foci (day 30) both in the central and in peripheral areas. It is noteworthy that tissue repair is more intensive in the zone of deep dermis with a decrease in the intensity of repair in superficial areas. In the group with the use of conventional surgical tactics and the later injection of allogeneic dermal fibroblasts, a pronounced slowdown in the course of the stages of inflammation is determined. On the 12th day, only tissue necrosis and colonies of microorganisms are determined. The release of inflammatory cells into the affected area begins after 12 days, reaching a pronounced degree by the 20th day. By 30 days, the burn wound is almost completely cleared of necrotic tissues. In all parts of the dermis, there is a pronounced inflammatory infiltrate and granulation tissue begins to form in the form of separate foci. Changes in the central and peripheral parts of the affected tissue have a similar microscopic picture.

A microscopic examination performed in two groups using allogeneic dermal fibroblasts revealed a significant difference in the course of the wound process in the affected area. AChT and early injection of allofibroblasts promotes earlier epithelialization of the wound surface with the onset of neoepithelial foci formation by 30 days after injury. With the use of CST with later use of allofibroblasts, the wound surface is seeded with colonies of microorganisms and the course of inflammatory and reparative processes is slowed down. And if in the ASI group on the 30th day foci of the formation of "neoepidermis" are already determined, then in the CST group by the 30th day necrotic masses with a pronounced inflammatory infiltration are still determined on the wound surface, and only in some area’s granulation tissue begins to form.

Mesenchymal stem cells (MSCs) represent a population of stem cells which may originate from various tissues other than skin. They are able to migrate and exhibit paracrine, trophic, and immunomodulatory effects, which makes them useful in clinical practice [19, 20]. In the treatment of burn wounds, MSCs obtained from adipose tissue are preferred due to their availability, simplicity of isolation procedure, and more pronounced stimulating properties of healing processes [21].

Earlier injection of MSCs with an active surgical treatment contributes to high reparative activity in the area of the wound surface. Starting from the 12th to the 20th day after the injection of the cell suspension, against the background of a pronounced inflammatory infiltration, not only the foci of granulation tissue are determined, but the zones of the formation of stratified squamous epithelium. By the 30th day, this process ends with complete epithelialization of the damaged area with well-formed stratified squamous epithelium and skin appendages. This process proceeds more actively in the peripheral zones of the wound. A conservative approach to surgical treatment, the relatively late injection of MSCs into the wound bed showed that the cleansing of the wound from necrotic tissues is delayed on the 12th and 20th days in the central zone of the wound surface, and massive inflammatory infiltration is present. Peripheral areas exhibit foci of granulation tissue formation in presence of similar inflammatory infiltration and seeding of the wound with microorganisms. By the 30th day, zones of tissue detritus with inflammatory infiltration continue to persist in the central and peripheral zones, especially in the central areas. Foci of stratified squamous epithelium are formed, mainly, in the peripheral regions.

An active approach to surgical treatment in combination with the injection of MSCs in the experiment revealed a high degree of regenerative processes with complete restoration of the stratified squamous epithelium in the damaged area by 30 days. The formation of the epithelium was detected already on the 12th day both in the central and in the peripheral areas. Regenerative processes proceeded more actively in the peripheral parts of the wound. Despite the use of MSCs with a conservative approach to surgical treatment, we revealed an increased duration of the inflammatory process with delayed wound cleansing from necrotic tissue with microbial colonization. In contrast to the animals of the 3rd group (ASI), by the 30th day, the formation of foci of stratified squamous epithelium had just begun in the affected area, mainly in peripheral areas of the wound.

Conclusion

In summary, when using allogeneic dermal fibroblasts and MSCs against the background of active surgical management, an accelerated course of reparative processes was noted. However, the use of allofibroblasts by the 30th day was associated only with development of neoepithelial foci, while the use of MSCs during this period showed a complete restoration of the structure of the skin and its appendages. The worst results were obtained when using the conventional surgical tactics of treatment, despite the injection of allofibroblasts and MSCs. In both groups, there was an increase in the timing of inflammatory and reparative processes. However, usage of allofibroblasts by 30 days only led to appearance of granulation tissue. Following injections of MSCs, not only granulation tissue was revealed, but also the foci of developing epithelial tissue. A more active formation of epithelium was detected in the peripheral areas due to growth of epithelial cells from the preserved skin and hair epithelium.

Conflict of interest

The authors declare no conflict of interest.

References

  1. Burns [Electronic resource]: World Health Organization. URL: https://www.who.int/ru/news-room/fact-sheets/detail/burns
  2. Yakupu A, Zhang J, Dong W, Song F, Dong J, Lu S. The epidemiological characteristic and trends of burns globally. BMC Public Health. 2022; 22: 1596. doi: 10.1186/s12889-022-13887-2
  3. Lumenta DB, Kamolz LP, Frey M. Adult burn patients with more than 60% TBSA involved - Meek and other techniques to overcome restricted skin harvest availability - the Viennese concept. J Burn Care Res. 2009; 30(2): 231-242. doi: 10.1097/BCR.0b013e318198a2d6
  4. Peck M, Pressman MA. The correlation between burn mortality rates from fire and flame and economic status of countries. Burns. 2013; 39(6): 1054-1059. doi: 10.1016/j.burns.2013.04.010
  5. Hayashi M, Yoshitake K, Tokunaka R, Yoshida Y, Oshima M, Tatsuta S, et al. Combination of meshed dermis graft and cultured epithelial autograft for massive burns. Medicine (Baltimore). 2018; 97(48): 13313. doi: 10.1097/MD.0000000000013313
  6. Stone RII, Natesan S, Kowalczewski CJ, Mangum LH, Clay NE, Clohessy RM, et al. Advancements in regenerative strategies through the continuum of burn care. Front Pharmacol. 2018; 9: 672. doi: 10.3389/fphar.2018.00672
  7. Medawar PR. The cultivation of adult mammalian skin epithelium in vitro. Quart J Microsc Sci. 1948; 89: 187-196.
  8. O’Connor NE, Mulliken JB, Banks-Schleger S, Kehinde O, Green H. Grafting of burns with cultured epithelium prepared from autologous epidermal cells. Lanсet. 1981; 1: 75-78. doi: 10.1016/S0140-6736(81)90006-4
  9. Karimi M, Bahrami S, Mirshekari H, Basri SMM, Nik AB, Aref AR, et al. Microfluidic systems for stem cell-based neural tissue engineering. Lab on a Chip. 2016; 16: 2551-2571. doi: 10.1039/c6lc00489j
  10. Weng T, Wu P, Zhang W, Zheng Y, Li Q, Jin R, et al. Regeneration of skin appendages and nerves: current status and further challenges. J Transl Med. 2020; 18(1): 53. doi: 10.1186/s12967-020-02248-5
  11. Jahromi MAM, Zangabad PS, Basri SMM, Zangabad KS, Ghamarypour A, Aref AR, et al. Nanomedicine and advanced technologies for burns: Preventing infection and facilitating wound healing. Adv Drug Deliv Rev. 2018; 123: 33-64. doi: 10.1016/j.addr.2017.08.001
  12. Zinoviev EV, Krainyukov PE, Asadulaev MS, Kostyakov DV, Wagner DO, Krylov PK. Clinical evaluation of the effectiveness of mesenchymal stem cells in thermal burns. Bulletin of N. I. Pirogov National Medical and Surgical Center. 2018; 13(4): 62-67 (In Russian). doi: 10.25881/BPNMSC.2018.88.91.011
  13. Li Y, Xia WD, Van der Merwe L, Dai WT, Lin C. Efficacy of stem cell therapy for burn wounds: A systematic review and meta-analysis of preclinical studies. Stem Cell Res Ther. 2020; 11: 322. doi: 10.1186/s13287-020-01839-9
  14. Yi H, Wang Y, Yang Z, Xie Z. Efficacy assessment of mesenchymal stem cell transplantation for burn wounds in animals: A systematic review. Stem Cell Res Ther. 2020; 11: 372. doi: 10.1186/s13287-020-01879-1
  15. Surowiecka A, Chrapusta A, Klimeczek-Chrapusta M, Korzeniowski T, Drukała J, Strużyna J. Mesenchymal stem cells in burn wound management. Int J Mol Sci. 2022; 23(23): 15339. doi: 10.3390/ijms232315339
  16. Francis MP, Sachs PC, Elmore LW, Holt SE. Isolating adipose-derived mesenchymal stem cells from lipoaspirate blood and saline fraction. Organogenesis. 2010; 6(1): 11-14. doi: 10.4161/org.6.1.10019
  17. Zuk PA, Min Zhu, Mizuno H. Multiline age cells from human adipose tissue: implications for cell-based therapies. Tissue Engineering. 2001; 7(2): 211-228. doi: 10.1089/107632701300062859
  18. Ahmadpour F, Rasouli HR, Talebi S, Golchin D, Esmailinejad MR, Razie A. Effects of exosomes derived from fibroblast cells on skin wound healing in Wistar rats. Burns. 2023; 49(6): 1372-1381. doi: 10.1016/j.burns.2023.02.003
  19. Ichiro MS, Ishikawa O. Mesenchymal stem cells: the roles and functions in cutaneous wound healing and tumor growth. J Dermatol Sci. 2017; 86: 83-89. doi: 10.1016/j.jdermsci.2016.11.005
  20. Malgieri A, Kantzari E, Patrizi MP, Gambardella S. Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art. Int J Clin Exp Med. 2010; 3(4): 248-269. PMCID: PMC2971538
  21. Chang YW, Wu YC, Huang SH, Wang HD, Kuo YR, Lee SS. Autologous and not allogeneic adipose-derived stem cells improve acute burn wound healing. PLoS One. 2018; 13(5): e0197744. doi: 10.1371/journal.pone.0197744

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["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"]=> 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(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"]=> 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) "30834" ["VALUE"]=> array(2) { ["TEXT"]=> string(513) "<p>Абдухаким М. Хаджибаев<sup>1</sup>, Даврон Б. Туляганов<sup>1</sup>, Абдулазиз Д. Фаязов<sup>1</sup>, Татьяна А. Вервекина<sup>1</sup>, Маиса Д. Уразметова<sup>1</sup>, Уткур Р. Камилов<sup>1</sup>, Оксана С. Чарышникова<sup>2</sup>, Наргиза А. Циферова<sup>2</sup> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(405) "

Абдухаким М. Хаджибаев1, Даврон Б. Туляганов1, Абдулазиз Д. Фаязов1, Татьяна А. Вервекина1, Маиса Д. Уразметова1, Уткур Р. Камилов1, Оксана С. Чарышникова2, Наргиза А. Циферова2

" ["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) "30835" ["VALUE"]=> array(2) { ["TEXT"]=> string(466) "<p><sup>1</sup> Республиканский научный центр экстренной медицинской помощи, Ташкент, Республика Узбекистан<br> <sup>2</sup> Центр передовых технологий при Министерстве высшего образования, науки и инноваций, Ташкент, Республика Узбекистан</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(424) "

1 Республиканский научный центр экстренной медицинской помощи, Ташкент, Республика Узбекистан
2 Центр передовых технологий при Министерстве высшего образования, науки и инноваций, Ташкент, Республика Узбекистан

" ["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) "30836" ["VALUE"]=> array(2) { ["TEXT"]=> string(2928) "<p style="text-align: justify;">Одним из основных вопросов современной комбустиологии остается поиск оптимальных методов восстановления эпителиального покрова при лечении больных с обширными глубокими ожогами. Разработка методов культивирования и применения стволовых клеток открывает новые перспективы в лечении тяжелообожженных больных. Данная статья посвящена изучению применения аллогенных дермальных фибробластов и мезенхимальных стволовых клеток жировой ткани в эксперименте. Представлены результаты применения аллогенных дермальных фибробластов и мезенхимальных стволовых клеток на фоне активной и традиционной хирургической тактики в лечении модели ожога у лабораторных животных (крыс). При применении аллогенных дермальных фибробластов и МСК на фоне активного хирургического ведения отмечено ускоренное течение репаративных процессов. При этом применение МСК показывает значительно высокую эффективность за счет стимуляции репаративных процессов. При применении традиционной хирургической тактики, несмотря на введение аллофибробластов и МСК, получены худшие результаты. Отмечалось вялое течение воспалительных и репаративных процессов. Однако, в этих группах тоже получены данные, свидетельствующие о более выраженном стимулирующем воздействии МСК, по сравнению с применением аллогенных фибробластов. Более активные репаративные процессы отмечены в периферических участках ожоговых ран.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Ожоги, клеточные технологии, аллофибробласты, мезенхимальные стволовые клетки, раневой процесс, эксперимент.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2872) "

Одним из основных вопросов современной комбустиологии остается поиск оптимальных методов восстановления эпителиального покрова при лечении больных с обширными глубокими ожогами. Разработка методов культивирования и применения стволовых клеток открывает новые перспективы в лечении тяжелообожженных больных. Данная статья посвящена изучению применения аллогенных дермальных фибробластов и мезенхимальных стволовых клеток жировой ткани в эксперименте. Представлены результаты применения аллогенных дермальных фибробластов и мезенхимальных стволовых клеток на фоне активной и традиционной хирургической тактики в лечении модели ожога у лабораторных животных (крыс). При применении аллогенных дермальных фибробластов и МСК на фоне активного хирургического ведения отмечено ускоренное течение репаративных процессов. При этом применение МСК показывает значительно высокую эффективность за счет стимуляции репаративных процессов. При применении традиционной хирургической тактики, несмотря на введение аллофибробластов и МСК, получены худшие результаты. Отмечалось вялое течение воспалительных и репаративных процессов. Однако, в этих группах тоже получены данные, свидетельствующие о более выраженном стимулирующем воздействии МСК, по сравнению с применением аллогенных фибробластов. Более активные репаративные процессы отмечены в периферических участках ожоговых ран.

Ключевые слова

Ожоги, клеточные технологии, аллофибробласты, мезенхимальные стволовые клетки, раневой процесс, эксперимент.

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Abdukhakim M. Khadjibayev1, Davron B. Tulyaganov1, Abdulaziz D. Fayazov1, Tat'yana A. Vervekina1, Maisa D. Urazmetova1, Utkur R. Kamilov1, Oksana S. Charishnikova2, Nargiza A. Tsiferova2

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1 Republican Research Center of Emergency Medicine, Tashkent, Republic of Uzbekistan
2 Center of Advanced Technologies, Ministry of Higher Education, Science and Innovation, Tashkent, Republic of Uzbekistan


Correspondence:
Dr. Abdukhakim M. Khadjibayev. Republican Research Center of Emergency Medicine, Kichik halqa yo'li, 2100107, Tashkent, Republic of Uzbekistan
Phone: +998 (71) 150-46-00
Fax: +998 (71) 150-46-01
E-mail: uzmedicine@mail.ru


Citation: Khadjibayev AM, Tulyaganov DB, Fayazov AD et al. Morphological features of the wound process after skin burns when using cellular technologies in an experimental model. Cell Ther Transplant 2023; 12(3): 50-59." ["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) "30840" ["VALUE"]=> array(2) { ["TEXT"]=> string(1635) "<p style="text-align: justify;">One of the main questions in modern combustiology remains the search for optimal methods for restoring the epithelial cover in the treatment of patients with extensive deep burns. The development of methods for culturing and using stem cells opens up new prospects in the treatment of severely burned patients. This article is devoted to the study of the use of allogeneic dermal fibroblasts and mesenchymal stem cells of adipose tissue in an experiment. The results of the use of allogeneic dermal fibroblasts and mesenchymal stem cells against the background of active and traditional surgical tactics in the treatment of a burn model in laboratory animals – rats are presented. When using allogeneic dermal fibroblasts and MSCs against the background of active surgical management, a more accelerated course of reparative processes was noted. At the same time, the use of MSCs shows significantly higher efficiency due to the stimulation of reparative processes. When using traditional surgical tactics, despite the introduction of allofibroblasts and MSCs, worse results were obtained. A sluggish course of inflammatory and reparative processes was noted. However, in these groups, data were also obtained indicating a more pronounced stimulating effect of MSCs compared to allogeneic fibroblasts. More active reparative processes were noted in the peripheral areas of burn wounds.</p> <h2>Keywords</h2> <p style="text-align: justify;"> Burns, cellular technologies, allofibroblasts, mesenchymal stem cells, wound process, experiment.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1579) "

One of the main questions in modern combustiology remains the search for optimal methods for restoring the ep