ISSN 1866-8836
Клеточная терапия и трансплантация
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Introduction

Iron takes part in several metabolic processes, including DNA synthesis, oxygen and electron transport. Most of the iron in human body is distributed within hemoglobin (65%; 2300 mg). Ca. 10% is present in muscles and other tissues, e.g., liver (200 mg), macrophages (500 mg), and bone marrow (150 mg) [23].

Ferritin is the main iron storage molecule. It makes ferrous ions available for critical cellular processes, while protecting lipids, DNA and proteins from potentially toxic effects of free iron. Increased iron load may, however, saturate the available transferring pool and lead to excessive levels of non-transferrin- bound iron which may be subsequently captured and stored either within ferritin, or hemosiderin molecules [14].

Therefore, serum ferritin is considered a simple and widely used surrogate marker for IO. However, many confounding factors, particularly in HCT recipients, may result in potential IO overestimation. E.g., inflammation, infections, liver damage and GvHD may also lead to elevated serum ferritin levels [21]. Repeated serum ferritin measurements can reveal potential causes and help to establish a general pattern of the iron overload over time.

On the basis of serum ferritin levels, the diagnosis of iron overload has been reported in up to 88% of long term HSCT survivors. When liver iron content is assessed by MRI technique, the prevalence of iron excess is reported to be 32% in allo-HCT recipients who survived 1 year or more following HCT [19].

The adverse impact of IO on the HSCT outcome was first demonstrated in thalassemia patients [10]. In MDS patients, a transfusion dependency was considered a prognostic factor in WHO classification–based Prognostic Scoring System (WPSS) and independently associated with reduced OS and increased NRM [1].

Different workers have presumed an iron overload to be a risk factor for clinical complications in HCT recipients, including higher occurrence of mucositis [3], increased infection rates [2, 7, 12, 15, 25], liver functions abnormality [9], GvHD severity [18, 6], and non-relapse mortality [4].

Hence, the aim of our single-center study was to confirm previous reports and assess a predictive value of the baseline ferritin levels for different early complications of HSCT procedure.

Patients and methods

We have retrospectively evaluated a group of ninety-one consecutive patients undergoing unmanipulated allo-HCT in R.M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation at the St. Petersburg Pavlov State Medical University, St. Petersburg, between 01/01/2013 and 03/09/2014. The inclusion criteria were as follows: (1) First allo-HCT from HLA-compatible related, unrelated or haplo-identical donors; (2) Primary malignant, or non-malignant disease; (3) Age: 5 to 60 years; (4) Karnofsky performance status ≥70 %.

The cohort included 42 men and 49 women with a median age at transplantation of 31.6 (range, 5 to 60) years. Underlying diseases were acute myeloid leukemia (n=68), myelodysplastic syndrome (n=10), myeloproliferative neoplasms (n=4; Primary myelofibrosis =3, Chronic myelomonocytic leukemia=1), bone marrow failure (n=7; Aplastic anemia=6, Fanconi anemia=1) and B-thalassemia major (n=2). Stem cell transplants were from (HLA)-identical siblings (n=16), haplo-identical (n=6), or unrelated volunteer donors; (n=69).

The conditioning regimens were myeloablative (MAC) in 26 patients, or reduced-intensity (RIC) in the rest of this group.

The follow-up period was 100 days after allo-HCT. Baseline characteristics of the patients are given in Table 1. We evaluated the effects of high pre-allo-HCT serum ferritin on early toxic, infectious and other complications, as well as early transplant outcomes.

Table 1. Patients baseline characteristics
Table 1. Patients baseline characteristics

The study was approved by the Institutional Review Board at the First St.Petersburg State Pavlov Medical University. Each patient has given an informed consent for the use of personal data.

The study cohort was divided into 2 groups, those with high versus low ferritin concentration (resp. HF and LF groups), on the basis of a 500-ng/mL threshold for increased ferritin concentration. Mucositis was graded on a scale of 0 to 4, according to Common Toxicity Criteria, version 4, from the National Cancer Institute. The International EORTC/MSG Consensus on opportunistic fungal infections (FI) was used for diagnosis of FI [5]

Bacterial infection was defined as recovery of a recognized pathogen from, at least, 2 different sites for 100 Days post- HCT (Data Form 2100). Recovery of neutrophils was blood or urine cultures yielding the same organism. For each patient, the numbers of bacterial, viral and fungal infections were calculated, according to CIBMTR registered when reaching the ANC numbers of >500/μL for the first 3 consecutive days. Acute graft-versus-host disease (aGvHD) was graded according to Gratwohl criteria [11]. A diagnosis of sinusoidal obstruction syndrome (hepatic veno-occlusive disease) was made on the basis of Seattle criteria, as described by McDonald et al [17].

Continuous variables in the 2 groups were compared by means of the Mann-Whitney test. Categorical variables were compared using the Chi-square test. Overall survival and transplant-related mortality were calculated, using the Kaplan-Meier method. Possible risk factors were tested using the log-rank test. Cutoff levels of ferritin amounts were determined using ROC- analysis. The calculations were made with SPSS.19.

Results

Fifty-three (58%) patients with increased serum ferritin concentrations (≥500 ng/mL) were classified as the high-ferritin group (HF), with a median of 1148 ng/mL (range, 650-4247). The rest of patients (n=38, 41.76%) were classified as LF group, and had serum ferritin concentrations (<500 ng/mL) with a median ferritin level of 232 (range, 12.1-466.3 ng/mL).

Active infections within last month prior to HCT were observed only in HF group, including 8 patients with probable invasive pulmonary aspergillosis; 2 cases of soft tissue infection; purulent sinusitis in 2 patients and fever of unknown origin in 2 cases, with a median ferritin level of 1057 ng/mL (606-1875). Hence, fungal infections prevailed among total infections by the date of allo-HCT, and 26.14% of patients in HF group with increased ferritin levels (P= 0.001; [OR], 0.73; 95% confidence interval [CI], 0.62–0.86).

Early complications of allogeneic-HCT

Mucositis

Post-transplant mucositis was observed in seventy patients: 28 (52%) in HF and 19 (50%) in LF group had mucositis grade I-II (P>0.05). 11(21%) in HF group versus 12 (32%) among LF patients had mucositis grade III-IV. No statistical differences were observed between the two groups (P>0.05).

Febrile neutropenia

Febrile neutropenia was observed in sixty-seven cases: 42 (79%) in HF vs 23 (60%) in LF group (P > 0.05). Despite the lack of a significant difference between the groups, we revealed a near-linear correlation between the numbers of febrile neutropenia episodes and increase in the mean ferritin levels (Fig. 1). The median for HF group was 1.5 febrile episodes/patient (0 to 6) vs 0.84 (0 to 3) in LF patients [P = 0.005; OR, 4.08; 95% (CI), 1.46–11.42] (Fig.2). Accordingly, the number of patients who required granulocyte colony- stimulating factor (G-CSF) injections in order to boost hematopoiesis and to shorten neutropenic period was: 25 (47%) vs 7(18%) in the HF and LF groups, respectively [P =0.005; (OR), 0.25 ; 95%(CI), (0.09–0.67)].

Figure 1. Pre-transplant serum ferritin levels before HSCTin the patients with different numbers of febrile neutropeniaepisodes posttransplant. Ordinate, mean ferritinlevels (ng/mL, M+m). The trend is significant by P=0.005.

Figure 1. Pre-transplant serum ferritin levels before HSCT in the patients with different numbers of febrile neutropenia episodes posttransplant. Ordinate, mean ferritin levels (ng/mL, M+m). The trend is significant by P=0.005.


Bacterial infections

Although the percentage of patients with developing bacterial infections was similar in both H F and LF groups (resp., 88.64%, 84.2%), there was a distinct correlation between the increased pre-HCT ferritin and median number of infectious episodes/ patient, i.e., 2.7 (0 to 7) in HF group, and 2.0 (0 to 6) in LF sample [P=0.009; (OR), 3.2; 95%(CI), (1.31–7.77)]. Incidence of febrile neutropenia and septicemia post-transplant was more frequent in the HF group (n=20; 30%) vs LF patients (n=8; 13%), at a marginal statistical difference (P>0.05), as shown in Fig. 1.

Figure 2 Association between pre allo-HCT serum ferritinand febrile neutropenic and infectious complicationsafter allo-HCT Abscisse, groups with differentpost-HCT compliations; Ordinate, number of febrileneutropenic episodes (median + range).

Figure 2 Association between pre allo-HCT serum ferritin and febrile neutropenic and infectious complications after allo-HCT Abscisse, groups with different post-HCT compliations; Ordinate, number of febrile neutropenic episodes (median + range).


Mixed infections as causes of pneumonia were observed in a large proportion of patients (bacterial, fungal, and viral pathogens): 58.8% and 60% in HF and LF groups, respectively.

Fungal infections

In our cohort study, probable or proven fungal infections were observed in 9 patients (17%) from HF group (one patient had two episodes) and 3 patients (7.9%) in LF group, with no statistically significant difference (P > 0.05).

CMV infection

During the early period after allo-HCT, CMV reactivation was observed in 38 patients (42% of total), including 23(43%) in HF group, and 15(39%) in LF patients, without statistically significant difference (P>0.05). Likewise, no differences were found for incidence of other viral infections (BK, JC), respectively, 20.8% vs 21% in HF and LF groups.

Moreover, we had tested correlation between other clinical features, RBC parameters, and presence of CMV reactivation signs. There were no significant connections found between donor RBC blood antigens, or donor/recipient ABO mismatch, and post-transplant infectious complications. Meanwhile, presence of A antigen (blood group II or IV) in the patients showed a highly significant correlation with CMV reactivation (CMV infection positive in 63% (24/39) of A(+) patients versus 37% (14/51) in the group of A(-) patients (r= 0.342; P<0.01).

Fig. 2A. Dependence between RBC A antigen in recipientsand CMV reactivation rates in the studied group(n=91; p=0.003).

Fig. 2A. Dependence between RBC A antigen in recipients and CMV reactivation rates in the studied group (n=91; p=0.003).


Engraftment time

The median time of neutrophil reconstitution (≥ 500×109) and platelet engraftment (Plt ≥ 20×109) were, respectively, 22 days (13-43) and 18 days (10-41) in HF group, versus 19.5 days (11-36) and 16.2 days (11-36) in LF group (Fig. 2). A significant HF/LF difference was noted for neutrophil recovery (P=0.047). Interestingly, that was independent of the stem cell dose infused: 5.2 (1.3-14.1)×106 versus 4.84 (1.9-10.1)×106 in HF and LF. Intensity of conditioning regimens did not also affect the engraftment rates in our cohort: MAC/RIC: 26.4/73.6% and 29.5/71.5 % in HF and LF groups, respectively.

Fig. 2. Reconstitution of neutrophils and platelets in theinitially low- and high-ferritin groups (F> or <500 ng/mL). Abscisse: Designations for different sub-groups;ordinate: duration of the blood cell reconstitution, days.

Fig. 2. Reconstitution of neutrophils and platelets in the initially low- and high-ferritin groups (F> or <500 ng/mL). Abscisse: Designations for different sub-roups; ordinate: duration of the blood cell reconstitution, days.

Hepatic veno-occlusive disease

Only 4 cases were observed in total cohort: 3, in HF and 1, in LF groups.The pre-HCT ferritin levels in these cases were as follows: 4247, 1631, 827.3, 112 ng/mL, and one case with primary myelofibrosis had severe VOD with multiorgan failure, and died on D7+ after transplantation. We did not find any significant statistical difference between the two groups P > 0.05, due to minimal statistics.

Acute graft-versus-host disease

Acute GvHD was diagnosed in 24 patients (45.28%), and 18 (47.36%) in HF and LF, respectively. This difference was not statistically significant (P>0.2). A tendency was noted towards higher occurence of severe aGvHD (Stage III-IV), including hepatic form in HF group (ferritin≥500) (P=0.07). That supports a theory that hepatic iron overload may imitate and worsen hepatic aGvHD.

Pneumonia

Increasing incidence of pneumonia was observed, regardless of its causes, in the first group (ferritin ≥500 ng/mL) compared to the second group: 17 cases (30.2%) vs 5 cases (13.15%) in HF and LF, respectively (P=0.04, [OR], 0.33 ; 95%[CI], (0.11–0.99).

Hemorrhagic cystitis

Hemorrhagic cystitis was documented in 19 patients (20% of total) with a median incidence on day 32 (range, 1-73). The median ferritin level was 716 ng/ml (12 to 1631), being similar in the HF and LF groups: 11 (20.75%) vs 8 (21%) in HF and LF groups, respectively (P>0.05).

RBC transfusion requirements

Number of RBC units transfused was counted for each patient within 100 days post-HCT, and a linear correlation was revealed between the increased pre -HCT ferritin and the number of RBC transfusions. Median number of RBC units/patient was 8.6 units (0 to 36) and 3.1 units (0 to 27) in HF and LF groups P=0.04, [OR], 3.85 ; 95%[CI], (0.9–15), as shown in Fig. 3(a).

In the same context, ferritin concentration was recorded only in 14 patients between days 70-100 post allo-HCT. Median ferritin level in this group was 2420 ng/mL (417 to 6362), at a mean number of 10.3 units per patient transfused in these cases (0 to 26). Meanwhile, the median initial ferritin level in this group was 943.4 (98 to 1850). Thus, we can conclude that high ferritin levels at the 3rd month post-HCT in these cases may simply reflect an iron overload caused by multiple transfusions (1 RBC unit contains 200 to 250 mg Fe), as shown in the Fig. 3a and 3b.

Linear correlation between the increased ferritin concentration pre-HCT and the number of RBC units transfused over 100 days post-HCT   Steadily increased ferritin levels in group of patients (n=14) in whom ferritin amounts were recorded in the third month after HCT, median number of RBC units transfused in these cases was 10.3 units /patient (range, 0-26).

Fig. 3 (a). Linear correlation between the increased ferritin concentration pre-HCT and the number of RBC units transfused over 100 days post-HCT. (b) Steadily increased ferritin levels in group of patients (n=14) in whom ferritin amounts were recorded in the third month after HCT, median number of RBC units transfused in these cases was 10.3 units /patient (range, 0-26).


Early post-transplant mortality

Fifteen patients died during 100 days: 12 (23%) in HF, and 3 (8%) in LF group, without any significant difference (P>0.05). Significant difference in the mortality which occurred in pre- and post-engraftment was observed: 5 fatal outcomes (9.4%) were recorded only in HF group during the pre-engraftment period (P=0.003); resp., 8 cases (15.1%) and one case (2.6%) in HF and LF during 2nd month of post-engraftment (P=0.02). Treatment-related mortality (TRM) was observed in 7 cases, five of them (9 %), in HF, and two (5 %), in LF group (P>0.05). Hence, we did not find any relationship between the ferritin concentrations (at the cutoff level of 500 ng/mL), and mortality until the D+100. However, on the basis of ROC analysis, we assumed the general median to be the cutoff value (>773 ng/mL) for ferritin, and revealed a statistical difference for the mortality by D+100, i.e., 10 cases (27.7%) in group with high ferritin (≥773), and 5 lethal cases (9%) in the low-ferritin group (<773 ng/mL), P=0.02.

Day 100 cumulative survival and disease-free survival

With the cutoff ferritin concentration at 500 ng/mL (mean value of the sample), a significant statistical difference between two groups was not observed in the D100 cumulative survival and DFS: 77% and 62% in group 1 (ferritin ≥500) vs 89% and 76% in group2 (ferritin<500), respectively, (P > 0.05).

However, when we considered serum ferritin cutoff value of >773 ng/mL (the group median level), a significant statistical difference was observed. The D100 cumulative survival was 91% in group (F<773), vs 74% in HF group (P=0.04). D100 disease-free survival was 79% in group (F<773), versus 58% in group with high ferritin (F≥773), P=0.019. Hence, the pre- HSCT ferritin concentration at the over-median levels may be associated with lower OS and DFS, and could be considered as a risk factor (Fig. 4).

Fig. 4 Kaplan-Meier curves: D+100 cumulative survival and DFS in two groups at ferritin cutoff value of ≥ 773 ng/mL.

    Fig. 4 Kaplan-Meier curves: D+100 cumulative survival and DFS in two groups at ferritin cutoff value of ≥ 773 ng/mL.
Fig. 4 Kaplan-Meier curves: D+100 cumulative survival and DFS in two groups at ferritin cutoff value of ≥ 773 ng/mL.


Discussion

The main objective of present study was to assess a predictive role of pre-allo-HCT ferritin concentrations, as a surrogate marker of iron overload in early transplant-related complications and outcome. The 500-ng/mL cutoff for serum ferritin concentration is less than in most previously reported series [3,8]. Our results suggest that a relatively mild iron overload in HCT recipients may also have toxic consequences. We did observe that high initial ferritin was significantly associated with increasing incidence of febrile neutropenia and bacterial infectious episodes, incidence of pneumonia and increased numbers of RBC units transfused post-HCT. Moreover, at an adjusted cutoff levels of ferritin (≥ 773 ng/mL), we noted significant associations between the increased pre-HCT ferritin concentration and poor overall survival, disease-free survival and higher transplant-related mortality. An association between increased pre-HCT ferritin level and active infections, especially, pre-existing pulmonary aspergillosis, was statistically significant. Other common complications, including mucositis, acute GvHD and CMV infection, did not demonstrate significant associations with ferritin contents. Due to small number of VOD cases, we could not find significant relationship with increasing ferritin.

Iron overload is known to be associated with increased susceptibility to different infections. Iron deprivation was found to be the key factor in the antimicrobial host defense. E.g., Pullarkat et al. [22] showed in a group of 190 patients with hematological malignancies that developing severe infectious complications were significantly higher in the high-ferritin category (OR=1.99, Wald test P=0.032). In contrast, Sucak et al. [24] showed no significant effect of pre-HCT iron status on bacteremia was observed (P>0.05). In our study, we have found that elevated pre transplant ferritin (>500 ng/ mL) was associated with increasing number of febrile neutropenia episodes (P=0.005), bacterial infections (P=0.009). That may reflect a role of IO in severe immune defect and predisposition to recurrent bacterial infections. Therefore, high ferritin level, as a marker of general IO, seems to be a sufficient cofactor in severe transplant-associated infections.

Also, in accordance with recently published studies [26], we found a delayed engraftment and increased percentage of patients who required G-CSF stimulation in the HF group (P=0.005).

According to Sucak et al. [24] the pre-HSCT high ferritin concentration correlated with pneumonia in allogeneic HCT recipients, thus being consistent with our results, where increased ferritin level (≥500) pre-HSCT proved to be associated with increasing pneumonia incidence (P = 0.04). Interestingly, the cases of isolated bacterial pneumonia were also frequent in the group with high ferritin levels (≥500 ng/mL ) constituting 35.29% from causes of pneumonia in this group and this also confirms negative impact of iron overload in immunity, also as known bacteria need iron in their life cycle.

Some authors suggest a relationship between the pre-transplant ferritin levels and risk of invasive fungal infections (IFI) [2]. In contrast, other studies show that elevated serum ferritin (≥1000 ng/mL) was not a significant risk factor for IFI in a multivariate regression model after adjusting for aGvHD [7]. In our experience, there was a tendency for increased incidence of fungal infections among the patients with high ferritin concentration. However this group was too small for definite conclusions with no statistical significance (P>0.05).

There are conflicting results for relationship between acute GvHD and IO, while some studies suggest that the incidence of aGvHD was still associated with ferritin levels ≥1000 ng/ mL [22]. Another study has shown that ferritin levels over 1910 ng/mL correlate with a significantly lower incidence of acute GvHD, as well as limited and extensive chronic GvHD [18], thus supporting a hypothesis on suppressive effects of iron excess upon adaptive immune responses [6]. In our cohort, there was no correlation between a GvHD and elevated ferritin concentration pre-allo-HCT (P>0.05), but it was noted that there is a tendency for the occurrence of severe forms aGvHD III-IV, including the form of hepatic in the high-ferritin group, thus being in favor of a theory that hepatic iron overload may simulate or worsen hepatic aGvHD, since 90% of excessive iron is stored in the liver.

Several previous studies showed that elevated pre allo-HCT serum ferritin was an independent risk factor for SOS [20]. In our observation only 4 (4.3%) cases of VOD were diagnosed, with initial median ferritin level of 1704.3 ng/mL (112-4247). Low number of the VOD cases may be due to use of RIC and non-MAC conditioning regimens, and the use of heparin prophylaxis, thus making it impossible to perform valid statistical evaluation. Because of the small VOD incidence no significant statistical difference between the two groups was observed (P > 0.05).

We also observed that the patients with higher pre allo-HSCT ferritin levels required more blood transfusions than those in LF group. This may be attributed to presence of anti-RBC antibodies arising in heavily transfused patients [8] and to increasing incidence of febrile neutropenia and bacterial infections. Under the inflammatory conditions, hepcidin is secreted as a defensive mechanism, thus causing inhibition of iron release from its stores, thus preventing iron uptake for normal hematopoiesis and leading to slower recovery of erythroid lineage after HCT [2].

A number of previous studies, which used an indirect indicator of iron excess (serum ferritin) have found an association between the ferritin amounts and post-transplant survival using quite different threshold ferritin levels: F≥3000 [3]; F≥2515 [4]; F≥1910 [18]; F≥1000 [16]; F≥599 [13] ; F≥500 [24]. Moreover, a negative impact of elevated ferritin proved to be associated with reduced overall and disease-free survival. However, when the pre-transplant IO was measured with MRI, such differences were not observed. E.g., Trottier et al. [27] did not find any association between pre-transplant iron excess defined by R2-MRI measured LIC and OS, NRM, relapse rate or GvHD. Similar results have been reported by Armand et al [4]. In our study, we observed significant correlation between pre allo-HCT ferritin >773 ng/mL and increased mortality, reduced OS and DFS at the end of 100 days post HSCT.

In conclusion, in accordance with previous findings, we observed increased incidence of infectious complications and adverse impact on engraftment rates. Serum ferritin may be considered the easiest way to estimate IO, being the most widely used method. Since serum ferritin is an acute phase reactant, its elevation may simply mirror inflammatory conditions, including an advanced disease phase that is shown to influence the outcomes in hematologic patients receiving allo-HSCT. The issue, whether high iron burden contributes directly to the poor outcome, or serum ferritin levels act as a surrogate marker for patient prognosis, requires further evaluation in prospective multicenter studies. Further studies using MRI assessment of tissue iron burden at various phases of HSCT, along with drawing appropriate correlations with clinical outcomes will be necessary in order to fully define the role of free iron in the patients undergoing HSCT.

Conflict of interest

None declared

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  17. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RA. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Int Med 1993; 118 (4):255-257.
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  19. Majhail NS, DeFor T, Lazarus HM, Burns LJ. High prevalence of iron overload in adult allogeneic hematopoietic cell transplant survivors. Biol Blood Marrow Transplant. 2008; 14(7): 790-794.
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  25. Tachibana T, Tanaka M, Takasaki H, Numata A, Ito S, Watanabe R, Hyo R, Ohshima R, Hagihara M, Sakai R, Fujisawa S, Tomita N, Fujita H, Maruta A, Ishigatsubo Y, Kanamori H. Pretransplant serum ferritin is associated with bloodstream infections within 100 days of allogeneic stem cell transplantation for myeloid malignancies. Int J Hematol 2011; 93:368-374.
  26. Tanaka M, Kanamori H, Matsumoto K, Tachibana T, Numata A, Ohashi K, Kobayashi T, Nakaseko C, Kanda Y, Yamazaki E, Fujisawa S, Ooi J, Sakura T, Aotsuka N, Onoda M, Machida S, Kato J, Usuki K et al., Clinical significance of pretransplant serum ferritin on the outcome of allogeneic hematopoietic SCT: a prospective cohort study by the Kanto Study Group for Cell Therapy. Bone Marrow Transplantation 2015, 50 (5):727-733
  27. Trottier BJ, Burns LJ, DeFor TE, Cooley S, Majhail NS. Association of iron overload with survival and complications in allogeneic hematopoietic cell transplant recipients: prospective cohort study using R2-MRI measured liver iron content. Blood 2013; 122:1678-1684.
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Introduction

Iron takes part in several metabolic processes, including DNA synthesis, oxygen and electron transport. Most of the iron in human body is distributed within hemoglobin (65%; 2300 mg). Ca. 10% is present in muscles and other tissues, e.g., liver (200 mg), macrophages (500 mg), and bone marrow (150 mg) [23].

Ferritin is the main iron storage molecule. It makes ferrous ions available for critical cellular processes, while protecting lipids, DNA and proteins from potentially toxic effects of free iron. Increased iron load may, however, saturate the available transferring pool and lead to excessive levels of non-transferrin- bound iron which may be subsequently captured and stored either within ferritin, or hemosiderin molecules [14].

Therefore, serum ferritin is considered a simple and widely used surrogate marker for IO. However, many confounding factors, particularly in HCT recipients, may result in potential IO overestimation. E.g., inflammation, infections, liver damage and GvHD may also lead to elevated serum ferritin levels [21]. Repeated serum ferritin measurements can reveal potential causes and help to establish a general pattern of the iron overload over time.

On the basis of serum ferritin levels, the diagnosis of iron overload has been reported in up to 88% of long term HSCT survivors. When liver iron content is assessed by MRI technique, the prevalence of iron excess is reported to be 32% in allo-HCT recipients who survived 1 year or more following HCT [19].

The adverse impact of IO on the HSCT outcome was first demonstrated in thalassemia patients [10]. In MDS patients, a transfusion dependency was considered a prognostic factor in WHO classification–based Prognostic Scoring System (WPSS) and independently associated with reduced OS and increased NRM [1].

Different workers have presumed an iron overload to be a risk factor for clinical complications in HCT recipients, including higher occurrence of mucositis [3], increased infection rates [2, 7, 12, 15, 25], liver functions abnormality [9], GvHD severity [18, 6], and non-relapse mortality [4].

Hence, the aim of our single-center study was to confirm previous reports and assess a predictive value of the baseline ferritin levels for different early complications of HSCT procedure.

Patients and methods

We have retrospectively evaluated a group of ninety-one consecutive patients undergoing unmanipulated allo-HCT in R.M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation at the St. Petersburg Pavlov State Medical University, St. Petersburg, between 01/01/2013 and 03/09/2014. The inclusion criteria were as follows: (1) First allo-HCT from HLA-compatible related, unrelated or haplo-identical donors; (2) Primary malignant, or non-malignant disease; (3) Age: 5 to 60 years; (4) Karnofsky performance status ≥70 %.

The cohort included 42 men and 49 women with a median age at transplantation of 31.6 (range, 5 to 60) years. Underlying diseases were acute myeloid leukemia (n=68), myelodysplastic syndrome (n=10), myeloproliferative neoplasms (n=4; Primary myelofibrosis =3, Chronic myelomonocytic leukemia=1), bone marrow failure (n=7; Aplastic anemia=6, Fanconi anemia=1) and B-thalassemia major (n=2). Stem cell transplants were from (HLA)-identical siblings (n=16), haplo-identical (n=6), or unrelated volunteer donors; (n=69).

The conditioning regimens were myeloablative (MAC) in 26 patients, or reduced-intensity (RIC) in the rest of this group.

The follow-up period was 100 days after allo-HCT. Baseline characteristics of the patients are given in Table 1. We evaluated the effects of high pre-allo-HCT serum ferritin on early toxic, infectious and other complications, as well as early transplant outcomes.

Table 1. Patients baseline characteristics
Table 1. Patients baseline characteristics

The study was approved by the Institutional Review Board at the First St.Petersburg State Pavlov Medical University. Each patient has given an informed consent for the use of personal data.

The study cohort was divided into 2 groups, those with high versus low ferritin concentration (resp. HF and LF groups), on the basis of a 500-ng/mL threshold for increased ferritin concentration. Mucositis was graded on a scale of 0 to 4, according to Common Toxicity Criteria, version 4, from the National Cancer Institute. The International EORTC/MSG Consensus on opportunistic fungal infections (FI) was used for diagnosis of FI [5]

Bacterial infection was defined as recovery of a recognized pathogen from, at least, 2 different sites for 100 Days post- HCT (Data Form 2100). Recovery of neutrophils was blood or urine cultures yielding the same organism. For each patient, the numbers of bacterial, viral and fungal infections were calculated, according to CIBMTR registered when reaching the ANC numbers of >500/μL for the first 3 consecutive days. Acute graft-versus-host disease (aGvHD) was graded according to Gratwohl criteria [11]. A diagnosis of sinusoidal obstruction syndrome (hepatic veno-occlusive disease) was made on the basis of Seattle criteria, as described by McDonald et al [17].

Continuous variables in the 2 groups were compared by means of the Mann-Whitney test. Categorical variables were compared using the Chi-square test. Overall survival and transplant-related mortality were calculated, using the Kaplan-Meier method. Possible risk factors were tested using the log-rank test. Cutoff levels of ferritin amounts were determined using ROC- analysis. The calculations were made with SPSS.19.

Results

Fifty-three (58%) patients with increased serum ferritin concentrations (≥500 ng/mL) were classified as the high-ferritin group (HF), with a median of 1148 ng/mL (range, 650-4247). The rest of patients (n=38, 41.76%) were classified as LF group, and had serum ferritin concentrations (<500 ng/mL) with a median ferritin level of 232 (range, 12.1-466.3 ng/mL).

Active infections within last month prior to HCT were observed only in HF group, including 8 patients with probable invasive pulmonary aspergillosis; 2 cases of soft tissue infection; purulent sinusitis in 2 patients and fever of unknown origin in 2 cases, with a median ferritin level of 1057 ng/mL (606-1875). Hence, fungal infections prevailed among total infections by the date of allo-HCT, and 26.14% of patients in HF group with increased ferritin levels (P= 0.001; [OR], 0.73; 95% confidence interval [CI], 0.62–0.86).

Early complications of allogeneic-HCT

Mucositis

Post-transplant mucositis was observed in seventy patients: 28 (52%) in HF and 19 (50%) in LF group had mucositis grade I-II (P>0.05). 11(21%) in HF group versus 12 (32%) among LF patients had mucositis grade III-IV. No statistical differences were observed between the two groups (P>0.05).

Febrile neutropenia

Febrile neutropenia was observed in sixty-seven cases: 42 (79%) in HF vs 23 (60%) in LF group (P > 0.05). Despite the lack of a significant difference between the groups, we revealed a near-linear correlation between the numbers of febrile neutropenia episodes and increase in the mean ferritin levels (Fig. 1). The median for HF group was 1.5 febrile episodes/patient (0 to 6) vs 0.84 (0 to 3) in LF patients [P = 0.005; OR, 4.08; 95% (CI), 1.46–11.42] (Fig.2). Accordingly, the number of patients who required granulocyte colony- stimulating factor (G-CSF) injections in order to boost hematopoiesis and to shorten neutropenic period was: 25 (47%) vs 7(18%) in the HF and LF groups, respectively [P =0.005; (OR), 0.25 ; 95%(CI), (0.09–0.67)].

Figure 1. Pre-transplant serum ferritin levels before HSCTin the patients with different numbers of febrile neutropeniaepisodes posttransplant. Ordinate, mean ferritinlevels (ng/mL, M+m). The trend is significant by P=0.005.

Figure 1. Pre-transplant serum ferritin levels before HSCT in the patients with different numbers of febrile neutropenia episodes posttransplant. Ordinate, mean ferritin levels (ng/mL, M+m). The trend is significant by P=0.005.


Bacterial infections

Although the percentage of patients with developing bacterial infections was similar in both H F and LF groups (resp., 88.64%, 84.2%), there was a distinct correlation between the increased pre-HCT ferritin and median number of infectious episodes/ patient, i.e., 2.7 (0 to 7) in HF group, and 2.0 (0 to 6) in LF sample [P=0.009; (OR), 3.2; 95%(CI), (1.31–7.77)]. Incidence of febrile neutropenia and septicemia post-transplant was more frequent in the HF group (n=20; 30%) vs LF patients (n=8; 13%), at a marginal statistical difference (P>0.05), as shown in Fig. 1.

Figure 2 Association between pre allo-HCT serum ferritinand febrile neutropenic and infectious complicationsafter allo-HCT Abscisse, groups with differentpost-HCT compliations; Ordinate, number of febrileneutropenic episodes (median + range).

Figure 2 Association between pre allo-HCT serum ferritin and febrile neutropenic and infectious complications after allo-HCT Abscisse, groups with different post-HCT compliations; Ordinate, number of febrile neutropenic episodes (median + range).


Mixed infections as causes of pneumonia were observed in a large proportion of patients (bacterial, fungal, and viral pathogens): 58.8% and 60% in HF and LF groups, respectively.

Fungal infections

In our cohort study, probable or proven fungal infections were observed in 9 patients (17%) from HF group (one patient had two episodes) and 3 patients (7.9%) in LF group, with no statistically significant difference (P > 0.05).

CMV infection

During the early period after allo-HCT, CMV reactivation was observed in 38 patients (42% of total), including 23(43%) in HF group, and 15(39%) in LF patients, without statistically significant difference (P>0.05). Likewise, no differences were found for incidence of other viral infections (BK, JC), respectively, 20.8% vs 21% in HF and LF groups.

Moreover, we had tested correlation between other clinical features, RBC parameters, and presence of CMV reactivation signs. There were no significant connections found between donor RBC blood antigens, or donor/recipient ABO mismatch, and post-transplant infectious complications. Meanwhile, presence of A antigen (blood group II or IV) in the patients showed a highly significant correlation with CMV reactivation (CMV infection positive in 63% (24/39) of A(+) patients versus 37% (14/51) in the group of A(-) patients (r= 0.342; P<0.01).

Fig. 2A. Dependence between RBC A antigen in recipientsand CMV reactivation rates in the studied group(n=91; p=0.003).

Fig. 2A. Dependence between RBC A antigen in recipients and CMV reactivation rates in the studied group (n=91; p=0.003).


Engraftment time

The median time of neutrophil reconstitution (≥ 500×109) and platelet engraftment (Plt ≥ 20×109) were, respectively, 22 days (13-43) and 18 days (10-41) in HF group, versus 19.5 days (11-36) and 16.2 days (11-36) in LF group (Fig. 2). A significant HF/LF difference was noted for neutrophil recovery (P=0.047). Interestingly, that was independent of the stem cell dose infused: 5.2 (1.3-14.1)×106 versus 4.84 (1.9-10.1)×106 in HF and LF. Intensity of conditioning regimens did not also affect the engraftment rates in our cohort: MAC/RIC: 26.4/73.6% and 29.5/71.5 % in HF and LF groups, respectively.

Fig. 2. Reconstitution of neutrophils and platelets in theinitially low- and high-ferritin groups (F> or <500 ng/mL). Abscisse: Designations for different sub-groups;ordinate: duration of the blood cell reconstitution, days.

Fig. 2. Reconstitution of neutrophils and platelets in the initially low- and high-ferritin groups (F> or <500 ng/mL). Abscisse: Designations for different sub-roups; ordinate: duration of the blood cell reconstitution, days.

Hepatic veno-occlusive disease

Only 4 cases were observed in total cohort: 3, in HF and 1, in LF groups.The pre-HCT ferritin levels in these cases were as follows: 4247, 1631, 827.3, 112 ng/mL, and one case with primary myelofibrosis had severe VOD with multiorgan failure, and died on D7+ after transplantation. We did not find any significant statistical difference between the two groups P > 0.05, due to minimal statistics.

Acute graft-versus-host disease

Acute GvHD was diagnosed in 24 patients (45.28%), and 18 (47.36%) in HF and LF, respectively. This difference was not statistically significant (P>0.2). A tendency was noted towards higher occurence of severe aGvHD (Stage III-IV), including hepatic form in HF group (ferritin≥500) (P=0.07). That supports a theory that hepatic iron overload may imitate and worsen hepatic aGvHD.

Pneumonia

Increasing incidence of pneumonia was observed, regardless of its causes, in the first group (ferritin ≥500 ng/mL) compared to the second group: 17 cases (30.2%) vs 5 cases (13.15%) in HF and LF, respectively (P=0.04, [OR], 0.33 ; 95%[CI], (0.11–0.99).

Hemorrhagic cystitis

Hemorrhagic cystitis was documented in 19 patients (20% of total) with a median incidence on day 32 (range, 1-73). The median ferritin level was 716 ng/ml (12 to 1631), being similar in the HF and LF groups: 11 (20.75%) vs 8 (21%) in HF and LF groups, respectively (P>0.05).

RBC transfusion requirements

Number of RBC units transfused was counted for each patient within 100 days post-HCT, and a linear correlation was revealed between the increased pre -HCT ferritin and the number of RBC transfusions. Median number of RBC units/patient was 8.6 units (0 to 36) and 3.1 units (0 to 27) in HF and LF groups P=0.04, [OR], 3.85 ; 95%[CI], (0.9–15), as shown in Fig. 3(a).

In the same context, ferritin concentration was recorded only in 14 patients between days 70-100 post allo-HCT. Median ferritin level in this group was 2420 ng/mL (417 to 6362), at a mean number of 10.3 units per patient transfused in these cases (0 to 26). Meanwhile, the median initial ferritin level in this group was 943.4 (98 to 1850). Thus, we can conclude that high ferritin levels at the 3rd month post-HCT in these cases may simply reflect an iron overload caused by multiple transfusions (1 RBC unit contains 200 to 250 mg Fe), as shown in the Fig. 3a and 3b.

Linear correlation between the increased ferritin concentration pre-HCT and the number of RBC units transfused over 100 days post-HCT   Steadily increased ferritin levels in group of patients (n=14) in whom ferritin amounts were recorded in the third month after HCT, median number of RBC units transfused in these cases was 10.3 units /patient (range, 0-26).

Fig. 3 (a). Linear correlation between the increased ferritin concentration pre-HCT and the number of RBC units transfused over 100 days post-HCT. (b) Steadily increased ferritin levels in group of patients (n=14) in whom ferritin amounts were recorded in the third month after HCT, median number of RBC units transfused in these cases was 10.3 units /patient (range, 0-26).


Early post-transplant mortality

Fifteen patients died during 100 days: 12 (23%) in HF, and 3 (8%) in LF group, without any significant difference (P>0.05). Significant difference in the mortality which occurred in pre- and post-engraftment was observed: 5 fatal outcomes (9.4%) were recorded only in HF group during the pre-engraftment period (P=0.003); resp., 8 cases (15.1%) and one case (2.6%) in HF and LF during 2nd month of post-engraftment (P=0.02). Treatment-related mortality (TRM) was observed in 7 cases, five of them (9 %), in HF, and two (5 %), in LF group (P>0.05). Hence, we did not find any relationship between the ferritin concentrations (at the cutoff level of 500 ng/mL), and mortality until the D+100. However, on the basis of ROC analysis, we assumed the general median to be the cutoff value (>773 ng/mL) for ferritin, and revealed a statistical difference for the mortality by D+100, i.e., 10 cases (27.7%) in group with high ferritin (≥773), and 5 lethal cases (9%) in the low-ferritin group (<773 ng/mL), P=0.02.

Day 100 cumulative survival and disease-free survival

With the cutoff ferritin concentration at 500 ng/mL (mean value of the sample), a significant statistical difference between two groups was not observed in the D100 cumulative survival and DFS: 77% and 62% in group 1 (ferritin ≥500) vs 89% and 76% in group2 (ferritin<500), respectively, (P > 0.05).

However, when we considered serum ferritin cutoff value of >773 ng/mL (the group median level), a significant statistical difference was observed. The D100 cumulative survival was 91% in group (F<773), vs 74% in HF group (P=0.04). D100 disease-free survival was 79% in group (F<773), versus 58% in group with high ferritin (F≥773), P=0.019. Hence, the pre- HSCT ferritin concentration at the over-median levels may be associated with lower OS and DFS, and could be considered as a risk factor (Fig. 4).

Fig. 4 Kaplan-Meier curves: D+100 cumulative survival and DFS in two groups at ferritin cutoff value of ≥ 773 ng/mL.

    Fig. 4 Kaplan-Meier curves: D+100 cumulative survival and DFS in two groups at ferritin cutoff value of ≥ 773 ng/mL.
Fig. 4 Kaplan-Meier curves: D+100 cumulative survival and DFS in two groups at ferritin cutoff value of ≥ 773 ng/mL.


Discussion

The main objective of present study was to assess a predictive role of pre-allo-HCT ferritin concentrations, as a surrogate marker of iron overload in early transplant-related complications and outcome. The 500-ng/mL cutoff for serum ferritin concentration is less than in most previously reported series [3,8]. Our results suggest that a relatively mild iron overload in HCT recipients may also have toxic consequences. We did observe that high initial ferritin was significantly associated with increasing incidence of febrile neutropenia and bacterial infectious episodes, incidence of pneumonia and increased numbers of RBC units transfused post-HCT. Moreover, at an adjusted cutoff levels of ferritin (≥ 773 ng/mL), we noted significant associations between the increased pre-HCT ferritin concentration and poor overall survival, disease-free survival and higher transplant-related mortality. An association between increased pre-HCT ferritin level and active infections, especially, pre-existing pulmonary aspergillosis, was statistically significant. Other common complications, including mucositis, acute GvHD and CMV infection, did not demonstrate significant associations with ferritin contents. Due to small number of VOD cases, we could not find significant relationship with increasing ferritin.

Iron overload is known to be associated with increased susceptibility to different infections. Iron deprivation was found to be the key factor in the antimicrobial host defense. E.g., Pullarkat et al. [22] showed in a group of 190 patients with hematological malignancies that developing severe infectious complications were significantly higher in the high-ferritin category (OR=1.99, Wald test P=0.032). In contrast, Sucak et al. [24] showed no significant effect of pre-HCT iron status on bacteremia was observed (P>0.05). In our study, we have found that elevated pre transplant ferritin (>500 ng/ mL) was associated with increasing number of febrile neutropenia episodes (P=0.005), bacterial infections (P=0.009). That may reflect a role of IO in severe immune defect and predisposition to recurrent bacterial infections. Therefore, high ferritin level, as a marker of general IO, seems to be a sufficient cofactor in severe transplant-associated infections.

Also, in accordance with recently published studies [26], we found a delayed engraftment and increased percentage of patients who required G-CSF stimulation in the HF group (P=0.005).

According to Sucak et al. [24] the pre-HSCT high ferritin concentration correlated with pneumonia in allogeneic HCT recipients, thus being consistent with our results, where increased ferritin level (≥500) pre-HSCT proved to be associated with increasing pneumonia incidence (P = 0.04). Interestingly, the cases of isolated bacterial pneumonia were also frequent in the group with high ferritin levels (≥500 ng/mL ) constituting 35.29% from causes of pneumonia in this group and this also confirms negative impact of iron overload in immunity, also as known bacteria need iron in their life cycle.

Some authors suggest a relationship between the pre-transplant ferritin levels and risk of invasive fungal infections (IFI) [2]. In contrast, other studies show that elevated serum ferritin (≥1000 ng/mL) was not a significant risk factor for IFI in a multivariate regression model after adjusting for aGvHD [7]. In our experience, there was a tendency for increased incidence of fungal infections among the patients with high ferritin concentration. However this group was too small for definite conclusions with no statistical significance (P>0.05).

There are conflicting results for relationship between acute GvHD and IO, while some studies suggest that the incidence of aGvHD was still associated with ferritin levels ≥1000 ng/ mL [22]. Another study has shown that ferritin levels over 1910 ng/mL correlate with a significantly lower incidence of acute GvHD, as well as limited and extensive chronic GvHD [18], thus supporting a hypothesis on suppressive effects of iron excess upon adaptive immune responses [6]. In our cohort, there was no correlation between a GvHD and elevated ferritin concentration pre-allo-HCT (P>0.05), but it was noted that there is a tendency for the occurrence of severe forms aGvHD III-IV, including the form of hepatic in the high-ferritin group, thus being in favor of a theory that hepatic iron overload may simulate or worsen hepatic aGvHD, since 90% of excessive iron is stored in the liver.

Several previous studies showed that elevated pre allo-HCT serum ferritin was an independent risk factor for SOS [20]. In our observation only 4 (4.3%) cases of VOD were diagnosed, with initial median ferritin level of 1704.3 ng/mL (112-4247). Low number of the VOD cases may be due to use of RIC and non-MAC conditioning regimens, and the use of heparin prophylaxis, thus making it impossible to perform valid statistical evaluation. Because of the small VOD incidence no significant statistical difference between the two groups was observed (P > 0.05).

We also observed that the patients with higher pre allo-HSCT ferritin levels required more blood transfusions than those in LF group. This may be attributed to presence of anti-RBC antibodies arising in heavily transfused patients [8] and to increasing incidence of febrile neutropenia and bacterial infections. Under the inflammatory conditions, hepcidin is secreted as a defensive mechanism, thus causing inhibition of iron release from its stores, thus preventing iron uptake for normal hematopoiesis and leading to slower recovery of erythroid lineage after HCT [2].

A number of previous studies, which used an indirect indicator of iron excess (serum ferritin) have found an association between the ferritin amounts and post-transplant survival using quite different threshold ferritin levels: F≥3000 [3]; F≥2515 [4]; F≥1910 [18]; F≥1000 [16]; F≥599 [13] ; F≥500 [24]. Moreover, a negative impact of elevated ferritin proved to be associated with reduced overall and disease-free survival. However, when the pre-transplant IO was measured with MRI, such differences were not observed. E.g., Trottier et al. [27] did not find any association between pre-transplant iron excess defined by R2-MRI measured LIC and OS, NRM, relapse rate or GvHD. Similar results have been reported by Armand et al [4]. In our study, we observed significant correlation between pre allo-HCT ferritin >773 ng/mL and increased mortality, reduced OS and DFS at the end of 100 days post HSCT.

In conclusion, in accordance with previous findings, we observed increased incidence of infectious complications and adverse impact on engraftment rates. Serum ferritin may be considered the easiest way to estimate IO, being the most widely used method. Since serum ferritin is an acute phase reactant, its elevation may simply mirror inflammatory conditions, including an advanced disease phase that is shown to influence the outcomes in hematologic patients receiving allo-HSCT. The issue, whether high iron burden contributes directly to the poor outcome, or serum ferritin levels act as a surrogate marker for patient prognosis, requires further evaluation in prospective multicenter studies. Further studies using MRI assessment of tissue iron burden at various phases of HSCT, along with drawing appropriate correlations with clinical outcomes will be necessary in order to fully define the role of free iron in the patients undergoing HSCT.

Conflict of interest

None declared

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Повышенные до трансплантации уровни ферритина могут быть ассоциированы с повышенной заболеваемостью и смертностью после алло-ТГСК. Пациенты и методы. В данном одноцентровом исследовании нами проводился анализ медицинских данных 91 больного (42 мужчины и 49 – женского пола) при среднем возрасте 32 года (5-60 лет), которым в период с января 2013 по декабрь 2914 гг. проводилась аллогенная ТГСК необработанных клеток. Результаты. В целом по данной группе пациентов, среднее значение концентрации ферритина в сыворотке крови составило 766 (от 12 до 4247) нг/мл. 53 больных (58,2%) имели исходные цифры сывороточного ферритина &gt;500 нг/мл и были отнесены к группе с высоким ферритином (ВФ). Повышенные концентрации ферритина были достоверно связаны с токсическими и/или инфекционными осложнениями ТГСК, т.е. с числом эпизодов фебрильной нейтропении (P =0,005), числом эпизодов бактериальной инфекции (P=0,009), пневмонипй (P=0,04), и потрбностью в трансвузиях эритроцитов (P=0,04) в течение 100 дней после ТГСК. Была обнаружена достоверная взаимосвязь между повышенными концентрациями ферритина до ТГСК (&gt;773 нг/мл) и общей выживаемостью (P=0,04), безрецидивной выживаемости (P=0,019), и смертности (P=0,02) в данной группе. Не было отмечено существенных корреляций между исходными уровнями ферритина и частотой мукозита или болезни «трансплантат против хозяина» (P&gt;0,05). </p> <h2> Заключение  </h2> <p> Измерение сывороточного ферритина в качестве лабораторного маркера перегрузки железом является весьма практичным для многих гематологических клиник. 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"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(4) "6570" ["VALUE"]=> array(2) { ["TEXT"]=> string(329) "<p class="Autor"> Мостафа Шахин,<sup>1,2</sup> Мария O. Иванова,<sup>1</sup> Иван С. Моисеев,<sup>1</sup> Сергей В. Бондарчук,<sup>3</sup> Борис В. Афанасьев<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(247) "

Мостафа Шахин,1,2 Мария O. Иванова,1 Иван С. Моисеев,1 Сергей В. Бондарчук,3 Борис В. Афанасьев1

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2 Отделение гематологии и трансплантации костного мозга, Госпиталь Тишрин, Дамаск, Сирия
3 Отделение гематологии, кафедра факультетской терапии, Военно-медицинская академия им. С.М. Кирова, 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(4) "6572" ["VALUE"]=> array(2) { ["TEXT"]=> string(3948) "<h2> Введение.  </h2> <p> Перегрузка железом (ПЖ) является важной проблемой при лечении больных, подвергающихся трансплантации гамопоэтических стволовых клеток (ТГСК). Повышенные до трансплантации уровни ферритина могут быть ассоциированы с повышенной заболеваемостью и смертностью после алло-ТГСК. Пациенты и методы. В данном одноцентровом исследовании нами проводился анализ медицинских данных 91 больного (42 мужчины и 49 – женского пола) при среднем возрасте 32 года (5-60 лет), которым в период с января 2013 по декабрь 2914 гг. проводилась аллогенная ТГСК необработанных клеток. Результаты. В целом по данной группе пациентов, среднее значение концентрации ферритина в сыворотке крови составило 766 (от 12 до 4247) нг/мл. 53 больных (58,2%) имели исходные цифры сывороточного ферритина &gt;500 нг/мл и были отнесены к группе с высоким ферритином (ВФ). Повышенные концентрации ферритина были достоверно связаны с токсическими и/или инфекционными осложнениями ТГСК, т.е. с числом эпизодов фебрильной нейтропении (P =0,005), числом эпизодов бактериальной инфекции (P=0,009), пневмонипй (P=0,04), и потрбностью в трансвузиях эритроцитов (P=0,04) в течение 100 дней после ТГСК. Была обнаружена достоверная взаимосвязь между повышенными концентрациями ферритина до ТГСК (&gt;773 нг/мл) и общей выживаемостью (P=0,04), безрецидивной выживаемости (P=0,019), и смертности (P=0,02) в данной группе. Не было отмечено существенных корреляций между исходными уровнями ферритина и частотой мукозита или болезни «трансплантат против хозяина» (P&gt;0,05). </p> <h2> Заключение  </h2> <p> Измерение сывороточного ферритина в качестве лабораторного маркера перегрузки железом является весьма практичным для многих гематологических клиник. В настоящем исследовании было показано, что исходное повышение сывороточного ферритина ассоциировано с повышенным риском фебрильных эпизодов, инфекционных состояний и более медленного восстановления миелоидного клеточного ростка и, тем самым, имеет определенную прогностическую ценность. Особый интерес представляет взаимосвязь между уровнями ферритина до трансплантации и повышенной потребностью в трансфузиях эритроцитов после алло-ТГСК. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3888) "

Введение. 

Перегрузка железом (ПЖ) является важной проблемой при лечении больных, подвергающихся трансплантации гамопоэтических стволовых клеток (ТГСК). Повышенные до трансплантации уровни ферритина могут быть ассоциированы с повышенной заболеваемостью и смертностью после алло-ТГСК. Пациенты и методы. В данном одноцентровом исследовании нами проводился анализ медицинских данных 91 больного (42 мужчины и 49 – женского пола) при среднем возрасте 32 года (5-60 лет), которым в период с января 2013 по декабрь 2914 гг. проводилась аллогенная ТГСК необработанных клеток. Результаты. В целом по данной группе пациентов, среднее значение концентрации ферритина в сыворотке крови составило 766 (от 12 до 4247) нг/мл. 53 больных (58,2%) имели исходные цифры сывороточного ферритина >500 нг/мл и были отнесены к группе с высоким ферритином (ВФ). Повышенные концентрации ферритина были достоверно связаны с токсическими и/или инфекционными осложнениями ТГСК, т.е. с числом эпизодов фебрильной нейтропении (P =0,005), числом эпизодов бактериальной инфекции (P=0,009), пневмонипй (P=0,04), и потрбностью в трансвузиях эритроцитов (P=0,04) в течение 100 дней после ТГСК. Была обнаружена достоверная взаимосвязь между повышенными концентрациями ферритина до ТГСК (>773 нг/мл) и общей выживаемостью (P=0,04), безрецидивной выживаемости (P=0,019), и смертности (P=0,02) в данной группе. Не было отмечено существенных корреляций между исходными уровнями ферритина и частотой мукозита или болезни «трансплантат против хозяина» (P>0,05).

Заключение 

Измерение сывороточного ферритина в качестве лабораторного маркера перегрузки железом является весьма практичным для многих гематологических клиник. В настоящем исследовании было показано, что исходное повышение сывороточного ферритина ассоциировано с повышенным риском фебрильных эпизодов, инфекционных состояний и более медленного восстановления миелоидного клеточного ростка и, тем самым, имеет определенную прогностическую ценность. Особый интерес представляет взаимосвязь между уровнями ферритина до трансплантации и повышенной потребностью в трансфузиях эритроцитов после алло-ТГСК.

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Mostafa Shaheen,1,2 Maria O. Ivanova,1 Ivan S. Moiseev,1 Sergey V. Bondarchuk,3 Boris V.Afanasyev1

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2. Hematology and Bone Marrow Transplantation Department, Tishreen Hospital, Damascus, Syria
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Introduction

Iron overload (IO) is an important issue when treating patients who undergo hematopoietic stem cell transplantation (HCT). Elevated pre-transplant serum ferritin levels have been associated with increased morbidity and mortality after allogeneic HCT.
Patients and Methods In the single-center study, we have reviewed medical records of ninety-one consecutive patients (42 males and 49 females), with a median age at HCT of 31.6 years (range, 5 to 60), who underwent allo-HCT with unmanipulated grafts between Jan 2013 and Dec 2014.

Results

The median pre-HCT serum ferritin concentration was 765.35 (range, 12.1-4247) ng/mL for the total group. Fifty-three patients (58.24%) had initial serum ferritin of >500 ng/mL, and were assigned to the high-ferritin group. Increased pre-transplant ferritin concentrations were significantly associated with toxic or infectious complications of HCT, i.e., number of febrile neutropenic episodes (P=0.005), number of bacterial infection episodes (P=0.009), pneumonias (P=0.04), and demand for multiple RBC transfusions (P=0.04) within 100 days post-HCT. The significant association was found between pre-HCT ferritin concentrations (>773 ng/mL) and overall survival (P=0.04), disease-free survival (P=0.019), and mortality (P=0.02) among the groups. No significant relationships were observed between the initial ferritin levels and incidence of mucositis, or graftversus- host disease (P>0.05).

Conclusion

Measurement of serum ferritin, as a surrogate laboratory marker for IO, is quite practical for many hematological clinics. In the present study it was shown that the baseline increase of serum ferritin contents, is associated with higher risk of febrile episodes, infectious conditions, and slower recovery of myeloid cells, thus being of certain predictive value. Of special interest is an association between the pre-transplant ferritin levels and increasing demand for RBC transfusions after allo-HCT.

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Ivanova,<sup>1</sup> Ivan S. Moiseev,<sup>1</sup> Sergey V. Bondarchuk,<sup>3</sup> Boris V.Afanasyev<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(182) "

Mostafa Shaheen,1,2 Maria O. Ivanova,1 Ivan S. Moiseev,1 Sergey V. Bondarchuk,3 Boris V.Afanasyev1

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Mostafa Shaheen,1,2 Maria O. Ivanova,1 Ivan S. Moiseev,1 Sergey V. Bondarchuk,3 Boris V.Afanasyev1

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Introduction

Iron overload (IO) is an important issue when treating patients who undergo hematopoietic stem cell transplantation (HCT). Elevated pre-transplant serum ferritin levels have been associated with increased morbidity and mortality after allogeneic HCT.
Patients and Methods In the single-center study, we have reviewed medical records of ninety-one consecutive patients (42 males and 49 females), with a median age at HCT of 31.6 years (range, 5 to 60), who underwent allo-HCT with unmanipulated grafts between Jan 2013 and Dec 2014.

Results

The median pre-HCT serum ferritin concentration was 765.35 (range, 12.1-4247) ng/mL for the total group. Fifty-three patients (58.24%) had initial serum ferritin of >500 ng/mL, and were assigned to the high-ferritin group. Increased pre-transplant ferritin concentrations were significantly associated with toxic or infectious complications of HCT, i.e., number of febrile neutropenic episodes (P=0.005), number of bacterial infection episodes (P=0.009), pneumonias (P=0.04), and demand for multiple RBC transfusions (P=0.04) within 100 days post-HCT. The significant association was found between pre-HCT ferritin concentrations (>773 ng/mL) and overall survival (P=0.04), disease-free survival (P=0.019), and mortality (P=0.02) among the groups. No significant relationships were observed between the initial ferritin levels and incidence of mucositis, or graftversus- host disease (P>0.05).

Conclusion

Measurement of serum ferritin, as a surrogate laboratory marker for IO, is quite practical for many hematological clinics. In the present study it was shown that the baseline increase of serum ferritin contents, is associated with higher risk of febrile episodes, infectious conditions, and slower recovery of myeloid cells, thus being of certain predictive value. Of special interest is an association between the pre-transplant ferritin levels and increasing demand for RBC transfusions after allo-HCT.

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Introduction

Iron overload (IO) is an important issue when treating patients who undergo hematopoietic stem cell transplantation (HCT). Elevated pre-transplant serum ferritin levels have been associated with increased morbidity and mortality after allogeneic HCT.
Patients and Methods In the single-center study, we have reviewed medical records of ninety-one consecutive patients (42 males and 49 females), with a median age at HCT of 31.6 years (range, 5 to 60), who underwent allo-HCT with unmanipulated grafts between Jan 2013 and Dec 2014.

Results

The median pre-HCT serum ferritin concentration was 765.35 (range, 12.1-4247) ng/mL for the total group. Fifty-three patients (58.24%) had initial serum ferritin of >500 ng/mL, and were assigned to the high-ferritin group. Increased pre-transplant ferritin concentrations were significantly associated with toxic or infectious complications of HCT, i.e., number of febrile neutropenic episodes (P=0.005), number of bacterial infection episodes (P=0.009), pneumonias (P=0.04), and demand for multiple RBC transfusions (P=0.04) within 100 days post-HCT. The significant association was found between pre-HCT ferritin concentrations (>773 ng/mL) and overall survival (P=0.04), disease-free survival (P=0.019), and mortality (P=0.02) among the groups. No significant relationships were observed between the initial ferritin levels and incidence of mucositis, or graftversus- host disease (P>0.05).

Conclusion

Measurement of serum ferritin, as a surrogate laboratory marker for IO, is quite practical for many hematological clinics. In the present study it was shown that the baseline increase of serum ferritin contents, is associated with higher risk of febrile episodes, infectious conditions, and slower recovery of myeloid cells, thus being of certain predictive value. Of special interest is an association between the pre-transplant ferritin levels and increasing demand for RBC transfusions after allo-HCT.

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Повышенные до трансплантации уровни ферритина могут быть ассоциированы с повышенной заболеваемостью и смертностью после алло-ТГСК. Пациенты и методы. В данном одноцентровом исследовании нами проводился анализ медицинских данных 91 больного (42 мужчины и 49 – женского пола) при среднем возрасте 32 года (5-60 лет), которым в период с января 2013 по декабрь 2914 гг. проводилась аллогенная ТГСК необработанных клеток. Результаты. В целом по данной группе пациентов, среднее значение концентрации ферритина в сыворотке крови составило 766 (от 12 до 4247) нг/мл. 53 больных (58,2%) имели исходные цифры сывороточного ферритина &gt;500 нг/мл и были отнесены к группе с высоким ферритином (ВФ). Повышенные концентрации ферритина были достоверно связаны с токсическими и/или инфекционными осложнениями ТГСК, т.е. с числом эпизодов фебрильной нейтропении (P =0,005), числом эпизодов бактериальной инфекции (P=0,009), пневмонипй (P=0,04), и потрбностью в трансвузиях эритроцитов (P=0,04) в течение 100 дней после ТГСК. Была обнаружена достоверная взаимосвязь между повышенными концентрациями ферритина до ТГСК (&gt;773 нг/мл) и общей выживаемостью (P=0,04), безрецидивной выживаемости (P=0,019), и смертности (P=0,02) в данной группе. Не было отмечено существенных корреляций между исходными уровнями ферритина и частотой мукозита или болезни «трансплантат против хозяина» (P&gt;0,05). </p> <h2> Заключение  </h2> <p> Измерение сывороточного ферритина в качестве лабораторного маркера перегрузки железом является весьма практичным для многих гематологических клиник. В настоящем исследовании было показано, что исходное повышение сывороточного ферритина ассоциировано с повышенным риском фебрильных эпизодов, инфекционных состояний и более медленного восстановления миелоидного клеточного ростка и, тем самым, имеет определенную прогностическую ценность. Особый интерес представляет взаимосвязь между уровнями ферритина до трансплантации и повышенной потребностью в трансфузиях эритроцитов после алло-ТГСК. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3888) "

Введение. 

Перегрузка железом (ПЖ) является важной проблемой при лечении больных, подвергающихся трансплантации гамопоэтических стволовых клеток (ТГСК). Повышенные до трансплантации уровни ферритина могут быть ассоциированы с повышенной заболеваемостью и смертностью после алло-ТГСК. Пациенты и методы. В данном одноцентровом исследовании нами проводился анализ медицинских данных 91 больного (42 мужчины и 49 – женского пола) при среднем возрасте 32 года (5-60 лет), которым в период с января 2013 по декабрь 2914 гг. проводилась аллогенная ТГСК необработанных клеток. Результаты. В целом по данной группе пациентов, среднее значение концентрации ферритина в сыворотке крови составило 766 (от 12 до 4247) нг/мл. 53 больных (58,2%) имели исходные цифры сывороточного ферритина >500 нг/мл и были отнесены к группе с высоким ферритином (ВФ). Повышенные концентрации ферритина были достоверно связаны с токсическими и/или инфекционными осложнениями ТГСК, т.е. с числом эпизодов фебрильной нейтропении (P =0,005), числом эпизодов бактериальной инфекции (P=0,009), пневмонипй (P=0,04), и потрбностью в трансвузиях эритроцитов (P=0,04) в течение 100 дней после ТГСК. Была обнаружена достоверная взаимосвязь между повышенными концентрациями ферритина до ТГСК (>773 нг/мл) и общей выживаемостью (P=0,04), безрецидивной выживаемости (P=0,019), и смертности (P=0,02) в данной группе. Не было отмечено существенных корреляций между исходными уровнями ферритина и частотой мукозита или болезни «трансплантат против хозяина» (P>0,05).

Заключение 

Измерение сывороточного ферритина в качестве лабораторного маркера перегрузки железом является весьма практичным для многих гематологических клиник. В настоящем исследовании было показано, что исходное повышение сывороточного ферритина ассоциировано с повышенным риском фебрильных эпизодов, инфекционных состояний и более медленного восстановления миелоидного клеточного ростка и, тем самым, имеет определенную прогностическую ценность. Особый интерес представляет взаимосвязь между уровнями ферритина до трансплантации и повышенной потребностью в трансфузиях эритроцитов после алло-ТГСК.

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Введение. 

Перегрузка железом (ПЖ) является важной проблемой при лечении больных, подвергающихся трансплантации гамопоэтических стволовых клеток (ТГСК). Повышенные до трансплантации уровни ферритина могут быть ассоциированы с повышенной заболеваемостью и смертностью после алло-ТГСК. Пациенты и методы. В данном одноцентровом исследовании нами проводился анализ медицинских данных 91 больного (42 мужчины и 49 – женского пола) при среднем возрасте 32 года (5-60 лет), которым в период с января 2013 по декабрь 2914 гг. проводилась аллогенная ТГСК необработанных клеток. Результаты. В целом по данной группе пациентов, среднее значение концентрации ферритина в сыворотке крови составило 766 (от 12 до 4247) нг/мл. 53 больных (58,2%) имели исходные цифры сывороточного ферритина >500 нг/мл и были отнесены к группе с высоким ферритином (ВФ). Повышенные концентрации ферритина были достоверно связаны с токсическими и/или инфекционными осложнениями ТГСК, т.е. с числом эпизодов фебрильной нейтропении (P =0,005), числом эпизодов бактериальной инфекции (P=0,009), пневмонипй (P=0,04), и потрбностью в трансвузиях эритроцитов (P=0,04) в течение 100 дней после ТГСК. Была обнаружена достоверная взаимосвязь между повышенными концентрациями ферритина до ТГСК (>773 нг/мл) и общей выживаемостью (P=0,04), безрецидивной выживаемости (P=0,019), и смертности (P=0,02) в данной группе. Не было отмечено существенных корреляций между исходными уровнями ферритина и частотой мукозита или болезни «трансплантат против хозяина» (P>0,05).

Заключение 

Измерение сывороточного ферритина в качестве лабораторного маркера перегрузки железом является весьма практичным для многих гематологических клиник. В настоящем исследовании было показано, что исходное повышение сывороточного ферритина ассоциировано с повышенным риском фебрильных эпизодов, инфекционных состояний и более медленного восстановления миелоидного клеточного ростка и, тем самым, имеет определенную прогностическую ценность. Особый интерес представляет взаимосвязь между уровнями ферритина до трансплантации и повышенной потребностью в трансфузиях эритроцитов после алло-ТГСК.

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3 Отделение гематологии, кафедра факультетской терапии, Военно-медицинская академия им. С.М. Кирова, Санкт-Петербург, Россия" } } } [1]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(2) "12" ["~IBLOCK_SECTION_ID"]=> string(2) "12" ["ID"]=> string(3) "481" ["~ID"]=> string(3) "481" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(250) "Трансплантация гемопоэтических клеток и другие варианты лечения при первичном миелофиброзе: обзор литературы и два клинических случая" ["~NAME"]=> string(250) "Трансплантация гемопоэтических клеток и другие варианты лечения при первичном миелофиброзе: обзор литературы и два клинических случая" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "22.09.2016 11:25:36" ["~TIMESTAMP_X"]=> string(19) "22.09.2016 11:25:36" ["DETAIL_PAGE_URL"]=> string(148) "/ru/archive/vypusk-5-nomer-2/regulyarnye-stati/transplantatsiya-gemopoeticheskikh-kletok-i-drugie-varianty-lecheniya-pri-pervichnom-mielofibroze-ob/" ["~DETAIL_PAGE_URL"]=> string(148) "/ru/archive/vypusk-5-nomer-2/regulyarnye-stati/transplantatsiya-gemopoeticheskikh-kletok-i-drugie-varianty-lecheniya-pri-pervichnom-mielofibroze-ob/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(46775) "

Introduction

Primary myelofibrosis (PMF) is BCR-ABL–negative myeloproliferative disorder characterized by splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis (EMH), circulating CD34 progenitor cells, reactive bone marrow fibrosis, angiogenesis and an abnormal cytokine expression. PMF is a disease usually affecting elderly people. The median age at diagnosis is about 65 years, and fewer than 20% of patients are younger than 50 years [7]. PMF should be distinguished from other closely related myeloid neoplasms including polycythemia vera (PV) and essential thrombocythemia (ET).

The disease course is heterogeneous and can be complicated by progressive bone marrow failure, symptomatic splenomegaly, severe constitutional symptoms, consumption, and clinical manifestations due to extramedullary hemopoiesis [39]. In about 8% to 30% of patients, the disease evolves into acute leukemia [12], [27]. Conventional drug therapy of PMF is merely palliative and does not prolong survival [41]. Allogeneic hemopoietic stem cell transplantation (allo- HSCT) offers the only chance for cure of PMF, but the conventional form of the procedure carries substantial morbidity and mortality and can be offered only to a minority of younger patients. Recently, the introduction of reduced-intensity allo-HSCT has made this therapy available to older patients not eligible for standard allo-HSCT.

Clinical manifestations

Clinical features in PMF are heterogeneous and include severe anemia, marked hepatosplenomegaly, constitutional symptoms (e.g., fatigue, night sweats, fever), cachexia, bone pain, splenic infarct, pruritus, thrombosis, and bleeding. Ineffective erythropoiesis and EMH are the main causes of anemia and organomegaly. Other disease complications include symptomatic portal hypertension that might lead to variceal bleeding or ascites and non-hepatosplenic EMH that might lead to cord compression, ascites, pleural effusion, pulmonary hypertension, or diffuse extremity pain. It is currently assumed that aberrant cytokine production by clonal cells and host immune reaction contributes to PMF-associated bone marrow stromal changes, ineffective erythropoiesis, EMH, cachexia, and constitutional symptoms [6]. Causes of death include leukemic progression that occurs in approximately 20% of patients but many patients also die of comorbid conditions including cardiovascular events and consequences of cytopenias including infection or bleeding [7].

Laboratory diagnostics

Current diagnosis of PMF is based on WHO criteria and includes clinical, morphologic, cytogenetic, and molecular assessments.

Typical laboratory features in patients with PMF include anemia (28% of PMF cases), peripheral blood leukoerythroblastosis, dacryocytosis, leukocytosis/thrombocytosis, increased lactate dehydrogenase (LDH), excess circulating blasts or CD34 cells, and bone marrow fibrosis, osteosclerosis, and angiogenesis (Figure 1). Differential diagnosis should be performed with polycythemia vera (PV) and essential thrombocythemia (ET). Patients who otherwise fulfill the diagnostic criteria for PV should be labeled as “PV” even if they display substantial bone marrow fibrosis [40].

Figure 1. Main aspects of PMF pathogenesis.[24]
Figure 1. Main aspects of PMF pathogenesis.[24]

Occasionally, overt bone marrow fibrosis might be absent and, in the presence of thrombocytosis, a false diagnosis of ET is made. The possibility of prefibrotic PMF, as opposed to ET, should be considered in the presence of persistently increased serum LDH, anemia, leukoerythroblastosis, increased circulating CD34+ cell count, and marked splenomegaly. It is underscored that the distinction between ET and prefibrotic PMF is clinically relevant because both OS and leukemia-free survival are significantly inferior in the latter [23]. Therefore, prefibrotic myelofibrosis is defined as separate entity in the new version of WHO classification 2016 [3].

The differential diagnosis of PMF should also include bone marrow fibrosis associated with non-neoplastic or other neoplastic conditions, including metastatic cancer, lymphoid neoplasm, or another myeloid malignancy, especially CML, MDS, chronic myelomonocytic leukemia (CMML), or AML. The presence of JAK2 or MPL mutation, with a combined mutational frequency of 70%, reliably excludes reactive bone marrow fibrosis or a nonmyeloid malignancy. More recently, calreticulin (CALR) gene mutations have been reported in patients with MF (and ET) who lack JAK2 V617F or MPL mutations [20]. Nangalia et al. identified a high prevalence of CALR mutations in JAK2/MPL-negative patients with MF. About 56% of patients with JAK2 V617F/MPL-negative MF had CALR mutations [29]. Identification of CALR mutation additionally confirms MF diagnosis.

The absence of BCR-ABL1 excludes the possibility of CML. MDS or CMML should be considered in presence of dyserythropoiesis/dysgranulopoiesis or peripheral blood monocytosis , respectively.

Prognostic factors

PMF is a heterogeneous disease in its presentation and evolution. Median survival is highly variable; a proportion of patients die shortly after diagnosis, whereas a few survive for 2 decades or longer. This fact has stimulated identification of prognostic factors and, as a result, several prognostic systems have been proposed.

The International Prognostic Scoring System (IPSS) uses five risk factors to predict prognosis and assign a patient to a risk group: age older than 65 years; hemoglobin less than 10 g/dL; leukocyte count more than 25 x 10 9 /L; circulating blood blasts 1% or more; and the presence of constitutional symptoms [7]. The Dynamic IPSS (DIPSS) uses the same five risk factors and has been validated to predict prognosis at any time during the disease course [31].

The DIPSS has been recently modified (DIPSS Plus) with the incorporation of three additional risk factors: red blood cell transfusion needed; platelet count < 100 x10 9 /L; and unfavorable karyotype [complex or sole or two abnormalities, including + 8, 7/7q , i(17q), inv(3), 5/5q , 12q or 11q23 rearrangement]. The four DIPSS-plus risk categories based on the eight risk factors are low (no risk factors), intermediate- 1 (one risk factor), intermediate-2 (two or 3 risk factors), and high (four or more risk factors) with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years [12], table 1. Furthermore, a >80% two-year mortality was predicted by monosomal karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts >9%, leukocytes 40 x109/L or more, or other unfavorable karyotype. Patients with the latter characteristics are operationally assigned a “very high risk” category and might be better served by immediate consideration for alloHSCT [42].

Several molecular prognostic markers might be soon included in DIPSSplus. A. Tefferi et.al. reported DIPSS-plus independent prognostic significance for calreticulin (CALR) (favorable) and ASXL1 (unfavorable) mutations. Survival was the longest in CALR+ASXL- (median 10.4 years) and the shortest in CALR-ASXL1+ patients (median, 2.3 years; HR, 5.9; 95%,CI, 3.5–10.0). The CALR/ASXL1 mutations-based prognostic model was DIPSS-plus independent (P<0.0001) and effective in identifying low-/intermediate-1-risk patients with shorter (median, 4 years) or longer (median 20 years) survival and high-/intermediate-2-risk patients with shorter (median, 2.3 years) survival. Multivariable analysis distinguished CALR-ASXL1+ mutational status as the most significant risk factor for survival: HR 3.7 vs 2.8 for age >65 years vs 2.7 for unfavorable karyotype [45]. In a large multicenter study evolving 879 patients with PMF other molecular markers (SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2) showed no prognostic significance [45].

Survival in PMF was also affected by increased serum IL-8 and IL-2R levels as well as serum-free light chain levels, both independent of DIPSS-plus [30], [43].

Risk factors for leukemia-free survival include ≥3% circulating blasts, platelet count <100 x 109/L, and presence of unfavorable karyotype . Although DIPSS has been shown to predict leukemia-free survival in the aforementioned DIPSS-plus study of 793 patients with PMF, the only two risk factors for leukemic transformation were unfavorable karyotype and platelet count <100 x 109/L; 10-year risk of leukemic transformation were 12% in the absence of these two risk factors and 31% in the presence of one or both risk factors [32].

Table 1. Prognostic risk models in PMF [7, 10, 12, 31]
Table 1. Prognostic risk models in PMF [7, 10, 12, 31]

* Constitutional symptoms constitute weight loss > 10% of baseline value in the year preceding diagnosis, unexplained fever, or excessive sweats persisting for > 1 month.38
**Unfavorable karyotype constitutes complex karyotype or sole or 2 abnormalities that include 8, 7/7q, i(17q), inv(3), 5/5q12p, or 11q23 rearrangement.

Figure 2. Chromosomal abnormalities in PMF. Typicalchromosomal abnormality in patient with PMF 47XY,XY,+8[8]/46,XY[12].

Figure 2. Chromosomal abnormalities in PMF. Typical chromosomal abnormality in patient with PMF 47XY, XY,+8[8]/46,XY[12].

Treatment strategy

Current drug therapy for PMF is not curative and has not been shown to prolong survival. AlloHSCT for PMF is potentially curative but dangerous; transplant-related death or severe morbidity occurs in a high percent of transplanted patients. As a result, more and more patients with PMF (or post-PV/ET MF) are seeking treatment with novel drugs. However, it should be noted that many patients can be observed without any therapeutic intervention and some can be effectively managed by conventional drug therapy.

Management of low or intermediate-1 risk patients

There is no evidence to support the specific therapy in asymptomatic patients with low or intermediate-1 risk disease [41]. Some patients with low or intermediate-1 risk might require therapy for symptomatic anemia, splenomegaly, non-hepatosplenic EMH, bone pain, EMH-associated pulmonary hypertension, or constitutional symptoms (e.g., fatigue, night sweats, and pruritus). In addition, cytoreductive therapy is reasonable but not mandated in the presence of extreme leukocytosis or thrombocytosis.

MF-associated anemia is usually treated with androgens, prednisone (0.5 mg/kg/day), danazol (600 mg/day) [6], thalidomide, or lenalidomide (10mg/day) [33].

Drug side effects include hepatotoxicity and virilizing effects for androgens, peripheral neuropathy for thalidomide, and myelosuppression for lenalidomide.

Response rates to each one of the aforementioned drugs are in the vicinity of 15-25% and response durations average about one to two years. Lenalidomide works best in the presence of del(5q31) [38].

First-line therapy for MF-associated splenomegaly is hydroxyurea, which is effective in reducing spleen size by half in approximately 40% of patients [26]. Spleen response to hydroxyurea lasts for an average of one year and treatment side effects include myelosuppression and mucocutaneous ulcers.

Interferon-α could be used in symptomatic patients with PMF. Interferon suppresses hematopoietic progenitors, bone marrow fibroblast progenitors and platelet-derived growth factor. The advent of a pegylated version of interferon has renewed interest in this class, perhaps for using early on in the course of ET or PV, with a goal of preventing or delaying fibrosis [19]. Long-term follow-up of 62 French and Belgian patients with MF treated with interferon-α has been recently reported; 46% experienced an improvement in splenomegaly, 82% experienced a mitigation in MF symptoms, and 73%, 64% and 78% of patients experienced an improvement in anemia, leukocytosis and thrombocytosis, respectively [16]. Complementing this study was a prospective trial of 32 lower-risk patients with early MF treated with recombinant or pegylated interferon [36]. An overall response rate of 78% was observed, with 3 complete remissions (9.4%), 12 partial remissions (37.5%), 3 clinical improvements (9.4%) and 7 with (22%) stable disease. Follow-up bone marrow biopsy results were available for 22 patients. Twelve patients had a reduction in cellularity that occurred after a median treatment duration of 2 years. Three patients, all of whom also experienced reductions in splenomegaly, had significant improvements in megakaryocyte morphology, marrow architecture and reductions of reticulin and collagen fibrosis (grade 3 to 1).

Management of intermediate-2 or high risk disease

PMF patients with high or intermediate-2 risk disease should be considered for investigational drug therapy or alloHSCT.

JAK1/JAK2 inhibitors are highly effective in patients with MF. Ruxolitinib was evaluated in 153 patients with PMF or post-PV/ET MF, in a Phase-1/2 study [47]. Dose limiting toxicity (DLT) was thrombocytopenia and the maximum tolerated dose was either 25 mg twice-daily or 100 mg once-daily. Adverse events included thrombocytopenia, anemia, and a “cytokine rebound reaction” upon drug discontinuation, characterized by acute relapse of symptoms and splenomegaly [47]. Non-hematologic adverse events were infrequent. Grade 3/4 thrombocytopenia or anemia (in transfusion-independent patients at baseline) respectively occurred in 39% and 43% of patients receiving the drug at 25 or 10 mg twice daily.

Among all evaluable patients, 44% experienced 50% decrease in palpable spleen size. Improvement in constitutional symptoms (fatigue, pruritus, abdominal discomfort, early satiety, night sweats, and exercise tolerance) and weight gain were seen in the majority of patients. Four (14%) of 28 transfusion- dependent patients became transfusion-independent. The drug’s effect on JAK2V617F allele burden or bone marrow pathology was negligible but a major reduction in proinflammatory cytokines (e.g., IL-1RA, IL-6, TNF-a, MIP- 1b) was documented and coincided with improvement in constitutional symptoms. Two randomized studies comparing ruxolitinib with either placebo or best supportive care have now been published [11], [47]. In the COMFORT-1 trial that compared the drug with placebo (n5309), the spleen response rate was approximately 42% for ruxolitinib versus <1% for placebo.

In addition, about 46% of patients experienced substantial improvement in their constitutional symptoms. However, the benefit of the drug was antagonized by ruxolitinib-associated anemia (31% vs. 13.9%) and thrombocytopenia (34.2% vs. 9.3%). In the COMFORT-2 trial that compared the drug with “best available therapy” (n5219), the spleen response was 28.5% with ruxolitinib vs. 0% otherwise but the drug was detrimental in terms of thrombocytopenia (44.5% vs. 9.6%), anemia (40.4% vs. 12.3%), and diarrhea (24.0% vs. 11.0%). The long-term outcome of ruxolitinib therapy in MF was recently reported and disclosed a very high treatment discontinuation rate (92% after a median time of 9.2 months) and the occurrence of severe withdrawal symptoms during ruxolitinib treatment discontinuation (“ruxolitinib withdrawal syndrome”) characterized by acute relapse of disease symptoms, accelerated splenomegaly, worsening of cytopenias, and occasional hemodynamic decompensation, including a septic shock-like syndrome [47].

Presently, ruxolitinib is the only FDA-approved JAK1/2 inhibitor for MF and the only non-HCT therapy to date associated with a proven survival benefit. In the phase III COMFORT-I study ruxolitinib was associated with an overall survival benefit relative to placebo in patients with intermediate- 2 or high-risk MF. With median follow-ups of 149.1 and 149.3 weeks for the ruxolitinib and placebo arms, respectively, the hazard ratio for overall survival continued to favor patients originally randomized to ruxolitinib compared with those originally randomized to placebo [hazard ratio 0.69 (95% CI: 0.46–1.03); P=0.067]. Different long-term outcomes have been reported by the Mayo Clinic and the MD Anderson Cancer Center (MDACC) in follow-up of their own institutional cohorts enrolled in the phase 1/2 study of ruxolitinib. Including adjustment for the Dynamic International Prognostic Scoring System score, the Mayo Clinic reported no significant difference in the survival rate of their 51 ruxolitinib-treated patients compared with a cohort of 410 patients with PMF who were treated with standard therapy at their center in the most recent 10-year period [46].

MDACC undertook a similar analysis, comparing the longterm outcomes of their patients with a historical control cohort of 310 patients culled from 3 databases who would have met eligibility for the study [48]. OS was significantly improved in ruxolitinib-treated patients compared with historical controls adjusted for International Prognostic Scoring System risk group. The 1-, 2-, and 3-year survival rates in high-risk patients treated with ruxolitinib were superior to the historical control group and a nonsignificant trend in survival was observed between intermediate-2-risk ruxolitinib treated and historical control patients.

In the absence of hematologic remissions, significant reduction in BM fibrosis and/or V617F allele burden, nor any proven modification of leukemia-free survival, other factors may explain the emerging survival advantage with ruxolitinib. Foremost is the enhancement of performance status related to reduction of splenomegaly and improvement of constitutional symptoms.

These data suggest that the survival advantage associated with ruxolitinib may be partly explained by reversion of the catabolic state associated with MF.

Allogeneic stem cell transplantation

AlloHSCT is arguably one of the riskiest interventions in modern medicine, so careful patient selection is of paramount importance. Transplantation for PV and ET, overall associated with a normal or near-normal life expectancy, is not indicated. On the other hand, alloHSCT should be an initial consideration for all patients with MF when first evaluated, and is the treatment of choice for high-risk symptomatic younger patients. What is fascinating and tantalizing in such cases is the capacity for this approach to restore normal trilineage hematopoiesis in a grossly perturbed marrow microenvironment, with rapid and striking reversal of the fibrosis that is the hallmark of this neoplasm [22].

Although a broad range of conditioning regimens of different intensities has been developed, the initial studies of alloHSCT for MF used high-intensity myeloablative conditioning (MAC) regimens, usually including total body irradiation (TBI) or busulfan. For MAC regimens, graft failure rates of less than 5% to 30% have been reported, reflecting the heterogeneity in patient populations and specific conditioning regimens [14], [18]. Published TRM rates of 10% to 35% at 1 year and OS from 30% to 67% at 5 years have been reported [5, 9, 13, 21, 25, 28].

The largest study to date was reported from the Center for International Blood and Marrow Transplant Research (CIBMTR), analyzing data in 289 patients with PMF [5]. Patients underwent a transplant between 1989 and 2002 at 118 centers, with a variety of conditioning regimens. A total of 162 patients received an HLA-matched sibling transplant, 101 received HLA-matched unrelated donor (URD) transplants, and 26 received transplants from HLA nonidentical related donors. Most of the patients received bone marrow as the stem cell source, and 83% were conditioned with a MAC regimen. The 100-day TRM was 18% for HLA-matched sibling patients and 33% for the URD patients. The graft failure rate was 9% for HLA-matched sibling transplants and 20% for URD transplants. Splenomegaly did not impact the graft failure rate. Graft-versus-host-disease (GVHD) grades II to IV occurred in 43% of sibling patients and 40% of the URD patients. The OS at 5 years was 37% for sibling transplants and 30% for URD transplants. Relapse-free survival (RFS) at 5 years was 33% for recipients of an HLA-identical sibling allografts and 27% for recipients of URD transplants. Positive predictors for survival included HLA-identical sibling donors, performance status greater than 90%, and absence of peripheral blood blasts at the time of transplantation. Patients who had a poor Karnofsky score, peripheral blood blasts, or received a transplant from a URD had a 15% probability of 3-year survival.

The largest prospective multicenter study to evaluate transplantation for MF was conducted through the European Group for Blood and Marrow Transplantation (EBMT) using a reduced intensity strategy [21]. Using the combination of fludarabine, busulfan (10 mg/kg) and antithymocyte globulin with a standard prophylactic immunosuppressive regimen, 98% of patients engrafted, with a nonrelapse mortality of 16% at 1 year. In addition, the estimated 5-year overall survival was 67%. Older age (over 55) and a mismatched donor adversely influenced survival. Subsequent post hoc analyses showed that JAK2 V617F negative disease also carried adverse prognostic significance [2]. These generally favorable results were mirrored histologically in those patients who had serial bone marrow biopsies following transplantation. These studies showed near or complete resolution of fibrosis in 69% and 93% of patients by day 100 and day 365. An additional notable finding from the multivariable analysis was that a history of splenectomy was associated with a higher risk of relapse.

JAK1/JAK2 inhibition as pre- and posttansplant therapy

Most of MF patients are in active disease phase at the time of allo-HSCT and have severe splenomegaly and constitutional symptoms. High disease burden may be one of the reasons why the results of allo-HSCT in MF patients are not satisfactory in some cases. Furthermore, a lot of studies report relatively high incidence of graft failure and poor graft function in MF patients compared to some other hematologic disorders [1, 5, 21, 34]. Several studies reported higher median time to neutrophil and platelets engraftment in patients with splenomegaly compared to patients with splenectomy, but this difference showed no significant impact on overall survival [1, 21]. Other data suggest that splenomegaly is an independent predictor of inferior overall survival after allo- HSCT [4]. Alchalby et al. showed that the other feature of active disease phase – constitutional symptoms also decrease OS after allo-HSCT [2].

Using JAK1/2 inhibitors to reduce spleen size and constitutional symptoms before HCT may be useful in improving transplant outcome. In a study by a German group, 14 patients received allo-HCT following a median of 6.5 months treatment with ruxolitinib [17]. Under ruxolitinib therapy, spleen size was reduced in 64% of patients and engraftment was achieved in 93% of patients. TRM was 7% and survival 79%, but the median follow-up was only 9 months. Another German group reported a retrospective analysis of results in 22 patients with PMF or after ET/PV MF who had received a median of 97 days of ruxolitinib before alloHSCT [37]. At the time of transplant, 86% had improvement in constitutional symptoms and 41% had a major response in spleen size. With a median follow-up of 12 months, the 1-year OS was 81% and PFS was 76%.

Recently Shanavas et al. has reported results of large multicenter retrospective study, which tested efficacy of pretransplant JAK1/2 inhibitors therapy [35]. 100 patients with MF who undergo alloHSCT after JAK1/2 inhibitors therapy were included in this study. Multivariate analysis showed that response to JAK1/2 inhibitors therapy significantly improves OS (p=0,03). Thus 2-years OS was 91% in patients who achieved clinical improvement and 32% in those patients who progressed to leukemic transformation on JAK1/2 inhibitors therapy.

The experience in administrating JAK1/2 inhibitors after allo-HSCT in MF patients is very scarce. We found only one report about posttransplant ruxolitinib therapy which was administrated to prevent relapse in 3 MF patients and 1 CMML patient [44]. Authors report no adverse events of toxicity during posttransplant therapy.

The beneficial impact of JAK1/2 inhibitors on transplant outcomes may be explained by its ability to modulate disease status compared to the other conventional therapies [47]. Pretransplant ruxolitinib therapy may reduce splenomegaly and constitutional symptoms and possibly reduce the graft failure rate. At the same time ruxolitinib reduce the proinflammatory and proangiogenic cytokines overproduction in MF patients [46]. Through this effect it can modulate immune response and reduce dendritic cells activation [15], neutrophils activation [49] and migration of alloreactive T-cells [8]. Possibly ruxolitinib pre- and postransplant therapy may reduce GVHD rate and improve transplant results in MF-patients (Figure 3). Currently ruxolitinib is effectively used for treatment of steroid-refractory acute and chronic GVHD [49]. Choi et al. showed that phamacologic blockade of JAK1/2 results in reduction of CXCR3 expression in T cells, mitigation of GvHD after allo-HSCT and preservation of graft versus leukemia effect in mouse models [8]. The authors suggest that JAK1/2 inhibitors might be a promising therapeutic approach to achieve the beneficial anti-leukemia effect and reduce GVHD rate in allo-HSCT.

Whether JAK1/2 inhibitors treatment before HCT can consistently improve patient performance status, the degree of splenomegaly, GVHD rate and lead to more favorable outcomes is an important area of ongoing investigation.

Figure 3. Pre-and posttransplant JAK1/2 inhibitors therapy.
Figure 3. Pre-and posttransplant JAK1/2 inhibitors therapy.

Clinical case descriptions

Here we report two female patients with postpolycythaemic myelofibrosis treated with allogeneic stem cell transplantation. Patient No.1 was a 46-year old woman with polycythaemia vera diagnosed 5 years prior to transplantation in 2010. At presentation she suffered from splenomegaly–associated symptoms – occasionally episodes of pain in the left upper quadrant. Complete blood count showed hemoglobin 189 g/L; WBC count, 21.5x109/L; myelocytes, 7%; metamyelocytes; 2%; band forms; 11%; segmented forms, 61%; monocytes, 10%; lymphocytes, 9%; platelets, 268x109/L. Ultrasound scan detected enlarged spleen (193x82 mm).

Bone marrow molecular biology analysis revealed a JAK2V617F mutation. Bone marrow cytogenetic analysis has shown a clonal aberration (47,XX+8) observed in 20/20 mitotic cells.

Erythrocytapheresis and hydroxyurea therapy were subsequently performed a symptomatic treatment, due to high hemoglobin level and splenomegaly.

After 5 years of follow-up, the patient developed the disease progression to myelofibrosis as documented by peripheral blood blastosis, LDH elevation, and histologically verified bone marrow fibrosis (Grade 2/3). At the time of progression, the JAK2 V617F-allele burden was 55% of the wild-type level. Thus, the patient was classified into the intermediate-2 risk category corresponding to DIPSSplus and, therefore, allo- HSCT was indicated.

To reduce splenomegaly, were performing pre-transplant ruxolitinib therapy for 3 months. The patient achieved clinical improvement, as evidenced by significant spleen reduction and disappearance of blasts in periphery. At that clinical stage, we performed allogeneic stem cell transplantation from 9/10 –HLA matched unrelated donor in December 2015. We used G-SCF-mobilized peripheral stem cells as stem cell source and transfused 6.6×109 СD34-positive cells per kg weight. Conditioning regimen consisted of fludarabine (180 mg/m2), busulfan (10 mg/kg p.o.). The patient continued to take ruxolitinib during conditioning until day -1. Post-transplant cyclophosphamide was administered at 100 mg/kg at day +3, +4, and ruxolitinib 10 mg was used from day +5 as GVHD prophylaxis. During early post-transplant period, the patient developed non-severe veno-occlusive liver disease. This complication resolved later spontaneously. Neutrophil and platelet engraftment, like as independence on red blood cell transfusion was achieved at day 20-21 after transplant. Complete hematological, cytogenetic and molecular remission was documented at day +30. A near-complete resolution of the bone marrow fibrosis was achieved at day +100. By the day +80, with continued ruxolitinib prophylaxis, the patient developed an overlap GVHD with moderate liver and skin involvement. The GVHD was resolved following Cyclosporine A administration. At 6 months post-transplant, she is alive and in complete remission.

Patient No.2 who received pre-transplant ruxolitinib therapy at our Institute was a 57-year old woman with primary myelofibrosis. At presentation n 2010 she had splenomegaly- associated symptoms, fatigue. CBC showed Hb at 111 g/L; platelets, 256×109/L; WBC, 6.4×109/L; myelocytes, 2%; metamyelocytes, 2%; band forms, 9%; segmented forms, 52%; monocytes, 7%; lymphocytes, 27%; eosinophils, 1%. She also had marked splenomegaly (20x10 mm).

In bone marrow karyotype, a clonal chromosome aberration, 46,XX t(11;16), was found. Molecular biology analysis of bone marrow cells revealed a typical CALR- mutation. Bone marrow trephine biopsy showed typical signs of overt primary myelofibrosis, i.e., atypical megakaryocytes with cluster formation and paratrabecular localization, along with Grade 3 bone marrow fibrosis (Fig. 4). The patient was attributed to the low-risk IPSS category, and started to receive Interferon-α and hydroxyurea for symptomatic splenomegaly. Despite therapy, she progressed 4 years later, as confirmed by peripheral blood blastosis and anemia.

Thus, the patient exhibited new unfavorable risk factors, having been reclassified to intermediate-2 risk group, according to DIPSS and DIPSSplus. Therefore, allogeneic stem cell transplant from full-matched unrelated donor was decided. Pre-transplant ruxolitinib therapy being performed for 6 months, in order to reduce splenomegaly. Splenomegaly was still prominent after 3 months of treatment, and pulse therapy with Dexametasone was also performed, resulting into the disease stabilization.

Figure 4. Bone marrow trephine biopsy before alloHSCT.A: Megakaryocyte proliferation with cluster formation. H&E staining.  Figure 4. Bone marrow trephine biopsy before alloHSCT.B: Bone marrow fibrosis grade 3. Gomori staining.
Figure 4. Bone marrow trephine biopsy before alloHSCT.
A: Megakaryocyte proliferation with cluster formation. H&E staining. B: Bone marrow fibrosis grade 3. Gomori staining.

Figure 5. Bone marrow trephine biopsy day +110 afteralloHSCT.
Figure 5. Bone marrow trephine biopsy day +110 after alloHSCT.

Normalization of bone marrow architecture, cellularity and megakaryocyte morphology. H&E staining.

AlloHSCT was performed in March 2015. We used G-SCF-mobilized peripheral stem cells as a stem cell source and transfused 5.1×109 СD34-positive cells per kg weight. Conditioning regimen consisted of Fludarabine (180 mg/ m2) busulfan (10 mg/kg p.o.). Ruxolitinib was stopped at the first day of conditioning regimen. Post-transplant cyclophosphamide 100 mg/kg at day +3, +4, tacrolimus and mycophenolate mofetil from day +5 were used as GVHD prophylaxis. Neutrophil and platelet engraftment was achieved at day 42 after transplant. Red blood cell transfusion independency was established at day 141 post-transplant. Complete hematological, cytogenetic and molecular remission was revealed at day +27. A near-complete resolution of bone marrow fibrosis was achieved at day +110 (Fig.5). There were no signs of acute or chronic GVHD. By 14 months post-transplant, the patient is alive and remains in complete remission.

Conclusion

Primary myelofibrosis is a myeloprolipherative neoplasm characterized by progressive clinical course. Several prognostic models and prognostic factors may help to differentiate this heterogeneous entity into different risk categories and predict survival in PMF patients. Prognostic models should be widely used to make PMF therapy more personalized. New target therapy with JAK1/JAK2 inhibitors showed high efficacy in reducing constitutional symptoms and splenomegaly in significant part of patients. Nevertheless alloHSCT remains to be the only treatment option with curative potential. Janus kinase inhibitors may be successfully used as “bridging” therapy before transplantation and possibly has beneficial impact on transplantation outcomes. Further trials are needed to validate Janus kinase inhibitors efficacy in pre- and posttransplant settings.

Considering the lack of long-term effective drug therapies for patients with MF, the potential risk of transplant-related complications seems justified in patients with DIPSS plus high- or intermediate 2–risk disease. The JAK2 inhibitor era provides a unique opportunity to begin to incorporate novel agents into the transplant algorithm for high-risk patients. Clinical trials, which examine the best way to use these agents in concert with allo-HCT and the optimal timing, will be the key to providing the best therapy for patients.

Conflict of interest

The authors declare no conflict of interest.

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Introduction

Primary myelofibrosis (PMF) is BCR-ABL–negative myeloproliferative disorder characterized by splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis (EMH), circulating CD34 progenitor cells, reactive bone marrow fibrosis, angiogenesis and an abnormal cytokine expression. PMF is a disease usually affecting elderly people. The median age at diagnosis is about 65 years, and fewer than 20% of patients are younger than 50 years [7]. PMF should be distinguished from other closely related myeloid neoplasms including polycythemia vera (PV) and essential thrombocythemia (ET).

The disease course is heterogeneous and can be complicated by progressive bone marrow failure, symptomatic splenomegaly, severe constitutional symptoms, consumption, and clinical manifestations due to extramedullary hemopoiesis [39]. In about 8% to 30% of patients, the disease evolves into acute leukemia [12], [27]. Conventional drug therapy of PMF is merely palliative and does not prolong survival [41]. Allogeneic hemopoietic stem cell transplantation (allo- HSCT) offers the only chance for cure of PMF, but the conventional form of the procedure carries substantial morbidity and mortality and can be offered only to a minority of younger patients. Recently, the introduction of reduced-intensity allo-HSCT has made this therapy available to older patients not eligible for standard allo-HSCT.

Clinical manifestations

Clinical features in PMF are heterogeneous and include severe anemia, marked hepatosplenomegaly, constitutional symptoms (e.g., fatigue, night sweats, fever), cachexia, bone pain, splenic infarct, pruritus, thrombosis, and bleeding. Ineffective erythropoiesis and EMH are the main causes of anemia and organomegaly. Other disease complications include symptomatic portal hypertension that might lead to variceal bleeding or ascites and non-hepatosplenic EMH that might lead to cord compression, ascites, pleural effusion, pulmonary hypertension, or diffuse extremity pain. It is currently assumed that aberrant cytokine production by clonal cells and host immune reaction contributes to PMF-associated bone marrow stromal changes, ineffective erythropoiesis, EMH, cachexia, and constitutional symptoms [6]. Causes of death include leukemic progression that occurs in approximately 20% of patients but many patients also die of comorbid conditions including cardiovascular events and consequences of cytopenias including infection or bleeding [7].

Laboratory diagnostics

Current diagnosis of PMF is based on WHO criteria and includes clinical, morphologic, cytogenetic, and molecular assessments.

Typical laboratory features in patients with PMF include anemia (28% of PMF cases), peripheral blood leukoerythroblastosis, dacryocytosis, leukocytosis/thrombocytosis, increased lactate dehydrogenase (LDH), excess circulating blasts or CD34 cells, and bone marrow fibrosis, osteosclerosis, and angiogenesis (Figure 1). Differential diagnosis should be performed with polycythemia vera (PV) and essential thrombocythemia (ET). Patients who otherwise fulfill the diagnostic criteria for PV should be labeled as “PV” even if they display substantial bone marrow fibrosis [40].

Figure 1. Main aspects of PMF pathogenesis.[24]
Figure 1. Main aspects of PMF pathogenesis.[24]

Occasionally, overt bone marrow fibrosis might be absent and, in the presence of thrombocytosis, a false diagnosis of ET is made. The possibility of prefibrotic PMF, as opposed to ET, should be considered in the presence of persistently increased serum LDH, anemia, leukoerythroblastosis, increased circulating CD34+ cell count, and marked splenomegaly. It is underscored that the distinction between ET and prefibrotic PMF is clinically relevant because both OS and leukemia-free survival are significantly inferior in the latter [23]. Therefore, prefibrotic myelofibrosis is defined as separate entity in the new version of WHO classification 2016 [3].

The differential diagnosis of PMF should also include bone marrow fibrosis associated with non-neoplastic or other neoplastic conditions, including metastatic cancer, lymphoid neoplasm, or another myeloid malignancy, especially CML, MDS, chronic myelomonocytic leukemia (CMML), or AML. The presence of JAK2 or MPL mutation, with a combined mutational frequency of 70%, reliably excludes reactive bone marrow fibrosis or a nonmyeloid malignancy. More recently, calreticulin (CALR) gene mutations have been reported in patients with MF (and ET) who lack JAK2 V617F or MPL mutations [20]. Nangalia et al. identified a high prevalence of CALR mutations in JAK2/MPL-negative patients with MF. About 56% of patients with JAK2 V617F/MPL-negative MF had CALR mutations [29]. Identification of CALR mutation additionally confirms MF diagnosis.

The absence of BCR-ABL1 excludes the possibility of CML. MDS or CMML should be considered in presence of dyserythropoiesis/dysgranulopoiesis or peripheral blood monocytosis , respectively.

Prognostic factors

PMF is a heterogeneous disease in its presentation and evolution. Median survival is highly variable; a proportion of patients die shortly after diagnosis, whereas a few survive for 2 decades or longer. This fact has stimulated identification of prognostic factors and, as a result, several prognostic systems have been proposed.

The International Prognostic Scoring System (IPSS) uses five risk factors to predict prognosis and assign a patient to a risk group: age older than 65 years; hemoglobin less than 10 g/dL; leukocyte count more than 25 x 10 9 /L; circulating blood blasts 1% or more; and the presence of constitutional symptoms [7]. The Dynamic IPSS (DIPSS) uses the same five risk factors and has been validated to predict prognosis at any time during the disease course [31].

The DIPSS has been recently modified (DIPSS Plus) with the incorporation of three additional risk factors: red blood cell transfusion needed; platelet count < 100 x10 9 /L; and unfavorable karyotype [complex or sole or two abnormalities, including + 8, 7/7q , i(17q), inv(3), 5/5q , 12q or 11q23 rearrangement]. The four DIPSS-plus risk categories based on the eight risk factors are low (no risk factors), intermediate- 1 (one risk factor), intermediate-2 (two or 3 risk factors), and high (four or more risk factors) with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years [12], table 1. Furthermore, a >80% two-year mortality was predicted by monosomal karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts >9%, leukocytes 40 x109/L or more, or other unfavorable karyotype. Patients with the latter characteristics are operationally assigned a “very high risk” category and might be better served by immediate consideration for alloHSCT [42].

Several molecular prognostic markers might be soon included in DIPSSplus. A. Tefferi et.al. reported DIPSS-plus independent prognostic significance for calreticulin (CALR) (favorable) and ASXL1 (unfavorable) mutations. Survival was the longest in CALR+ASXL- (median 10.4 years) and the shortest in CALR-ASXL1+ patients (median, 2.3 years; HR, 5.9; 95%,CI, 3.5–10.0). The CALR/ASXL1 mutations-based prognostic model was DIPSS-plus independent (P<0.0001) and effective in identifying low-/intermediate-1-risk patients with shorter (median, 4 years) or longer (median 20 years) survival and high-/intermediate-2-risk patients with shorter (median, 2.3 years) survival. Multivariable analysis distinguished CALR-ASXL1+ mutational status as the most significant risk factor for survival: HR 3.7 vs 2.8 for age >65 years vs 2.7 for unfavorable karyotype [45]. In a large multicenter study evolving 879 patients with PMF other molecular markers (SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2) showed no prognostic significance [45].

Survival in PMF was also affected by increased serum IL-8 and IL-2R levels as well as serum-free light chain levels, both independent of DIPSS-plus [30], [43].

Risk factors for leukemia-free survival include ≥3% circulating blasts, platelet count <100 x 109/L, and presence of unfavorable karyotype . Although DIPSS has been shown to predict leukemia-free survival in the aforementioned DIPSS-plus study of 793 patients with PMF, the only two risk factors for leukemic transformation were unfavorable karyotype and platelet count <100 x 109/L; 10-year risk of leukemic transformation were 12% in the absence of these two risk factors and 31% in the presence of one or both risk factors [32].

Table 1. Prognostic risk models in PMF [7, 10, 12, 31]
Table 1. Prognostic risk models in PMF [7, 10, 12, 31]

* Constitutional symptoms constitute weight loss > 10% of baseline value in the year preceding diagnosis, unexplained fever, or excessive sweats persisting for > 1 month.38
**Unfavorable karyotype constitutes complex karyotype or sole or 2 abnormalities that include 8, 7/7q, i(17q), inv(3), 5/5q12p, or 11q23 rearrangement.

Figure 2. Chromosomal abnormalities in PMF. Typicalchromosomal abnormality in patient with PMF 47XY,XY,+8[8]/46,XY[12].

Figure 2. Chromosomal abnormalities in PMF. Typical chromosomal abnormality in patient with PMF 47XY, XY,+8[8]/46,XY[12].

Treatment strategy

Current drug therapy for PMF is not curative and has not been shown to prolong survival. AlloHSCT for PMF is potentially curative but dangerous; transplant-related death or severe morbidity occurs in a high percent of transplanted patients. As a result, more and more patients with PMF (or post-PV/ET MF) are seeking treatment with novel drugs. However, it should be noted that many patients can be observed without any therapeutic intervention and some can be effectively managed by conventional drug therapy.

Management of low or intermediate-1 risk patients

There is no evidence to support the specific therapy in asymptomatic patients with low or intermediate-1 risk disease [41]. Some patients with low or intermediate-1 risk might require therapy for symptomatic anemia, splenomegaly, non-hepatosplenic EMH, bone pain, EMH-associated pulmonary hypertension, or constitutional symptoms (e.g., fatigue, night sweats, and pruritus). In addition, cytoreductive therapy is reasonable but not mandated in the presence of extreme leukocytosis or thrombocytosis.

MF-associated anemia is usually treated with androgens, prednisone (0.5 mg/kg/day), danazol (600 mg/day) [6], thalidomide, or lenalidomide (10mg/day) [33].

Drug side effects include hepatotoxicity and virilizing effects for androgens, peripheral neuropathy for thalidomide, and myelosuppression for lenalidomide.

Response rates to each one of the aforementioned drugs are in the vicinity of 15-25% and response durations average about one to two years. Lenalidomide works best in the presence of del(5q31) [38].

First-line therapy for MF-associated splenomegaly is hydroxyurea, which is effective in reducing spleen size by half in approximately 40% of patients [26]. Spleen response to hydroxyurea lasts for an average of one year and treatment side effects include myelosuppression and mucocutaneous ulcers.

Interferon-α could be used in symptomatic patients with PMF. Interferon suppresses hematopoietic progenitors, bone marrow fibroblast progenitors and platelet-derived growth factor. The advent of a pegylated version of interferon has renewed interest in this class, perhaps for using early on in the course of ET or PV, with a goal of preventing or delaying fibrosis [19]. Long-term follow-up of 62 French and Belgian patients with MF treated with interferon-α has been recently reported; 46% experienced an improvement in splenomegaly, 82% experienced a mitigation in MF symptoms, and 73%, 64% and 78% of patients experienced an improvement in anemia, leukocytosis and thrombocytosis, respectively [16]. Complementing this study was a prospective trial of 32 lower-risk patients with early MF treated with recombinant or pegylated interferon [36]. An overall response rate of 78% was observed, with 3 complete remissions (9.4%), 12 partial remissions (37.5%), 3 clinical improvements (9.4%) and 7 with (22%) stable disease. Follow-up bone marrow biopsy results were available for 22 patients. Twelve patients had a reduction in cellularity that occurred after a median treatment duration of 2 years. Three patients, all of whom also experienced reductions in splenomegaly, had significant improvements in megakaryocyte morphology, marrow architecture and reductions of reticulin and collagen fibrosis (grade 3 to 1).

Management of intermediate-2 or high risk disease

PMF patients with high or intermediate-2 risk disease should be considered for investigational drug therapy or alloHSCT.

JAK1/JAK2 inhibitors are highly effective in patients with MF. Ruxolitinib was evaluated in 153 patients with PMF or post-PV/ET MF, in a Phase-1/2 study [47]. Dose limiting toxicity (DLT) was thrombocytopenia and the maximum tolerated dose was either 25 mg twice-daily or 100 mg once-daily. Adverse events included thrombocytopenia, anemia, and a “cytokine rebound reaction” upon drug discontinuation, characterized by acute relapse of symptoms and splenomegaly [47]. Non-hematologic adverse events were infrequent. Grade 3/4 thrombocytopenia or anemia (in transfusion-independent patients at baseline) respectively occurred in 39% and 43% of patients receiving the drug at 25 or 10 mg twice daily.

Among all evaluable patients, 44% experienced 50% decrease in palpable spleen size. Improvement in constitutional symptoms (fatigue, pruritus, abdominal discomfort, early satiety, night sweats, and exercise tolerance) and weight gain were seen in the majority of patients. Four (14%) of 28 transfusion- dependent patients became transfusion-independent. The drug’s effect on JAK2V617F allele burden or bone marrow pathology was negligible but a major reduction in proinflammatory cytokines (e.g., IL-1RA, IL-6, TNF-a, MIP- 1b) was documented and coincided with improvement in constitutional symptoms. Two randomized studies comparing ruxolitinib with either placebo or best supportive care have now been published [11], [47]. In the COMFORT-1 trial that compared the drug with placebo (n5309), the spleen response rate was approximately 42% for ruxolitinib versus <1% for placebo.

In addition, about 46% of patients experienced substantial improvement in their constitutional symptoms. However, the benefit of the drug was antagonized by ruxolitinib-associated anemia (31% vs. 13.9%) and thrombocytopenia (34.2% vs. 9.3%). In the COMFORT-2 trial that compared the drug with “best available therapy” (n5219), the spleen response was 28.5% with ruxolitinib vs. 0% otherwise but the drug was detrimental in terms of thrombocytopenia (44.5% vs. 9.6%), anemia (40.4% vs. 12.3%), and diarrhea (24.0% vs. 11.0%). The long-term outcome of ruxolitinib therapy in MF was recently reported and disclosed a very high treatment discontinuation rate (92% after a median time of 9.2 months) and the occurrence of severe withdrawal symptoms during ruxolitinib treatment discontinuation (“ruxolitinib withdrawal syndrome”) characterized by acute relapse of disease symptoms, accelerated splenomegaly, worsening of cytopenias, and occasional hemodynamic decompensation, including a septic shock-like syndrome [47].

Presently, ruxolitinib is the only FDA-approved JAK1/2 inhibitor for MF and the only non-HCT therapy to date associated with a proven survival benefit. In the phase III COMFORT-I study ruxolitinib was associated with an overall survival benefit relative to placebo in patients with intermediate- 2 or high-risk MF. With median follow-ups of 149.1 and 149.3 weeks for the ruxolitinib and placebo arms, respectively, the hazard ratio for overall survival continued to favor patients originally randomized to ruxolitinib compared with those originally randomized to placebo [hazard ratio 0.69 (95% CI: 0.46–1.03); P=0.067]. Different long-term outcomes have been reported by the Mayo Clinic and the MD Anderson Cancer Center (MDACC) in follow-up of their own institutional cohorts enrolled in the phase 1/2 study of ruxolitinib. Including adjustment for the Dynamic International Prognostic Scoring System score, the Mayo Clinic reported no significant difference in the survival rate of their 51 ruxolitinib-treated patients compared with a cohort of 410 patients with PMF who were treated with standard therapy at their center in the most recent 10-year period [46].

MDACC undertook a similar analysis, comparing the longterm outcomes of their patients with a historical control cohort of 310 patients culled from 3 databases who would have met eligibility for the study [48]. OS was significantly improved in ruxolitinib-treated patients compared with historical controls adjusted for International Prognostic Scoring System risk group. The 1-, 2-, and 3-year survival rates in high-risk patients treated with ruxolitinib were superior to the historical control group and a nonsignificant trend in survival was observed between intermediate-2-risk ruxolitinib treated and historical control patients.

In the absence of hematologic remissions, significant reduction in BM fibrosis and/or V617F allele burden, nor any proven modification of leukemia-free survival, other factors may explain the emerging survival advantage with ruxolitinib. Foremost is the enhancement of performance status related to reduction of splenomegaly and improvement of constitutional symptoms.

These data suggest that the survival advantage associated with ruxolitinib may be partly explained by reversion of the catabolic state associated with MF.

Allogeneic stem cell transplantation

AlloHSCT is arguably one of the riskiest interventions in modern medicine, so careful patient selection is of paramount importance. Transplantation for PV and ET, overall associated with a normal or near-normal life expectancy, is not indicated. On the other hand, alloHSCT should be an initial consideration for all patients with MF when first evaluated, and is the treatment of choice for high-risk symptomatic younger patients. What is fascinating and tantalizing in such cases is the capacity for this approach to restore normal trilineage hematopoiesis in a grossly perturbed marrow microenvironment, with rapid and striking reversal of the fibrosis that is the hallmark of this neoplasm [22].

Although a broad range of conditioning regimens of different intensities has been developed, the initial studies of alloHSCT for MF used high-intensity myeloablative conditioning (MAC) regimens, usually including total body irradiation (TBI) or busulfan. For MAC regimens, graft failure rates of less than 5% to 30% have been reported, reflecting the heterogeneity in patient populations and specific conditioning regimens [14], [18]. Published TRM rates of 10% to 35% at 1 year and OS from 30% to 67% at 5 years have been reported [5, 9, 13, 21, 25, 28].

The largest study to date was reported from the Center for International Blood and Marrow Transplant Research (CIBMTR), analyzing data in 289 patients with PMF [5]. Patients underwent a transplant between 1989 and 2002 at 118 centers, with a variety of conditioning regimens. A total of 162 patients received an HLA-matched sibling transplant, 101 received HLA-matched unrelated donor (URD) transplants, and 26 received transplants from HLA nonidentical related donors. Most of the patients received bone marrow as the stem cell source, and 83% were conditioned with a MAC regimen. The 100-day TRM was 18% for HLA-matched sibling patients and 33% for the URD patients. The graft failure rate was 9% for HLA-matched sibling transplants and 20% for URD transplants. Splenomegaly did not impact the graft failure rate. Graft-versus-host-disease (GVHD) grades II to IV occurred in 43% of sibling patients and 40% of the URD patients. The OS at 5 years was 37% for sibling transplants and 30% for URD transplants. Relapse-free survival (RFS) at 5 years was 33% for recipients of an HLA-identical sibling allografts and 27% for recipients of URD transplants. Positive predictors for survival included HLA-identical sibling donors, performance status greater than 90%, and absence of peripheral blood blasts at the time of transplantation. Patients who had a poor Karnofsky score, peripheral blood blasts, or received a transplant from a URD had a 15% probability of 3-year survival.

The largest prospective multicenter study to evaluate transplantation for MF was conducted through the European Group for Blood and Marrow Transplantation (EBMT) using a reduced intensity strategy [21]. Using the combination of fludarabine, busulfan (10 mg/kg) and antithymocyte globulin with a standard prophylactic immunosuppressive regimen, 98% of patients engrafted, with a nonrelapse mortality of 16% at 1 year. In addition, the estimated 5-year overall survival was 67%. Older age (over 55) and a mismatched donor adversely influenced survival. Subsequent post hoc analyses showed that JAK2 V617F negative disease also carried adverse prognostic significance [2]. These generally favorable results were mirrored histologically in those patients who had serial bone marrow biopsies following transplantation. These studies showed near or complete resolution of fibrosis in 69% and 93% of patients by day 100 and day 365. An additional notable finding from the multivariable analysis was that a history of splenectomy was associated with a higher risk of relapse.

JAK1/JAK2 inhibition as pre- and posttansplant therapy

Most of MF patients are in active disease phase at the time of allo-HSCT and have severe splenomegaly and constitutional symptoms. High disease burden may be one of the reasons why the results of allo-HSCT in MF patients are not satisfactory in some cases. Furthermore, a lot of studies report relatively high incidence of graft failure and poor graft function in MF patients compared to some other hematologic disorders [1, 5, 21, 34]. Several studies reported higher median time to neutrophil and platelets engraftment in patients with splenomegaly compared to patients with splenectomy, but this difference showed no significant impact on overall survival [1, 21]. Other data suggest that splenomegaly is an independent predictor of inferior overall survival after allo- HSCT [4]. Alchalby et al. showed that the other feature of active disease phase – constitutional symptoms also decrease OS after allo-HSCT [2].

Using JAK1/2 inhibitors to reduce spleen size and constitutional symptoms before HCT may be useful in improving transplant outcome. In a study by a German group, 14 patients received allo-HCT following a median of 6.5 months treatment with ruxolitinib [17]. Under ruxolitinib therapy, spleen size was reduced in 64% of patients and engraftment was achieved in 93% of patients. TRM was 7% and survival 79%, but the median follow-up was only 9 months. Another German group reported a retrospective analysis of results in 22 patients with PMF or after ET/PV MF who had received a median of 97 days of ruxolitinib before alloHSCT [37]. At the time of transplant, 86% had improvement in constitutional symptoms and 41% had a major response in spleen size. With a median follow-up of 12 months, the 1-year OS was 81% and PFS was 76%.

Recently Shanavas et al. has reported results of large multicenter retrospective study, which tested efficacy of pretransplant JAK1/2 inhibitors therapy [35]. 100 patients with MF who undergo alloHSCT after JAK1/2 inhibitors therapy were included in this study. Multivariate analysis showed that response to JAK1/2 inhibitors therapy significantly improves OS (p=0,03). Thus 2-years OS was 91% in patients who achieved clinical improvement and 32% in those patients who progressed to leukemic transformation on JAK1/2 inhibitors therapy.

The experience in administrating JAK1/2 inhibitors after allo-HSCT in MF patients is very scarce. We found only one report about posttransplant ruxolitinib therapy which was administrated to prevent relapse in 3 MF patients and 1 CMML patient [44]. Authors report no adverse events of toxicity during posttransplant therapy.

The beneficial impact of JAK1/2 inhibitors on transplant outcomes may be explained by its ability to modulate disease status compared to the other conventional therapies [47]. Pretransplant ruxolitinib therapy may reduce splenomegaly and constitutional symptoms and possibly reduce the graft failure rate. At the same time ruxolitinib reduce the proinflammatory and proangiogenic cytokines overproduction in MF patients [46]. Through this effect it can modulate immune response and reduce dendritic cells activation [15], neutrophils activation [49] and migration of alloreactive T-cells [8]. Possibly ruxolitinib pre- and postransplant therapy may reduce GVHD rate and improve transplant results in MF-patients (Figure 3). Currently ruxolitinib is effectively used for treatment of steroid-refractory acute and chronic GVHD [49]. Choi et al. showed that phamacologic blockade of JAK1/2 results in reduction of CXCR3 expression in T cells, mitigation of GvHD after allo-HSCT and preservation of graft versus leukemia effect in mouse models [8]. The authors suggest that JAK1/2 inhibitors might be a promising therapeutic approach to achieve the beneficial anti-leukemia effect and reduce GVHD rate in allo-HSCT.

Whether JAK1/2 inhibitors treatment before HCT can consistently improve patient performance status, the degree of splenomegaly, GVHD rate and lead to more favorable outcomes is an important area of ongoing investigation.

Figure 3. Pre-and posttransplant JAK1/2 inhibitors therapy.
Figure 3. Pre-and posttransplant JAK1/2 inhibitors therapy.

Clinical case descriptions

Here we report two female patients with postpolycythaemic myelofibrosis treated with allogeneic stem cell transplantation. Patient No.1 was a 46-year old woman with polycythaemia vera diagnosed 5 years prior to transplantation in 2010. At presentation she suffered from splenomegaly–associated symptoms – occasionally episodes of pain in the left upper quadrant. Complete blood count showed hemoglobin 189 g/L; WBC count, 21.5x109/L; myelocytes, 7%; metamyelocytes; 2%; band forms; 11%; segmented forms, 61%; monocytes, 10%; lymphocytes, 9%; platelets, 268x109/L. Ultrasound scan detected enlarged spleen (193x82 mm).

Bone marrow molecular biology analysis revealed a JAK2V617F mutation. Bone marrow cytogenetic analysis has shown a clonal aberration (47,XX+8) observed in 20/20 mitotic cells.

Erythrocytapheresis and hydroxyurea therapy were subsequently performed a symptomatic treatment, due to high hemoglobin level and splenomegaly.

After 5 years of follow-up, the patient developed the disease progression to myelofibrosis as documented by peripheral blood blastosis, LDH elevation, and histologically verified bone marrow fibrosis (Grade 2/3). At the time of progression, the JAK2 V617F-allele burden was 55% of the wild-type level. Thus, the patient was classified into the intermediate-2 risk category corresponding to DIPSSplus and, therefore, allo- HSCT was indicated.

To reduce splenomegaly, were performing pre-transplant ruxolitinib therapy for 3 months. The patient achieved clinical improvement, as evidenced by significant spleen reduction and disappearance of blasts in periphery. At that clinical stage, we performed allogeneic stem cell transplantation from 9/10 –HLA matched unrelated donor in December 2015. We used G-SCF-mobilized peripheral stem cells as stem cell source and transfused 6.6×109 СD34-positive cells per kg weight. Conditioning regimen consisted of fludarabine (180 mg/m2), busulfan (10 mg/kg p.o.). The patient continued to take ruxolitinib during conditioning until day -1. Post-transplant cyclophosphamide was administered at 100 mg/kg at day +3, +4, and ruxolitinib 10 mg was used from day +5 as GVHD prophylaxis. During early post-transplant period, the patient developed non-severe veno-occlusive liver disease. This complication resolved later spontaneously. Neutrophil and platelet engraftment, like as independence on red blood cell transfusion was achieved at day 20-21 after transplant. Complete hematological, cytogenetic and molecular remission was documented at day +30. A near-complete resolution of the bone marrow fibrosis was achieved at day +100. By the day +80, with continued ruxolitinib prophylaxis, the patient developed an overlap GVHD with moderate liver and skin involvement. The GVHD was resolved following Cyclosporine A administration. At 6 months post-transplant, she is alive and in complete remission.

Patient No.2 who received pre-transplant ruxolitinib therapy at our Institute was a 57-year old woman with primary myelofibrosis. At presentation n 2010 she had splenomegaly- associated symptoms, fatigue. CBC showed Hb at 111 g/L; platelets, 256×109/L; WBC, 6.4×109/L; myelocytes, 2%; metamyelocytes, 2%; band forms, 9%; segmented forms, 52%; monocytes, 7%; lymphocytes, 27%; eosinophils, 1%. She also had marked splenomegaly (20x10 mm).

In bone marrow karyotype, a clonal chromosome aberration, 46,XX t(11;16), was found. Molecular biology analysis of bone marrow cells revealed a typical CALR- mutation. Bone marrow trephine biopsy showed typical signs of overt primary myelofibrosis, i.e., atypical megakaryocytes with cluster formation and paratrabecular localization, along with Grade 3 bone marrow fibrosis (Fig. 4). The patient was attributed to the low-risk IPSS category, and started to receive Interferon-α and hydroxyurea for symptomatic splenomegaly. Despite therapy, she progressed 4 years later, as confirmed by peripheral blood blastosis and anemia.

Thus, the patient exhibited new unfavorable risk factors, having been reclassified to intermediate-2 risk group, according to DIPSS and DIPSSplus. Therefore, allogeneic stem cell transplant from full-matched unrelated donor was decided. Pre-transplant ruxolitinib therapy being performed for 6 months, in order to reduce splenomegaly. Splenomegaly was still prominent after 3 months of treatment, and pulse therapy with Dexametasone was also performed, resulting into the disease stabilization.

Figure 4. Bone marrow trephine biopsy before alloHSCT.A: Megakaryocyte proliferation with cluster formation. H&E staining.  Figure 4. Bone marrow trephine biopsy before alloHSCT.B: Bone marrow fibrosis grade 3. Gomori staining.
Figure 4. Bone marrow trephine biopsy before alloHSCT.
A: Megakaryocyte proliferation with cluster formation. H&E staining. B: Bone marrow fibrosis grade 3. Gomori staining.

Figure 5. Bone marrow trephine biopsy day +110 afteralloHSCT.
Figure 5. Bone marrow trephine biopsy day +110 after alloHSCT.

Normalization of bone marrow architecture, cellularity and megakaryocyte morphology. H&E staining.

AlloHSCT was performed in March 2015. We used G-SCF-mobilized peripheral stem cells as a stem cell source and transfused 5.1×109 СD34-positive cells per kg weight. Conditioning regimen consisted of Fludarabine (180 mg/ m2) busulfan (10 mg/kg p.o.). Ruxolitinib was stopped at the first day of conditioning regimen. Post-transplant cyclophosphamide 100 mg/kg at day +3, +4, tacrolimus and mycophenolate mofetil from day +5 were used as GVHD prophylaxis. Neutrophil and platelet engraftment was achieved at day 42 after transplant. Red blood cell transfusion independency was established at day 141 post-transplant. Complete hematological, cytogenetic and molecular remission was revealed at day +27. A near-complete resolution of bone marrow fibrosis was achieved at day +110 (Fig.5). There were no signs of acute or chronic GVHD. By 14 months post-transplant, the patient is alive and remains in complete remission.

Conclusion

Primary myelofibrosis is a myeloprolipherative neoplasm characterized by progressive clinical course. Several prognostic models and prognostic factors may help to differentiate this heterogeneous entity into different risk categories and predict survival in PMF patients. Prognostic models should be widely used to make PMF therapy more personalized. New target therapy with JAK1/JAK2 inhibitors showed high efficacy in reducing constitutional symptoms and splenomegaly in significant part of patients. Nevertheless alloHSCT remains to be the only treatment option with curative potential. Janus kinase inhibitors may be successfully used as “bridging” therapy before transplantation and possibly has beneficial impact on transplantation outcomes. Further trials are needed to validate Janus kinase inhibitors efficacy in pre- and posttransplant settings.

Considering the lack of long-term effective drug therapies for patients with MF, the potential risk of transplant-related complications seems justified in patients with DIPSS plus high- or intermediate 2–risk disease. The JAK2 inhibitor era provides a unique opportunity to begin to incorporate novel agents into the transplant algorithm for high-risk patients. Clinical trials, which examine the best way to use these agents in concert with allo-HCT and the optimal timing, will be the key to providing the best therapy for patients.

Conflict of interest

The authors declare no conflict of interest.

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ПМФ может осложняться костномозговой недостаточностью, спленомегалией, общими (конституциональными) симптомами и клиническими признаками экстрамедуллярного гемопоэза. Острый лейкоз развивается нередко у больных ПМФ (до 30%). Обычшая цитостатическая терапия ПМФ не влияет на показатели выживаемости пациентов. В тоже время аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) является единственной излечивающей процедурой для ПМФ. Диагноз ПМФ осуществляется на основании соответствующих указаний ВОЗ и включает в себя клинические, морфологические, цитогенетические и молекулярные критерии. Это заболевание следует отличать от родственных ему миелоидных неоплазий, например – истинной полицитемии и эссенциальной тромбоцитемии (ЭТ). Дифференциальный диагноз ПМФ должен также включать фиброз костного мозга, связанный с другими неопухолевыми и неопластическими заболеваниями. В дополнение к мутациям JAK2 V617F or MPL, недавно предложен также в качестве генного маркера ген CALR, который характерен для миелофиброза и ЭТ. </p> <p> Прогностические подходы следуют из основной концепции ПМФ как гетерогенного заболевания с довольно индивидуальными проявлениями и эволюцией, и весьма различной продолжительностью жизни (до 20 лет и более). </p> <p> Соответствующая балльная шкала (IPSS) применяет 5 факторов риска для предсказания прогноза и распределения больных по группам риска. Эти факторы риска повышенного риска при оценке безлейкозной выживаемости – следующие: ≥3% бластов в кровотоке, число тромбоцитов &lt;100×109/л, и наличие неблагоприятного кариотипа . </p> <p> Лекарственное лечение ПМФ не является эффективным в плане общей или бессобытийной выживаемости. Алло-ТГСК при ПМФ является потенциально исцеляющим, но весьма опасным методом. В то же время многих пациентов можно наблюдать в течение длительного времени, а некоторых больных можно успешно лечить обычными методами терапии. </p> <p> Для больных с низким ли промежуточным-1 риском не нужды в специфическомлечении при отсутствии выраженных симптомов. Циторедуктивная терапия может быть обоснованной в случаях чрезмерного лейко- или тромбоцитоза. Побочные эффекты препаратов могут включать гепатотоксические или вирилизирующие эффекты андрогенов, периферическую нейропатию (талидомид) и миелосупрессию (леналидомид). Терапия первой линии с гидроксимочевиной может уменьшить размер селезенки до 40% на срок до 1 года. Побочные эффекты мочевины включают миелосупрессию и язвы кожи и слизистых. Пегилированный интерферон применяется в настоящее время при ранней терапии ЭТ и истинной полицитемии с целью предотвратить или отсрочить развитие фиброза. Пациенты с промежуточным-2 или высоким риском трансплантации должны проходить лечение новыми исследовательскими препаратами или посредством алло-ТГСК. Так, ингибиторы JAK1/JAK2 (например – Ruxolitinib) высокоэффективны при ПМФ или ЭТ. В настоящее врем руксолитиниб является единственным JAK2-ингибитором, разрешенным FDA препаратом для лечении миелофиброза и уникальным методом нетрансплантационной терапии, связанной с повышенной выживаемостью этих пациентов. Алло-ТГСК является очень эффективной, будучи, однако, рискованной пройедурой, будучи методом выбора для более молодых пациентов с признаками ПМФ высокой степени риска. 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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(4) "6161" ["VALUE"]=> array(2) { ["TEXT"]=> string(224) "<p class="Autor"> Елена В. Морозова, Мария В. Барабанщикова, Татьяна Л. Гиндина, Вадим В. Байков, Борис В. Афанасьев </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(202) "

Елена В. Морозова, Мария В. Барабанщикова, Татьяна Л. Гиндина, Вадим В. Байков, Борис В. Афанасьев

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "6162" ["VALUE"]=> array(2) { ["TEXT"]=> string(346) "НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой Первого Санкт-Петербургского государственного медицинского Университета им. И.П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(346) "НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой Первого Санкт-Петербургского государственного медицинского Университета им. И.П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~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(4) "6151" ["VALUE"]=> array(2) { ["TEXT"]=> string(7896) "<p> Первичный миелофиброз (ПМФ) является BCR/ABL–негативное миелопролиферативное заболевание со спленомегалией, наличием лейкоэритробластов, экстрамедуллярным гемопоэзом, реактивным фиброзом костного мозга и неоангиогенезом с аномальной продукцией цитокинов, которое поражает, главным образом, пожилых лиц. ПМФ может осложняться костномозговой недостаточностью, спленомегалией, общими (конституциональными) симптомами и клиническими признаками экстрамедуллярного гемопоэза. Острый лейкоз развивается нередко у больных ПМФ (до 30%). Обычшая цитостатическая терапия ПМФ не влияет на показатели выживаемости пациентов. В тоже время аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) является единственной излечивающей процедурой для ПМФ. Диагноз ПМФ осуществляется на основании соответствующих указаний ВОЗ и включает в себя клинические, морфологические, цитогенетические и молекулярные критерии. Это заболевание следует отличать от родственных ему миелоидных неоплазий, например – истинной полицитемии и эссенциальной тромбоцитемии (ЭТ). Дифференциальный диагноз ПМФ должен также включать фиброз костного мозга, связанный с другими неопухолевыми и неопластическими заболеваниями. В дополнение к мутациям JAK2 V617F or MPL, недавно предложен также в качестве генного маркера ген CALR, который характерен для миелофиброза и ЭТ. </p> <p> Прогностические подходы следуют из основной концепции ПМФ как гетерогенного заболевания с довольно индивидуальными проявлениями и эволюцией, и весьма различной продолжительностью жизни (до 20 лет и более). </p> <p> Соответствующая балльная шкала (IPSS) применяет 5 факторов риска для предсказания прогноза и распределения больных по группам риска. Эти факторы риска повышенного риска при оценке безлейкозной выживаемости – следующие: ≥3% бластов в кровотоке, число тромбоцитов &lt;100×109/л, и наличие неблагоприятного кариотипа . </p> <p> Лекарственное лечение ПМФ не является эффективным в плане общей или бессобытийной выживаемости. Алло-ТГСК при ПМФ является потенциально исцеляющим, но весьма опасным методом. В то же время многих пациентов можно наблюдать в течение длительного времени, а некоторых больных можно успешно лечить обычными методами терапии. </p> <p> Для больных с низким ли промежуточным-1 риском не нужды в специфическомлечении при отсутствии выраженных симптомов. Циторедуктивная терапия может быть обоснованной в случаях чрезмерного лейко- или тромбоцитоза. Побочные эффекты препаратов могут включать гепатотоксические или вирилизирующие эффекты андрогенов, периферическую нейропатию (талидомид) и миелосупрессию (леналидомид). Терапия первой линии с гидроксимочевиной может уменьшить размер селезенки до 40% на срок до 1 года. Побочные эффекты мочевины включают миелосупрессию и язвы кожи и слизистых. Пегилированный интерферон применяется в настоящее время при ранней терапии ЭТ и истинной полицитемии с целью предотвратить или отсрочить развитие фиброза. Пациенты с промежуточным-2 или высоким риском трансплантации должны проходить лечение новыми исследовательскими препаратами или посредством алло-ТГСК. Так, ингибиторы JAK1/JAK2 (например – Ruxolitinib) высокоэффективны при ПМФ или ЭТ. В настоящее врем руксолитиниб является единственным JAK2-ингибитором, разрешенным FDA препаратом для лечении миелофиброза и уникальным методом нетрансплантационной терапии, связанной с повышенной выживаемостью этих пациентов. Алло-ТГСК является очень эффективной, будучи, однако, рискованной пройедурой, будучи методом выбора для более молодых пациентов с признаками ПМФ высокой степени риска. Очевидный эффект ТГСК при ПМФ состоит в быстром восстановлении нормального трехросткового кроветворения, появлении функционального микроокружения и ослаблении процесса миелофиброза. </p> <h2>Заключение</h2> <p> Ввиду отсутствия методов терапии ПМФ, ведущих к длительному эффекту, доказан потенциальный риск осложнений, связанных с трансплантацией у больных высокой и промежуточной-2 степеней риска. Ингибиторы JAK2 дают уникальную возможность внедрения этих новых препаратов в программы трансплантации для пациентов группы высокого риска. Общие выводы данной статьи проиллюстрированы двумя клиническими примерами из опыта авторов, которые показывают успешные результаты алло-ТГСК при миелофиброзе. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7808) "

Первичный миелофиброз (ПМФ) является BCR/ABL–негативное миелопролиферативное заболевание со спленомегалией, наличием лейкоэритробластов, экстрамедуллярным гемопоэзом, реактивным фиброзом костного мозга и неоангиогенезом с аномальной продукцией цитокинов, которое поражает, главным образом, пожилых лиц. ПМФ может осложняться костномозговой недостаточностью, спленомегалией, общими (конституциональными) симптомами и клиническими признаками экстрамедуллярного гемопоэза. Острый лейкоз развивается нередко у больных ПМФ (до 30%). Обычшая цитостатическая терапия ПМФ не влияет на показатели выживаемости пациентов. В тоже время аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) является единственной излечивающей процедурой для ПМФ. Диагноз ПМФ осуществляется на основании соответствующих указаний ВОЗ и включает в себя клинические, морфологические, цитогенетические и молекулярные критерии. Это заболевание следует отличать от родственных ему миелоидных неоплазий, например – истинной полицитемии и эссенциальной тромбоцитемии (ЭТ). Дифференциальный диагноз ПМФ должен также включать фиброз костного мозга, связанный с другими неопухолевыми и неопластическими заболеваниями. В дополнение к мутациям JAK2 V617F or MPL, недавно предложен также в качестве генного маркера ген CALR, который характерен для миелофиброза и ЭТ.

Прогностические подходы следуют из основной концепции ПМФ как гетерогенного заболевания с довольно индивидуальными проявлениями и эволюцией, и весьма различной продолжительностью жизни (до 20 лет и более).

Соответствующая балльная шкала (IPSS) применяет 5 факторов риска для предсказания прогноза и распределения больных по группам риска. Эти факторы риска повышенного риска при оценке безлейкозной выживаемости – следующие: ≥3% бластов в кровотоке, число тромбоцитов <100×109/л, и наличие неблагоприятного кариотипа .

Лекарственное лечение ПМФ не является эффективным в плане общей или бессобытийной выживаемости. Алло-ТГСК при ПМФ является потенциально исцеляющим, но весьма опасным методом. В то же время многих пациентов можно наблюдать в течение длительного времени, а некоторых больных можно успешно лечить обычными методами терапии.

Для больных с низким ли промежуточным-1 риском не нужды в специфическомлечении при отсутствии выраженных симптомов. Циторедуктивная терапия может быть обоснованной в случаях чрезмерного лейко- или тромбоцитоза. Побочные эффекты препаратов могут включать гепатотоксические или вирилизирующие эффекты андрогенов, периферическую нейропатию (талидомид) и миелосупрессию (леналидомид). Терапия первой линии с гидроксимочевиной может уменьшить размер селезенки до 40% на срок до 1 года. Побочные эффекты мочевины включают миелосупрессию и язвы кожи и слизистых. Пегилированный интерферон применяется в настоящее время при ранней терапии ЭТ и истинной полицитемии с целью предотвратить или отсрочить развитие фиброза. Пациенты с промежуточным-2 или высоким риском трансплантации должны проходить лечение новыми исследовательскими препаратами или посредством алло-ТГСК. Так, ингибиторы JAK1/JAK2 (например – Ruxolitinib) высокоэффективны при ПМФ или ЭТ. В настоящее врем руксолитиниб является единственным JAK2-ингибитором, разрешенным FDA препаратом для лечении миелофиброза и уникальным методом нетрансплантационной терапии, связанной с повышенной выживаемостью этих пациентов. Алло-ТГСК является очень эффективной, будучи, однако, рискованной пройедурой, будучи методом выбора для более молодых пациентов с признаками ПМФ высокой степени риска. Очевидный эффект ТГСК при ПМФ состоит в быстром восстановлении нормального трехросткового кроветворения, появлении функционального микроокружения и ослаблении процесса миелофиброза.

Заключение

Ввиду отсутствия методов терапии ПМФ, ведущих к длительному эффекту, доказан потенциальный риск осложнений, связанных с трансплантацией у больных высокой и промежуточной-2 степеней риска. Ингибиторы JAK2 дают уникальную возможность внедрения этих новых препаратов в программы трансплантации для пациентов группы высокого риска. Общие выводы данной статьи проиллюстрированы двумя клиническими примерами из опыта авторов, которые показывают успешные результаты алло-ТГСК при миелофиброзе.

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Elena V. Morozova, Maria V. Barabanshikova, Tatiana L. Gindina, V.V. Baykov, Boris V. Afanasyev

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PMF may be accomplished by gradual bone marrow failure, splenomegaly, severe general (constitutional) signs, and clinical features of extramedullary hemopoiesis. Acute leukemia develops in up to 30% of PMF. A conventional cytostatic therapy of PMF does not affect the survival rates. Meanwhile, allogeneic hemopoietic stem cell transplantation (allo-HSCT) is the only curative procedure for the PMF.<br> <br> PMF diagnosis is performed by appropriate WHO criteria and includes clinical, morphologic, cytogenetic, and molecular parameters. This disorder should be discerned from other myeloid neoplasias, i.e., polycythemia vera and essential thrombocythemia (ET). Differential diagnosis of PMF should also consider marrow fibrosis caused by other non-neoplastic or neoplastic conditions. In addition to JAK2 V617F or MPL mutations, a more recently found calreticulin (CALR) gene marker have been proposed for the MF (and essential patients with MF and ET).<br> <br> Prognostic aspects are derived from a concept of PMF as a heterogeneous disorder with rather individual manifestation and evolution, with highly variable median survival of up to &gt;20 years.<br> <br> An appropriate scoring scale (IPSS) uses five risk factors to predict prognosis and stratify the patients into risk groups. The risk factors for leukemia-free survival include ≥3% circulating blasts, platelet count &lt;100 x 109/L, and presence of unfavorable karyotype .<br> <br> Drug therapy for PMF is not effective, in terms of overall or event-free survival. AlloHSCT for PMF is potentially curative, but still hazardous. Meanwhile, many patients may be observed for sufficient time without any therapy, whereas some of them are effectively managed by conventional treatment.<br> <br> For low or intermediate-1 risk patients, there is no need for specific therapy in asymptomatic patients. Cytoreductive therapy may be reasonable in cases of extreme leuko- or thrombocytosis. The drug side effects include hepatotoxicity and virilizing effects for androgens, peripheral neuropathy (thalidomide), and myelosuppression (lenalidomide). The first-line therapy with hydroxyurea may reduce the spleen size in 40% of patients, with the spleen response lasting for ca. 1 year. Adverse effects of urea include myelosuppression and mucocutaneous ulcers.<br> <br> Pegylated interferon is currently applied, early on in the course of ET or PV, with a goal of preventing or delaying fibrosis. The patients with intermediate-2 or high risk disease should be treated with investigational drugs, or alloHSCT. E.g., JAK1/JAK2 inhibitors (Ruxolitinib) are highly effective in PMF or ET MF. At the present time, ruxolitinib is the only FDA-approved JAK2 inhibitor for MF and the only modern non-HSCT therapy associated with increased survival. AlloHSCT is quite efficient, however, a hazardous intervention, thus being a method of choice for high-risk symptomatic younger patients with PMF. An evident effect of HSCT in MF is a quick restoration of normal trilineage hematopoiesis and functional microenvironment, with rapid and reversal of the myelofibrosis. In conclusion, considering the lack of long-term effective drug therapies for patients with MF, a potential risk of transplant-related complications seems to be proven in patients with DIPSS plus high- or intermediate 2–risk disease. JAK2 inhibitor provides a unique opportunity of implementing these novel agents into the transplant programs for high-risk patients. The general conclusions are illustrated by two clinical examples from authors’ experience showing successful outcomes of allo-HSCT in PMF. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3938) "

Primary myelofibrosis (PMF) is BCR/ABL–negative myeloproliferative disorder with splenomegaly, leukoerythroblasts, extramedullary hematopoiesis, reactive bone marrow fibrosis and neoangiogenesis with abnormal cytokine production, generally, affecting elderly persons. PMF may be accomplished by gradual bone marrow failure, splenomegaly, severe general (constitutional) signs, and clinical features of extramedullary hemopoiesis. Acute leukemia develops in up to 30% of PMF. A conventional cytostatic therapy of PMF does not affect the survival rates. Meanwhile, allogeneic hemopoietic stem cell transplantation (allo-HSCT) is the only curative procedure for the PMF.

PMF diagnosis is performed by appropriate WHO criteria and includes clinical, morphologic, cytogenetic, and molecular parameters. This disorder should be discerned from other myeloid neoplasias, i.e., polycythemia vera and essential thrombocythemia (ET). Differential diagnosis of PMF should also consider marrow fibrosis caused by other non-neoplastic or neoplastic conditions. In addition to JAK2 V617F or MPL mutations, a more recently found calreticulin (CALR) gene marker have been proposed for the MF (and essential patients with MF and ET).

Prognostic aspects are derived from a concept of PMF as a heterogeneous disorder with rather individual manifestation and evolution, with highly variable median survival of up to >20 years.

An appropriate scoring scale (IPSS) uses five risk factors to predict prognosis and stratify the patients into risk groups. The risk factors for leukemia-free survival include ≥3% circulating blasts, platelet count <100 x 109/L, and presence of unfavorable karyotype .

Drug therapy for PMF is not effective, in terms of overall or event-free survival. AlloHSCT for PMF is potentially curative, but still hazardous. Meanwhile, many patients may be observed for sufficient time without any therapy, whereas some of them are effectively managed by conventional treatment.

For low or intermediate-1 risk patients, there is no need for specific therapy in asymptomatic patients. Cytoreductive therapy may be reasonable in cases of extreme leuko- or thrombocytosis. The drug side effects include hepatotoxicity and virilizing effects for androgens, peripheral neuropathy (thalidomide), and myelosuppression (lenalidomide). The first-line therapy with hydroxyurea may reduce the spleen size in 40% of patients, with the spleen response lasting for ca. 1 year. Adverse effects of urea include myelosuppression and mucocutaneous ulcers.

Pegylated interferon is currently applied, early on in the course of ET or PV, with a goal of preventing or delaying fibrosis. The patients with intermediate-2 or high risk disease should be treated with investigational drugs, or alloHSCT. E.g., JAK1/JAK2 inhibitors (Ruxolitinib) are highly effective in PMF or ET MF. At the present time, ruxolitinib is the only FDA-approved JAK2 inhibitor for MF and the only modern non-HSCT therapy associated with increased survival. AlloHSCT is quite efficient, however, a hazardous intervention, thus being a method of choice for high-risk symptomatic younger patients with PMF. An evident effect of HSCT in MF is a quick restoration of normal trilineage hematopoiesis and functional microenvironment, with rapid and reversal of the myelofibrosis. In conclusion, considering the lack of long-term effective drug therapies for patients with MF, a potential risk of transplant-related complications seems to be proven in patients with DIPSS plus high- or intermediate 2–risk disease. JAK2 inhibitor provides a unique opportunity of implementing these novel agents into the transplant programs for high-risk patients. The general conclusions are illustrated by two clinical examples from authors’ experience showing successful outcomes of allo-HSCT in PMF.

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Elena V. Morozova, Maria V. Barabanshikova, Tatiana L. Gindina, V.V. Baykov, Boris V. Afanasyev

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PMF may be accomplished by gradual bone marrow failure, splenomegaly, severe general (constitutional) signs, and clinical features of extramedullary hemopoiesis. Acute leukemia develops in up to 30% of PMF. A conventional cytostatic therapy of PMF does not affect the survival rates. Meanwhile, allogeneic hemopoietic stem cell transplantation (allo-HSCT) is the only curative procedure for the PMF.<br> <br> PMF diagnosis is performed by appropriate WHO criteria and includes clinical, morphologic, cytogenetic, and molecular parameters. This disorder should be discerned from other myeloid neoplasias, i.e., polycythemia vera and essential thrombocythemia (ET). Differential diagnosis of PMF should also consider marrow fibrosis caused by other non-neoplastic or neoplastic conditions. In addition to JAK2 V617F or MPL mutations, a more recently found calreticulin (CALR) gene marker have been proposed for the MF (and essential patients with MF and ET).<br> <br> Prognostic aspects are derived from a concept of PMF as a heterogeneous disorder with rather individual manifestation and evolution, with highly variable median survival of up to &gt;20 years.<br> <br> An appropriate scoring scale (IPSS) uses five risk factors to predict prognosis and stratify the patients into risk groups. The risk factors for leukemia-free survival include ≥3% circulating blasts, platelet count &lt;100 x 109/L, and presence of unfavorable karyotype .<br> <br> Drug therapy for PMF is not effective, in terms of overall or event-free survival. AlloHSCT for PMF is potentially curative, but still hazardous. Meanwhile, many patients may be observed for sufficient time without any therapy, whereas some of them are effectively managed by conventional treatment.<br> <br> For low or intermediate-1 risk patients, there is no need for specific therapy in asymptomatic patients. Cytoreductive therapy may be reasonable in cases of extreme leuko- or thrombocytosis. The drug side effects include hepatotoxicity and virilizing effects for androgens, peripheral neuropathy (thalidomide), and myelosuppression (lenalidomide). The first-line therapy with hydroxyurea may reduce the spleen size in 40% of patients, with the spleen response lasting for ca. 1 year. Adverse effects of urea include myelosuppression and mucocutaneous ulcers.<br> <br> Pegylated interferon is currently applied, early on in the course of ET or PV, with a goal of preventing or delaying fibrosis. The patients with intermediate-2 or high risk disease should be treated with investigational drugs, or alloHSCT. E.g., JAK1/JAK2 inhibitors (Ruxolitinib) are highly effective in PMF or ET MF. At the present time, ruxolitinib is the only FDA-approved JAK2 inhibitor for MF and the only modern non-HSCT therapy associated with increased survival. AlloHSCT is quite efficient, however, a hazardous intervention, thus being a method of choice for high-risk symptomatic younger patients with PMF. An evident effect of HSCT in MF is a quick restoration of normal trilineage hematopoiesis and functional microenvironment, with rapid and reversal of the myelofibrosis. In conclusion, considering the lack of long-term effective drug therapies for patients with MF, a potential risk of transplant-related complications seems to be proven in patients with DIPSS plus high- or intermediate 2–risk disease. JAK2 inhibitor provides a unique opportunity of implementing these novel agents into the transplant programs for high-risk patients. The general conclusions are illustrated by two clinical examples from authors’ experience showing successful outcomes of allo-HSCT in PMF. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3938) "

Primary myelofibrosis (PMF) is BCR/ABL–negative myeloproliferative disorder with splenomegaly, leukoerythroblasts, extramedullary hematopoiesis, reactive bone marrow fibrosis and neoangiogenesis with abnormal cytokine production, generally, affecting elderly persons. PMF may be accomplished by gradual bone marrow failure, splenomegaly, severe general (constitutional) signs, and clinical features of extramedullary hemopoiesis. Acute leukemia develops in up to 30% of PMF. A conventional cytostatic therapy of PMF does not affect the survival rates. Meanwhile, allogeneic hemopoietic stem cell transplantation (allo-HSCT) is the only curative procedure for the PMF.

PMF diagnosis is performed by appropriate WHO criteria and includes clinical, morphologic, cytogenetic, and molecular parameters. This disorder should be discerned from other myeloid neoplasias, i.e., polycythemia vera and essential thrombocythemia (ET). Differential diagnosis of PMF should also consider marrow fibrosis caused by other non-neoplastic or neoplastic conditions. In addition to JAK2 V617F or MPL mutations, a more recently found calreticulin (CALR) gene marker have been proposed for the MF (and essential patients with MF and ET).

Prognostic aspects are derived from a concept of PMF as a heterogeneous disorder with rather individual manifestation and evolution, with highly variable median survival of up to >20 years.

An appropriate scoring scale (IPSS) uses five risk factors to predict prognosis and stratify the patients into risk groups. The risk factors for leukemia-free survival include ≥3% circulating blasts, platelet count <100 x 109/L, and presence of unfavorable karyotype .

Drug therapy for PMF is not effective, in terms of overall or event-free survival. AlloHSCT for PMF is potentially curative, but still hazardous. Meanwhile, many patients may be observed for sufficient time without any therapy, whereas some of them are effectively managed by conventional treatment.

For low or intermediate-1 risk patients, there is no need for specific therapy in asymptomatic patients. Cytoreductive therapy may be reasonable in cases of extreme leuko- or thrombocytosis. The drug side effects include hepatotoxicity and virilizing effects for androgens, peripheral neuropathy (thalidomide), and myelosuppression (lenalidomide). The first-line therapy with hydroxyurea may reduce the spleen size in 40% of patients, with the spleen response lasting for ca. 1 year. Adverse effects of urea include myelosuppression and mucocutaneous ulcers.

Pegylated interferon is currently applied, early on in the course of ET or PV, with a goal of preventing or delaying fibrosis. The patients with intermediate-2 or high risk disease should be treated with investigational drugs, or alloHSCT. E.g., JAK1/JAK2 inhibitors (Ruxolitinib) are highly effective in PMF or ET MF. At the present time, ruxolitinib is the only FDA-approved JAK2 inhibitor for MF and the only modern non-HSCT therapy associated with increased survival. AlloHSCT is quite efficient, however, a hazardous intervention, thus being a method of choice for high-risk symptomatic younger patients with PMF. An evident effect of HSCT in MF is a quick restoration of normal trilineage hematopoiesis and functional microenvironment, with rapid and reversal of the myelofibrosis. In conclusion, considering the lack of long-term effective drug therapies for patients with MF, a potential risk of transplant-related complications seems to be proven in patients with DIPSS plus high- or intermediate 2–risk disease. JAK2 inhibitor provides a unique opportunity of implementing these novel agents into the transplant programs for high-risk patients. The general conclusions are illustrated by two clinical examples from authors’ experience showing successful outcomes of allo-HSCT in PMF.

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Primary myelofibrosis (PMF) is BCR/ABL–negative myeloproliferative disorder with splenomegaly, leukoerythroblasts, extramedullary hematopoiesis, reactive bone marrow fibrosis and neoangiogenesis with abnormal cytokine production, generally, affecting elderly persons. PMF may be accomplished by gradual bone marrow failure, splenomegaly, severe general (constitutional) signs, and clinical features of extramedullary hemopoiesis. Acute leukemia develops in up to 30% of PMF. A conventional cytostatic therapy of PMF does not affect the survival rates. Meanwhile, allogeneic hemopoietic stem cell transplantation (allo-HSCT) is the only curative procedure for the PMF.

PMF diagnosis is performed by appropriate WHO criteria and includes clinical, morphologic, cytogenetic, and molecular parameters. This disorder should be discerned from other myeloid neoplasias, i.e., polycythemia vera and essential thrombocythemia (ET). Differential diagnosis of PMF should also consider marrow fibrosis caused by other non-neoplastic or neoplastic conditions. In addition to JAK2 V617F or MPL mutations, a more recently found calreticulin (CALR) gene marker have been proposed for the MF (and essential patients with MF and ET).

Prognostic aspects are derived from a concept of PMF as a heterogeneous disorder with rather individual manifestation and evolution, with highly variable median survival of up to >20 years.

An appropriate scoring scale (IPSS) uses five risk factors to predict prognosis and stratify the patients into risk groups. The risk factors for leukemia-free survival include ≥3% circulating blasts, platelet count <100 x 109/L, and presence of unfavorable karyotype .

Drug therapy for PMF is not effective, in terms of overall or event-free survival. AlloHSCT for PMF is potentially curative, but still hazardous. Meanwhile, many patients may be observed for sufficient time without any therapy, whereas some of them are effectively managed by conventional treatment.

For low or intermediate-1 risk patients, there is no need for specific therapy in asymptomatic patients. Cytoreductive therapy may be reasonable in cases of extreme leuko- or thrombocytosis. The drug side effects include hepatotoxicity and virilizing effects for androgens, peripheral neuropathy (thalidomide), and myelosuppression (lenalidomide). The first-line therapy with hydroxyurea may reduce the spleen size in 40% of patients, with the spleen response lasting for ca. 1 year. Adverse effects of urea include myelosuppression and mucocutaneous ulcers.

Pegylated interferon is currently applied, early on in the course of ET or PV, with a goal of preventing or delaying fibrosis. The patients with intermediate-2 or high risk disease should be treated with investigational drugs, or alloHSCT. E.g., JAK1/JAK2 inhibitors (Ruxolitinib) are highly effective in PMF or ET MF. At the present time, ruxolitinib is the only FDA-approved JAK2 inhibitor for MF and the only modern non-HSCT therapy associated with increased survival. AlloHSCT is quite efficient, however, a hazardous intervention, thus being a method of choice for high-risk symptomatic younger patients with PMF. An evident effect of HSCT in MF is a quick restoration of normal trilineage hematopoiesis and functional microenvironment, with rapid and reversal of the myelofibrosis. In conclusion, considering the lack of long-term effective drug therapies for patients with MF, a potential risk of transplant-related complications seems to be proven in patients with DIPSS plus high- or intermediate 2–risk disease. JAK2 inhibitor provides a unique opportunity of implementing these novel agents into the transplant programs for high-risk patients. The general conclusions are illustrated by two clinical examples from authors’ experience showing successful outcomes of allo-HSCT in PMF.

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ПМФ может осложняться костномозговой недостаточностью, спленомегалией, общими (конституциональными) симптомами и клиническими признаками экстрамедуллярного гемопоэза. Острый лейкоз развивается нередко у больных ПМФ (до 30%). Обычшая цитостатическая терапия ПМФ не влияет на показатели выживаемости пациентов. В тоже время аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) является единственной излечивающей процедурой для ПМФ. Диагноз ПМФ осуществляется на основании соответствующих указаний ВОЗ и включает в себя клинические, морфологические, цитогенетические и молекулярные критерии. Это заболевание следует отличать от родственных ему миелоидных неоплазий, например – истинной полицитемии и эссенциальной тромбоцитемии (ЭТ). Дифференциальный диагноз ПМФ должен также включать фиброз костного мозга, связанный с другими неопухолевыми и неопластическими заболеваниями. В дополнение к мутациям JAK2 V617F or MPL, недавно предложен также в качестве генного маркера ген CALR, который характерен для миелофиброза и ЭТ. </p> <p> Прогностические подходы следуют из основной концепции ПМФ как гетерогенного заболевания с довольно индивидуальными проявлениями и эволюцией, и весьма различной продолжительностью жизни (до 20 лет и более). </p> <p> Соответствующая балльная шкала (IPSS) применяет 5 факторов риска для предсказания прогноза и распределения больных по группам риска. Эти факторы риска повышенного риска при оценке безлейкозной выживаемости – следующие: ≥3% бластов в кровотоке, число тромбоцитов &lt;100×109/л, и наличие неблагоприятного кариотипа . </p> <p> Лекарственное лечение ПМФ не является эффективным в плане общей или бессобытийной выживаемости. Алло-ТГСК при ПМФ является потенциально исцеляющим, но весьма опасным методом. В то же время многих пациентов можно наблюдать в течение длительного времени, а некоторых больных можно успешно лечить обычными методами терапии. </p> <p> Для больных с низким ли промежуточным-1 риском не нужды в специфическомлечении при отсутствии выраженных симптомов. Циторедуктивная терапия может быть обоснованной в случаях чрезмерного лейко- или тромбоцитоза. Побочные эффекты препаратов могут включать гепатотоксические или вирилизирующие эффекты андрогенов, периферическую нейропатию (талидомид) и миелосупрессию (леналидомид). Терапия первой линии с гидроксимочевиной может уменьшить размер селезенки до 40% на срок до 1 года. Побочные эффекты мочевины включают миелосупрессию и язвы кожи и слизистых. Пегилированный интерферон применяется в настоящее время при ранней терапии ЭТ и истинной полицитемии с целью предотвратить или отсрочить развитие фиброза. Пациенты с промежуточным-2 или высоким риском трансплантации должны проходить лечение новыми исследовательскими препаратами или посредством алло-ТГСК. Так, ингибиторы JAK1/JAK2 (например – Ruxolitinib) высокоэффективны при ПМФ или ЭТ. В настоящее врем руксолитиниб является единственным JAK2-ингибитором, разрешенным FDA препаратом для лечении миелофиброза и уникальным методом нетрансплантационной терапии, связанной с повышенной выживаемостью этих пациентов. Алло-ТГСК является очень эффективной, будучи, однако, рискованной пройедурой, будучи методом выбора для более молодых пациентов с признаками ПМФ высокой степени риска. Очевидный эффект ТГСК при ПМФ состоит в быстром восстановлении нормального трехросткового кроветворения, появлении функционального микроокружения и ослаблении процесса миелофиброза. </p> <h2>Заключение</h2> <p> Ввиду отсутствия методов терапии ПМФ, ведущих к длительному эффекту, доказан потенциальный риск осложнений, связанных с трансплантацией у больных высокой и промежуточной-2 степеней риска. Ингибиторы JAK2 дают уникальную возможность внедрения этих новых препаратов в программы трансплантации для пациентов группы высокого риска. Общие выводы данной статьи проиллюстрированы двумя клиническими примерами из опыта авторов, которые показывают успешные результаты алло-ТГСК при миелофиброзе. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7808) "

Первичный миелофиброз (ПМФ) является BCR/ABL–негативное миелопролиферативное заболевание со спленомегалией, наличием лейкоэритробластов, экстрамедуллярным гемопоэзом, реактивным фиброзом костного мозга и неоангиогенезом с аномальной продукцией цитокинов, которое поражает, главным образом, пожилых лиц. ПМФ может осложняться костномозговой недостаточностью, спленомегалией, общими (конституциональными) симптомами и клиническими признаками экстрамедуллярного гемопоэза. Острый лейкоз развивается нередко у больных ПМФ (до 30%). Обычшая цитостатическая терапия ПМФ не влияет на показатели выживаемости пациентов. В тоже время аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) является единственной излечивающей процедурой для ПМФ. Диагноз ПМФ осуществляется на основании соответствующих указаний ВОЗ и включает в себя клинические, морфологические, цитогенетические и молекулярные критерии. Это заболевание следует отличать от родственных ему миелоидных неоплазий, например – истинной полицитемии и эссенциальной тромбоцитемии (ЭТ). Дифференциальный диагноз ПМФ должен также включать фиброз костного мозга, связанный с другими неопухолевыми и неопластическими заболеваниями. В дополнение к мутациям JAK2 V617F or MPL, недавно предложен также в качестве генного маркера ген CALR, который характерен для миелофиброза и ЭТ.

Прогностические подходы следуют из основной концепции ПМФ как гетерогенного заболевания с довольно индивидуальными проявлениями и эволюцией, и весьма различной продолжительностью жизни (до 20 лет и более).

Соответствующая балльная шкала (IPSS) применяет 5 факторов риска для предсказания прогноза и распределения больных по группам риска. Эти факторы риска повышенного риска при оценке безлейкозной выживаемости – следующие: ≥3% бластов в кровотоке, число тромбоцитов <100×109/л, и наличие неблагоприятного кариотипа .

Лекарственное лечение ПМФ не является эффективным в плане общей или бессобытийной выживаемости. Алло-ТГСК при ПМФ является потенциально исцеляющим, но весьма опасным методом. В то же время многих пациентов можно наблюдать в течение длительного времени, а некоторых больных можно успешно лечить обычными методами терапии.

Для больных с низким ли промежуточным-1 риском не нужды в специфическомлечении при отсутствии выраженных симптомов. Циторедуктивная терапия может быть обоснованной в случаях чрезмерного лейко- или тромбоцитоза. Побочные эффекты препаратов могут включать гепатотоксические или вирилизирующие эффекты андрогенов, периферическую нейропатию (талидомид) и миелосупрессию (леналидомид). Терапия первой линии с гидроксимочевиной может уменьшить размер селезенки до 40% на срок до 1 года. Побочные эффекты мочевины включают миелосупрессию и язвы кожи и слизистых. Пегилированный интерферон применяется в настоящее время при ранней терапии ЭТ и истинной полицитемии с целью предотвратить или отсрочить развитие фиброза. Пациенты с промежуточным-2 или высоким риском трансплантации должны проходить лечение новыми исследовательскими препаратами или посредством алло-ТГСК. Так, ингибиторы JAK1/JAK2 (например – Ruxolitinib) высокоэффективны при ПМФ или ЭТ. В настоящее врем руксолитиниб является единственным JAK2-ингибитором, разрешенным FDA препаратом для лечении миелофиброза и уникальным методом нетрансплантационной терапии, связанной с повышенной выживаемостью этих пациентов. Алло-ТГСК является очень эффективной, будучи, однако, рискованной пройедурой, будучи методом выбора для более молодых пациентов с признаками ПМФ высокой степени риска. Очевидный эффект ТГСК при ПМФ состоит в быстром восстановлении нормального трехросткового кроветворения, появлении функционального микроокружения и ослаблении процесса миелофиброза.

Заключение

Ввиду отсутствия методов терапии ПМФ, ведущих к длительному эффекту, доказан потенциальный риск осложнений, связанных с трансплантацией у больных высокой и промежуточной-2 степеней риска. Ингибиторы JAK2 дают уникальную возможность внедрения этих новых препаратов в программы трансплантации для пациентов группы высокого риска. Общие выводы данной статьи проиллюстрированы двумя клиническими примерами из опыта авторов, которые показывают успешные результаты алло-ТГСК при миелофиброзе.

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Первичный миелофиброз (ПМФ) является BCR/ABL–негативное миелопролиферативное заболевание со спленомегалией, наличием лейкоэритробластов, экстрамедуллярным гемопоэзом, реактивным фиброзом костного мозга и неоангиогенезом с аномальной продукцией цитокинов, которое поражает, главным образом, пожилых лиц. ПМФ может осложняться костномозговой недостаточностью, спленомегалией, общими (конституциональными) симптомами и клиническими признаками экстрамедуллярного гемопоэза. Острый лейкоз развивается нередко у больных ПМФ (до 30%). Обычшая цитостатическая терапия ПМФ не влияет на показатели выживаемости пациентов. В тоже время аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) является единственной излечивающей процедурой для ПМФ. Диагноз ПМФ осуществляется на основании соответствующих указаний ВОЗ и включает в себя клинические, морфологические, цитогенетические и молекулярные критерии. Это заболевание следует отличать от родственных ему миелоидных неоплазий, например – истинной полицитемии и эссенциальной тромбоцитемии (ЭТ). Дифференциальный диагноз ПМФ должен также включать фиброз костного мозга, связанный с другими неопухолевыми и неопластическими заболеваниями. В дополнение к мутациям JAK2 V617F or MPL, недавно предложен также в качестве генного маркера ген CALR, который характерен для миелофиброза и ЭТ.

Прогностические подходы следуют из основной концепции ПМФ как гетерогенного заболевания с довольно индивидуальными проявлениями и эволюцией, и весьма различной продолжительностью жизни (до 20 лет и более).

Соответствующая балльная шкала (IPSS) применяет 5 факторов риска для предсказания прогноза и распределения больных по группам риска. Эти факторы риска повышенного риска при оценке безлейкозной выживаемости – следующие: ≥3% бластов в кровотоке, число тромбоцитов <100×109/л, и наличие неблагоприятного кариотипа .

Лекарственное лечение ПМФ не является эффективным в плане общей или бессобытийной выживаемости. Алло-ТГСК при ПМФ является потенциально исцеляющим, но весьма опасным методом. В то же время многих пациентов можно наблюдать в течение длительного времени, а некоторых больных можно успешно лечить обычными методами терапии.

Для больных с низким ли промежуточным-1 риском не нужды в специфическомлечении при отсутствии выраженных симптомов. Циторедуктивная терапия может быть обоснованной в случаях чрезмерного лейко- или тромбоцитоза. Побочные эффекты препаратов могут включать гепатотоксические или вирилизирующие эффекты андрогенов, периферическую нейропатию (талидомид) и миелосупрессию (леналидомид). Терапия первой линии с гидроксимочевиной может уменьшить размер селезенки до 40% на срок до 1 года. Побочные эффекты мочевины включают миелосупрессию и язвы кожи и слизистых. Пегилированный интерферон применяется в настоящее время при ранней терапии ЭТ и истинной полицитемии с целью предотвратить или отсрочить развитие фиброза. Пациенты с промежуточным-2 или высоким риском трансплантации должны проходить лечение новыми исследовательскими препаратами или посредством алло-ТГСК. Так, ингибиторы JAK1/JAK2 (например – Ruxolitinib) высокоэффективны при ПМФ или ЭТ. В настоящее врем руксолитиниб является единственным JAK2-ингибитором, разрешенным FDA препаратом для лечении миелофиброза и уникальным методом нетрансплантационной терапии, связанной с повышенной выживаемостью этих пациентов. Алло-ТГСК является очень эффективной, будучи, однако, рискованной пройедурой, будучи методом выбора для более молодых пациентов с признаками ПМФ высокой степени риска. Очевидный эффект ТГСК при ПМФ состоит в быстром восстановлении нормального трехросткового кроветворения, появлении функционального микроокружения и ослаблении процесса миелофиброза.

Заключение

Ввиду отсутствия методов терапии ПМФ, ведущих к длительному эффекту, доказан потенциальный риск осложнений, связанных с трансплантацией у больных высокой и промежуточной-2 степеней риска. Ингибиторы JAK2 дают уникальную возможность внедрения этих новых препаратов в программы трансплантации для пациентов группы высокого риска. Общие выводы данной статьи проиллюстрированы двумя клиническими примерами из опыта авторов, которые показывают успешные результаты алло-ТГСК при миелофиброзе.

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Introduction

Acute lymphoblastic leukemia (ALL) represents from 25 to 30% of all malignancies in childhood, and less common (ca.1%) in adults. Modern programmed chemotherapy (CT) allows of achieving stable remission in up to 90% of children and 40% of adults. However, efficiency of chemotherapy in high-risk ALL patients is still inferior in the both age groups; five-year disease-free survival (DFS) does not exceed 40% and 25%, respectively [7, 11, 12].

Allogeneic hematopoietic transplantation (allo-HSCT) is an effective method of treatment for the high-risk ALL patients, both due to a cytostatic effect of conditioning regimen upon leukemic clonogenic cells, and immunoadoptive «graft-versus-leukemia» effect exerted by donor T cells [1, 14]. However, higher risk of a non-transplant-related mortality (NRM) limits wider application of this treatment modality. High probability of severe graft-versus-host disease (GvHD) is also possible, due to excessive alloreactivity of graft, thus often leading to death [19]. Generally, an increased therapeutic efficiency is observed, due to advent of novel targeted therapies, wider application of reduced-toxicity conditioning (RIC) regimens, and improved quality of supportive care. Therefore, current indications for allo-HSCT in pediatric and adult ALL are subject to permanent revisions [9]. The aim of our study was to evaluate clinical efficacy of allo-HSCT in ALL, and to identify significant factors which may affect general outcome in this clinical setting.

Patients and methods 

The study included 354 patients with ALL (1 to 61 years old) who underwent allo-HSCTs from 1995 to 2015.

Age distribution of the patients was as follows: under 10 years, 72 (21%); 11-20 years, 131 (37%); 21-30 years, 100 (28%); 31-40 years, 29 (8%); over 40 years, 22 (6%). The median age was 22 years.

The patients were classified into distinct cohorts, according to EGIL phenotypic classification, as follows: B-ALL Philadelphia chromosome (Ph)-negative was identified in 54% of total case number including pro-B ALL (23%), common-B ALL (36%), pre-B ALL (17%), mature-B ALL (4%), B-lineage (20%). The patients with Ph (+) B-ALL made up 27% of total ALL cohort. In this group, we found pro-B ALL (11%), common-B ALL (70%), pre-B ALL (4%), and B-lin (15%). T-cell ALL was revealed in 19% of cases: pro-T (12%); pre-T (44%); cortic-T (9%), mature-T (3%) and T-lineage (32%).

Primary cytogenetic data were available for 74% of the patients, and initial molecular biology diagnostics was performed in 57% of the cases. Cytogenetic and molecular (RTPCR) findings in the patients are shown in Fig. 1 and 2.

Figure 1. Distribution of patients depending on cytogenetic abnormalities
Figure 2. Distribution of patients depending on molecular abnormalities

Indications for allo-HSCT in the 1st remission were as follows: (1) high risk group (leukocytosis ≥ 30.0×109/L for B-ALL; ≥ 100.0×109/L for T-ALL, BI ALL and TI/TII / T IV EGIL phenotypes; (2) specific chromosome translocations, i.e., t(9; 22) (q34;q11), t(4; 11) (q21;q23), or t(8; 14)(q24.1;q32); complex karyotypic abnormalities (≥ 5), hypodiploid karyotype (<44 chromosomes), and/or absence of remission following induction therapy.

Myeloablative conditioning (MAC) included Busulfan 16 mg/kg and Cyclophosphamide 120 mg/kg. Reduced intensity conditioning (RIC) regimens contained a combination of Fludarabine (150 mg/m2) and Busulfan (8mg/kg), or Melphalan (140 mg/m2).

Acute and chronic GVHD prophylaxis included Cyclosporin A, or Tacrolimus combined with Methotrexate (15 mg/m2 on D+1 and 10 mg/m2 on the D+3 and D+6), or Mycophenolate Mofetil (30 mg/kg 2 times daily). GVHD prophylaxis for matched unrelated allo-HSCT was enhanced by antilymphocyte globulin (ATGAM) at a dose of 60 mg/kg. Since 2014, GVHD prophylaxis, especially in haploidentical HSCTs, included Cyclophosphamide (50 mg/kg on D + 3 and D + 4 post-transplant).

Conditioning regimens with reduced toxicity were administered to heavily pretreated patients with different complications associated with chemotherapy, subjects over 40 years old and pts with high comorbidity index. General characteristics of recipients, donors and graft properties are shown in Figure 3.

At the time of allo-HSCT, 24% of patients were in 1st remission, 26% – in 2nd remission, 17%, in ≥ 3rd remission, whereas 4% of the patients had active disease.

Statistical evaluation was performed with SPSS Statistics version 17. Overall survival (OS) was calculated with Kaplan-Meier method, whereas non-relapse mortality (NRM), and relapse incidence (RI) were assessed with R Statistic software. A log-rank test was used to compare OS, and exact Fisher test was applied for the share analysis. Distinct milestones were taken for evaluation, i.e., dates of birth, HSCT, early death and relapse. Initial terms of acute and chronic GVHD were also taken for clinical analysis. The survivors remaining in remission state by the end of data acquisition were censored by the 01/10/2015.

Results

Five-year OS of patients after allo-HSCT was 47% if transplanted in remission, as compared to 18% for the patients who underwent HSCT in active disease (p <0.0001), relapse rates were 26% and 50% (P <0.0001), respectively (Fig. 4).

Further analysis was performed for those patients who were in remission at the time of allo-HSCT (n=159). The type of ALL has no effect on overall and event-free survival. Fiveyear OS of children and adults was 48% and 47% (p>0.2).

The disease state pre-transplant exerted some influence upon the OS rates in children and adults, i.e., 79% vs 60% for allo-HSCT in 1st remission; 40% vs 43% in 2nd remission, and 33% vs 23% for the patients treated in ≥ 3rd remission (Fig. 5). The RI after allo-HSCT in children and adults were also comparable for patients transplanted in the 1st remission (21% vs 32%), 2nd remission (33% vs 17%), and 17% vs 23% for the patients transplanted in ≥3rd remission (p>0.2). Type of the donor and source of the graft did not affect OS. However, OS in cases of allo-HSCT from HLA-matched donor was higher than from HLA-mismatch donor (51% vs 25%, p=0.002), as seen from Fig. 6. Moreover, OS rate after allo-HSCT from matched related donors was 62%, from unrelated donors – 44%, from unrelated HLA-mismatched donors – 25% (p>0.07).

Figure 3. Characteristics of recipients, donors and transplant types
Figure 3. Characteristics of recipients, donors and transplant types


Figure 4. Overall survival and relapse incidence after allo-HSCTFigure 4. Overall survival and relapse incidence after allo-HSCT
Figure 4. Overall survival and relapse incidence after allo-HSCT


Figure 5. Overall survival in pediatric and adult ALL depending on the disease status at the time of allo-HSCTFigure 5. Overall survival in pediatric and adult ALL depending on the disease status at the time of allo-HSCT
Figure 5. Overall survival in pediatric and adult ALL depending on the disease status at the time of allo-HSCT


Figure 6. Overall survival after allo-HSCT depending on the donor type and HLA-compatibility of the donor and recipientFigure 6. Overall survival after allo-HSCT depending on the donor type and HLA-compatibility of the donor and recipient
Figure 6. Overall survival after allo-HSCT depending on the donor type and HLA-compatibility of the donor and recipient


Figure 7. The influence of cytogenetic risk group at therelapse incidence

Figure 7. The influence of cytogenetic risk group at the relapse incidence


Most patients received MAC regimens (n= 89). OS in this group was 53% vs 40% in RIC group (n =70, p =0.04). Intensity of the conditioning regimen did not show statistically significant impact on the NRM (28% and 35%, p=0.06) and on the RI (24% and 30% respectively, p=0.09). RI in children and adults were also comparable when treated in the 1st remission – 21% and 32%, when transplanted in the 2nd remission – 33% and 17%, if treated in the ≥3rd remission, 17% and 23% respectively, p>0.2. In our study the RI differed for distinct cytogenetic risk groups: in high risk group it was 36%, in the intermediate-risk group, 31%, p= 0.2 (Fig. 7). In most cases, a relapse occurred within 1st year after allo-HSCT (57%). In some patients with early ALL relapse, clonal evolution was detectable, i.e., emergence of new cytogenetic abnormalities (Table 1).

Table 1. Post-transplant evolution of leukemia clones in relapsed ALL             Table 1. Post-transplant evolution of leukemia clones in relapsed ALL
Table 1. Post-transplant evolution of leukemia clones in relapsed ALL

Immunoadoptive therapy (donor lymphocyte infusions) was carried out in 73 patients (20%) for prevention and/or treatment of relapses. Seventeen patients received DLI as monotherapy. For 56 patients, DLI was applied in combination with cytoreductive chemotherapy, tyrosine kinase inhibitors (TKI), or recombinant interleukin-2. The overall response rate was 38% (Table 2). Preventive DLI tended to be more effective than therapeutic one (respectively, 52% vs 31%, p=0.08).

Table 2. Efficacy of donor lymphocyte infusions after allo-HSCT

Table 2. Efficacy of donor lymphocyte infusions after allo-HSCT


Non-relapse mortality did not differ between children and adults (32% vs. 37%, p>0.2), being also dependent on the pre-transplant disease stage, i.e., 21% and 25% for the 1st remission, 31% and 43%, for the 2nd remission; 50% and 61% for the ≥ 3rd remission (Fig. 8).

Acute GVHD was noted in 34% of patients, including clinically severe complications (grade III to IV) observed in 13.8% of patients. No statistically significant differences in acute GVHD incidence were revealed between the groups of related and unrelated allo-HSCT (p=0.1).

Chronic GVHD after allo-HSCT was evaluated in patients surviving more than 100 days. The incidence of chronic GVHD was 40.9%, including extended clinical forms (33.4%). OS rate among patients with chronic GVHD was 68%, as compared to the patients free of chronic GVHD (52%, p =0.03).

In multivariate analysis, only ALL phenotype (Ph (+) B-ALL and T-ALL vs Ph (-) B-ALL [2.21 (95% CI 1.3-3.4), p=0.05] and acute GVHD [grade 0-1 versus grade 2-4: 1.49 (95% CI 0.9-2.8), p=0.04] influenced the RI values.

Discussion

In our study, patient age (children/adults) had no effect on OS, EFS, RI and incidence of GVHD. Disease state at the time of allo-HSCT showed the greatest impact upon OS (47% when transplanted in remission vs 18%, in active disease), and upon RI, thus being in accordance with similar results of e.g., F. Hutchinson Cancer Research Center: disease-free survival was 33% vs 9%, and relapse rates – 22% vs 45% [5]. The number of previous treatment cycles before allo-HSCT was also of sufficient importance. Both OS overall survival and RI were the highest after HSCT in the 1st remission, with decreased survival for the patients treated in 2nd or 3rd remission, along with lower NRM rates. This trend is in accordance with results obtained by other researchers, where the patients in 1st and in the 2nd remission showed a sufficient difference in relapse risk [6, 10, 18].

More recently, a distinct trend is seen towards allo-HSCT in other ALL patients than those with high-risk cytogenetics. In the study of the Dutch-Belgian HOVON cooperative group, the comparisons were made between the patients with/without available donors. Allo-HSCT has shown to benefit the patients from both high and standard-risk groups. For standard risk group, the OS rates were 69% versus 49% (p<0.05) and RI, 14% vs 52% (p <0.001). Appropriate levels for the high-risk groups were 53% vs 41% (p= 0.5), and 34% vs 61%, p = 0.03, respectively [4]. In our study, however, the OS and RI proved to be similar for high and standard-risk ALL.

The disease relapse after allo-HSCT has significant impact upon outcomes. Early detection of the minimal residual disease and/or falling donor chimerism after allo-HSCT, especially in high risk group patients, may be a clinical indication for DLI and/or target therapy (TKI, blinatumomab) [13]. Although DLI has limited benefit in ALL [3, 17], our data demonstrated that preventive DLI may be more effective than therapeutic DLI.

Sufficient HLA-incompatibility between the donor and recipient, both for major and minor antigens, is also known the exert a negative effect on the results of allo-HSCT, by association of severe immunological complications which enhance mortality of patients [8, 20]. It was also confirmed by our results obtained in the groups with different types of HSC donors. Reduced intensity of conditioning regimens did not affect the RI, due to immunoadoptive graft-versus-leukemia effect and usage of donor lymphocyte infusions for prophylactic and preventive purposes [9, 15, 16].

In some patients who had no available HLA-matched donors, the HSCs were taken from haploidentical family members. Most of the patients treated with haplo-HSCT exhibited active malignant disease at the time of allo-HSCT, and the disease progression after allo-HSCT was a main cause of death. Noteworthy, we didn’t observe any uncontrolled severe GVHD in this group. In our experience, haplo-HSCT is a promising approach with post-transplant cyclophosphamide used for the GVHD prophylaxis in the patients with very high risk and late relapses. These data correspond to a study published by Bacigalupo et al. [2]. The authors have shown that mortality in this setting was, mainly, due to malignancy relapse (22%), whereas fatal GVHD was diagnosed only in 2%.

Conclusions

Allo-HSCT from an HLA-matched related or unrelated donor is recommended for the patients with high-risk ALL in the 1st remission, and for all patients in the 2nd remission. Due to advent of new drugs (targeted therapy, monoclonal antibodies) the indications for allo-HSCT are constantly changing. In adult patients, a trend for transplantation in the 2nd remission is evident, thus corresponding to appropriate recommendations for children. An additional criterion for allogeneic transplantation is the 1st remission and grafting from HLA-mismatched or alternative donor is a high level of minimal residual disease, thus requiring further research.

Conflict of interest

None declared

References

  1. Afanasyev BV, Zubarovskaia LS, Semenova EV, Ivanova NE, Alianskiĭ AL, Morozova EV, Mikhaĭlova NB, Darskaia EI, Estrina MA, Golovacheva AA, Babenko EV, Bondarenko SN, Ganapiev AA, Bogomol’nyĭ MP. Experience of non-related allogeneic transplantation of stem hematopoietic cells in the Clinic of Bone Marrow Transplantation at I.P. Pavlov St.Petersburg Medical University. Terapevticheskyi Archiv 2007; 79 (7):36-43 (In Russian).
  2. Bacigalupo A, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, Bregante S, Van Lint MT, Geroldi S, Luchetti S, Grasso R, Pozzi S,Colombo N, Tedone E, Varaldo R, Raiola AM. Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update. Bone Marrow Transplant 2015; 50 (Suppl 2): S37-39.
  3. Collins RH Jr, Goldstein S, Giralt S, Levine J, Porter D, Drobyski W, Barrett J, Johnson M, Kirk A, Horowitz M, Parker P. Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant. 2000; 26 (5): 511-516.
  4. Cornelissen JJ, van der Holt B, Verhoef GEG, van ’t Veer MB, van Oers MHJ, Schouten HC, Ossenkoppele G, Sonneveld P, Maertens J, van Marwijk KM, Schaafsma MR, Wijermans PW, Biesma DH, Wittebol S, Voogt PJ, Baars JW, Zache´e P, Verdonck LF, Loewenberg D, Dekker AW. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood 2009; 113:1375-1382.
  5. Doney K, Haegglund H, Leisenring W, Chauncey T, Appelbaum FR, Storb R. Predictive factors for outcome of allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia. Biol Blood Marrow Transplant 2003; 9 (7):472-481.
  6. Doney K, Gooley TA, Deeg HJ, Flowers MED, Storb R, Appelbaum FR. Allogeneic hematopoietic cell transplantation with full-intensity conditioning for adult acute lymphoblastic leukemia: results from a single center, 1998-2006. Biol Blood Marrow Transplant. 2011; 17 (8): 1187-1195.
  7. Karachunsky AI, Roumyantseva YuV, Roumyantsev AG. Treatment evolution of pediatric acute lymphoblastic leukemia: critical application of international experience in Russia. Voprosy Gematologii/Oncologii I Immunopatologii v Pediatrii 2011 10 (2): 15-31 (In Russian).
  8. Kuzmich EV, Makarenko OA, Alynskiy AA, Timofeeva NP, Ivanova NE, Bondarenko SN, Zubarovskaya LS, Afanasyev BV. Impact of matching of HLA class I and class II alleles in the donor and recipient on the risk graft-versushost disease after unrelated allogenic HSCT: a single center experience. Hum Immunol 2013; 74 (Suppl. 1): 122.
  9. Mohty M, Labopin M, Volin L, Gratwohl A, Socié G, Esteve J, Tabrizi R, Nagler A, Rocha V. Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Blood 2010; 116:4439-4443.
  10. Nishiwaki S, Miyamura K, Ohashi K, Kurokawa M, Taniguchi S, Fukuda T, Ikegame K, Takahashi S, Mori T, Imai K, Iida H, Hidaka M, Sakamaki H, Morishima Y, Kato K, Suzuki R, Tanaka J. Impact of a donor source on adult Philadelphia chromosome-negative acute lymphoblastic leukemia: a retrospective analysis from the Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation. Ann Oncol 2013; 24:1594–1602.
  11. Parovichnikova EN, Davidyan YuR, Domracheva EV, Bondarenko SN, Kaporskaya TS, Ryltsova TV, Kondakova EV, Baranova OYu, Savchenko VG. Detection of chromosomal aberrations determines the disease diagnosis in adult patients with Ph-negative acute lymphoblastic leukemia: results of Russian Multicentric Study – RALL Group. Gematologiya i Transfusiologiya 2012; 57 (3):18-19 (In Russian).
  12. Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemia: An update. J Clin Oncol 2011; 29:551-565.
  13. Pulsipher MA, Bader P, Klingebiel T, Cooper LJ. Allogeneic transplantation for pediatric acute lymphoblastic leukemia: the emerging role of peritransplantation minimal residual disease/chimerism monitoring and novel chemotherapeutic, molecular, and immune approaches aimed at preventing relapse. Biol Blood Marrow Transplant. 2009; 15 (1 Suppl): 62-71.
  14. Roumyantsev AG, Maschan AA. Hematopoietic Stem Cell Transplantation in Children. A Doctors’ Manual. MIA Publishers, Moscow, 2003, 912 p. ((In Russian).
  15. Semenova EV, Stancheva NV, Bondarenko SN, Vavilov VN, Bagge DA, Paina OV, Rasumova SV, Borovkova AS, Bykova TA, Rats AA, Zoubarovskata LS, Afanasyev BV. Treatment of refractory acute lymphoblastic leukemia in children and adolescents: remission reinduction followed by allogeneic hematopoietic stem cell transplantation. Klinicheskaya Onkogematologyia 2013; 6 (1): 53-58 (In Russian).
  16. Slesarchuk ОА, Babenko EV, Semenova EV, Bondarenko SN, Éstrina MA, Morozova EV, Paina OV, Vavilov VN, Smirnov BI, Zubarovskaia LS, Afanasyev BV. Efficiency of donor lymphocyte infusions in patients following different types of hematopoietic stem cell transplantation. Terapevticheskyi Archiv 2013; 85 (7): 26-33 (In Russian).
  17. Spyridonidis A, Labopin M, Schmid C, Volin L, Yakoub-Agha I, Stadler M, Milpied N, Socie G, Browne P, Lenhoff S, Sanz MA, Aljurf M, Mohty M, Rocha V; Immunotherapy Subcommittee of Acute Leukemia Working Party. Outcomes and prognostic factors of adults with acute lymphoblastic leukemia who relapse after allogeneic hematopoietic cell transplantation. An analysis on behalf of the Acute Leukemia Working Party of EBMT. Leukemia. 2012; 26 (6):1211-1217.
  18. Sureda A, Bader P, Cesaro S, Dreger P, Duarte RF, Dufour C, Falkenburg JH, Farge-Bancel D, Gennery A, Kröger N, Lanza F, Marsh JC, Nagler A, Peters C, Velardi A, Mohty M, Madrigal A. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant 2015: 50 (8):1037-1056.
  19. Tracey J, Zhang MJ, Thiel E, Sobocinski KA, Eapen M. Transplantation conditioning regimens and outcomes after allogeneic hematopoietic cell transplantation in children and adoltscents with acute lymphoblastic leukemia. Biol Blood Marrow Transplant 2013; 19:255-259.
  20. Wang TF, Huang H, Tzeng CH, Wang PN, Wu T, Sun J, Tang JL, Hu J, Lin SF, Kao RH. Impact of donor characteristics and HLA matching on survival of Chinese patients with hematologic malignancies undergoing unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2012; 18 (12):1939-1944.

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Introduction

Acute lymphoblastic leukemia (ALL) represents from 25 to 30% of all malignancies in childhood, and less common (ca.1%) in adults. Modern programmed chemotherapy (CT) allows of achieving stable remission in up to 90% of children and 40% of adults. However, efficiency of chemotherapy in high-risk ALL patients is still inferior in the both age groups; five-year disease-free survival (DFS) does not exceed 40% and 25%, respectively [7, 11, 12].

Allogeneic hematopoietic transplantation (allo-HSCT) is an effective method of treatment for the high-risk ALL patients, both due to a cytostatic effect of conditioning regimen upon leukemic clonogenic cells, and immunoadoptive «graft-versus-leukemia» effect exerted by donor T cells [1, 14]. However, higher risk of a non-transplant-related mortality (NRM) limits wider application of this treatment modality. High probability of severe graft-versus-host disease (GvHD) is also possible, due to excessive alloreactivity of graft, thus often leading to death [19]. Generally, an increased therapeutic efficiency is observed, due to advent of novel targeted therapies, wider application of reduced-toxicity conditioning (RIC) regimens, and improved quality of supportive care. Therefore, current indications for allo-HSCT in pediatric and adult ALL are subject to permanent revisions [9]. The aim of our study was to evaluate clinical efficacy of allo-HSCT in ALL, and to identify significant factors which may affect general outcome in this clinical setting.

Patients and methods 

The study included 354 patients with ALL (1 to 61 years old) who underwent allo-HSCTs from 1995 to 2015.

Age distribution of the patients was as follows: under 10 years, 72 (21%); 11-20 years, 131 (37%); 21-30 years, 100 (28%); 31-40 years, 29 (8%); over 40 years, 22 (6%). The median age was 22 years.

The patients were classified into distinct cohorts, according to EGIL phenotypic classification, as follows: B-ALL Philadelphia chromosome (Ph)-negative was identified in 54% of total case number including pro-B ALL (23%), common-B ALL (36%), pre-B ALL (17%), mature-B ALL (4%), B-lineage (20%). The patients with Ph (+) B-ALL made up 27% of total ALL cohort. In this group, we found pro-B ALL (11%), common-B ALL (70%), pre-B ALL (4%), and B-lin (15%). T-cell ALL was revealed in 19% of cases: pro-T (12%); pre-T (44%); cortic-T (9%), mature-T (3%) and T-lineage (32%).

Primary cytogenetic data were available for 74% of the patients, and initial molecular biology diagnostics was performed in 57% of the cases. Cytogenetic and molecular (RTPCR) findings in the patients are shown in Fig. 1 and 2.

Figure 1. Distribution of patients depending on cytogenetic abnormalities
Figure 2. Distribution of patients depending on molecular abnormalities

Indications for allo-HSCT in the 1st remission were as follows: (1) high risk group (leukocytosis ≥ 30.0×109/L for B-ALL; ≥ 100.0×109/L for T-ALL, BI ALL and TI/TII / T IV EGIL phenotypes; (2) specific chromosome translocations, i.e., t(9; 22) (q34;q11), t(4; 11) (q21;q23), or t(8; 14)(q24.1;q32); complex karyotypic abnormalities (≥ 5), hypodiploid karyotype (<44 chromosomes), and/or absence of remission following induction therapy.

Myeloablative conditioning (MAC) included Busulfan 16 mg/kg and Cyclophosphamide 120 mg/kg. Reduced intensity conditioning (RIC) regimens contained a combination of Fludarabine (150 mg/m2) and Busulfan (8mg/kg), or Melphalan (140 mg/m2).

Acute and chronic GVHD prophylaxis included Cyclosporin A, or Tacrolimus combined with Methotrexate (15 mg/m2 on D+1 and 10 mg/m2 on the D+3 and D+6), or Mycophenolate Mofetil (30 mg/kg 2 times daily). GVHD prophylaxis for matched unrelated allo-HSCT was enhanced by antilymphocyte globulin (ATGAM) at a dose of 60 mg/kg. Since 2014, GVHD prophylaxis, especially in haploidentical HSCTs, included Cyclophosphamide (50 mg/kg on D + 3 and D + 4 post-transplant).

Conditioning regimens with reduced toxicity were administered to heavily pretreated patients with different complications associated with chemotherapy, subjects over 40 years old and pts with high comorbidity index. General characteristics of recipients, donors and graft properties are shown in Figure 3.

At the time of allo-HSCT, 24% of patients were in 1st remission, 26% – in 2nd remission, 17%, in ≥ 3rd remission, whereas 4% of the patients had active disease.

Statistical evaluation was performed with SPSS Statistics version 17. Overall survival (OS) was calculated with Kaplan-Meier method, whereas non-relapse mortality (NRM), and relapse incidence (RI) were assessed with R Statistic software. A log-rank test was used to compare OS, and exact Fisher test was applied for the share analysis. Distinct milestones were taken for evaluation, i.e., dates of birth, HSCT, early death and relapse. Initial terms of acute and chronic GVHD were also taken for clinical analysis. The survivors remaining in remission state by the end of data acquisition were censored by the 01/10/2015.

Results

Five-year OS of patients after allo-HSCT was 47% if transplanted in remission, as compared to 18% for the patients who underwent HSCT in active disease (p <0.0001), relapse rates were 26% and 50% (P <0.0001), respectively (Fig. 4).

Further analysis was performed for those patients who were in remission at the time of allo-HSCT (n=159). The type of ALL has no effect on overall and event-free survival. Fiveyear OS of children and adults was 48% and 47% (p>0.2).

The disease state pre-transplant exerted some influence upon the OS rates in children and adults, i.e., 79% vs 60% for allo-HSCT in 1st remission; 40% vs 43% in 2nd remission, and 33% vs 23% for the patients treated in ≥ 3rd remission (Fig. 5). The RI after allo-HSCT in children and adults were also comparable for patients transplanted in the 1st remission (21% vs 32%), 2nd remission (33% vs 17%), and 17% vs 23% for the patients transplanted in ≥3rd remission (p>0.2). Type of the donor and source of the graft did not affect OS. However, OS in cases of allo-HSCT from HLA-matched donor was higher than from HLA-mismatch donor (51% vs 25%, p=0.002), as seen from Fig. 6. Moreover, OS rate after allo-HSCT from matched related donors was 62%, from unrelated donors – 44%, from unrelated HLA-mismatched donors – 25% (p>0.07).

Figure 3. Characteristics of recipients, donors and transplant types
Figure 3. Characteristics of recipients, donors and transplant types


Figure 4. Overall survival and relapse incidence after allo-HSCTFigure 4. Overall survival and relapse incidence after allo-HSCT
Figure 4. Overall survival and relapse incidence after allo-HSCT


Figure 5. Overall survival in pediatric and adult ALL depending on the disease status at the time of allo-HSCTFigure 5. Overall survival in pediatric and adult ALL depending on the disease status at the time of allo-HSCT
Figure 5. Overall survival in pediatric and adult ALL depending on the disease status at the time of allo-HSCT


Figure 6. Overall survival after allo-HSCT depending on the donor type and HLA-compatibility of the donor and recipientFigure 6. Overall survival after allo-HSCT depending on the donor type and HLA-compatibility of the donor and recipient
Figure 6. Overall survival after allo-HSCT depending on the donor type and HLA-compatibility of the donor and recipient


Figure 7. The influence of cytogenetic risk group at therelapse incidence

Figure 7. The influence of cytogenetic risk group at the relapse incidence


Most patients received MAC regimens (n= 89). OS in this group was 53% vs 40% in RIC group (n =70, p =0.04). Intensity of the conditioning regimen did not show statistically significant impact on the NRM (28% and 35%, p=0.06) and on the RI (24% and 30% respectively, p=0.09). RI in children and adults were also comparable when treated in the 1st remission – 21% and 32%, when transplanted in the 2nd remission – 33% and 17%, if treated in the ≥3rd remission, 17% and 23% respectively, p>0.2. In our study the RI differed for distinct cytogenetic risk groups: in high risk group it was 36%, in the intermediate-risk group, 31%, p= 0.2 (Fig. 7). In most cases, a relapse occurred within 1st year after allo-HSCT (57%). In some patients with early ALL relapse, clonal evolution was detectable, i.e., emergence of new cytogenetic abnormalities (Table 1).

Table 1. Post-transplant evolution of leukemia clones in relapsed ALL             Table 1. Post-transplant evolution of leukemia clones in relapsed ALL
Table 1. Post-transplant evolution of leukemia clones in relapsed ALL

Immunoadoptive therapy (donor lymphocyte infusions) was carried out in 73 patients (20%) for prevention and/or treatment of relapses. Seventeen patients received DLI as monotherapy. For 56 patients, DLI was applied in combination with cytoreductive chemotherapy, tyrosine kinase inhibitors (TKI), or recombinant interleukin-2. The overall response rate was 38% (Table 2). Preventive DLI tended to be more effective than therapeutic one (respectively, 52% vs 31%, p=0.08).

Table 2. Efficacy of donor lymphocyte infusions after allo-HSCT

Table 2. Efficacy of donor lymphocyte infusions after allo-HSCT


Non-relapse mortality did not differ between children and adults (32% vs. 37%, p>0.2), being also dependent on the pre-transplant disease stage, i.e., 21% and 25% for the 1st remission, 31% and 43%, for the 2nd remission; 50% and 61% for the ≥ 3rd remission (Fig. 8).

Acute GVHD was noted in 34% of patients, including clinically severe complications (grade III to IV) observed in 13.8% of patients. No statistically significant differences in acute GVHD incidence were revealed between the groups of related and unrelated allo-HSCT (p=0.1).

Chronic GVHD after allo-HSCT was evaluated in patients surviving more than 100 days. The incidence of chronic GVHD was 40.9%, including extended clinical forms (33.4%). OS rate among patients with chronic GVHD was 68%, as compared to the patients free of chronic GVHD (52%, p =0.03).

In multivariate analysis, only ALL phenotype (Ph (+) B-ALL and T-ALL vs Ph (-) B-ALL [2.21 (95% CI 1.3-3.4), p=0.05] and acute GVHD [grade 0-1 versus grade 2-4: 1.49 (95% CI 0.9-2.8), p=0.04] influenced the RI values.

Discussion

In our study, patient age (children/adults) had no effect on OS, EFS, RI and incidence of GVHD. Disease state at the time of allo-HSCT showed the greatest impact upon OS (47% when transplanted in remission vs 18%, in active disease), and upon RI, thus being in accordance with similar results of e.g., F. Hutchinson Cancer Research Center: disease-free survival was 33% vs 9%, and relapse rates – 22% vs 45% [5]. The number of previous treatment cycles before allo-HSCT was also of sufficient importance. Both OS overall survival and RI were the highest after HSCT in the 1st remission, with decreased survival for the patients treated in 2nd or 3rd remission, along with lower NRM rates. This trend is in accordance with results obtained by other researchers, where the patients in 1st and in the 2nd remission showed a sufficient difference in relapse risk [6, 10, 18].

More recently, a distinct trend is seen towards allo-HSCT in other ALL patients than those with high-risk cytogenetics. In the study of the Dutch-Belgian HOVON cooperative group, the comparisons were made between the patients with/without available donors. Allo-HSCT has shown to benefit the patients from both high and standard-risk groups. For standard risk group, the OS rates were 69% versus 49% (p<0.05) and RI, 14% vs 52% (p <0.001). Appropriate levels for the high-risk groups were 53% vs 41% (p= 0.5), and 34% vs 61%, p = 0.03, respectively [4]. In our study, however, the OS and RI proved to be similar for high and standard-risk ALL.

The disease relapse after allo-HSCT has significant impact upon outcomes. Early detection of the minimal residual disease and/or falling donor chimerism after allo-HSCT, especially in high risk group patients, may be a clinical indication for DLI and/or target therapy (TKI, blinatumomab) [13]. Although DLI has limited benefit in ALL [3, 17], our data demonstrated that preventive DLI may be more effective than therapeutic DLI.

Sufficient HLA-incompatibility between the donor and recipient, both for major and minor antigens, is also known the exert a negative effect on the results of allo-HSCT, by association of severe immunological complications which enhance mortality of patients [8, 20]. It was also confirmed by our results obtained in the groups with different types of HSC donors. Reduced intensity of conditioning regimens did not affect the RI, due to immunoadoptive graft-versus-leukemia effect and usage of donor lymphocyte infusions for prophylactic and preventive purposes [9, 15, 16].

In some patients who had no available HLA-matched donors, the HSCs were taken from haploidentical family members. Most of the patients treated with haplo-HSCT exhibited active malignant disease at the time of allo-HSCT, and the disease progression after allo-HSCT was a main cause of death. Noteworthy, we didn’t observe any uncontrolled severe GVHD in this group. In our experience, haplo-HSCT is a promising approach with post-transplant cyclophosphamide used for the GVHD prophylaxis in the patients with very high risk and late relapses. These data correspond to a study published by Bacigalupo et al. [2]. The authors have shown that mortality in this setting was, mainly, due to malignancy relapse (22%), whereas fatal GVHD was diagnosed only in 2%.

Conclusions

Allo-HSCT from an HLA-matched related or unrelated donor is recommended for the patients with high-risk ALL in the 1st remission, and for all patients in the 2nd remission. Due to advent of new drugs (targeted therapy, monoclonal antibodies) the indications for allo-HSCT are constantly changing. In adult patients, a trend for transplantation in the 2nd remission is evident, thus corresponding to appropriate recommendations for children. An additional criterion for allogeneic transplantation is the 1st remission and grafting from HLA-mismatched or alternative donor is a high level of minimal residual disease, thus requiring further research.

Conflict of interest

None declared

References

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["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(4) "5993" ["VALUE"]=> array(2) { ["TEXT"]=> string(542) "<p class="Autor"> Сергей Н. Бондаренко, Иван С. Моисеев, Ольга А. Слесарчук, Елена И. Дарская, Кирилл А. Екушев, Анна Г. Смирнова, Александр Л. Алянский, Татьяна Л. Гиндина, Елена В. Бабенко, Елена В. Кузьмич, Елена В. Семенова, Александр Д. Кулагин, Людмила С. Зубаровская, Борис В. Афанасьев </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(520) "

Сергей Н. Бондаренко, Иван С. Моисеев, Ольга А. Слесарчук, Елена И. Дарская, Кирилл А. Екушев, Анна Г. Смирнова, Александр Л. Алянский, Татьяна Л. Гиндина, Елена В. Бабенко, Елена В. Кузьмич, Елена В. Семенова, Александр Д. Кулагин, Людмила С. Зубаровская, Борис В. Афанасьев

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "5987" ["VALUE"]=> array(2) { ["TEXT"]=> string(306) "НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой, Первый Санкт-Петербургский медицинский Университет им. И.П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(306) "НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой, Первый Санкт-Петербургский медицинский Университет им. 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(4) "5981" ["VALUE"]=> array(2) { ["TEXT"]=> string(3135) "Целью работы была оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при остром лимфобластном лейкозе (ОЛЛ) и выявление факторов, влияющие на результаты лечения. Материалы и методы. В исследование включено 354 пациента в возрасте от 1 до 61 года с диагнозом ОЛЛ, которым была проведена алло-ТГСК за период с 1995 по 2015 гг. На момент алло-ТГСК 24% пациентов находились в 1-й ремиссии, 26% – во 2-й ремиссии, 17% – в ремиссии ≥3 и 34% пациентов вне ремиссии. Результаты. Общая выживаемость (ОВ) пациентов после алло-ТГСК в ремиссии заболевания составила 47%, а вне ремиссии – 18% (р&lt;0,0001), частота рецидивов – 26% и 50% (р&lt;0,0001), соответственно. Общая 5-летняя выживаемость у детей и взрослых составила 48% и 47% (р&gt;0,2). Стадия заболевания влияла на ОВ как у детей, так и у взрослых: в первой ремиссии – 79% и 60%, во второй ремиссии – 40% и 43%, в 3 и более ремиссии – 33% и 23%. Частота рецидивов у детей и взрослых также были сопоставимы, в первой ремиссии 21% против 32%, во второй ремиссии 33% против 17%, и в 3 и более ремиссии 17% против 23% (р&gt;0,2). Большинству пациентов с ОЛЛ перед алло-ТГСК проводился режим кондиционирования МАК (n=89). ОВ в этой группе составила 53% против 40% при режиме кондиционирования РИК (n=70), р=0,04. Выбор режима кондиционирования не показал статистически значимой разницы на частоту рецидивов, 24% и 30% (МАК и РИК, соответственно), р&gt;0,09. NRM у детей и взрослых не отличалась (32% против 37%, p&gt;0,2), и также зависела от стадии заболевания: в первой ремиссии – 21% и 25%, во второй ремиссии – 31% и 43%, в 3 и более ремиссии – 50% и 61%. Заключение. Алло-ТГСК от HLA-совместимого родственного или неродственного донора показана пациентам ОЛЛ высокой группы риска в первой ремиссии и всем пациентам во второй ремиссии." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3111) "Целью работы была оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при остром лимфобластном лейкозе (ОЛЛ) и выявление факторов, влияющие на результаты лечения. Материалы и методы. В исследование включено 354 пациента в возрасте от 1 до 61 года с диагнозом ОЛЛ, которым была проведена алло-ТГСК за период с 1995 по 2015 гг. На момент алло-ТГСК 24% пациентов находились в 1-й ремиссии, 26% – во 2-й ремиссии, 17% – в ремиссии ≥3 и 34% пациентов вне ремиссии. Результаты. Общая выживаемость (ОВ) пациентов после алло-ТГСК в ремиссии заболевания составила 47%, а вне ремиссии – 18% (р<0,0001), частота рецидивов – 26% и 50% (р<0,0001), соответственно. Общая 5-летняя выживаемость у детей и взрослых составила 48% и 47% (р>0,2). Стадия заболевания влияла на ОВ как у детей, так и у взрослых: в первой ремиссии – 79% и 60%, во второй ремиссии – 40% и 43%, в 3 и более ремиссии – 33% и 23%. Частота рецидивов у детей и взрослых также были сопоставимы, в первой ремиссии 21% против 32%, во второй ремиссии 33% против 17%, и в 3 и более ремиссии 17% против 23% (р>0,2). Большинству пациентов с ОЛЛ перед алло-ТГСК проводился режим кондиционирования МАК (n=89). ОВ в этой группе составила 53% против 40% при режиме кондиционирования РИК (n=70), р=0,04. Выбор режима кондиционирования не показал статистически значимой разницы на частоту рецидивов, 24% и 30% (МАК и РИК, соответственно), р>0,09. NRM у детей и взрослых не отличалась (32% против 37%, p>0,2), и также зависела от стадии заболевания: в первой ремиссии – 21% и 25%, во второй ремиссии – 31% и 43%, в 3 и более ремиссии – 50% и 61%. Заключение. Алло-ТГСК от HLA-совместимого родственного или неродственного донора показана пациентам ОЛЛ высокой группы риска в первой ремиссии и всем пациентам во второй ремиссии." 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Bondarenko, Ivan S. Moiseev, Olga A. Slesarchuk, Elena I. Darskaya, Kirill A. Ekushev, Anna G. Smirnova, Alexander L. Alyanskiy, Tatyana L. Gindina, Elena V. Babenko, Elena V. Kuzmich, Elena V. Semenova, Alexander D. Kulagin, Luydmila S. Zubarovskaya, Boris V. Afanasyev </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(318) "

Sergey N. Bondarenko, Ivan S. Moiseev, Olga A. Slesarchuk, Elena I. Darskaya, Kirill A. Ekushev, Anna G. Smirnova, Alexander L. Alyanskiy, Tatyana L. Gindina, Elena V. Babenko, Elena V. Kuzmich, Elena V. Semenova, Alexander D. Kulagin, Luydmila S. Zubarovskaya, Boris V. Afanasyev

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Patients and methods. The study included 354 ALL patients aged 1 to 61 years who underwent allo-HSCT over a period of 1995 to 2015. Before HSCT, 24% of patients were in the 1st remission, 26% – in 2nd remission, 17%, in the ≥ 3rd remission; 34% of patients had active disease. Results. Overall survival (OS) was 47% when HSCT was performed in remission status versus 18% in patients transplanted in active disease state (p &lt;.0001). Appropriate relapse incidence (RI) comprised 26% and 50%, respectively (P &lt;.0001). Five-year OS was similar in children and adults (48% and 47% respectively, p&gt;0.2). Pre-transplant remission state showed certain correlations with OS in pediatric and adult transplant patients, i.e., 79% vs 60% for HSCT in 1st remission; 40% vs 43% in 2nd remission, and 33% vs 23% for the patients treated in ≥ 3rd remission. ALL RI in children and adults were also comparable for HSCT carried out in 1st remission (21% vs 32%), 2nd remission (33% vs 17%), and 17% vs 23% for HSCT performed in ≥3rd remission (p&gt;0.2). Most ALL patients underwent myeloablative conditioning regimen (MAC) before allo-HSCT (n=89). OS in MAC group was 53% versus 40% among patients who underwent reduced-intensity conditioning (RIC) regimens (n=70, p=0.04). The conditioning regimen intensity did not correlate with the RI after allo-HSCT (24% and 30% (MAC vs RIC respectively), p=0.09). Non-relapse mortality (NRM) did not significantly differ for children and adults (32% vs 37%, p&gt;0.2), being dependent on the disease state: 21% vs 25% after HSCT in the 1st remission; 31% and 43%, when treated in the 2nd remission, and 50% vs 61% if transplanted in ≥3rd remission. Conclusion. Allo-HSCT from an HLA-matched related or unrelated donor is indicated in patients with high-risk ALL in first remission and in all the patients in the second remission." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2087) "The aim of this study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute lymphoblastic leukemia (ALL), and to specify significant factors affecting clinical outcomes. Patients and methods. The study included 354 ALL patients aged 1 to 61 years who underwent allo-HSCT over a period of 1995 to 2015. Before HSCT, 24% of patients were in the 1st remission, 26% – in 2nd remission, 17%, in the ≥ 3rd remission; 34% of patients had active disease. Results. Overall survival (OS) was 47% when HSCT was performed in remission status versus 18% in patients transplanted in active disease state (p <.0001). Appropriate relapse incidence (RI) comprised 26% and 50%, respectively (P <.0001). Five-year OS was similar in children and adults (48% and 47% respectively, p>0.2). Pre-transplant remission state showed certain correlations with OS in pediatric and adult transplant patients, i.e., 79% vs 60% for HSCT in 1st remission; 40% vs 43% in 2nd remission, and 33% vs 23% for the patients treated in ≥ 3rd remission. ALL RI in children and adults were also comparable for HSCT carried out in 1st remission (21% vs 32%), 2nd remission (33% vs 17%), and 17% vs 23% for HSCT performed in ≥3rd remission (p>0.2). Most ALL patients underwent myeloablative conditioning regimen (MAC) before allo-HSCT (n=89). OS in MAC group was 53% versus 40% among patients who underwent reduced-intensity conditioning (RIC) regimens (n=70, p=0.04). The conditioning regimen intensity did not correlate with the RI after allo-HSCT (24% and 30% (MAC vs RIC respectively), p=0.09). Non-relapse mortality (NRM) did not significantly differ for children and adults (32% vs 37%, p>0.2), being dependent on the disease state: 21% vs 25% after HSCT in the 1st remission; 31% and 43%, when treated in the 2nd remission, and 50% vs 61% if transplanted in ≥3rd remission. Conclusion. Allo-HSCT from an HLA-matched related or unrelated donor is indicated in patients with high-risk ALL in first remission and in all the patients in the second remission." 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Bondarenko, Ivan S. Moiseev, Olga A. Slesarchuk, Elena I. Darskaya, Kirill A. Ekushev, Anna G. Smirnova, Alexander L. Alyanskiy, Tatyana L. Gindina, Elena V. Babenko, Elena V. Kuzmich, Elena V. Semenova, Alexander D. Kulagin, Luydmila S. Zubarovskaya, Boris V. Afanasyev </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(318) "

Sergey N. Bondarenko, Ivan S. Moiseev, Olga A. Slesarchuk, Elena I. Darskaya, Kirill A. Ekushev, Anna G. Smirnova, Alexander L. Alyanskiy, Tatyana L. Gindina, Elena V. Babenko, Elena V. Kuzmich, Elena V. Semenova, Alexander D. Kulagin, Luydmila S. Zubarovskaya, Boris V. Afanasyev

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Sergey N. Bondarenko, Ivan S. Moiseev, Olga A. Slesarchuk, Elena I. Darskaya, Kirill A. Ekushev, Anna G. Smirnova, Alexander L. Alyanskiy, Tatyana L. Gindina, Elena V. Babenko, Elena V. Kuzmich, Elena V. Semenova, Alexander D. Kulagin, Luydmila S. Zubarovskaya, Boris V. Afanasyev

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "6004" ["VALUE"]=> array(2) { ["TEXT"]=> string(2107) "The aim of this study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute lymphoblastic leukemia (ALL), and to specify significant factors affecting clinical outcomes. Patients and methods. The study included 354 ALL patients aged 1 to 61 years who underwent allo-HSCT over a period of 1995 to 2015. Before HSCT, 24% of patients were in the 1st remission, 26% – in 2nd remission, 17%, in the ≥ 3rd remission; 34% of patients had active disease. Results. Overall survival (OS) was 47% when HSCT was performed in remission status versus 18% in patients transplanted in active disease state (p &lt;.0001). Appropriate relapse incidence (RI) comprised 26% and 50%, respectively (P &lt;.0001). Five-year OS was similar in children and adults (48% and 47% respectively, p&gt;0.2). Pre-transplant remission state showed certain correlations with OS in pediatric and adult transplant patients, i.e., 79% vs 60% for HSCT in 1st remission; 40% vs 43% in 2nd remission, and 33% vs 23% for the patients treated in ≥ 3rd remission. ALL RI in children and adults were also comparable for HSCT carried out in 1st remission (21% vs 32%), 2nd remission (33% vs 17%), and 17% vs 23% for HSCT performed in ≥3rd remission (p&gt;0.2). Most ALL patients underwent myeloablative conditioning regimen (MAC) before allo-HSCT (n=89). OS in MAC group was 53% versus 40% among patients who underwent reduced-intensity conditioning (RIC) regimens (n=70, p=0.04). The conditioning regimen intensity did not correlate with the RI after allo-HSCT (24% and 30% (MAC vs RIC respectively), p=0.09). Non-relapse mortality (NRM) did not significantly differ for children and adults (32% vs 37%, p&gt;0.2), being dependent on the disease state: 21% vs 25% after HSCT in the 1st remission; 31% and 43%, when treated in the 2nd remission, and 50% vs 61% if transplanted in ≥3rd remission. Conclusion. Allo-HSCT from an HLA-matched related or unrelated donor is indicated in patients with high-risk ALL in first remission and in all the patients in the second remission." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2087) "The aim of this study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute lymphoblastic leukemia (ALL), and to specify significant factors affecting clinical outcomes. Patients and methods. The study included 354 ALL patients aged 1 to 61 years who underwent allo-HSCT over a period of 1995 to 2015. Before HSCT, 24% of patients were in the 1st remission, 26% – in 2nd remission, 17%, in the ≥ 3rd remission; 34% of patients had active disease. Results. Overall survival (OS) was 47% when HSCT was performed in remission status versus 18% in patients transplanted in active disease state (p <.0001). Appropriate relapse incidence (RI) comprised 26% and 50%, respectively (P <.0001). Five-year OS was similar in children and adults (48% and 47% respectively, p>0.2). Pre-transplant remission state showed certain correlations with OS in pediatric and adult transplant patients, i.e., 79% vs 60% for HSCT in 1st remission; 40% vs 43% in 2nd remission, and 33% vs 23% for the patients treated in ≥ 3rd remission. ALL RI in children and adults were also comparable for HSCT carried out in 1st remission (21% vs 32%), 2nd remission (33% vs 17%), and 17% vs 23% for HSCT performed in ≥3rd remission (p>0.2). Most ALL patients underwent myeloablative conditioning regimen (MAC) before allo-HSCT (n=89). OS in MAC group was 53% versus 40% among patients who underwent reduced-intensity conditioning (RIC) regimens (n=70, p=0.04). The conditioning regimen intensity did not correlate with the RI after allo-HSCT (24% and 30% (MAC vs RIC respectively), p=0.09). Non-relapse mortality (NRM) did not significantly differ for children and adults (32% vs 37%, p>0.2), being dependent on the disease state: 21% vs 25% after HSCT in the 1st remission; 31% and 43%, when treated in the 2nd remission, and 50% vs 61% if transplanted in ≥3rd remission. Conclusion. Allo-HSCT from an HLA-matched related or unrelated donor is indicated in patients with high-risk ALL in first remission and in all the patients in the second remission." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2087) "The aim of this study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute lymphoblastic leukemia (ALL), and to specify significant factors affecting clinical outcomes. Patients and methods. The study included 354 ALL patients aged 1 to 61 years who underwent allo-HSCT over a period of 1995 to 2015. Before HSCT, 24% of patients were in the 1st remission, 26% – in 2nd remission, 17%, in the ≥ 3rd remission; 34% of patients had active disease. Results. Overall survival (OS) was 47% when HSCT was performed in remission status versus 18% in patients transplanted in active disease state (p <.0001). Appropriate relapse incidence (RI) comprised 26% and 50%, respectively (P <.0001). Five-year OS was similar in children and adults (48% and 47% respectively, p>0.2). Pre-transplant remission state showed certain correlations with OS in pediatric and adult transplant patients, i.e., 79% vs 60% for HSCT in 1st remission; 40% vs 43% in 2nd remission, and 33% vs 23% for the patients treated in ≥ 3rd remission. ALL RI in children and adults were also comparable for HSCT carried out in 1st remission (21% vs 32%), 2nd remission (33% vs 17%), and 17% vs 23% for HSCT performed in ≥3rd remission (p>0.2). Most ALL patients underwent myeloablative conditioning regimen (MAC) before allo-HSCT (n=89). OS in MAC group was 53% versus 40% among patients who underwent reduced-intensity conditioning (RIC) regimens (n=70, p=0.04). The conditioning regimen intensity did not correlate with the RI after allo-HSCT (24% and 30% (MAC vs RIC respectively), p=0.09). Non-relapse mortality (NRM) did not significantly differ for children and adults (32% vs 37%, p>0.2), being dependent on the disease state: 21% vs 25% after HSCT in the 1st remission; 31% and 43%, when treated in the 2nd remission, and 50% vs 61% if transplanted in ≥3rd remission. Conclusion. 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Материалы и методы. В исследование включено 354 пациента в возрасте от 1 до 61 года с диагнозом ОЛЛ, которым была проведена алло-ТГСК за период с 1995 по 2015 гг. На момент алло-ТГСК 24% пациентов находились в 1-й ремиссии, 26% – во 2-й ремиссии, 17% – в ремиссии ≥3 и 34% пациентов вне ремиссии. Результаты. Общая выживаемость (ОВ) пациентов после алло-ТГСК в ремиссии заболевания составила 47%, а вне ремиссии – 18% (р&lt;0,0001), частота рецидивов – 26% и 50% (р&lt;0,0001), соответственно. Общая 5-летняя выживаемость у детей и взрослых составила 48% и 47% (р&gt;0,2). Стадия заболевания влияла на ОВ как у детей, так и у взрослых: в первой ремиссии – 79% и 60%, во второй ремиссии – 40% и 43%, в 3 и более ремиссии – 33% и 23%. Частота рецидивов у детей и взрослых также были сопоставимы, в первой ремиссии 21% против 32%, во второй ремиссии 33% против 17%, и в 3 и более ремиссии 17% против 23% (р&gt;0,2). Большинству пациентов с ОЛЛ перед алло-ТГСК проводился режим кондиционирования МАК (n=89). ОВ в этой группе составила 53% против 40% при режиме кондиционирования РИК (n=70), р=0,04. Выбор режима кондиционирования не показал статистически значимой разницы на частоту рецидивов, 24% и 30% (МАК и РИК, соответственно), р&gt;0,09. NRM у детей и взрослых не отличалась (32% против 37%, p&gt;0,2), и также зависела от стадии заболевания: в первой ремиссии – 21% и 25%, во второй ремиссии – 31% и 43%, в 3 и более ремиссии – 50% и 61%. Заключение. Алло-ТГСК от HLA-совместимого родственного или неродственного донора показана пациентам ОЛЛ высокой группы риска в первой ремиссии и всем пациентам во второй ремиссии." 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Стадия заболевания влияла на ОВ как у детей, так и у взрослых: в первой ремиссии – 79% и 60%, во второй ремиссии – 40% и 43%, в 3 и более ремиссии – 33% и 23%. Частота рецидивов у детей и взрослых также были сопоставимы, в первой ремиссии 21% против 32%, во второй ремиссии 33% против 17%, и в 3 и более ремиссии 17% против 23% (р>0,2). Большинству пациентов с ОЛЛ перед алло-ТГСК проводился режим кондиционирования МАК (n=89). ОВ в этой группе составила 53% против 40% при режиме кондиционирования РИК (n=70), р=0,04. Выбор режима кондиционирования не показал статистически значимой разницы на частоту рецидивов, 24% и 30% (МАК и РИК, соответственно), р>0,09. NRM у детей и взрослых не отличалась (32% против 37%, p>0,2), и также зависела от стадии заболевания: в первой ремиссии – 21% и 25%, во второй ремиссии – 31% и 43%, в 3 и более ремиссии – 50% и 61%. Заключение. Алло-ТГСК от HLA-совместимого родственного или неродственного донора показана пациентам ОЛЛ высокой группы риска в первой ремиссии и всем пациентам во второй ремиссии." ["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(3111) "Целью работы была оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при остром лимфобластном лейкозе (ОЛЛ) и выявление факторов, влияющие на результаты лечения. Материалы и методы. В исследование включено 354 пациента в возрасте от 1 до 61 года с диагнозом ОЛЛ, которым была проведена алло-ТГСК за период с 1995 по 2015 гг. На момент алло-ТГСК 24% пациентов находились в 1-й ремиссии, 26% – во 2-й ремиссии, 17% – в ремиссии ≥3 и 34% пациентов вне ремиссии. Результаты. 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Introduction

Precise mechanisms of cellular therapy of heart disorders with hematopoietic stem cells are unknown so far. However, they draw attention of clinicians and researchers, due to distinct positive effects observed in several studies. E.g., primary pre-clinical studies carried out in USA [9], and initial clinical studies in Düsseldorf (Germany) performed by Strauer et al. [13] and in Rostock by Steinhoff et al. [12] used autologous bone marrow cells (ABMC) for treatment of coronary artery disease (CAD). Trials with CAD patients have revealed a positive functional response of the cellular therapy. Over the last 12 years since introduction of this treatment modality, some distinct positive results are shown in randomized clinical studies. This treatment still has not become a standard of medication for CAD patients, despite of several meta-analyses [1, 5] have shown some benefits of the cellular therapy.

A general idea of possible paracrine effects produced by the cellular therapy cannot explain a variety of its actions and needs further interpretations. Intensive collateral formation (neoangiogenesis) in the areas of cell injections is a proven effect of cellular therapy. There are some effects, however, which cannot be explained solely by neoangiogenesis. To our mind, these effects represent indirect evidence for regeneration of endothelial lining in coronary arteries, including those of microcirculatory bed. Hence, the aim of our work was to provide an update of results confirming potential regenerative effects of intracoronary bone marrow cell infusions.

Material and methods

Since 2003, a study at the St.Petersburg State I.Pavlov Medical University (SPBMU) has performed a controlled non-randomized open label study aimed for clinical evaluation of ABMC intracoronary infusions to ninety-seven patients with sufficiently affected coronary bed, however, being non-eligible for coronary bypass (CABG), or coronary angioplastics. The patients received intracoronary injections of ABMC obtained by multiple sternal and iliac punctures and isolated by a two-stage gradient centrifugation (900 g for 15 min followed by 700 g for 15 min) using hydroxyethyl starch solution for separation. A total yield of nucleated cells per sample was 6.8±3.5×108 including 9±7.9×108 mononuclear cells, a mean number of CD34+ cells was 1.6±0.9×106. Cell viability was of myelokaryocytes was 95-98%.

A comparison group consisted of thirty-seven patients who were not treated with ABMC. Coronary angiography was performed in all patients before ABMC injection. Heart visualization was performed by single photon emission computed tomography (SPECT) in 17 patients or positron emissive tomography (PET) examination in 10 patients before treatment and 1-2 years after ABMC injections, in order to assess local myocardial perfusion and metabolic rates.

Results

Clinical effect of AMBC injections was revealed in the study group, in terms of decreased anginal symptoms by one functional class (68%), by two functional classes (12%) whereas 20% of the patients did not feel any changes in their performance. Such effect was evident at 6 to 9 months after single AMBC injections. A similar long-term monitoring in control group did not reveal any changes in the functional class of angina pectoris. This positive effect of cellular therapy retains for about 3 years, followed by a decrease in antianginal effects at 4 to 5 years post-treatment [2, 7, 11]. Coronary angiography performed at these terms showed stable state of the coronary vessels, absence of additional atherosclerotic lesions and retained collateral circulation.

Our data on a distinct stepwise increase in myocardial perfusion within the 1st year post-treatment also were confirmed by the results of PET examination with labeled ammonium. Improved myocardial metabolism in most myocardial segments was shown with fluordeoxyglucose (FDG) marker (Table.1). The most positive changes were noted for those segments with initially lesser capture of the radiolabeled drug. The same changes were found in a group of 10 patients (Fig. 1). An increase in these physiological parameters was detectable since 3 months after cellular therapy, followed by even more positive changes 6 and 12 mo after a single ABMC infusion [8, 11].

Table 1. PET data with FDG as a metabolic marker in patient M: dynamics of myocardial glucose consumption 12 mopost-treatment. Every of 17 segments of the heart had increased FDG marker, but the most positive changes wasnoted in those segments with initially lesser capture of radiolabeled drug (FDG)

Table 1. PET data with FDG as a metabolic marker in patient M: dynamics of myocardial glucose consumption 12 mo post-treatment. Every of 17 segments of the heart had increased FDG marker, but the most positive changes was noted in those segments with initially lesser capture of radiolabeled drug (FDG)


Fig. 1. Mean myocardial consumption of glucose is increasedafter 12-mo follow-up in a group of 10 patientsas shown by PET with FDG marker. The consumptionindex is increased by 57% (p=0.0001)

Fig. 1. Mean myocardial consumption of glucose is increased after 12-mo follow-up in a group of 10 patients as shown by PET with FDG marker. The consumption index is increased by 57% (p=0.0001)


One should note that improvement of myocardial perfusion was also traceable over wide myocardial areas by SPECT visualization, and, again, the most pronounced changes were seen for the segments with initially diminished capture of technetril-99mTc. Increased perfusion and higher metabolic recovery paralleled each other following intracoronary ABMC infusion. These radiological findings were accompanied by improved contractibility of the left ventricular myocardium, according to the echocardiography data. These positive changes were considered a result of improved collateral blood circulation [8, 11].

Moreover, our team has performed a longitudinal study of myocardial recovery in nineteen CAD patients subjected to intracoronary ABMC infusion. Serial SPECT evaluation performed for up to 3 years after the ABMC treatment has confirmed a decreased functional deficiency of the heart, thus suggesting an improved myocardial perfusion in the patients. The observed shrinkage of hypoperfused areas was case-dependent. Appropriate pro year changes were 0.79±9.7% to 5.4±8.7% of the total ischemic area (<60% of normal values). The perfusion deficiency was increased four years later, thus indicating to worsening of blood supply (Fig. 2). It should be noted that repeated coronography did not, as a rule, exhibit a sufficient dynamics of initially affected coronary arteries (11).

Fig. 2. Changes of myocardial areas with severe perfusion deficiency (>60%, mean values) before treatment and atdifferent time intervals after ABMC infusions, as assessed by SPECT technique in 17 patients. Decrease in perfusiondeficiency was noted for 3 years, thus suggesting improvement of blood supply. Heart perfusion was again decreased4 years later, as seen from suboptimal blood supply.

Fig. 2. Changes of myocardial areas with severe perfusion deficiency (>60%, mean values) before treatment and at different time intervals after ABMC infusions, as assessed by SPECT technique in 17 patients. Decrease in perfusion deficiency was noted for 3 years, thus suggesting improvement of blood supply. Heart perfusion was again decreased 4 years later, as seen from suboptimal blood supply.


Figure 3. Evaluation of myocardial perfusion by means of a single-photon computer tomography (SPECT) at the timebefore and 4 years after infusion of autologous bone marrow cells (ABMC), as well as 1 year after repeated ABMCinjection to the coronary vessels. Blue color, good blood supply; white and yellow, deficient blood flow.

Figure 3. Evaluation of myocardial perfusion by means of a single-photon computer tomography (SPECT) at the time before and 4 years after infusion of autologous bone marrow cells (ABMC), as well as 1 year after repeated ABMC injection to the coronary vessels. Blue color, good blood supply; white and yellow, deficient blood flow.


a. Before ABMC Perfusion deficiency, 18.4%. Loading test, 75 Watt
b. 12 mo after ABMC. Perfusion deficiency, 8.7%. Loading test, 100 Watt
c. 22 mo. Perfusion deficiency, 6.1%. Loading test, 125 Watt
d. 39 mo. Perfusion deficiency, 6%. Loading test, 125 Watt
e. 48 mo, Perfusion deficiency, 14%. Loading test, 75 Watt
f. 60 mo (and 12 mo after repeated ABMC). Perfusion deficiency 6,8%. Loading test 125 Watt Repeated AMBC injections led to the secondary improvement of myocardial perfusion over a period of 6 to 12 months, as documented by SPECT assays with technetryl-99mTc (Fig. 3). A distinct therapeutic effect was also confirmed within 3 subsequent years, as evidenced by decrease in functional class of CAD.

Discussion

The mechanisms of collateral networks arising due to angiogenesis are discussed in the most works concerning potential effects of stem cells upon the ischemic myocardium. Some workers consider development of new collateral vessels among the main effects of cellular therapy. In most cases, the cytokine-mediated, or paracrine, effects seem to represent an immediate result of the cell therapy, i.e., the injected cells may be cytokine suppliers which provide an augmented local regeneration. One should note that the infused stem cells are active producers of growth factors boosting enhanced regeneration. The injected cells are, however, prone to subsequent death, due to their damage upon isolation and in vitro manipulations, as well as depletion of growth factors. In such instance, favorable effects of the cellular therapy should be, generally, limited by 3 to 6 months, being ascribed to the cytokine effects. In most cases, however, duration of the positive changes may be as long as 3 to 4 years, thus suggesting participation of an intrinsic regeneration component, e.g., an increased activity of resident cardiac stem cells [6].

Alternative hypotheses concerning de novo cardiomyocyte production are proposed by several workers. At the present time, some data are obtained in favor of myocardial cell renewal which, however, proceeds at slow rates [3]. The most convincing arguments for the cell regenerative component are presented by Quaini et al. who studied cellular chimerism in transplanted heart in patients with severe heart failure [10]. The authors transplanted female hearts to the male recipients, and a sufficient amount of male (Y chromosome- positive) cells was detected in grafts of female origin, thus suggesting some cellular regenerative mechanisms following the heart transplantation. The mean ratio of male cells in female allografts was, respectively, 18% for myocardiocytes; 20% among vascular smooth muscle cells, and 14%, for capillary endotheliocytes. The samples were taken at the D+4 to D+552 post-transplant . This result suggests an intensive blood-born homing of some male cells to the female heart transplant. Appropriate precursor cells may be hematopoietic, or endothelial by their origin. Hence, it should be noted that different cell populations are subject to renewal, i.e., cardiomyocytes, vascular smooth muscle cells, and capillary endotheliocytes which may expand in the cardiac graft. One may suggest that similar cells could regenerate in autologous heart of the patient with cardiovascular disorders, presuming the same regenerative pathways.

Additional data about potential intrinsic cell substitution, along with cytokine actions of the injected stem cells are presented by Dimmeler et al [15] in murine experiments. This model included trials with induced death of suicide gene-containing cells after their introduction to the myocardial syncytium, vascular endothelium, and vascular walls. In a model of acute myocardial infarction, the injected bone marrow cells were committed for endothelial differentiation, thus causing a sufficient improvement of myocardial contractibility. Induced cell death of the endothelium-committed cells was associated with decreased cardiac efflux. Interestingly, an induced death of the myocardium-committed cells did not exert such an effect. Moreover, elimination of NO synthase-expressing endothelial cells was associated with a decrease in capillary and arteriolar density. These data reflect potential effects of endothelial population upon functional ability of myocardium.

The endotheliocyte layer regulates transfer of stem cells through the vascular barrier via increased expression of adhesion molecules at the endothelium surface. The cells with different phenotypes exhibit different ability for transendothelial migration. One may suggest that reconstitution of endothelial function, including the cellular transport functions, may play a sufficient role in cardiac regeneration.

The first experimental work suggesting a mechanism of bone marrow stem cell effects upon endothelial dysfunction was presented by the workers from the USA [14]. Using an animal model of atherosclerosis-prone mice, they demonstrated that treatment with bone marrow endothelial precursors caused enhancement of NO production by endothelial cells, along with increase of endothelium-dependent vascular relaxation and decreased thickness of lipid plaques. This finding allows to suggest that reconstution of endothelial dysfunction with bone marrow cells may be indispensable for effective atherosclerosis treatment, both by correction of endothelial dysfunction, and prevention of lipid plaque development.

Functional and morphological interrelations between coronary endotheliocytes and cardiomyocytes are quite complex, multifaceted, being mediated not only by NO, but also by a number of other substances produced by endothelial cells which, in turn, may actively modify the cardiomyocyte functions [4]. Therefore, a correction of endothelial function in coronary vessels may be among future tasks for cellular therapy, being quite important for treatment of myocardial heart insufficiency.

Conclusion

Intracoronary injections of ABMC in CAD patients are accompanied by increased radiomarker capture over the entire myocardium, including the segments with satisfactory blood flow and hypoperfused areas, thus suggesting a diffuse mechanism for improved blood circulation and heart metabolism. Gradual fading of clinical and radiological improvement in cardiac blood supply is observed 3 to 4 years after cellular therapy, despite retained collateral flow and stabilization of atherosclerotic coronary damage. Subsequent improvement in blood supply resulting from repeated ABMC injections argues for additional, probably functional, mechanisms of increased blood supply associated with the cellular therapy.

This supplementary mechanism of cell therapy upon intracoronary ABMC injection may be potentially based on correction of endothelial dysfunction in coronary arterioles and capillary bed. The NO-dependent relaxation of coronary arterioles is connected with smooth muscle cell functions which may regenerate following the cellular therapy. This mode of correction is presumed to occur due to hematopoietic or endothelial precursors.

A renewal of endothelial or smooth muscle cells at the account of the bone marrow cells may be a sufficient component of restored functioning of a blood flow regulation, i.e., via endothelial production of NO and other substances which are able to modify the interactions between endothelium and cardiomyocytes.

Renewal rates of endotheliocytes in the cardiac vessels may proceed more rapidly that among cardiomyocytes, being, however, much slower than regeneration of blood cells. Therefore, the effects of restored endothelium cannot be expected earlier than several months after intracoronary ABMC injection. Therefore, a probable duration of appropriate effect, as seen from time dynamics of clinical and radiological signs after ABMC treatment, may be as long as 3 to 4 years. A distinct therapeutic effect was also confirmed by decrease in CAD functional class, thus allowing to recommend intracoronary AMBC injections every 3-4 years. We need, however, additional studies, in order to test our hypothesis concerning restoration of local endothelial function, and influence of this process upon the cardiomyocyte function.

Conflict of interest

None declared

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  7. Nemkov AS, Belyĭ SA, Nesteruk IuA, et al. Quality of life in patients with coronary artery disease after stem cell therapy. Vestn Khir Im I I Grek. 2012;171(1):16-20. (In Russian).
  8. Nesteruk JA,Nemkov AS, Beliy SA, et al. Evaluation of myocardial blood supply and methabolism after autologous bone marrow mononuclear cells intracoronary infusion. Regional Blood Supply and Microcirculation 2014; 13(3):23- 30. (In Russian)
  9. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410:701–705.
  10. Quaini F, Urbanek K, Beltrami AP, Finato N, Beltrami CA, Nadal-Ginard B, Kajstura J, Leri A, Anversa P. Chimerism of the Transplanted Heart. N Engl J Med 2002; 346:5-15.
  11. Sedov VM, Burnos SN, Nemkov AS, et al. Changes of myocardial perfusion after intracoronary administration of autologous bone marrow mononuclear cells in patients with coronary artery disease. Five-year follow-up. Regional Blood Supply and Microcirculation 2011; 10(2):19-23. (In Russian).
  12. Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, Schümichen C, Nienaber CA, Freund M, Steinhoff G. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003; 361(9351):45-46.
  13. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913–1918.
  14. Yao L, Heuser-Baker J, Herlea Pana O, et al. Bone marrow endothelial progenitors augment atherosclerotic plaque regression in a mouse model of plasma lipid lowering. Stem Cells 2012; 30(12): 2720–2731.
  15. Yoon Ch-H, Koyanagi M, Iekushi K, Seeger F, Urbich C, Zeiher A, Dimmeler S. Mechanism of improved cardiac function after bone marrow mononuclear cell therapy. Role of cardiovascular lineage commitment. Circulation 2010;121:2001-2020.

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Introduction

Precise mechanisms of cellular therapy of heart disorders with hematopoietic stem cells are unknown so far. However, they draw attention of clinicians and researchers, due to distinct positive effects observed in several studies. E.g., primary pre-clinical studies carried out in USA [9], and initial clinical studies in Düsseldorf (Germany) performed by Strauer et al. [13] and in Rostock by Steinhoff et al. [12] used autologous bone marrow cells (ABMC) for treatment of coronary artery disease (CAD). Trials with CAD patients have revealed a positive functional response of the cellular therapy. Over the last 12 years since introduction of this treatment modality, some distinct positive results are shown in randomized clinical studies. This treatment still has not become a standard of medication for CAD patients, despite of several meta-analyses [1, 5] have shown some benefits of the cellular therapy.

A general idea of possible paracrine effects produced by the cellular therapy cannot explain a variety of its actions and needs further interpretations. Intensive collateral formation (neoangiogenesis) in the areas of cell injections is a proven effect of cellular therapy. There are some effects, however, which cannot be explained solely by neoangiogenesis. To our mind, these effects represent indirect evidence for regeneration of endothelial lining in coronary arteries, including those of microcirculatory bed. Hence, the aim of our work was to provide an update of results confirming potential regenerative effects of intracoronary bone marrow cell infusions.

Material and methods

Since 2003, a study at the St.Petersburg State I.Pavlov Medical University (SPBMU) has performed a controlled non-randomized open label study aimed for clinical evaluation of ABMC intracoronary infusions to ninety-seven patients with sufficiently affected coronary bed, however, being non-eligible for coronary bypass (CABG), or coronary angioplastics. The patients received intracoronary injections of ABMC obtained by multiple sternal and iliac punctures and isolated by a two-stage gradient centrifugation (900 g for 15 min followed by 700 g for 15 min) using hydroxyethyl starch solution for separation. A total yield of nucleated cells per sample was 6.8±3.5×108 including 9±7.9×108 mononuclear cells, a mean number of CD34+ cells was 1.6±0.9×106. Cell viability was of myelokaryocytes was 95-98%.

A comparison group consisted of thirty-seven patients who were not treated with ABMC. Coronary angiography was performed in all patients before ABMC injection. Heart visualization was performed by single photon emission computed tomography (SPECT) in 17 patients or positron emissive tomography (PET) examination in 10 patients before treatment and 1-2 years after ABMC injections, in order to assess local myocardial perfusion and metabolic rates.

Results

Clinical effect of AMBC injections was revealed in the study group, in terms of decreased anginal symptoms by one functional class (68%), by two functional classes (12%) whereas 20% of the patients did not feel any changes in their performance. Such effect was evident at 6 to 9 months after single AMBC injections. A similar long-term monitoring in control group did not reveal any changes in the functional class of angina pectoris. This positive effect of cellular therapy retains for about 3 years, followed by a decrease in antianginal effects at 4 to 5 years post-treatment [2, 7, 11]. Coronary angiography performed at these terms showed stable state of the coronary vessels, absence of additional atherosclerotic lesions and retained collateral circulation.

Our data on a distinct stepwise increase in myocardial perfusion within the 1st year post-treatment also were confirmed by the results of PET examination with labeled ammonium. Improved myocardial metabolism in most myocardial segments was shown with fluordeoxyglucose (FDG) marker (Table.1). The most positive changes were noted for those segments with initially lesser capture of the radiolabeled drug. The same changes were found in a group of 10 patients (Fig. 1). An increase in these physiological parameters was detectable since 3 months after cellular therapy, followed by even more positive changes 6 and 12 mo after a single ABMC infusion [8, 11].

Table 1. PET data with FDG as a metabolic marker in patient M: dynamics of myocardial glucose consumption 12 mopost-treatment. Every of 17 segments of the heart had increased FDG marker, but the most positive changes wasnoted in those segments with initially lesser capture of radiolabeled drug (FDG)

Table 1. PET data with FDG as a metabolic marker in patient M: dynamics of myocardial glucose consumption 12 mo post-treatment. Every of 17 segments of the heart had increased FDG marker, but the most positive changes was noted in those segments with initially lesser capture of radiolabeled drug (FDG)


Fig. 1. Mean myocardial consumption of glucose is increasedafter 12-mo follow-up in a group of 10 patientsas shown by PET with FDG marker. The consumptionindex is increased by 57% (p=0.0001)

Fig. 1. Mean myocardial consumption of glucose is increased after 12-mo follow-up in a group of 10 patients as shown by PET with FDG marker. The consumption index is increased by 57% (p=0.0001)


One should note that improvement of myocardial perfusion was also traceable over wide myocardial areas by SPECT visualization, and, again, the most pronounced changes were seen for the segments with initially diminished capture of technetril-99mTc. Increased perfusion and higher metabolic recovery paralleled each other following intracoronary ABMC infusion. These radiological findings were accompanied by improved contractibility of the left ventricular myocardium, according to the echocardiography data. These positive changes were considered a result of improved collateral blood circulation [8, 11].

Moreover, our team has performed a longitudinal study of myocardial recovery in nineteen CAD patients subjected to intracoronary ABMC infusion. Serial SPECT evaluation performed for up to 3 years after the ABMC treatment has confirmed a decreased functional deficiency of the heart, thus suggesting an improved myocardial perfusion in the patients. The observed shrinkage of hypoperfused areas was case-dependent. Appropriate pro year changes were 0.79±9.7% to 5.4±8.7% of the total ischemic area (<60% of normal values). The perfusion deficiency was increased four years later, thus indicating to worsening of blood supply (Fig. 2). It should be noted that repeated coronography did not, as a rule, exhibit a sufficient dynamics of initially affected coronary arteries (11).

Fig. 2. Changes of myocardial areas with severe perfusion deficiency (>60%, mean values) before treatment and atdifferent time intervals after ABMC infusions, as assessed by SPECT technique in 17 patients. Decrease in perfusiondeficiency was noted for 3 years, thus suggesting improvement of blood supply. Heart perfusion was again decreased4 years later, as seen from suboptimal blood supply.

Fig. 2. Changes of myocardial areas with severe perfusion deficiency (>60%, mean values) before treatment and at different time intervals after ABMC infusions, as assessed by SPECT technique in 17 patients. Decrease in perfusion deficiency was noted for 3 years, thus suggesting improvement of blood supply. Heart perfusion was again decreased 4 years later, as seen from suboptimal blood supply.


Figure 3. Evaluation of myocardial perfusion by means of a single-photon computer tomography (SPECT) at the timebefore and 4 years after infusion of autologous bone marrow cells (ABMC), as well as 1 year after repeated ABMCinjection to the coronary vessels. Blue color, good blood supply; white and yellow, deficient blood flow.

Figure 3. Evaluation of myocardial perfusion by means of a single-photon computer tomography (SPECT) at the time before and 4 years after infusion of autologous bone marrow cells (ABMC), as well as 1 year after repeated ABMC injection to the coronary vessels. Blue color, good blood supply; white and yellow, deficient blood flow.


a. Before ABMC Perfusion deficiency, 18.4%. Loading test, 75 Watt
b. 12 mo after ABMC. Perfusion deficiency, 8.7%. Loading test, 100 Watt
c. 22 mo. Perfusion deficiency, 6.1%. Loading test, 125 Watt
d. 39 mo. Perfusion deficiency, 6%. Loading test, 125 Watt
e. 48 mo, Perfusion deficiency, 14%. Loading test, 75 Watt
f. 60 mo (and 12 mo after repeated ABMC). Perfusion deficiency 6,8%. Loading test 125 Watt Repeated AMBC injections led to the secondary improvement of myocardial perfusion over a period of 6 to 12 months, as documented by SPECT assays with technetryl-99mTc (Fig. 3). A distinct therapeutic effect was also confirmed within 3 subsequent years, as evidenced by decrease in functional class of CAD.

Discussion

The mechanisms of collateral networks arising due to angiogenesis are discussed in the most works concerning potential effects of stem cells upon the ischemic myocardium. Some workers consider development of new collateral vessels among the main effects of cellular therapy. In most cases, the cytokine-mediated, or paracrine, effects seem to represent an immediate result of the cell therapy, i.e., the injected cells may be cytokine suppliers which provide an augmented local regeneration. One should note that the infused stem cells are active producers of growth factors boosting enhanced regeneration. The injected cells are, however, prone to subsequent death, due to their damage upon isolation and in vitro manipulations, as well as depletion of growth factors. In such instance, favorable effects of the cellular therapy should be, generally, limited by 3 to 6 months, being ascribed to the cytokine effects. In most cases, however, duration of the positive changes may be as long as 3 to 4 years, thus suggesting participation of an intrinsic regeneration component, e.g., an increased activity of resident cardiac stem cells [6].

Alternative hypotheses concerning de novo cardiomyocyte production are proposed by several workers. At the present time, some data are obtained in favor of myocardial cell renewal which, however, proceeds at slow rates [3]. The most convincing arguments for the cell regenerative component are presented by Quaini et al. who studied cellular chimerism in transplanted heart in patients with severe heart failure [10]. The authors transplanted female hearts to the male recipients, and a sufficient amount of male (Y chromosome- positive) cells was detected in grafts of female origin, thus suggesting some cellular regenerative mechanisms following the heart transplantation. The mean ratio of male cells in female allografts was, respectively, 18% for myocardiocytes; 20% among vascular smooth muscle cells, and 14%, for capillary endotheliocytes. The samples were taken at the D+4 to D+552 post-transplant . This result suggests an intensive blood-born homing of some male cells to the female heart transplant. Appropriate precursor cells may be hematopoietic, or endothelial by their origin. Hence, it should be noted that different cell populations are subject to renewal, i.e., cardiomyocytes, vascular smooth muscle cells, and capillary endotheliocytes which may expand in the cardiac graft. One may suggest that similar cells could regenerate in autologous heart of the patient with cardiovascular disorders, presuming the same regenerative pathways.

Additional data about potential intrinsic cell substitution, along with cytokine actions of the injected stem cells are presented by Dimmeler et al [15] in murine experiments. This model included trials with induced death of suicide gene-containing cells after their introduction to the myocardial syncytium, vascular endothelium, and vascular walls. In a model of acute myocardial infarction, the injected bone marrow cells were committed for endothelial differentiation, thus causing a sufficient improvement of myocardial contractibility. Induced cell death of the endothelium-committed cells was associated with decreased cardiac efflux. Interestingly, an induced death of the myocardium-committed cells did not exert such an effect. Moreover, elimination of NO synthase-expressing endothelial cells was associated with a decrease in capillary and arteriolar density. These data reflect potential effects of endothelial population upon functional ability of myocardium.

The endotheliocyte layer regulates transfer of stem cells through the vascular barrier via increased expression of adhesion molecules at the endothelium surface. The cells with different phenotypes exhibit different ability for transendothelial migration. One may suggest that reconstitution of endothelial function, including the cellular transport functions, may play a sufficient role in cardiac regeneration.

The first experimental work suggesting a mechanism of bone marrow stem cell effects upon endothelial dysfunction was presented by the workers from the USA [14]. Using an animal model of atherosclerosis-prone mice, they demonstrated that treatment with bone marrow endothelial precursors caused enhancement of NO production by endothelial cells, along with increase of endothelium-dependent vascular relaxation and decreased thickness of lipid plaques. This finding allows to suggest that reconstution of endothelial dysfunction with bone marrow cells may be indispensable for effective atherosclerosis treatment, both by correction of endothelial dysfunction, and prevention of lipid plaque development.

Functional and morphological interrelations between coronary endotheliocytes and cardiomyocytes are quite complex, multifaceted, being mediated not only by NO, but also by a number of other substances produced by endothelial cells which, in turn, may actively modify the cardiomyocyte functions [4]. Therefore, a correction of endothelial function in coronary vessels may be among future tasks for cellular therapy, being quite important for treatment of myocardial heart insufficiency.

Conclusion

Intracoronary injections of ABMC in CAD patients are accompanied by increased radiomarker capture over the entire myocardium, including the segments with satisfactory blood flow and hypoperfused areas, thus suggesting a diffuse mechanism for improved blood circulation and heart metabolism. Gradual fading of clinical and radiological improvement in cardiac blood supply is observed 3 to 4 years after cellular therapy, despite retained collateral flow and stabilization of atherosclerotic coronary damage. Subsequent improvement in blood supply resulting from repeated ABMC injections argues for additional, probably functional, mechanisms of increased blood supply associated with the cellular therapy.

This supplementary mechanism of cell therapy upon intracoronary ABMC injection may be potentially based on correction of endothelial dysfunction in coronary arterioles and capillary bed. The NO-dependent relaxation of coronary arterioles is connected with smooth muscle cell functions which may regenerate following the cellular therapy. This mode of correction is presumed to occur due to hematopoietic or endothelial precursors.

A renewal of endothelial or smooth muscle cells at the account of the bone marrow cells may be a sufficient component of restored functioning of a blood flow regulation, i.e., via endothelial production of NO and other substances which are able to modify the interactions between endothelium and cardiomyocytes.

Renewal rates of endotheliocytes in the cardiac vessels may proceed more rapidly that among cardiomyocytes, being, however, much slower than regeneration of blood cells. Therefore, the effects of restored endothelium cannot be expected earlier than several months after intracoronary ABMC injection. Therefore, a probable duration of appropriate effect, as seen from time dynamics of clinical and radiological signs after ABMC treatment, may be as long as 3 to 4 years. A distinct therapeutic effect was also confirmed by decrease in CAD functional class, thus allowing to recommend intracoronary AMBC injections every 3-4 years. We need, however, additional studies, in order to test our hypothesis concerning restoration of local endothelial function, and influence of this process upon the cardiomyocyte function.

Conflict of interest

None declared

References

  1. Abdel-Latif A, Bolli R, Tleyjeh IM, et al. Adult bone marrow-derived cells for cardiac repair. A systematic review and meta-analysis. Arch Intern Med 2007; 167(10):989-997.
  2. Burnos SN, Nemkov AS, Belyĭ SA, Lukashenko VI. Ejection fraction and sizes of the left ventricle of the heart after intracoronary administration of autologous mononuclear cells of the bone marrow in patients with coronary artery disease with low ejection fraction.// Vestn Khir Im I I Grek 2011;170(4):16-19. (In Russian)
  3. Leri A, Kajstura J, Anversa P. Mechanisms of myocardial regeneration. Trends Cardiovasc Med 2011; 21(2):52–58.
  4. Lynn LS, Lam CSP, Segers VFM, Brutsaert DL, De Keulenaer GW. Cardiac endothelium–myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction. Eur Heart J 2015; doi:10.1093/eurheartj/ ehv132
  5. Jeevanantham V, Butler M, Saad A, et al. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters : a systematic review and meta-analysis. Circulation 2012;126:551-568
  6. Marban E, Cheng Ke. Heart to heart: the elusive mechanism of cell therapy. Circulation 2010; 121:1981-1984.
  7. Nemkov AS, Belyĭ SA, Nesteruk IuA, et al. Quality of life in patients with coronary artery disease after stem cell therapy. Vestn Khir Im I I Grek. 2012;171(1):16-20. (In Russian).
  8. Nesteruk JA,Nemkov AS, Beliy SA, et al. Evaluation of myocardial blood supply and methabolism after autologous bone marrow mononuclear cells intracoronary infusion. Regional Blood Supply and Microcirculation 2014; 13(3):23- 30. (In Russian)
  9. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410:701–705.
  10. Quaini F, Urbanek K, Beltrami AP, Finato N, Beltrami CA, Nadal-Ginard B, Kajstura J, Leri A, Anversa P. Chimerism of the Transplanted Heart. N Engl J Med 2002; 346:5-15.
  11. Sedov VM, Burnos SN, Nemkov AS, et al. Changes of myocardial perfusion after intracoronary administration of autologous bone marrow mononuclear cells in patients with coronary artery disease. Five-year follow-up. Regional Blood Supply and Microcirculation 2011; 10(2):19-23. (In Russian).
  12. Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, Schümichen C, Nienaber CA, Freund M, Steinhoff G. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003; 361(9351):45-46.
  13. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913–1918.
  14. Yao L, Heuser-Baker J, Herlea Pana O, et al. Bone marrow endothelial progenitors augment atherosclerotic plaque regression in a mouse model of plasma lipid lowering. Stem Cells 2012; 30(12): 2720–2731.
  15. Yoon Ch-H, Koyanagi M, Iekushi K, Seeger F, Urbich C, Zeiher A, Dimmeler S. Mechanism of improved cardiac function after bone marrow mononuclear cell therapy. Role of cardiovascular lineage commitment. Circulation 2010;121:2001-2020.

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["DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(5) { [0]=> string(3) "488" [1]=> string(3) "489" [2]=> string(3) "490" [3]=> string(3) "491" [4]=> string(3) "492" } ["~DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["~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(4) "6316" ["VALUE"]=> string(19) "20.12.2016 14:29:00" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(19) "20.12.2016 14:29:00" ["~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(4) "6317" ["VALUE"]=> string(19) "17.06.2016 14:29:00" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(19) "17.06.2016 14:29:00" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "6318" ["VALUE"]=> string(3) "486" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "486" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(5) { [0]=> string(4) "6529" [1]=> string(4) "6530" [2]=> string(4) "6531" [3]=> string(4) "6532" [4]=> string(4) "6533" } ["VALUE"]=> array(5) { [0]=> string(3) "486" [1]=> string(3) "493" [2]=> string(3) "494" [3]=> string(3) "495" [4]=> string(3) "496" } ["DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(5) { [0]=> string(3) "486" [1]=> string(3) "493" [2]=> string(3) "494" [3]=> string(3) "495" [4]=> string(3) "496" } ["~DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "6320" ["VALUE"]=> array(2) { ["TEXT"]=> string(216) "<p class="Autor"> Александр С. Немков, Сергей А. Белый, Владимир В. Комок, Олег А. Гриненко, Николай С. Буненков </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(194) "

Александр С. Немков, Сергей А. Белый, Владимир В. Комок, Олег А. Гриненко, Николай С. Буненков

" ["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(4) "6321" ["VALUE"]=> array(2) { ["TEXT"]=> string(286) "Отделение сердечно-сосудистой хирургии, Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(286) "Отделение сердечно-сосудистой хирургии, 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(4) "6322" ["VALUE"]=> array(2) { ["TEXT"]=> string(1757) "<p> На протяжении 12 лет клеточной терапии в кардиологии, по данным рандомизированных исследований достигнуты определенные положительные результаты. Однако до сих пор не выяснены конкретные механизмы действия гемопоэтических стволовых клеток в этих клинических ситуациях. Усиленный неоангиогенез при введении стволовых клеток является доказанным механизмом улучшения поступления крови в сердце. В то же время отмечается снижение эффекта реваскуляризации через 3-4 года, а через 3-4 месяца после проведения повторной клеточной терапии опять происходит активное формирование коллатеральных сосудов с последующим улучшением сердечной функции, что предполагает наличие дополнительного механизма улучшения коронарного кровотока. Восстановление регуляторных функций эндотелия и гладкомышечных клеток, включая повышение активности NO-синтазы эндотелия и его взаимодействия с миокардиоцитами может явиться возможным механизмом такого эффекта. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1745) "

На протяжении 12 лет клеточной терапии в кардиологии, по данным рандомизированных исследований достигнуты определенные положительные результаты. Однако до сих пор не выяснены конкретные механизмы действия гемопоэтических стволовых клеток в этих клинических ситуациях. Усиленный неоангиогенез при введении стволовых клеток является доказанным механизмом улучшения поступления крови в сердце. В то же время отмечается снижение эффекта реваскуляризации через 3-4 года, а через 3-4 месяца после проведения повторной клеточной терапии опять происходит активное формирование коллатеральных сосудов с последующим улучшением сердечной функции, что предполагает наличие дополнительного механизма улучшения коронарного кровотока. Восстановление регуляторных функций эндотелия и гладкомышечных клеток, включая повышение активности NO-синтазы эндотелия и его взаимодействия с миокардиоцитами может явиться возможным механизмом такого эффекта.

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Alexander S. Nemkov, Sergey. A. Belyi, Vladimir V. Komok, Oleg A. Grinenko, Nikolay S. Bunenkov

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Over 12 years of cellular therapy in cardiology, some dictinct positive results are obtained in randomized studies. However, exact mechanisms of hematopoietic stem cell actions are still unclear under these clinical conditions. Paracrine effects of cell therapy cannot explain all these effects. Enhanced neoangiogenesis upon stem cell injection is a proven mechanism for improvement of blood supply to the heart. Meanwhile, a decreased revascularization effect 3-4 years after cell therapy is followed by repeated myocardial improvement 6-9 mo after repeated cell infusions with active development of collateral vessels, thus suggesting an additional mechanism for improvement of coronary blood supply. Restoration of regulatory functions of endothelium and smooth muscle cells, including increased NO synthase activity of endothelium and its interactions with myocardiocytes may represent a probable mechanism for this action.

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Over 12 years of cellular therapy in cardiology, some dictinct positive results are obtained in randomized studies. However, exact mechanisms of hematopoietic stem cell actions are still unclear under these clinical conditions. Paracrine effects of cell therapy cannot explain all these effects. Enhanced neoangiogenesis upon stem cell injection is a proven mechanism for improvement of blood supply to the heart. Meanwhile, a decreased revascularization effect 3-4 years after cell therapy is followed by repeated myocardial improvement 6-9 mo after repeated cell infusions with active development of collateral vessels, thus suggesting an additional mechanism for improvement of coronary blood supply. Restoration of regulatory functions of endothelium and smooth muscle cells, including increased NO synthase activity of endothelium and its interactions with myocardiocytes may represent a probable mechanism for this action.

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Александр С. Немков, Сергей А. Белый, Владимир В. Комок, Олег А. Гриненко, Николай С. Буненков

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На протяжении 12 лет клеточной терапии в кардиологии, по данным рандомизированных исследований достигнуты определенные положительные результаты. Однако до сих пор не выяснены конкретные механизмы действия гемопоэтических стволовых клеток в этих клинических ситуациях. Усиленный неоангиогенез при введении стволовых клеток является доказанным механизмом улучшения поступления крови в сердце. В то же время отмечается снижение эффекта реваскуляризации через 3-4 года, а через 3-4 месяца после проведения повторной клеточной терапии опять происходит активное формирование коллатеральных сосудов с последующим улучшением сердечной функции, что предполагает наличие дополнительного механизма улучшения коронарного кровотока. Восстановление регуляторных функций эндотелия и гладкомышечных клеток, включая повышение активности NO-синтазы эндотелия и его взаимодействия с миокардиоцитами может явиться возможным механизмом такого эффекта.

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На протяжении 12 лет клеточной терапии в кардиологии, по данным рандомизированных исследований достигнуты определенные положительные результаты. Однако до сих пор не выяснены конкретные механизмы действия гемопоэтических стволовых клеток в этих клинических ситуациях. Усиленный неоангиогенез при введении стволовых клеток является доказанным механизмом улучшения поступления крови в сердце. В то же время отмечается снижение эффекта реваскуляризации через 3-4 года, а через 3-4 месяца после проведения повторной клеточной терапии опять происходит активное формирование коллатеральных сосудов с последующим улучшением сердечной функции, что предполагает наличие дополнительного механизма улучшения коронарного кровотока. Восстановление регуляторных функций эндотелия и гладкомышечных клеток, включая повышение активности NO-синтазы эндотелия и его взаимодействия с миокардиоцитами может явиться возможным механизмом такого эффекта.

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Introduction

Management of patients subjected to extensive body irradiation as a part of conditioning therapy still remains a major challenge. Survival of radiation-induced bone marrow failure depends on the dose of radiation received and the intensity of supportive care which can protect from otherwise lethal infection and give surviving stem cells a chance to replenish blood cell populations. Since radiation effects on blood stem cells occur at doses generally lower than those on other critical organs, the rapidly emerging changes in the peripheral blood cell lineages determine the treatment options. In fact, total body irradiation (TBI) at doses more than 7-8 Gy in humans corresponds to medullar eradication. Under this threshold, spontaneous recovery from residual hematopoietic stem and progenitor cells may be expected within 30–50 days, however, preceded by cytopenic phases of granulocytic, megakaryocytic and erythrocytic lineages. Interestingly, even after TBI, intrinsically radioresistant stem cells have been detected in distinct bone marrow (BM) areas comprising a residual hematopoietic stem and progenitor cell pool [10]. Acute irradiation does not only imply damage to the bone marrow. In a dose-dependent matter, it can also emerge as gastrointestinal and cerebrovascular syndromes leading to development of multiple organ dysfunction (1). Damage to the whole organism is related to a systemic inflammatory response. Different target organs are affected due to activation of innate immune system, resulting in a significant release of inflammatory cytokines [4]. The pathophysiology of such tissue damage appears comparable to that of acute graftversus- host disease (GvHD) following allogeneic stem cell transplantation where a similar ”cytokine storm” has been observed [6]. In absence of appropriate treatment, oxidative stress after high dose ionizing radiation has been involved in delayed morbidity [4]. Management of acute radiation syndrome relies, therefore, on tissue damage repair processes that might be supported by therapies aimed for mitigation of inflammation [4].

Efforts to improve outcome after irradiation focus on the stem cell niche. Therefore, prospective therapies should augment the hematopoietic niche activity to accelerate the in vivo recovery of blood cell populations. Several studies have demonstrated that BM osteoblasts regulate the HSC pool size in vivo via the Jagged1-Notch signaling pathway [7]. For example, parathyroid hormone receptor activation can increase the number of osteoblastic cells, thus resulting in Notch1-mediated expansion of HSC [2]. Mesenchymal stromal cells (MSC) comprise an integrative part of the BM stroma, being also described as osteoblastic progenitors [8]. MSC are multipotential nonhematopoietic progenitor cells capable of differentiating into multiple lineages of the mesenchyme. In bone marrow, the local stromal cells surround HSC and their progeny. The hematopoietic niche provides a sheltering microenvironment that provides maintenance and self-renewal of HSC by shielding them from differentiation and apoptotic stimuli that would otherwise challenge stem cell reserves. Moreover, the hematopoietic niche also controls proliferation and differentiation of HSC and release of mature progeny into peripheral blood flow. Regulation of HSC quiescence, by maintenance of resting HSC in endosteal niche, control of HSC proliferation, differentiation and recruitment in the vascular niche can be ascribed to bone-marrow stromal cells [27]. Thus, physiological role of MSCs is not a mere replacement of mesenchymal tissues such as bone. Moreover, their primary and most important function is to inhibit immunosurveillance and to establish a protective and regenerative microenvironment for HSC.

Clinically, MSCs have been proven to intervene with acute organ impairment. When co-transplanted with HSC, MSCs augment hematopoietic recovery after chemo- or radiotherapy significantly decreasing the time to full hematopoietic and particularly platelet reconstitution [12]. Additionally, there is evidence for MSC effectiveness in the treatment of steroid resistant GvHD without any side effects, even when obtained from BM of third-party donors [18]. No HLA-match is needed between donor and recipient because MSCs have been shown to be hypoimmunogenic and are not recognized by the recipient immune system even after repeated injections [18]. Finally, MSCs secrete a variety of bioactive molecules [22]. Among those, some essential hematopoietic growth factors including IL-6, IL-11, leukemia inhibitory factor (LIF), stem cell factor (SCF) and Flt3 ligand are produced, as well as factors with immunomodulatory effects, e.g. transforming growth factor-β1 (TGF-β1), prostaglandin E2, indoleamine 2,3-dioxygenase, and others [21]. Additionally, vascular endothelial growth factor (VEGF) secreted by MSCs in abundance might interfere with early apoptotic cell death after irradiation [10]. Therefore, MSCs might be a good candidate for modulation of the hematopoietic niche activity. In summary, MSCs have emerged as a promising therapeutic tool for tissue regeneration and repair. Further clinical interest has been raised by the observation that MSCs are immunoprivileged and might be transplanted from unrelated, i.e. allogeneic donors [21,27]. Altogether, we assumed that MSCs, with their comprehensive trophic potential, could serve as a readily available treatment option after severe radiation exposure. The aim of our study was to evaluate essential biological parameters of MSC, with respect to their lineage- specific differentiation capacity, in vivo survival rates, as well as their ability to rescue lethally irradiated hosts.

Methods and Results

In vitro differentiation of human MSC (hMSC)

As first experiments, we investigated the capability of human BM-derived MSCs (hMSCs) to differentiate into progenitors for hematopoietic (HSC) and endothelial cells (EC). The human MSCs were thoroughly characterized according to the ISCT (International Society for Cellular Therapy) criteria [5], including flow cytometry and their capability to differentiate into three mesodermal lineages [16]. To avoid any contamination of MSCs with HSC, cloned cells were used exclusively. Cloned human MSCs were subjected to differentiation into (i) hematopoietic cells using serum-containing or serum-depleted growth conditions and (ii) endothelial cells (for technical details see ref. 14). Fibroblastoid MSCs (Fig. 1a) formed blast-like cells with noticeably decreased diameter from originally 28.9 ± 6.6 to 15.7 ± 3.5 μm during the differentiation into hematopoietic (Fig. 1b) and endothelial (Fig. 1c) lineages. The in vitro conditions led to cluster formation appearing as an in vitro equivalent of stromal structures from which differentiation proceeded. The cells committed to hematopoietic lineage changed their gene expression towards appropriate profiles of blood cell progenitors (CD117, CD133, CD45) and mature (CD14, CD16, glycophorinA GlyA, CD31, podoplanin PDPN) hematopoietic cells (Fig. 2a). Interestingly, the erythropoietin receptor (EPOR) was upregulated in almost all clones and under all conditions suggesting a definite role for EPO in proliferation and differentiation of mesodermal progenitors. Additionally,

Figure 1: Human MSC display a fibroblastoid morphology during in vitro expansion but form blast-like cells after inductionof differentiation. One clonal hMSC culture is shown during expansion (a), differentiation into hematopoietic(b) or endothelial (c) cells.

Figure 1: Human MSC display a fibroblastoid morphology during in vitro expansion but form blast-like cells after induction of differentiation. One clonal hMSC culture is shown during expansion (a), differentiation into hematopoietic (b) or endothelial (c) cells.


Figure 2: Human MSC significantly upregulate expressions of hematopoietic and endothelial genes after inductionof differentiation. Shown are the fold changes of gene expressions of indicated hematopoietic (a) and endothelial(b) genes after differentiation compared to undifferentiated hMSC. GlyA, Glycophorin A; vWF, von Willebrand factor;VEGFR, vascular endothelial growth factor receptor.

Figure 2: Human MSC significantly upregulate expressions of hematopoietic and endothelial genes after inductionof differentiation. Shown are the fold changes of gene expressions of indicated hematopoietic (a) and endothelial(b) genes after differentiation compared to undifferentiated hMSC. GlyA, Glycophorin A; vWF, von Willebrand factor;VEGFR, vascular endothelial growth factor receptor.

Figure 2: Human MSC significantly upregulate expressions of hematopoietic and endothelial genes after induction of differentiation. Shown are the fold changes of gene expressions of indicated hematopoietic (a) and endothelial (b) genes after differentiation compared to undifferentiated hMSC. GlyA, Glycophorin A; vWF, von Willebrand factor; VEGFR, vascular endothelial growth factor receptor.

a variety of transcription factors responsible for erythropoiesis (SCL/tal1), erythro-megakaryopoiesis (GATA1, GATA2), lymphopoiesis (GATA3), and myelopoiesis (NOTCH1, RUNX1) were upregulated upon serum-containing differentiation. As SCL and RUNX1 are transcription factors essential for HSC formation by instructing lineage specification (9), we suggested an efficient induction of this differentiation pathway in MSCs. Using immunofluorescence, a subpopulation of antigen-positive cells with small round or polymorphic nuclei was detected, showing expression of hematopoietic progenitor and mature antigen expression (not shown, refer to ref. 14), albeit to a rather low degree. In parallel, the same cells were able to acquire endothelial morphology and expressed endothelial genes upon cultivation with endothelial promoting factors (Fig. 2b). At the protein level, single double positive cells for CD31/vWF (von Willebrand factor) and VEGFR-2/CD34 were detected [14].

Hematopoietic and endothelial progenitors share expression of a number of genes, including VEGFR-2, CD34, SCL, GATA2, RUNX1, and CD31, suggesting that investigated hMSCs possess in vitro hemangioblastic capacity, and might act as extrinsic differentiation factors and lineage-inducing regulators. Most potent differentiation was achieved in cultures where the majority of hMSCs adopted stromal function, thus inducing a minor part for differentiation. We concluded from the in vitro results, that MSCs might reconstitute the hematopoietic system. Hypothetically, one pluripotent stem cell would suffice to rescue lethally irradiated hosts. In reality, however, approx. 6 cells are needed [13], i.e. six pluripotent MSCs with the respective potential might suffice to restore hematopoiesis in vivo.

MSCs promote hematopoietic recovery after lethal irradiation

To test in vivo ability of murine MSCs to replenish the hematopoiesis after eradication, lethally irradiated (9.5 Gy) female recipients of the C57Bl/6J-CD45.1 strain were subjected to i.v. transplantation with 106 eGFP-marked male bulk-culture C57Bl/6J mouse MSCs (mMSCs). Mouse MSC were cultured in DMEM/Ham´s F12 + 20% preselected FCS + Glutamin + ß-mercaptoethanol and cells after 9-12 passages used for transplantation. Leukocyte and thrombocyte recovery was similar to recipients transplanted with HSCs (Fig. 3) reaching normalization of white blood cell counts after 4 weeks. Seven months later, the recipients were hematologically well, with a normal distribution of peripheral cell populations (Table 1). Similar experiments were carried out with clonal mMSCs showing one clone (IXH8) with superior survival promoting properties (Table 2). Noteworthy, the IXH8 clone was different from all other cultures showing long-stretched morphology and increased CD34 and CD45, however, without CD105 expression (Table 2).

Figure 3: Mouse MSC rescue mice after total body irradiation.Transplantation of bulk mMSC led to a normalizationof the peripheral white blood cell count within 4weeks. Thrombocyte recovery needed approx. 8 weeksfor normalization.

Figure 3: Mouse MSC rescue mice after total body irradiation. Transplantation of bulk mMSC led to a normalization of the peripheral white blood cell count within 4 weeks. Thrombocyte recovery needed approx. 8 weeks for normalization.






Table 1: Peripheral blood cell populations in mMSC transplanted animals.Shown is the distribution of white blood cells 5 months after bulk mMSC transplantation estimated using Pappenheim-stained blood smears.
  Table 1: Peripheral blood cell populations in mMSC transplanted animals. Shown is the distribution of white blood cells 5 months after bulk mMSC transplantation estimated using Pappenheim-stained blood smears.

Table 2: Phenotypical characterization of mMSC and recipients’ survival rates after transplantation.Cultures of eGFP-transduced bulk and cloned mMSC after extended expansion were positive for CD59, CD105 and Sca-1 butnegative for the hematopoietic markers CD34, CD45, CD117 and for CD90 by flow cytometry. Clone IXH8 was different fromall other cultures in its expression of CD34/CD45 and negativity of CD105 (shown in bold italic). Transplantation with this cloneresulted in the highest survival rate of the irradiated recipients, suggesting elevated CD34 and CD45 and no CD105 expressionsmight be a prerequisite of the high rescue capability. nd, not done.

Table 2: Phenotypical characterization of mMSC and recipients’ survival rates after transplantation.
Cultures of eGFP-transduced bulk and cloned mMSC after extended expansion were positive for CD59, CD105 and Sca-1 but negative for the hematopoietic markers CD34, CD45, CD117 and for CD90 by flow cytometry. Clone IXH8 was different from all other cultures in its expression of CD34/CD45 and negativity of CD105 (shown in bold italic). Transplantation with this clone resulted in the highest survival rate of the irradiated recipients, suggesting elevated CD34 and CD45 and no CD105 expressions might be a prerequisite of the high rescue capability. nd, not done.

Transplanted donor cells are detectable short- but not long-term

To trace donor chimerism in recipients, we stained recipient peripheral blood (PB), BM and thymus cells with CD45.2 antibodies and carried out flow cytometry. Interestingly, no CD45.2-positive cells were found at any time point, thus not showing regeneration through donor cells. Y-chromosome-based chimerism analysis in female recipients using specific Y-chromosome primers for quantitative PCR could not detect donor cells in any of investigated tissues including PB and BM (not shown), although animals survived up to the final evaluation after 7 months. Spectral karyotyping of clonal mMSC revealed loss of Y-chromosome (Fig. 4), whereas bulk cultures were still Y-positive at passage13 (not shown).

Figure 4: Spectral karyotyping of mMSC. Shown is the SKY analysis of clone IXH8. SKY analysis of a representativediploid metaphase revealed the loss of the Y-chromosome and this has been observed in all metaphases analyzed.
Figure 4: Spectral karyotyping of mMSC. Shown is the SKY analysis of clone IXH8. SKY analysis of a representative diploid metaphase revealed the loss of the Y-chromosome and this has been observed in all metaphases analyzed.

Next, we used eGFP-specific primers for quantitative PCRbased donor cell detection. Primers for stably integrated eGFP-sequences, however, also failed to detect any donor cells, and no eGFP-positive cells were found in blood, BM or thymus by flow cytometry. Although we cannot completely rule out single donor cells below the detection limit, hematopoietic recovery in recipients is unlikely due to replacement with donor cells. This conclusion contradicts earlier results of hematopoietic recovery after myeloablative TBI with blood-derived mMSCs [11, 15] showing donor characteristics in blood and BM. One fundamental difference between both cell sources is potential in vitro immortalization, altering BM seeding capability of MSC. Therefore, our results support the concept of impaired transplantability of expanded MSC [24] but also challenge the hypothesis of high plasticity of MSC [1].

The distribution kinetics of eGFP+ donor cells after i.v. transplantation identified fast disappearance from PB, reaching ca. 2% after 8 hours and no cells at d10 (Fig. 5a). In contrast, mMSC trapped in lungs quickly (Fig. 5b), however without long-term residence and embolization as shown by lack of donor signals after d+10. Accordingly, no donor cells were detectable evident in the spleen, liver, BM (Fig. 5b), aorta, kidney, intestine, fat, thymus or lymph nodes (not shown). Although we did not find donor derived MSC in the BM, the morphology of this organ was preserved by MSC transplantation showing a normal distribution between different compartments (Fig. 6). Without MSCs, adipocytes are shown to dominate within short time, thus destroying the marrow structure.

Figure 5: Donor mMSC are not detectable at longer terms.(a) Tracking of eGFP-labeled clonal IXH8 donor mMSC after transplantation revealed a fast decrease in peripheral blood (PB). Within 8hours, approx. 2% were quantified in PB and none after 10 days (n = 8 for each time point).   Figure 5: Donor mMSC are not detectable at longer terms.(b) mMSC accumulated in lungs (Lu) within24 h and disappeared within 10 days (240 h). Spleen (Sp), liver (Li) and BM were negative at d1 and d10. nd, not detected.

Figure 5: Donor mMSC are not detectable at longer terms.
(a) Tracking of eGFP-labeled clonal IXH8 donor mMSC after transplantation revealed a fast decrease in peripheral blood (PB). Within 8 hours, approx. 2% were quantified in PB and none after 10 days (n = 8 for each time point). (b) mMSC accumulated in lungs (Lu) within 24 h and disappeared within 10 days (240 h). Spleen (Sp), liver (Li) and BM were negative at d1 and d10. nd, not detected.

Figure 6. Histomorphology of BM with and without MSC transplantation.Paraffin embedded long bones from MSC-transplanted or control animals were cut and the number of adipocytes counted in 2 designatedareas (A) per bone from mice with MSC transplantation after 4 (B), 12 (D), 24 (F) and 36 (H) hours or without MSC transplantation(C, E, G, and I respectively). The lower figure shows the number of adipocytes at each time point.

   Figure 6. Histomorphology of BM with and without MSC transplantation.Paraffin embedded long bones from MSC-transplanted or control animals were cut and the number of adipocytes counted in 2 designatedareas (A) per bone from mice with MSC transplantation after 4 (B), 12 (D), 24 (F) and 36 (H) hours or without MSC transplantation(C, E, G, and I respectively). The lower figure shows the number of adipocytes at each time point.

Figure 6. Histomorphology of BM with and without MSC transplantation.
Paraffin embedded long bones from MSC-transplanted or control animals were cut and the number of adipocytes counted in 2 designated
areas (A) per bone from mice with MSC transplantation after 4 (B), 12 (D), 24 (F) and 36 (H) hours or without MSC transplantation
(C, E, G, and I respectively). The lower figure shows the number of adipocytes at each time point.

MSCs change the BM gene expression

While donor mMSC did not home to the BM, we observed a long term recipients´ survival and assumed an influence of MSCs on the BM function. Therefore we carried out microarray analysis of bone marrow cells from MSC-transplanted animals, and compared their gene expression profiles to that of HSC-transplanted animals and age-matched controls [14]. The gene expression profile in BM changed significantly, clustering into separate group as compared to untreated BM or HSC-transplanted mice. Validation of selected genes with high variance proved a beneficial role of MSC in endogenous hematopoietic reconstitution. MSCs caused upregulated protection from oxidative stress, cell cycle, anti-inflammatory and detoxication events (e.g. BRPK, Cdkn1a, Thbs2, Gstm5 gene expression) in a complex way, along with downregulation of lymphoid development, pro-inflammatory events, protein degradation and adhesion/matrix formation for improved cell motility (e.g. gene expressions of Vpreb1, Rag2, Klk6, Klk1b5, Uchl1, Sykb, Gpam, Col5a3, Emid1) [14]. Upon summarising the microarray expression data, we have shown upregulation of the genes which are beneficial to BM reconstitution, whereas the genes with supposed radiation- related BM deterioration were downregulated (Fig. 7).

Figure 7. MSC transplantation into lethally irradiated animals changes the gene expression in the bone marrow.Gene expression data were generated using microarray analysis and significantly regulated genes clustered into functional groups.Shown are upregulated functional gene groups (MSC up) or downregulated (MSC down) in MSC-transplanted animals.
Figure 7. MSC transplantation into lethally irradiated animals changes the gene expression in the bone marrow.
Gene expression data were generated using microarray analysis and significantly regulated genes clustered into functional groups.
Shown are upregulated functional gene groups (MSC up) or downregulated (MSC down) in MSC-transplanted animals.

Potential paracrine mechanism of MSC

Potential mechanisms mediating bone marrow protection by MSCs entrapped in the lung, still remain unclear. Recently, we could show that injection of MSC-derived microvesicles to lethally irradiated animals provided similar protective effects, as transplantation of MSCs per se (Fig. 8). The microvesicles represent a fraction of ultra-small lipid bilayer particles of 30 to 1000 nm size (including exosome fraction) which are known to shuttle proteins, lipids, mRNA and microRNA [25]. Any of these components could participate in radiation protection and recovery of the bone marrow. Interestingly, the microvesicle-associated reconstitution of platelet scores occurred at a faster time frames, as compared to MSCs injections. Further work should reveal a more precise mechanism conferring radiation protection associated with MSC microvesicles.

Discussion

In this study we present an evidence that donor MSCs do not directly reconstitute the hematopoietic system following radiation insult. However, these cells may provide salvage for the surviving HSCs. Acute irradiation produces excessive inflammatory responses (23) which contribute to HSC death if untreated. Along with other organs, the lung is also heavily affected by radiation damage and might retard MSCs. Mesenchymal cells interfere with inflammation by changing overall gene expression profile, both in lungs where they are captured, and in bone marrow compartments. Assuming this, a direct MSC homing to the bone marrow is not necessary for changed gene expression patterns. This mechanism has been described in murine model of myocardial infarction where hMSCs have been shown to produce antiapoptotic TSG6 without significant engraftment [19]. A paracrine, differentiation-independent effect of MSCs did also ameliorate kidney injury [17, 26].

Figure 8: Transplantation of mMSC-derived microvesicles rescues lethally irradiated animals.Leukocyte counts after mMSC-derived microvesicle injection normalized with similar kinetics as with mMSC, whereas thrombocytecounts showed a much faster normalization (a)(n=15). Electron microscopy of microvesicles released from mMSC (b) and purified byultracentrifugation (c).

   Figure 8: Transplantation of mMSC-derived microvesicles rescues lethally irradiated animals.Leukocyte counts after mMSC-derived microvesicle injection normalized with similar kinetics as with mMSC, whereas thrombocytecounts showed a much faster normalization (a)(n=15). Electron microscopy of microvesicles released from mMSC (b) and purified byultracentrifugation (c).
Figure 8: Transplantation of mMSC-derived microvesicles rescues lethally irradiated animals.
Leukocyte counts after mMSC-derived microvesicle injection normalized with similar kinetics as with mMSC, whereas thrombocyte
counts showed a much faster normalization (a)(n=15). Electron microscopy of microvesicles released from mMSC (b) and purified by
ultracentrifugation (c).


What could be expected from MSC as a potential therapeutic tool? Secretion of broad-range bioactive molecules is now believed to be the main mechanism by which the therapeutic effects of MSCs are achieved [20]. MSCs may secrete active factors that (a) inhibit apoptosis and limit the extent of cellular damage; (b) inhibit fibrosis or scarring at the injured sites; (c) protect microvasculature and stimulate angiogenesis, thus improving perfusion rates; and (d) promote proliferation of tissue- specific progenitor cells, as shown for cardiac-, neural- and kidney-specific stem cells [26,27]. In parallel, we have shown in a model with acute irradiation that MSCs boosted anti-inflammatory, anti-apoptotic, detoxifying, cell cycle and anti-oxidative stress control, whereas proinflammatory effects, extracellular matrix formation, and adhesion properties were decreased. In general, MSC injections may result into systemic improvements counteracting deleterious effects of myelosuppression [14].

In conclusion, transplanted MSC might export their inherent trophic effect to unorthodox sites [3], e.g. to lungs. Our results present another piece of evidence for this highly effective paracrine mechanism which may work, e.g., in BM populations, suggesting MSC-infusion to be an efficient treatment option following acute irradiation. Despite some limitations in our existing knowledge, a capacity of MSCs, or MSC-derived microvesicles, to exert hematopoietic support via a bystander mechanisms, might indicate that persistent engraftment at the site of damage is not a mandatory prerequisite. Importantly, a very short-term residence of MSCs in lung and/or the entire organism might critically contribute to the safety of this cell-based therapy, by avoiding potential side effects as tumor formation or maldifferentiation.

Acknowledgements

There are no commercial associations that might create a conflict of interest in connection with this paper.

This work was supported by the Federal Ministry of Education and Research, Germany, grant number 13N8904 and by the “Deutsche José Carreras Leukämie-Stiftung e.V.”, grant number DJCLS R 12/30.

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  6. Ferrara JLM, Levy R, Chao NJ. Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol Blood Marrow Transplant 1999; 5:347–356.
  7. Fliedner TM, Chao NJ, Bader JL, Boettger A, Case C Jr et al. Stem cells, multiorgan failure in radiation emergency medical preparedness: a U.S./European Consultation Workshop. Stem Cells 2009; 27:1205-1211.
  8. Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 1974; 17: 331–340.
  9. Graf T, Enver T. Forcing cells to change lineages. Nature 2009, 462:587-594.
  10. Hérodin F, Drouet M. Cytokine-based treatment of accidentally irradiated victims and new approaches. Exp Hematol 2005; 33:1071-1080.
  11. Huss R, Lange C, Weissinger EM, Kolb HJ, Thalmeier K. Evidence of peripheral blood derived, plasticadherent CD34(-/low) hematopoietic stem cell clones with mesenchymal stem cell characteristics. Stem Cells 2000; 18:252–260.
  12. Koç ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE et al. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 2000; 18:307–316.
  13. Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S et al. Multi-organ, multilineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105:369–377.
  14. Lange C, Brunswig-Spickenheier B, Cappallo-Obermann H, Eggert K, Gehling UM et al. Radiation rescue: mesenchymal stromal cells protect from lethal irradiation. PLoS One 2011; 5: 6(1):e14486. doi: 10.1371/journal.pone.0014486.
  15. Lange C, Kaltz C, Thalmeier K, Kolb HJ, Huss R. Hematopoietic reconstitution of syngeneic mice with a peripheral blood-derived, monoclonal CD34-, Sca-1+, Thy-1(low), c-kit+ stem cell line. J Hematother Stem Cell Res 1999; 8:335–342.
  16. Lange C, Schroeder J, Lioznov MV, Zander AR. High-potential human mesenchymal stem cells. Stem Cells Dev 2005; 14:70-80.
  17. Lange C, Tögel F, Ittrich H, Clayton F, Nolte-Ernsting C, Zander AR, Westenfelder C. Administered mesenchymal stem cells are renoprotective in ischemia/reperfusion acute renal failures in rats. Kidney Int 2005; 68:1613-1617.
  18. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H et al. Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versushost disease: a phase II study. Lancet 2008; 371:1579–1586.
  19. Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J et al. Intravenous hMSC improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009; 5:54-63.
  20. Meirelles L da S, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev 2009; 20:419-427.
  21. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110:3499–3506.
  22. Phinney DG, Prockop DJ. Concise review: mesenchymal stem/ multipotent stromal cells: the state of transdifferentiation and modes of tissue repair current views. Stem Cells 2007; 25:2896–2902.
  23. Remberger M, Sundberg B. Cytokine production during myeloablative and reduced intensity therapy before allogeneic stem cell transplantation. Haematologica 2004; 89:710- 716.
  24. Rombouts WJ, Ploemacher RE. Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia 2003; 17:160-170.
  25. Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009; 9:581-593.
  26. Tögel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 2005; 289:F31-42.
  27. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008; 8:726-736.
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Introduction

Management of patients subjected to extensive body irradiation as a part of conditioning therapy still remains a major challenge. Survival of radiation-induced bone marrow failure depends on the dose of radiation received and the intensity of supportive care which can protect from otherwise lethal infection and give surviving stem cells a chance to replenish blood cell populations. Since radiation effects on blood stem cells occur at doses generally lower than those on other critical organs, the rapidly emerging changes in the peripheral blood cell lineages determine the treatment options. In fact, total body irradiation (TBI) at doses more than 7-8 Gy in humans corresponds to medullar eradication. Under this threshold, spontaneous recovery from residual hematopoietic stem and progenitor cells may be expected within 30–50 days, however, preceded by cytopenic phases of granulocytic, megakaryocytic and erythrocytic lineages. Interestingly, even after TBI, intrinsically radioresistant stem cells have been detected in distinct bone marrow (BM) areas comprising a residual hematopoietic stem and progenitor cell pool [10]. Acute irradiation does not only imply damage to the bone marrow. In a dose-dependent matter, it can also emerge as gastrointestinal and cerebrovascular syndromes leading to development of multiple organ dysfunction (1). Damage to the whole organism is related to a systemic inflammatory response. Different target organs are affected due to activation of innate immune system, resulting in a significant release of inflammatory cytokines [4]. The pathophysiology of such tissue damage appears comparable to that of acute graftversus- host disease (GvHD) following allogeneic stem cell transplantation where a similar ”cytokine storm” has been observed [6]. In absence of appropriate treatment, oxidative stress after high dose ionizing radiation has been involved in delayed morbidity [4]. Management of acute radiation syndrome relies, therefore, on tissue damage repair processes that might be supported by therapies aimed for mitigation of inflammation [4].

Efforts to improve outcome after irradiation focus on the stem cell niche. Therefore, prospective therapies should augment the hematopoietic niche activity to accelerate the in vivo recovery of blood cell populations. Several studies have demonstrated that BM osteoblasts regulate the HSC pool size in vivo via the Jagged1-Notch signaling pathway [7]. For example, parathyroid hormone receptor activation can increase the number of osteoblastic cells, thus resulting in Notch1-mediated expansion of HSC [2]. Mesenchymal stromal cells (MSC) comprise an integrative part of the BM stroma, being also described as osteoblastic progenitors [8]. MSC are multipotential nonhematopoietic progenitor cells capable of differentiating into multiple lineages of the mesenchyme. In bone marrow, the local stromal cells surround HSC and their progeny. The hematopoietic niche provides a sheltering microenvironment that provides maintenance and self-renewal of HSC by shielding them from differentiation and apoptotic stimuli that would otherwise challenge stem cell reserves. Moreover, the hematopoietic niche also controls proliferation and differentiation of HSC and release of mature progeny into peripheral blood flow. Regulation of HSC quiescence, by maintenance of resting HSC in endosteal niche, control of HSC proliferation, differentiation and recruitment in the vascular niche can be ascribed to bone-marrow stromal cells [27]. Thus, physiological role of MSCs is not a mere replacement of mesenchymal tissues such as bone. Moreover, their primary and most important function is to inhibit immunosurveillance and to establish a protective and regenerative microenvironment for HSC.

Clinically, MSCs have been proven to intervene with acute organ impairment. When co-transplanted with HSC, MSCs augment hematopoietic recovery after chemo- or radiotherapy significantly decreasing the time to full hematopoietic and particularly platelet reconstitution [12]. Additionally, there is evidence for MSC effectiveness in the treatment of steroid resistant GvHD without any side effects, even when obtained from BM of third-party donors [18]. No HLA-match is needed between donor and recipient because MSCs have been shown to be hypoimmunogenic and are not recognized by the recipient immune system even after repeated injections [18]. Finally, MSCs secrete a variety of bioactive molecules [22]. Among those, some essential hematopoietic growth factors including IL-6, IL-11, leukemia inhibitory factor (LIF), stem cell factor (SCF) and Flt3 ligand are produced, as well as factors with immunomodulatory effects, e.g. transforming growth factor-β1 (TGF-β1), prostaglandin E2, indoleamine 2,3-dioxygenase, and others [21]. Additionally, vascular endothelial growth factor (VEGF) secreted by MSCs in abundance might interfere with early apoptotic cell death after irradiation [10]. Therefore, MSCs might be a good candidate for modulation of the hematopoietic niche activity. In summary, MSCs have emerged as a promising therapeutic tool for tissue regeneration and repair. Further clinical interest has been raised by the observation that MSCs are immunoprivileged and might be transplanted from unrelated, i.e. allogeneic donors [21,27]. Altogether, we assumed that MSCs, with their comprehensive trophic potential, could serve as a readily available treatment option after severe radiation exposure. The aim of our study was to evaluate essential biological parameters of MSC, with respect to their lineage- specific differentiation capacity, in vivo survival rates, as well as their ability to rescue lethally irradiated hosts.

Methods and Results

In vitro differentiation of human MSC (hMSC)

As first experiments, we investigated the capability of human BM-derived MSCs (hMSCs) to differentiate into progenitors for hematopoietic (HSC) and endothelial cells (EC). The human MSCs were thoroughly characterized according to the ISCT (International Society for Cellular Therapy) criteria [5], including flow cytometry and their capability to differentiate into three mesodermal lineages [16]. To avoid any contamination of MSCs with HSC, cloned cells were used exclusively. Cloned human MSCs were subjected to differentiation into (i) hematopoietic cells using serum-containing or serum-depleted growth conditions and (ii) endothelial cells (for technical details see ref. 14). Fibroblastoid MSCs (Fig. 1a) formed blast-like cells with noticeably decreased diameter from originally 28.9 ± 6.6 to 15.7 ± 3.5 μm during the differentiation into hematopoietic (Fig. 1b) and endothelial (Fig. 1c) lineages. The in vitro conditions led to cluster formation appearing as an in vitro equivalent of stromal structures from which differentiation proceeded. The cells committed to hematopoietic lineage changed their gene expression towards appropriate profiles of blood cell progenitors (CD117, CD133, CD45) and mature (CD14, CD16, glycophorinA GlyA, CD31, podoplanin PDPN) hematopoietic cells (Fig. 2a). Interestingly, the erythropoietin receptor (EPOR) was upregulated in almost all clones and under all conditions suggesting a definite role for EPO in proliferation and differentiation of mesodermal progenitors. Additionally,

Figure 1: Human MSC display a fibroblastoid morphology during in vitro expansion but form blast-like cells after inductionof differentiation. One clonal hMSC culture is shown during expansion (a), differentiation into hematopoietic(b) or endothelial (c) cells.

Figure 1: Human MSC display a fibroblastoid morphology during in vitro expansion but form blast-like cells after induction of differentiation. One clonal hMSC culture is shown during expansion (a), differentiation into hematopoietic (b) or endothelial (c) cells.


Figure 2: Human MSC significantly upregulate expressions of hematopoietic and endothelial genes after inductionof differentiation. Shown are the fold changes of gene expressions of indicated hematopoietic (a) and endothelial(b) genes after differentiation compared to undifferentiated hMSC. GlyA, Glycophorin A; vWF, von Willebrand factor;VEGFR, vascular endothelial growth factor receptor.

Figure 2: Human MSC significantly upregulate expressions of hematopoietic and endothelial genes after inductionof differentiation. Shown are the fold changes of gene expressions of indicated hematopoietic (a) and endothelial(b) genes after differentiation compared to undifferentiated hMSC. GlyA, Glycophorin A; vWF, von Willebrand factor;VEGFR, vascular endothelial growth factor receptor.

Figure 2: Human MSC significantly upregulate expressions of hematopoietic and endothelial genes after induction of differentiation. Shown are the fold changes of gene expressions of indicated hematopoietic (a) and endothelial (b) genes after differentiation compared to undifferentiated hMSC. GlyA, Glycophorin A; vWF, von Willebrand factor; VEGFR, vascular endothelial growth factor receptor.

a variety of transcription factors responsible for erythropoiesis (SCL/tal1), erythro-megakaryopoiesis (GATA1, GATA2), lymphopoiesis (GATA3), and myelopoiesis (NOTCH1, RUNX1) were upregulated upon serum-containing differentiation. As SCL and RUNX1 are transcription factors essential for HSC formation by instructing lineage specification (9), we suggested an efficient induction of this differentiation pathway in MSCs. Using immunofluorescence, a subpopulation of antigen-positive cells with small round or polymorphic nuclei was detected, showing expression of hematopoietic progenitor and mature antigen expression (not shown, refer to ref. 14), albeit to a rather low degree. In parallel, the same cells were able to acquire endothelial morphology and expressed endothelial genes upon cultivation with endothelial promoting factors (Fig. 2b). At the protein level, single double positive cells for CD31/vWF (von Willebrand factor) and VEGFR-2/CD34 were detected [14].

Hematopoietic and endothelial progenitors share expression of a number of genes, including VEGFR-2, CD34, SCL, GATA2, RUNX1, and CD31, suggesting that investigated hMSCs possess in vitro hemangioblastic capacity, and might act as extrinsic differentiation factors and lineage-inducing regulators. Most potent differentiation was achieved in cultures where the majority of hMSCs adopted stromal function, thus inducing a minor part for differentiation. We concluded from the in vitro results, that MSCs might reconstitute the hematopoietic system. Hypothetically, one pluripotent stem cell would suffice to rescue lethally irradiated hosts. In reality, however, approx. 6 cells are needed [13], i.e. six pluripotent MSCs with the respective potential might suffice to restore hematopoiesis in vivo.

MSCs promote hematopoietic recovery after lethal irradiation

To test in vivo ability of murine MSCs to replenish the hematopoiesis after eradication, lethally irradiated (9.5 Gy) female recipients of the C57Bl/6J-CD45.1 strain were subjected to i.v. transplantation with 106 eGFP-marked male bulk-culture C57Bl/6J mouse MSCs (mMSCs). Mouse MSC were cultured in DMEM/Ham´s F12 + 20% preselected FCS + Glutamin + ß-mercaptoethanol and cells after 9-12 passages used for transplantation. Leukocyte and thrombocyte recovery was similar to recipients transplanted with HSCs (Fig. 3) reaching normalization of white blood cell counts after 4 weeks. Seven months later, the recipients were hematologically well, with a normal distribution of peripheral cell populations (Table 1). Similar experiments were carried out with clonal mMSCs showing one clone (IXH8) with superior survival promoting properties (Table 2). Noteworthy, the IXH8 clone was different from all other cultures showing long-stretched morphology and increased CD34 and CD45, however, without CD105 expression (Table 2).

Figure 3: Mouse MSC rescue mice after total body irradiation.Transplantation of bulk mMSC led to a normalizationof the peripheral white blood cell count within 4weeks. Thrombocyte recovery needed approx. 8 weeksfor normalization.

Figure 3: Mouse MSC rescue mice after total body irradiation. Transplantation of bulk mMSC led to a normalization of the peripheral white blood cell count within 4 weeks. Thrombocyte recovery needed approx. 8 weeks for normalization.






Table 1: Peripheral blood cell populations in mMSC transplanted animals.Shown is the distribution of white blood cells 5 months after bulk mMSC transplantation estimated using Pappenheim-stained blood smears.
  Table 1: Peripheral blood cell populations in mMSC transplanted animals. Shown is the distribution of white blood cells 5 months after bulk mMSC transplantation estimated using Pappenheim-stained blood smears.

Table 2: Phenotypical characterization of mMSC and recipients’ survival rates after transplantation.Cultures of eGFP-transduced bulk and cloned mMSC after extended expansion were positive for CD59, CD105 and Sca-1 butnegative for the hematopoietic markers CD34, CD45, CD117 and for CD90 by flow cytometry. Clone IXH8 was different fromall other cultures in its expression of CD34/CD45 and negativity of CD105 (shown in bold italic). Transplantation with this cloneresulted in the highest survival rate of the irradiated recipients, suggesting elevated CD34 and CD45 and no CD105 expressionsmight be a prerequisite of the high rescue capability. nd, not done.

Table 2: Phenotypical characterization of mMSC and recipients’ survival rates after transplantation.
Cultures of eGFP-transduced bulk and cloned mMSC after extended expansion were positive for CD59, CD105 and Sca-1 but negative for the hematopoietic markers CD34, CD45, CD117 and for CD90 by flow cytometry. Clone IXH8 was different from all other cultures in its expression of CD34/CD45 and negativity of CD105 (shown in bold italic). Transplantation with this clone resulted in the highest survival rate of the irradiated recipients, suggesting elevated CD34 and CD45 and no CD105 expressions might be a prerequisite of the high rescue capability. nd, not done.

Transplanted donor cells are detectable short- but not long-term

To trace donor chimerism in recipients, we stained recipient peripheral blood (PB), BM and thymus cells with CD45.2 antibodies and carried out flow cytometry. Interestingly, no CD45.2-positive cells were found at any time point, thus not showing regeneration through donor cells. Y-chromosome-based chimerism analysis in female recipients using specific Y-chromosome primers for quantitative PCR could not detect donor cells in any of investigated tissues including PB and BM (not shown), although animals survived up to the final evaluation after 7 months. Spectral karyotyping of clonal mMSC revealed loss of Y-chromosome (Fig. 4), whereas bulk cultures were still Y-positive at passage13 (not shown).

Figure 4: Spectral karyotyping of mMSC. Shown is the SKY analysis of clone IXH8. SKY analysis of a representativediploid metaphase revealed the loss of the Y-chromosome and this has been observed in all metaphases analyzed.
Figure 4: Spectral karyotyping of mMSC. Shown is the SKY analysis of clone IXH8. SKY analysis of a representative diploid metaphase revealed the loss of the Y-chromosome and this has been observed in all metaphases analyzed.

Next, we used eGFP-specific primers for quantitative PCRbased donor cell detection. Primers for stably integrated eGFP-sequences, however, also failed to detect any donor cells, and no eGFP-positive cells were found in blood, BM or thymus by flow cytometry. Although we cannot completely rule out single donor cells below the detection limit, hematopoietic recovery in recipients is unlikely due to replacement with donor cells. This conclusion contradicts earlier results of hematopoietic recovery after myeloablative TBI with blood-derived mMSCs [11, 15] showing donor characteristics in blood and BM. One fundamental difference between both cell sources is potential in vitro immortalization, altering BM seeding capability of MSC. Therefore, our results support the concept of impaired transplantability of expanded MSC [24] but also challenge the hypothesis of high plasticity of MSC [1].

The distribution kinetics of eGFP+ donor cells after i.v. transplantation identified fast disappearance from PB, reaching ca. 2% after 8 hours and no cells at d10 (Fig. 5a). In contrast, mMSC trapped in lungs quickly (Fig. 5b), however without long-term residence and embolization as shown by lack of donor signals after d+10. Accordingly, no donor cells were detectable evident in the spleen, liver, BM (Fig. 5b), aorta, kidney, intestine, fat, thymus or lymph nodes (not shown). Although we did not find donor derived MSC in the BM, the morphology of this organ was preserved by MSC transplantation showing a normal distribution between different compartments (Fig. 6). Without MSCs, adipocytes are shown to dominate within short time, thus destroying the marrow structure.

Figure 5: Donor mMSC are not detectable at longer terms.(a) Tracking of eGFP-labeled clonal IXH8 donor mMSC after transplantation revealed a fast decrease in peripheral blood (PB). Within 8hours, approx. 2% were quantified in PB and none after 10 days (n = 8 for each time point).   Figure 5: Donor mMSC are not detectable at longer terms.(b) mMSC accumulated in lungs (Lu) within24 h and disappeared within 10 days (240 h). Spleen (Sp), liver (Li) and BM were negative at d1 and d10. nd, not detected.

Figure 5: Donor mMSC are not detectable at longer terms.
(a) Tracking of eGFP-labeled clonal IXH8 donor mMSC after transplantation revealed a fast decrease in peripheral blood (PB). Within 8 hours, approx. 2% were quantified in PB and none after 10 days (n = 8 for each time point). (b) mMSC accumulated in lungs (Lu) within 24 h and disappeared within 10 days (240 h). Spleen (Sp), liver (Li) and BM were negative at d1 and d10. nd, not detected.

Figure 6. Histomorphology of BM with and without MSC transplantation.Paraffin embedded long bones from MSC-transplanted or control animals were cut and the number of adipocytes counted in 2 designatedareas (A) per bone from mice with MSC transplantation after 4 (B), 12 (D), 24 (F) and 36 (H) hours or without MSC transplantation(C, E, G, and I respectively). The lower figure shows the number of adipocytes at each time point.

   Figure 6. Histomorphology of BM with and without MSC transplantation.Paraffin embedded long bones from MSC-transplanted or control animals were cut and the number of adipocytes counted in 2 designatedareas (A) per bone from mice with MSC transplantation after 4 (B), 12 (D), 24 (F) and 36 (H) hours or without MSC transplantation(C, E, G, and I respectively). The lower figure shows the number of adipocytes at each time point.

Figure 6. Histomorphology of BM with and without MSC transplantation.
Paraffin embedded long bones from MSC-transplanted or control animals were cut and the number of adipocytes counted in 2 designated
areas (A) per bone from mice with MSC transplantation after 4 (B), 12 (D), 24 (F) and 36 (H) hours or without MSC transplantation
(C, E, G, and I respectively). The lower figure shows the number of adipocytes at each time point.

MSCs change the BM gene expression

While donor mMSC did not home to the BM, we observed a long term recipients´ survival and assumed an influence of MSCs on the BM function. Therefore we carried out microarray analysis of bone marrow cells from MSC-transplanted animals, and compared their gene expression profiles to that of HSC-transplanted animals and age-matched controls [14]. The gene expression profile in BM changed significantly, clustering into separate group as compared to untreated BM or HSC-transplanted mice. Validation of selected genes with high variance proved a beneficial role of MSC in endogenous hematopoietic reconstitution. MSCs caused upregulated protection from oxidative stress, cell cycle, anti-inflammatory and detoxication events (e.g. BRPK, Cdkn1a, Thbs2, Gstm5 gene expression) in a complex way, along with downregulation of lymphoid development, pro-inflammatory events, protein degradation and adhesion/matrix formation for improved cell motility (e.g. gene expressions of Vpreb1, Rag2, Klk6, Klk1b5, Uchl1, Sykb, Gpam, Col5a3, Emid1) [14]. Upon summarising the microarray expression data, we have shown upregulation of the genes which are beneficial to BM reconstitution, whereas the genes with supposed radiation- related BM deterioration were downregulated (Fig. 7).

Figure 7. MSC transplantation into lethally irradiated animals changes the gene expression in the bone marrow.Gene expression data were generated using microarray analysis and significantly regulated genes clustered into functional groups.Shown are upregulated functional gene groups (MSC up) or downregulated (MSC down) in MSC-transplanted animals.
Figure 7. MSC transplantation into lethally irradiated animals changes the gene expression in the bone marrow.
Gene expression data were generated using microarray analysis and significantly regulated genes clustered into functional groups.
Shown are upregulated functional gene groups (MSC up) or downregulated (MSC down) in MSC-transplanted animals.

Potential paracrine mechanism of MSC

Potential mechanisms mediating bone marrow protection by MSCs entrapped in the lung, still remain unclear. Recently, we could show that injection of MSC-derived microvesicles to lethally irradiated animals provided similar protective effects, as transplantation of MSCs per se (Fig. 8). The microvesicles represent a fraction of ultra-small lipid bilayer particles of 30 to 1000 nm size (including exosome fraction) which are known to shuttle proteins, lipids, mRNA and microRNA [25]. Any of these components could participate in radiation protection and recovery of the bone marrow. Interestingly, the microvesicle-associated reconstitution of platelet scores occurred at a faster time frames, as compared to MSCs injections. Further work should reveal a more precise mechanism conferring radiation protection associated with MSC microvesicles.

Discussion

In this study we present an evidence that donor MSCs do not directly reconstitute the hematopoietic system following radiation insult. However, these cells may provide salvage for the surviving HSCs. Acute irradiation produces excessive inflammatory responses (23) which contribute to HSC death if untreated. Along with other organs, the lung is also heavily affected by radiation damage and might retard MSCs. Mesenchymal cells interfere with inflammation by changing overall gene expression profile, both in lungs where they are captured, and in bone marrow compartments. Assuming this, a direct MSC homing to the bone marrow is not necessary for changed gene expression patterns. This mechanism has been described in murine model of myocardial infarction where hMSCs have been shown to produce antiapoptotic TSG6 without significant engraftment [19]. A paracrine, differentiation-independent effect of MSCs did also ameliorate kidney injury [17, 26].

Figure 8: Transplantation of mMSC-derived microvesicles rescues lethally irradiated animals.Leukocyte counts after mMSC-derived microvesicle injection normalized with similar kinetics as with mMSC, whereas thrombocytecounts showed a much faster normalization (a)(n=15). Electron microscopy of microvesicles released from mMSC (b) and purified byultracentrifugation (c).

   Figure 8: Transplantation of mMSC-derived microvesicles rescues lethally irradiated animals.Leukocyte counts after mMSC-derived microvesicle injection normalized with similar kinetics as with mMSC, whereas thrombocytecounts showed a much faster normalization (a)(n=15). Electron microscopy of microvesicles released from mMSC (b) and purified byultracentrifugation (c).
Figure 8: Transplantation of mMSC-derived microvesicles rescues lethally irradiated animals.
Leukocyte counts after mMSC-derived microvesicle injection normalized with similar kinetics as with mMSC, whereas thrombocyte
counts showed a much faster normalization (a)(n=15). Electron microscopy of microvesicles released from mMSC (b) and purified by
ultracentrifugation (c).


What could be expected from MSC as a potential therapeutic tool? Secretion of broad-range bioactive molecules is now believed to be the main mechanism by which the therapeutic effects of MSCs are achieved [20]. MSCs may secrete active factors that (a) inhibit apoptosis and limit the extent of cellular damage; (b) inhibit fibrosis or scarring at the injured sites; (c) protect microvasculature and stimulate angiogenesis, thus improving perfusion rates; and (d) promote proliferation of tissue- specific progenitor cells, as shown for cardiac-, neural- and kidney-specific stem cells [26,27]. In parallel, we have shown in a model with acute irradiation that MSCs boosted anti-inflammatory, anti-apoptotic, detoxifying, cell cycle and anti-oxidative stress control, whereas proinflammatory effects, extracellular matrix formation, and adhesion properties were decreased. In general, MSC injections may result into systemic improvements counteracting deleterious effects of myelosuppression [14].

In conclusion, transplanted MSC might export their inherent trophic effect to unorthodox sites [3], e.g. to lungs. Our results present another piece of evidence for this highly effective paracrine mechanism which may work, e.g., in BM populations, suggesting MSC-infusion to be an efficient treatment option following acute irradiation. Despite some limitations in our existing knowledge, a capacity of MSCs, or MSC-derived microvesicles, to exert hematopoietic support via a bystander mechanisms, might indicate that persistent engraftment at the site of damage is not a mandatory prerequisite. Importantly, a very short-term residence of MSCs in lung and/or the entire organism might critically contribute to the safety of this cell-based therapy, by avoiding potential side effects as tumor formation or maldifferentiation.

Acknowledgements

There are no commercial associations that might create a conflict of interest in connection with this paper.

This work was supported by the Federal Ministry of Education and Research, Germany, grant number 13N8904 and by the “Deutsche José Carreras Leukämie-Stiftung e.V.”, grant number DJCLS R 12/30.

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Высокодозная радиаци- онная терапия вызывает тяжелое повреждение, в особенности – гемопоэтических стволовых клеток и клеток-предшественников. Попытки улучшения кли- нических исходов после облучения сосредоточены на гемопоэтической нише. Мезенхимные стромальные клетки (МСК) представляют собой интегральную часть стромального микроокружения. При совмест- ной трансплантации с гемопоэтическими стволовыми клетками (ГСК), МСК способны усиливать восстанов- ление кроветворения после химио- и радиационной терапии. Целью нашего исследования была оценка основных биологических параметров МСК, в плане их способности к специфической линейной диффе- ренцировке, выживаемости организма, а также их способности к радиопротекции летально облученных реципиентов. Материалы и методы. Дифференциров- ку in vitro МСК человека в направлении гемопоэтиче- ских (ГСК) или эндотелиальных клеток изучали путем RT-qPCR поверхностных маркеров и других белков. Для тестирования in vivo способности мышиных МСК защищать летально облученных (9.5 Гр) мышей, животных трансплантировали мышиными МСК, ме- чеными eGFP. Длительность донорского химеризма определяли в крови, костном мозге и тимусе по марке- рам CD45.2 и Y-хромосомы. Анализ профилей генной экспрессии в клетках костного мозга проводили по сравнению с соответствующими контролями посред- ством биочипов. Результаты. При дифференцировке гемопоэтических стволовых клеток человека in vitro отмечалась изменения генной экспрессии со спектром экспрессии, типичным для кроветворных предше- ственников и зрелых клеток. Во время дифференци- ровки в средах с сывороткой наблюдалась повышен- ная экспрессия множества факторов, ответственных за эритропоэз, мегакариоцитопоэз, лимфо- и мииело- поэз. Была выявлена популяция клеток с небольшими круглыми или полиморфными ядрами, которые экс- прессировали антигенные маркеры, характерные для клеток-предшественников или зрелых форм, хотя и небольшой степени. Те же клетки приобретали мор- фологические черты эндотелия и экспрессировали гены, специфичные для эндотелиальных клеток при культивировании со специфическими факторами дифференцировки.  </p> <p> После введения МСК, летально облученные мыши выживали с нормальным восстановлением кроветво- рения, как при введении кроветворных клеток. Через 7 мес. после облучения реципиенты МСК имели нор- мальное соотношение популяций периферической крови. Не было указаний на наличие сколько-нибудь длительного донорского химеризма после трансплан- тации. Оценка распределения eGFP+ донорских кле- ток после внутривенной трансфузии показала бы- строе исчезновение МСК из периферической крови, до 2% через 8 часов после введения с задержкой клеток в легких, однако без их длительной персистенции и эмболизации сосудов. Исследование экспрессии ге- нов в клетках костного мозга у животных, леченных МСК, показало повышение активности генов, способ- ствующих восстановлению кроветворения, наряду со снижением активности генов, ассоциированных с ра- диационным повреждением костного мозга. Инъек- ции летально облученныи животным микровезикул, происходящих из МСК, приводили к тем же протек- тивным эффектам, что и трансплантация МСКС как таковых. Заключение. Наши результаты представляют дополнительные данные о возможных механизмах вы- сокоэффективного паракринного механизма, который актуален, в частности, для популяций костного мозга, что указывает на то, что инфузии МСК являются эф- фективным средством лечения последствий острого облучения. Кроме того, трансплантация МСК может оказывать свой трофический эффект в необычных ме- стах, в точм числе – легочной ткани реципиента. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(308) "Мезенхимные стромальные клетки защищают от последствий предварительного облучения при трансплантации гемопоэтических стволовых клеток: анализ возможных механизмов" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(308) "Мезенхимные стромальные клетки защищают от последствий предварительного облучения при трансплантации гемопоэтических стволовых клеток: анализ возможных механизмов" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(308) "Мезенхимные стромальные клетки защищают от последствий предварительного облучения при трансплантации гемопоэтических стволовых клеток: анализ возможных механизмов" ["SECTION_META_TITLE"]=> string(308) "Мезенхимные стромальные клетки защищают от последствий предварительного облучения при трансплантации гемопоэтических стволовых клеток: анализ возможных механизмов" 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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(4) "6698" ["VALUE"]=> array(2) { ["TEXT"]=> string(282) "<p class="Autor"> Клаудиа Ланге,<sup>1</sup> Рудольф Раймер,<sup>2</sup> Йозеф Зустин,<sup>3</sup> Бербель Брунсвиг-Шпикенхайер<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(212) "

Клаудиа Ланге,1 Рудольф Раймер,2 Йозеф Зустин,3 Бербель Брунсвиг-Шпикенхайер1

" ["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(4) "6699" ["VALUE"]=> array(2) { ["TEXT"]=> string(606) "1. Клиника трансплантации стволовых клеток, Департамент клеточной и генной терапии, Университетский медицинский<br> центр Гамбург-Эппендорф<br> 2. Технологическая платформа микроскопии и анализа изображений, Институт Хайнриха Петте, Гамбург,<br> 3. Институт патологии, Университетский медицинский центр Гамбург Эппендорф" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(588) "1. Клиника трансплантации стволовых клеток, Департамент клеточной и генной терапии, Университетский медицинский
центр Гамбург-Эппендорф
2. Технологическая платформа микроскопии и анализа изображений, Институт Хайнриха Петте, Гамбург,
3. Институт патологии, Университетский медицинский центр Гамбург Эппендорф" ["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(4) "6700" ["VALUE"]=> array(2) { ["TEXT"]=> string(6841) "<p> Ионизирующее излучение широко применяется в качестве кондиционирующей терапии при транс- плантации костного мозга. Высокодозная радиаци- онная терапия вызывает тяжелое повреждение, в особенности – гемопоэтических стволовых клеток и клеток-предшественников. Попытки улучшения кли- нических исходов после облучения сосредоточены на гемопоэтической нише. Мезенхимные стромальные клетки (МСК) представляют собой интегральную часть стромального микроокружения. При совмест- ной трансплантации с гемопоэтическими стволовыми клетками (ГСК), МСК способны усиливать восстанов- ление кроветворения после химио- и радиационной терапии. Целью нашего исследования была оценка основных биологических параметров МСК, в плане их способности к специфической линейной диффе- ренцировке, выживаемости организма, а также их способности к радиопротекции летально облученных реципиентов. Материалы и методы. Дифференциров- ку in vitro МСК человека в направлении гемопоэтиче- ских (ГСК) или эндотелиальных клеток изучали путем RT-qPCR поверхностных маркеров и других белков. Для тестирования in vivo способности мышиных МСК защищать летально облученных (9.5 Гр) мышей, животных трансплантировали мышиными МСК, ме- чеными eGFP. Длительность донорского химеризма определяли в крови, костном мозге и тимусе по марке- рам CD45.2 и Y-хромосомы. Анализ профилей генной экспрессии в клетках костного мозга проводили по сравнению с соответствующими контролями посред- ством биочипов. Результаты. При дифференцировке гемопоэтических стволовых клеток человека in vitro отмечалась изменения генной экспрессии со спектром экспрессии, типичным для кроветворных предше- ственников и зрелых клеток. Во время дифференци- ровки в средах с сывороткой наблюдалась повышен- ная экспрессия множества факторов, ответственных за эритропоэз, мегакариоцитопоэз, лимфо- и мииело- поэз. Была выявлена популяция клеток с небольшими круглыми или полиморфными ядрами, которые экс- прессировали антигенные маркеры, характерные для клеток-предшественников или зрелых форм, хотя и небольшой степени. Те же клетки приобретали мор- фологические черты эндотелия и экспрессировали гены, специфичные для эндотелиальных клеток при культивировании со специфическими факторами дифференцировки.  </p> <p> После введения МСК, летально облученные мыши выживали с нормальным восстановлением кроветво- рения, как при введении кроветворных клеток. Через 7 мес. после облучения реципиенты МСК имели нор- мальное соотношение популяций периферической крови. Не было указаний на наличие сколько-нибудь длительного донорского химеризма после трансплан- тации. Оценка распределения eGFP+ донорских кле- ток после внутривенной трансфузии показала бы- строе исчезновение МСК из периферической крови, до 2% через 8 часов после введения с задержкой клеток в легких, однако без их длительной персистенции и эмболизации сосудов. Исследование экспрессии ге- нов в клетках костного мозга у животных, леченных МСК, показало повышение активности генов, способ- ствующих восстановлению кроветворения, наряду со снижением активности генов, ассоциированных с ра- диационным повреждением костного мозга. Инъек- ции летально облученныи животным микровезикул, происходящих из МСК, приводили к тем же протек- тивным эффектам, что и трансплантация МСКС как таковых. Заключение. Наши результаты представляют дополнительные данные о возможных механизмах вы- сокоэффективного паракринного механизма, который актуален, в частности, для популяций костного мозга, что указывает на то, что инфузии МСК являются эф- фективным средством лечения последствий острого облучения. Кроме того, трансплантация МСК может оказывать свой трофический эффект в необычных ме- стах, в точм числе – легочной ткани реципиента. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6817) "

Ионизирующее излучение широко применяется в качестве кондиционирующей терапии при транс- плантации костного мозга. Высокодозная радиаци- онная терапия вызывает тяжелое повреждение, в особенности – гемопоэтических стволовых клеток и клеток-предшественников. Попытки улучшения кли- нических исходов после облучения сосредоточены на гемопоэтической нише. Мезенхимные стромальные клетки (МСК) представляют собой интегральную часть стромального микроокружения. При совмест- ной трансплантации с гемопоэтическими стволовыми клетками (ГСК), МСК способны усиливать восстанов- ление кроветворения после химио- и радиационной терапии. Целью нашего исследования была оценка основных биологических параметров МСК, в плане их способности к специфической линейной диффе- ренцировке, выживаемости организма, а также их способности к радиопротекции летально облученных реципиентов. Материалы и методы. Дифференциров- ку in vitro МСК человека в направлении гемопоэтиче- ских (ГСК) или эндотелиальных клеток изучали путем RT-qPCR поверхностных маркеров и других белков. Для тестирования in vivo способности мышиных МСК защищать летально облученных (9.5 Гр) мышей, животных трансплантировали мышиными МСК, ме- чеными eGFP. Длительность донорского химеризма определяли в крови, костном мозге и тимусе по марке- рам CD45.2 и Y-хромосомы. Анализ профилей генной экспрессии в клетках костного мозга проводили по сравнению с соответствующими контролями посред- ством биочипов. Результаты. При дифференцировке гемопоэтических стволовых клеток человека in vitro отмечалась изменения генной экспрессии со спектром экспрессии, типичным для кроветворных предше- ственников и зрелых клеток. Во время дифференци- ровки в средах с сывороткой наблюдалась повышен- ная экспрессия множества факторов, ответственных за эритропоэз, мегакариоцитопоэз, лимфо- и мииело- поэз. Была выявлена популяция клеток с небольшими круглыми или полиморфными ядрами, которые экс- прессировали антигенные маркеры, характерные для клеток-предшественников или зрелых форм, хотя и небольшой степени. Те же клетки приобретали мор- фологические черты эндотелия и экспрессировали гены, специфичные для эндотелиальных клеток при культивировании со специфическими факторами дифференцировки. 

После введения МСК, летально облученные мыши выживали с нормальным восстановлением кроветво- рения, как при введении кроветворных клеток. Через 7 мес. после облучения реципиенты МСК имели нор- мальное соотношение популяций периферической крови. Не было указаний на наличие сколько-нибудь длительного донорского химеризма после трансплан- тации. Оценка распределения eGFP+ донорских кле- ток после внутривенной трансфузии показала бы- строе исчезновение МСК из периферической крови, до 2% через 8 часов после введения с задержкой клеток в легких, однако без их длительной персистенции и эмболизации сосудов. Исследование экспрессии ге- нов в клетках костного мозга у животных, леченных МСК, показало повышение активности генов, способ- ствующих восстановлению кроветворения, наряду со снижением активности генов, ассоциированных с ра- диационным повреждением костного мозга. Инъек- ции летально облученныи животным микровезикул, происходящих из МСК, приводили к тем же протек- тивным эффектам, что и трансплантация МСКС как таковых. Заключение. Наши результаты представляют дополнительные данные о возможных механизмах вы- сокоэффективного паракринного механизма, который актуален, в частности, для популяций костного мозга, что указывает на то, что инфузии МСК являются эф- фективным средством лечения последствий острого облучения. Кроме того, трансплантация МСК может оказывать свой трофический эффект в необычных ме- стах, в точм числе – легочной ткани реципиента.

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Claudia Lange,1 Rudolph Reimer,2 Jozef Zustin,3 Bärbel Brunswig-Spickenheier1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_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) "38" ["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(4) "6703" ["VALUE"]=> array(2) { ["TEXT"]=> string(302) "1. Clinic for Stem Cell Transplantation, Dept. Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf,<br> 2. Technology Platform Microscopy &amp; Image Analysis, Heinrich-Pette-Institut Hamburg,<br> 3. Institute of Pathology, University Medical Center Hamburg-Eppendorf," ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(286) "1. Clinic for Stem Cell Transplantation, Dept. Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf,
2. Technology Platform Microscopy & Image Analysis, Heinrich-Pette-Institut Hamburg,
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Abstract 

Ionizing irradiation is widely used as conditioning therapy in bone marrow (BM) transplantation. High-dose radiation treatment induces profound tissue damage, especially, of hematopoietic stem cells and progenitor cells. Efforts to improve clinical outcomes post- irradiation are focused on the hematopoietic stem cell niche. Mesenchymal stromal cells (MSCs) represent an integrative part of the BM stromal microenvironment. When co-transplanted with HSC, MSCs augment hematopoietic recovery after chemo- or radiotherapy. The aim of our study was to evaluate essential biological parameters of MSCs, with respect to their lineage-specific differentiation capacity, in vivo survival rates, as well as their ability to rescue lethally irradiated hosts. Materials and Methods. In vitro differentiation of human BM-derived MSCs (hMSCs) for hematopoietic (HSC) and endothelial cells (EC) was studied by reverse transcription- quantitative PCR (RT-qPCR) of lineage-specific surface markers and other proteins. To test in vivo ability of murine MSCs to rescue lethally irradiated (9.5 Gy) mice, the animals were transplanted with eGFP-marked murine MSCs (mMSCs). Long-term donor chimerism was assessed in blood, BM and thymus using CD45.2 and Y chromosome markers. A microarray analysis of bone marrow cells from MSC-transplanted animals was also performed, in order to compare their gene expression profiles to appropriate controls.

Results

Upon in vitro differentiation of hMSCs, the hematopoietically differentiated cells changed their gene expression towards a typical profile of progenitor and mature hematopoietic cells. A variety of transcription factors responsible for erythropoiesis, megakaryopoiesis, lympho- and myelopoiesis were up-regulated during differentiation in serum-containing media. A population of cells with small round or polymorphic nuclei was detected which expressed hematopoietic progenitor and mature antigen markers, albeit to a rather low degree. The same cells were able to acquire endothelial morphology and expressed endothelial genes upon cultivation with endothelial promoting factors. Following MSCs transplantation, the lethally irradiated mice showed normal hematopoietic recovery comparable to effects of HSC infusions. Seven months later, the recipients had normal distribution of peripheral blood cell populations. No evidence of donor chimerism was shown at any time

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Claudia Lange,1 Rudolph Reimer,2 Jozef Zustin,3 Bärbel Brunswig-Spickenheier1

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Claudia Lange,1 Rudolph Reimer,2 Jozef Zustin,3 Bärbel Brunswig-Spickenheier1

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Abstract 

Ionizing irradiation is widely used as conditioning therapy in bone marrow (BM) transplantation. High-dose radiation treatment induces profound tissue damage, especially, of hematopoietic stem cells and progenitor cells. Efforts to improve clinical outcomes post- irradiation are focused on the hematopoietic stem cell niche. Mesenchymal stromal cells (MSCs) represent an integrative part of the BM stromal microenvironment. When co-transplanted with HSC, MSCs augment hematopoietic recovery after chemo- or radiotherapy. The aim of our study was to evaluate essential biological parameters of MSCs, with respect to their lineage-specific differentiation capacity, in vivo survival rates, as well as their ability to rescue lethally irradiated hosts. Materials and Methods. In vitro differentiation of human BM-derived MSCs (hMSCs) for hematopoietic (HSC) and endothelial cells (EC) was studied by reverse transcription- quantitative PCR (RT-qPCR) of lineage-specific surface markers and other proteins. To test in vivo ability of murine MSCs to rescue lethally irradiated (9.5 Gy) mice, the animals were transplanted with eGFP-marked murine MSCs (mMSCs). Long-term donor chimerism was assessed in blood, BM and thymus using CD45.2 and Y chromosome markers. A microarray analysis of bone marrow cells from MSC-transplanted animals was also performed, in order to compare their gene expression profiles to appropriate controls.

Results

Upon in vitro differentiation of hMSCs, the hematopoietically differentiated cells changed their gene expression towards a typical profile of progenitor and mature hematopoietic cells. A variety of transcription factors responsible for erythropoiesis, megakaryopoiesis, lympho- and myelopoiesis were up-regulated during differentiation in serum-containing media. A population of cells with small round or polymorphic nuclei was detected which expressed hematopoietic progenitor and mature antigen markers, albeit to a rather low degree. The same cells were able to acquire endothelial morphology and expressed endothelial genes upon cultivation with endothelial promoting factors. Following MSCs transplantation, the lethally irradiated mice showed normal hematopoietic recovery comparable to effects of HSC infusions. Seven months later, the recipients had normal distribution of peripheral blood cell populations. No evidence of donor chimerism was shown at any time

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Abstract 

Ionizing irradiation is widely used as conditioning therapy in bone marrow (BM) transplantation. High-dose radiation treatment induces profound tissue damage, especially, of hematopoietic stem cells and progenitor cells. Efforts to improve clinical outcomes post- irradiation are focused on the hematopoietic stem cell niche. Mesenchymal stromal cells (MSCs) represent an integrative part of the BM stromal microenvironment. When co-transplanted with HSC, MSCs augment hematopoietic recovery after chemo- or radiotherapy. The aim of our study was to evaluate essential biological parameters of MSCs, with respect to their lineage-specific differentiation capacity, in vivo survival rates, as well as their ability to rescue lethally irradiated hosts. Materials and Methods. In vitro differentiation of human BM-derived MSCs (hMSCs) for hematopoietic (HSC) and endothelial cells (EC) was studied by reverse transcription- quantitative PCR (RT-qPCR) of lineage-specific surface markers and other proteins. To test in vivo ability of murine MSCs to rescue lethally irradiated (9.5 Gy) mice, the animals were transplanted with eGFP-marked murine MSCs (mMSCs). Long-term donor chimerism was assessed in blood, BM and thymus using CD45.2 and Y chromosome markers. A microarray analysis of bone marrow cells from MSC-transplanted animals was also performed, in order to compare their gene expression profiles to appropriate controls.

Results

Upon in vitro differentiation of hMSCs, the hematopoietically differentiated cells changed their gene expression towards a typical profile of progenitor and mature hematopoietic cells. A variety of transcription factors responsible for erythropoiesis, megakaryopoiesis, lympho- and myelopoiesis were up-regulated during differentiation in serum-containing media. A population of cells with small round or polymorphic nuclei was detected which expressed hematopoietic progenitor and mature antigen markers, albeit to a rather low degree. The same cells were able to acquire endothelial morphology and expressed endothelial genes upon cultivation with endothelial promoting factors. Following MSCs transplantation, the lethally irradiated mice showed normal hematopoietic recovery comparable to effects of HSC infusions. Seven months later, the recipients had normal distribution of peripheral blood cell populations. No evidence of donor chimerism was shown at any time

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["TEXT"]=> string(6841) "<p> Ионизирующее излучение широко применяется в качестве кондиционирующей терапии при транс- плантации костного мозга. Высокодозная радиаци- онная терапия вызывает тяжелое повреждение, в особенности – гемопоэтических стволовых клеток и клеток-предшественников. Попытки улучшения кли- нических исходов после облучения сосредоточены на гемопоэтической нише. Мезенхимные стромальные клетки (МСК) представляют собой интегральную часть стромального микроокружения. При совмест- ной трансплантации с гемопоэтическими стволовыми клетками (ГСК), МСК способны усиливать восстанов- ление кроветворения после химио- и радиационной терапии. Целью нашего исследования была оценка основных биологических параметров МСК, в плане их способности к специфической линейной диффе- ренцировке, выживаемости организма, а также их способности к радиопротекции летально облученных реципиентов. Материалы и методы. Дифференциров- ку in vitro МСК человека в направлении гемопоэтиче- ских (ГСК) или эндотелиальных клеток изучали путем RT-qPCR поверхностных маркеров и других белков. Для тестирования in vivo способности мышиных МСК защищать летально облученных (9.5 Гр) мышей, животных трансплантировали мышиными МСК, ме- чеными eGFP. Длительность донорского химеризма определяли в крови, костном мозге и тимусе по марке- рам CD45.2 и Y-хромосомы. Анализ профилей генной экспрессии в клетках костного мозга проводили по сравнению с соответствующими контролями посред- ством биочипов. Результаты. При дифференцировке гемопоэтических стволовых клеток человека in vitro отмечалась изменения генной экспрессии со спектром экспрессии, типичным для кроветворных предше- ственников и зрелых клеток. Во время дифференци- ровки в средах с сывороткой наблюдалась повышен- ная экспрессия множества факторов, ответственных за эритропоэз, мегакариоцитопоэз, лимфо- и мииело- поэз. Была выявлена популяция клеток с небольшими круглыми или полиморфными ядрами, которые экс- прессировали антигенные маркеры, характерные для клеток-предшественников или зрелых форм, хотя и небольшой степени. Те же клетки приобретали мор- фологические черты эндотелия и экспрессировали гены, специфичные для эндотелиальных клеток при культивировании со специфическими факторами дифференцировки.  </p> <p> После введения МСК, летально облученные мыши выживали с нормальным восстановлением кроветво- рения, как при введении кроветворных клеток. Через 7 мес. после облучения реципиенты МСК имели нор- мальное соотношение популяций периферической крови. Не было указаний на наличие сколько-нибудь длительного донорского химеризма после трансплан- тации. Оценка распределения eGFP+ донорских кле- ток после внутривенной трансфузии показала бы- строе исчезновение МСК из периферической крови, до 2% через 8 часов после введения с задержкой клеток в легких, однако без их длительной персистенции и эмболизации сосудов. Исследование экспрессии ге- нов в клетках костного мозга у животных, леченных МСК, показало повышение активности генов, способ- ствующих восстановлению кроветворения, наряду со снижением активности генов, ассоциированных с ра- диационным повреждением костного мозга. Инъек- ции летально облученныи животным микровезикул, происходящих из МСК, приводили к тем же протек- тивным эффектам, что и трансплантация МСКС как таковых. Заключение. Наши результаты представляют дополнительные данные о возможных механизмах вы- сокоэффективного паракринного механизма, который актуален, в частности, для популяций костного мозга, что указывает на то, что инфузии МСК являются эф- фективным средством лечения последствий острого облучения. Кроме того, трансплантация МСК может оказывать свой трофический эффект в необычных ме- стах, в точм числе – легочной ткани реципиента. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6817) "

Ионизирующее излучение широко применяется в качестве кондиционирующей терапии при транс- плантации костного мозга. Высокодозная радиаци- онная терапия вызывает тяжелое повреждение, в особенности – гемопоэтических стволовых клеток и клеток-предшественников. Попытки улучшения кли- нических исходов после облучения сосредоточены на гемопоэтической нише. Мезенхимные стромальные клетки (МСК) представляют собой интегральную часть стромального микроокружения. При совмест- ной трансплантации с гемопоэтическими стволовыми клетками (ГСК), МСК способны усиливать восстанов- ление кроветворения после химио- и радиационной терапии. Целью нашего исследования была оценка основных биологических параметров МСК, в плане их способности к специфической линейной диффе- ренцировке, выживаемости организма, а также их способности к радиопротекции летально облученных реципиентов. Материалы и методы. Дифференциров- ку in vitro МСК человека в направлении гемопоэтиче- ских (ГСК) или эндотелиальных клеток изучали путем RT-qPCR поверхностных маркеров и других белков. Для тестирования in vivo способности мышиных МСК защищать летально облученных (9.5 Гр) мышей, животных трансплантировали мышиными МСК, ме- чеными eGFP. Длительность донорского химеризма определяли в крови, костном мозге и тимусе по марке- рам CD45.2 и Y-хромосомы. Анализ профилей генной экспрессии в клетках костного мозга проводили по сравнению с соответствующими контролями посред- ством биочипов. Результаты. При дифференцировке гемопоэтических стволовых клеток человека in vitro отмечалась изменения генной экспрессии со спектром экспрессии, типичным для кроветворных предше- ственников и зрелых клеток. Во время дифференци- ровки в средах с сывороткой наблюдалась повышен- ная экспрессия множества факторов, ответственных за эритропоэз, мегакариоцитопоэз, лимфо- и мииело- поэз. Была выявлена популяция клеток с небольшими круглыми или полиморфными ядрами, которые экс- прессировали антигенные маркеры, характерные для клеток-предшественников или зрелых форм, хотя и небольшой степени. Те же клетки приобретали мор- фологические черты эндотелия и экспрессировали гены, специфичные для эндотелиальных клеток при культивировании со специфическими факторами дифференцировки. 

После введения МСК, летально облученные мыши выживали с нормальным восстановлением кроветво- рения, как при введении кроветворных клеток. Через 7 мес. после облучения реципиенты МСК имели нор- мальное соотношение популяций периферической крови. Не было указаний на наличие сколько-нибудь длительного донорского химеризма после трансплан- тации. Оценка распределения eGFP+ донорских кле- ток после внутривенной трансфузии показала бы- строе исчезновение МСК из периферической крови, до 2% через 8 часов после введения с задержкой клеток в легких, однако без их длительной персистенции и эмболизации сосудов. Исследование экспрессии ге- нов в клетках костного мозга у животных, леченных МСК, показало повышение активности генов, способ- ствующих восстановлению кроветворения, наряду со снижением активности генов, ассоциированных с ра- диационным повреждением костного мозга. Инъек- ции летально облученныи животным микровезикул, происходящих из МСК, приводили к тем же протек- тивным эффектам, что и трансплантация МСКС как таковых. Заключение. Наши результаты представляют дополнительные данные о возможных механизмах вы- сокоэффективного паракринного механизма, который актуален, в частности, для популяций костного мозга, что указывает на то, что инфузии МСК являются эф- фективным средством лечения последствий острого облучения. Кроме того, трансплантация МСК может оказывать свой трофический эффект в необычных ме- стах, в точм числе – легочной ткани реципиента.

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Ионизирующее излучение широко применяется в качестве кондиционирующей терапии при транс- плантации костного мозга. Высокодозная радиаци- онная терапия вызывает тяжелое повреждение, в особенности – гемопоэтических стволовых клеток и клеток-предшественников. Попытки улучшения кли- нических исходов после облучения сосредоточены на гемопоэтической нише. Мезенхимные стромальные клетки (МСК) представляют собой интегральную часть стромального микроокружения. При совмест- ной трансплантации с гемопоэтическими стволовыми клетками (ГСК), МСК способны усиливать восстанов- ление кроветворения после химио- и радиационной терапии. Целью нашего исследования была оценка основных биологических параметров МСК, в плане их способности к специфической линейной диффе- ренцировке, выживаемости организма, а также их способности к радиопротекции летально облученных реципиентов. Материалы и методы. Дифференциров- ку in vitro МСК человека в направлении гемопоэтиче- ских (ГСК) или эндотелиальных клеток изучали путем RT-qPCR поверхностных маркеров и других белков. Для тестирования in vivo способности мышиных МСК защищать летально облученных (9.5 Гр) мышей, животных трансплантировали мышиными МСК, ме- чеными eGFP. Длительность донорского химеризма определяли в крови, костном мозге и тимусе по марке- рам CD45.2 и Y-хромосомы. Анализ профилей генной экспрессии в клетках костного мозга проводили по сравнению с соответствующими контролями посред- ством биочипов. Результаты. При дифференцировке гемопоэтических стволовых клеток человека in vitro отмечалась изменения генной экспрессии со спектром экспрессии, типичным для кроветворных предше- ственников и зрелых клеток. Во время дифференци- ровки в средах с сывороткой наблюдалась повышен- ная экспрессия множества факторов, ответственных за эритропоэз, мегакариоцитопоэз, лимфо- и мииело- поэз. Была выявлена популяция клеток с небольшими круглыми или полиморфными ядрами, которые экс- прессировали антигенные маркеры, характерные для клеток-предшественников или зрелых форм, хотя и небольшой степени. Те же клетки приобретали мор- фологические черты эндотелия и экспрессировали гены, специфичные для эндотелиальных клеток при культивировании со специфическими факторами дифференцировки. 

После введения МСК, летально облученные мыши выживали с нормальным восстановлением кроветво- рения, как при введении кроветворных клеток. Через 7 мес. после облучения реципиенты МСК имели нор- мальное соотношение популяций периферической крови. Не было указаний на наличие сколько-нибудь длительного донорского химеризма после трансплан- тации. Оценка распределения eGFP+ донорских кле- ток после внутривенной трансфузии показала бы- строе исчезновение МСК из периферической крови, до 2% через 8 часов после введения с задержкой клеток в легких, однако без их длительной персистенции и эмболизации сосудов. Исследование экспрессии ге- нов в клетках костного мозга у животных, леченных МСК, показало повышение активности генов, способ- ствующих восстановлению кроветворения, наряду со снижением активности генов, ассоциированных с ра- диационным повреждением костного мозга. Инъек- ции летально облученныи животным микровезикул, происходящих из МСК, приводили к тем же протек- тивным эффектам, что и трансплантация МСКС как таковых. Заключение. Наши результаты представляют дополнительные данные о возможных механизмах вы- сокоэффективного паракринного механизма, который актуален, в частности, для популяций костного мозга, что указывает на то, что инфузии МСК являются эф- фективным средством лечения последствий острого облучения. Кроме того, трансплантация МСК может оказывать свой трофический эффект в необычных ме- стах, в точм числе – легочной ткани реципиента.

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Introduction

In 2009, over 150 000 people in the US were waiting for an organ transplant, and only 18% of them received one. Nearly 9000 people died while on the waiting list. The lack of available donors is a major driving force for developing the concept of artificial organs. Strategies for construction or reconstruction of new tissues and organs include: 1) Creating biocompatible templates onto which stem cells and their derivative cells can be seeded; 2) Creating natural templates by decellularization, and seeding stem cells or stem cell-derived cells onto these; and 3) Generating complex tissues directly from stem cells and matrix materials using bioreactors or 3D-printing.

Culturing cells under 3D conditions provides key advantages that make this strategy imperative in approaching the problem of organ replacement. In conventional 2D cultures, primary cells rapidly lose their function, in large part due to perturbed cell-cell contacts. This can lead to rapid loss of polarity and differentiation, as is seen for example in hepatocytes obtained from biopsies. Dissociated hepatocytes in 2D monoculture revert to expression of alpha fetoprotein (AFP) and experience a downregulation of integrins and P450 activity. By contrast, primary hepatocytes cultured under 3D conditions in a microgravity vessel remain fully functional for at least 6 weeks with respect to albumin secretion, integrin beta 6 expression, P450 responsiveness and downregulation of AFP. In short, a liver-like functional status is retained. Thus, 2D monocultures of animal primary cells or of human immortalized cell lines are not representative of normal human tissue. 3D microenvironments provide more complex and physiological cell-cell and cell-matrix interactions, and provide a more reliable platform for physiologically relevant tissue models, disease models and drug testing.

Figure 1. An example of a 3D-printed tissue scaffold [3].

Figure 1. An example of a 3D-printed tissue scaffold [3].


In designing 3D bioprinting strategies, several important
technical issues need to be considered, including:

  1. Choice of printing technology (microextrusion, laser induced forward transfer – LIFT)
  2. Choice of biomatrix/hydrogel (alginate, chytosan, etc.)
  3. Printing parameters (temperature, spatial resolution, cell density, etc.)
  4. Interactions between multiple cell types
  5. Use of multiple biomatrices
  6. The need for associated microfluidics

The choice of printing technology is especially important.

Microextrusion technology is essentially the same as used in thermal inkjet printing, and can attain a spatial resolution down to about 100 um using biogels. Currently available printing platforms provide multiple printing heads and differential temperature control for utilization of diverse materials. Printing parameters must be optimized for each material applied, and material-specific shear forces are relevant when working with labile cells.

Another promising technology is laser-induced forward transfer (LIFT) printing, which uses laser light to force cells from a fluid interface onto a surface, rather than extruding cells through a printing head. This ensures high spatial resolution (<100 um), corresponding essentially to single-cell seeding, and high-speed cell placement (1000 droplets/sec). LIFT is not dependent on using a biomaterial as vehicle, and thus shear forces are less relevant. However, laser power is a significant factor.

3-D bioprinting

One promising approach to 3D organ fabrication is to use special bioprinters to prepare tissue scaffolds and constructs that reproduce some of the complex interactions occuring among different cell types within a tissue (Figure 1). Relevant studies have resulted in the production of organ-like cellular complexes, for example tubular/glomerular kidney structures (Figure 2).

Figure 2. First 3D printed kidney tissue (http://ir.organovo.com/news/press-releases/press-releases-details/2015/Organovo-Describes-First-Fully-Cellular-3D-Bioprinted-Kidney-Tissue/).
Figure 2. First 3D printed kidney tissue (http://ir.organovo.com/news/press-releases/press-releases-details/2015/Organovo-Describes-First-Full....

Figure 3. An example of a modern bioprinter.
Figure 3. An example of a modern bioprinter.

Natural templates

An alternative, and also still experimental, approach to organ manufacture is represented by decellularization and subsequent recellularization of native organs, exemplified by attempts using animal organs, including rat heart [4, 6], rat kidney [1] and monkey lung [2]. As an example of this approach, bone marrow derived mesenchymal stem cells or lung-derived microvascular endothelial cells have been seeded into decellularized lung scaffolds and have generated epithelia that histologically resemble natural respiratory airways [2].

An important challenge when designing tissue scaffolds is the adequate incorporation of vascularization. One potential approach, termed “nano-origami”, involves complex nanostructures that are constructed as topographically patterned 2D substrates that can be seeded with cells and then rolled or folded into a 3D shape [5], see also http://www.materialsviews.com/advanced-origami-nanostructures-from-flowers-to-boxes/http://nextbig future.com/2012/04/logic-gated-nanorobot-for-targeted.html).

Relevance for hematology

A main area of potential relevance of 3D bioprinting for hematologists is in modeling hematopoiesis in a more natural tissue microenvironment. A variety of differentiating blood cells, accessory cells and immune cells exist within the structural microenvironment of bone marrow, creating intimate functional and regulatory relationships. Thus, generating appropriately patterned 3D tissue models could create promising opportunities for investigations of normal and altered hematopoiesis in a realistic biological niche.

Conclusions

3D bioprinting is a field in rapid development. Increasing numbers of studies are highlighting some of the potential applications, including more physiological and penetrating investigation of tissue and organ development and function, the generation of personalized drug testing and disease models, and scaffold and tissue printing for clinical use. 3D bioprinting is likely to contribute substantially to tissue engineering efforts related to organ replacement.

Conflict of interest

None declared

References

  1. Bonandrini B, Figliuzzi M, Papadimou E, Morigi M, Perico N, Casiraghi F, Dipl C, Sangalli F, Conti S, Benigni A, Remuzzi A, Remuzzi G. Recellularization of well-preserved acellular kidney scaffold using embryonic stem cells. Tissue Eng Part A 2014;20 (9-10):1486-1498.
  2. Bonvillain RW, Scarritt ME, Pashos NC, Mayeaux JP, Meshberger CL, Betancourt AM, Sullivan DE, Bunnell BA. Nonhuman primate lung decellularization and recellularization using a specialized large-organ bioreactor. J Vis Exp 2013;82:e50825.
  3. Kolesky DB, Truby RL, Gladman AS, Busbee TA, Homan KA, Lewis JA. 3D bioprinting of vascularized, heterogeneous cell-laden tissue constructs. Adv Mater 2014;26(19):3124- 3130.
  4. Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 2008;14(2):213-221.
  5. Sun Y, Weng S, Fu J. Microengineered synthetic cellular microenvironment for stem cells. Nanomed Nanobiotech 2012; 4(4):414–427.
  6. Vunjak-Novakovic G, Lui KO, Tandon N, Chien KR. Bioengineering heart muscle: a paradigm for regenerative medicine. Annu Rev Biomed Eng 2011;13:245-267.

" ["~DETAIL_TEXT"]=> string(9000) "

Introduction

In 2009, over 150 000 people in the US were waiting for an organ transplant, and only 18% of them received one. Nearly 9000 people died while on the waiting list. The lack of available donors is a major driving force for developing the concept of artificial organs. Strategies for construction or reconstruction of new tissues and organs include: 1) Creating biocompatible templates onto which stem cells and their derivative cells can be seeded; 2) Creating natural templates by decellularization, and seeding stem cells or stem cell-derived cells onto these; and 3) Generating complex tissues directly from stem cells and matrix materials using bioreactors or 3D-printing.

Culturing cells under 3D conditions provides key advantages that make this strategy imperative in approaching the problem of organ replacement. In conventional 2D cultures, primary cells rapidly lose their function, in large part due to perturbed cell-cell contacts. This can lead to rapid loss of polarity and differentiation, as is seen for example in hepatocytes obtained from biopsies. Dissociated hepatocytes in 2D monoculture revert to expression of alpha fetoprotein (AFP) and experience a downregulation of integrins and P450 activity. By contrast, primary hepatocytes cultured under 3D conditions in a microgravity vessel remain fully functional for at least 6 weeks with respect to albumin secretion, integrin beta 6 expression, P450 responsiveness and downregulation of AFP. In short, a liver-like functional status is retained. Thus, 2D monocultures of animal primary cells or of human immortalized cell lines are not representative of normal human tissue. 3D microenvironments provide more complex and physiological cell-cell and cell-matrix interactions, and provide a more reliable platform for physiologically relevant tissue models, disease models and drug testing.

Figure 1. An example of a 3D-printed tissue scaffold [3].

Figure 1. An example of a 3D-printed tissue scaffold [3].


In designing 3D bioprinting strategies, several important
technical issues need to be considered, including:

  1. Choice of printing technology (microextrusion, laser induced forward transfer – LIFT)
  2. Choice of biomatrix/hydrogel (alginate, chytosan, etc.)
  3. Printing parameters (temperature, spatial resolution, cell density, etc.)
  4. Interactions between multiple cell types
  5. Use of multiple biomatrices
  6. The need for associated microfluidics

The choice of printing technology is especially important.

Microextrusion technology is essentially the same as used in thermal inkjet printing, and can attain a spatial resolution down to about 100 um using biogels. Currently available printing platforms provide multiple printing heads and differential temperature control for utilization of diverse materials. Printing parameters must be optimized for each material applied, and material-specific shear forces are relevant when working with labile cells.

Another promising technology is laser-induced forward transfer (LIFT) printing, which uses laser light to force cells from a fluid interface onto a surface, rather than extruding cells through a printing head. This ensures high spatial resolution (<100 um), corresponding essentially to single-cell seeding, and high-speed cell placement (1000 droplets/sec). LIFT is not dependent on using a biomaterial as vehicle, and thus shear forces are less relevant. However, laser power is a significant factor.

3-D bioprinting

One promising approach to 3D organ fabrication is to use special bioprinters to prepare tissue scaffolds and constructs that reproduce some of the complex interactions occuring among different cell types within a tissue (Figure 1). Relevant studies have resulted in the production of organ-like cellular complexes, for example tubular/glomerular kidney structures (Figure 2).

Figure 2. First 3D printed kidney tissue (http://ir.organovo.com/news/press-releases/press-releases-details/2015/Organovo-Describes-First-Fully-Cellular-3D-Bioprinted-Kidney-Tissue/).
Figure 2. First 3D printed kidney tissue (http://ir.organovo.com/news/press-releases/press-releases-details/2015/Organovo-Describes-First-Full....

Figure 3. An example of a modern bioprinter.
Figure 3. An example of a modern bioprinter.

Natural templates

An alternative, and also still experimental, approach to organ manufacture is represented by decellularization and subsequent recellularization of native organs, exemplified by attempts using animal organs, including rat heart [4, 6], rat kidney [1] and monkey lung [2]. As an example of this approach, bone marrow derived mesenchymal stem cells or lung-derived microvascular endothelial cells have been seeded into decellularized lung scaffolds and have generated epithelia that histologically resemble natural respiratory airways [2].

An important challenge when designing tissue scaffolds is the adequate incorporation of vascularization. One potential approach, termed “nano-origami”, involves complex nanostructures that are constructed as topographically patterned 2D substrates that can be seeded with cells and then rolled or folded into a 3D shape [5], see also http://www.materialsviews.com/advanced-origami-nanostructures-from-flowers-to-boxes/http://nextbig future.com/2012/04/logic-gated-nanorobot-for-targeted.html).

Relevance for hematology

A main area of potential relevance of 3D bioprinting for hematologists is in modeling hematopoiesis in a more natural tissue microenvironment. A variety of differentiating blood cells, accessory cells and immune cells exist within the structural microenvironment of bone marrow, creating intimate functional and regulatory relationships. Thus, generating appropriately patterned 3D tissue models could create promising opportunities for investigations of normal and altered hematopoiesis in a realistic biological niche.

Conclusions

3D bioprinting is a field in rapid development. Increasing numbers of studies are highlighting some of the potential applications, including more physiological and penetrating investigation of tissue and organ development and function, the generation of personalized drug testing and disease models, and scaffold and tissue printing for clinical use. 3D bioprinting is likely to contribute substantially to tissue engineering efforts related to organ replacement.

Conflict of interest

None declared

References

  1. Bonandrini B, Figliuzzi M, Papadimou E, Morigi M, Perico N, Casiraghi F, Dipl C, Sangalli F, Conti S, Benigni A, Remuzzi A, Remuzzi G. Recellularization of well-preserved acellular kidney scaffold using embryonic stem cells. Tissue Eng Part A 2014;20 (9-10):1486-1498.
  2. Bonvillain RW, Scarritt ME, Pashos NC, Mayeaux JP, Meshberger CL, Betancourt AM, Sullivan DE, Bunnell BA. Nonhuman primate lung decellularization and recellularization using a specialized large-organ bioreactor. J Vis Exp 2013;82:e50825.
  3. Kolesky DB, Truby RL, Gladman AS, Busbee TA, Homan KA, Lewis JA. 3D bioprinting of vascularized, heterogeneous cell-laden tissue constructs. Adv Mater 2014;26(19):3124- 3130.
  4. Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 2008;14(2):213-221.
  5. Sun Y, Weng S, Fu J. Microengineered synthetic cellular microenvironment for stem cells. Nanomed Nanobiotech 2012; 4(4):414–427.
  6. Vunjak-Novakovic G, Lui KO, Tandon N, Chien KR. Bioengineering heart muscle: a paradigm for regenerative medicine. Annu Rev Biomed Eng 2011;13:245-267.

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Гловер</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(48) "

Джоэл К. Гловер

" ["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(4) "5961" ["VALUE"]=> array(2) { ["TEXT"]=> string(352) "Отдел молекулярной медицины, Институт фундаментальных медицинских наук, Университет Осло, Норвегия Норвежский центр исследования стволовых клеток, Университетский госпиталь Осло, Норвегия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(352) "Отдел молекулярной медицины, Институт фундаментальных медицинских наук, Университет Осло, Норвегия Норвежский центр исследования стволовых клеток, Университетский госпиталь Осло, Норвегия" ["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(4) "5835" ["VALUE"]=> array(2) { ["TEXT"]=> string(2502) "Статья касается различных стратегий размножения стволовых клеток и их потомства в ходе моделирования новых органов и тканей, в т.ч. – искусственных биосовместимых матриц, естественных бескле- точных матриц, а также создания сложных тканей непосредственно из стволовых клеток и элементов матрикса с применением биореактора или трехмерного печатания (принтинга). В целом, культивирование клеток в 3D-системе позволяет поддерживать полноценные морфологические и функциональные свойства специализированных клеток, как, например, гепатоцитов. В частности, обещающим подходом к созданию трехмерных органных структур с помощью специальных биопринтеров для приготовления основы тканей. Соответствующие исследования привели к производству органоподобных клеточных комплексов, как, например, почечных структур. Есть некоторые технические проблемы, которые следует рассматривать для каждого отдельного случая, включая тип принтера, выбор типа биоматрикса, параметры печатания и т.д. Технологии микроэкструзии и лазер-индуцированного переноса считаются перспективными в этом плане. Естественные субстраты для тканевых и органных «костяков» можно получить путем удаления клеток и последующего посева клеток, как уже показано в экспериментах на животных. Производство 3D-моделей может создать условия для исследовании гемопоэза в его естественном микроокружении." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2502) "Статья касается различных стратегий размножения стволовых клеток и их потомства в ходе моделирования новых органов и тканей, в т.ч. – искусственных биосовместимых матриц, естественных бескле- точных матриц, а также создания сложных тканей непосредственно из стволовых клеток и элементов матрикса с применением биореактора или трехмерного печатания (принтинга). В целом, культивирование клеток в 3D-системе позволяет поддерживать полноценные морфологические и функциональные свойства специализированных клеток, как, например, гепатоцитов. В частности, обещающим подходом к созданию трехмерных органных структур с помощью специальных биопринтеров для приготовления основы тканей. Соответствующие исследования привели к производству органоподобных клеточных комплексов, как, например, почечных структур. Есть некоторые технические проблемы, которые следует рассматривать для каждого отдельного случая, включая тип принтера, выбор типа биоматрикса, параметры печатания и т.д. Технологии микроэкструзии и лазер-индуцированного переноса считаются перспективными в этом плане. Естественные субстраты для тканевых и органных «костяков» можно получить путем удаления клеток и последующего посева клеток, как уже показано в экспериментах на животных. Производство 3D-моделей может создать условия для исследовании гемопоэза в его естественном микроокружении." 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Glover</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(35) "

Joel C. Glover

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Generally, culturing cells under 3D conditions allows to retain fully morphological and functional integrity of specialized cells as shown with hepatocytes. In particular, a promising approach to 3D organ fabrication is to use special bioprinters to prepare tissue scaffolds. Relevant studies have resulted in the production of organ-like cellular complexes, for example tubular/glomerular kidney structures. There are some technical issues which should be considered in any single case, including type of printing technology, choice of biomatrix type, printing parameters, etc.<br> <br> Microextrusion tenchique and laser-induced forward transfer (LIFT) approach are considered as prospective printing technologies. Natural substrates for tissue and organ scaffolds could be obtained by decellularization and subsequent cell seeding, as already shown in animal experiments. Generating 3D tissue models could create promising opportunities for hematopoiesis research in its natural microenvironment.<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1322) "The article considers different strategies for seeding stem cells and their progeny and construction of new tissues and organs, i.e., artificial biocompatible templates, natural decellularized templates, and generating complex tissues directly from stem cells and matrix materials using bioreactors or 3D-printing. Generally, culturing cells under 3D conditions allows to retain fully morphological and functional integrity of specialized cells as shown with hepatocytes. In particular, a promising approach to 3D organ fabrication is to use special bioprinters to prepare tissue scaffolds. Relevant studies have resulted in the production of organ-like cellular complexes, for example tubular/glomerular kidney structures. There are some technical issues which should be considered in any single case, including type of printing technology, choice of biomatrix type, printing parameters, etc.

Microextrusion tenchique and laser-induced forward transfer (LIFT) approach are considered as prospective printing technologies. Natural substrates for tissue and organ scaffolds could be obtained by decellularization and subsequent cell seeding, as already shown in animal experiments. Generating 3D tissue models could create promising opportunities for hematopoiesis research in its natural microenvironment.
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Joel C. Glover

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Microextrusion tenchique and laser-induced forward transfer (LIFT) approach are considered as prospective printing technologies. Natural substrates for tissue and organ scaffolds could be obtained by decellularization and subsequent cell seeding, as already shown in animal experiments. Generating 3D tissue models could create promising opportunities for hematopoiesis research in its natural microenvironment.
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Microextrusion tenchique and laser-induced forward transfer (LIFT) approach are considered as prospective printing technologies. Natural substrates for tissue and organ scaffolds could be obtained by decellularization and subsequent cell seeding, as already shown in animal experiments. Generating 3D tissue models could create promising opportunities for hematopoiesis research in its natural microenvironment.
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