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Introduction

Graft -versus-host disease (GVHD) is one the most life-threatening complications in allogeneic stem cell transplantation (HSCT). With more the 40000 transplants per year, more than 10 thousand patients have this complication [1, 2]. Clinically signifi cant forms of GVHD occur in 20-50% of HSCT recipients, and it is associated with signifi cant mortality and morbidity reaching 30% in severe cases [3, 4]. Only a few large studies have been published with analysis of GVHD risk factors.
Flowers et al. in the cohort of 2941 related and unrelated graft recipients has demonstrated that unrelated donor, HLA mismatch, female donor in male recipient and donor age were the risk factors for both acute and chronic GVHD, while intensity of the conditioning was a predictor of acute GVHD, whereas patient age and peripheral blood stem cell (PBSC) graft ing were the predictors of the chronic GVHD. Also GVHD was less frequent in CML than in acute leukemia. Th e GVHD prophylaxis with antithymocyte immunoglobulin (ATG) did not reach statistical signifi cance [5]. High cellularity of the graft and high prevalence of CD3-positive cells in the graft was another predictor of acute GVHD with conventional prophylaxis, especially in PBSC recipients [6]. In another large study, the use of PBSC compared to bone marrow (BM) was the risk factor for both acute and chronic GVHD [7].
The Center for International Blood and Marrow Transplant Research (CIBMTR) study with data from 226 centers has identifi ed total body irradiation PBSC, ethnicity, poor performance study and positive cytomegalovirus status of donor and recipient as the signifi cant risk factors of acute GVHD [7]. Th e study also showed that ABO incompatibility was not a signifi cant factor, and the incidence of GVHD in CML is higher probably due to transplantation techniques.
The abovementioned studies were conducted relatively long ago, and were based on population of patients receiving predominantly cyclosporine and methotrexate (MTX) as prophylaxis, and ATG in unrelated donors. However, transplantation technologies have signifi cantly evolved over time. Novel prophylaxis regimens have been introduced, like mTOR inhibitors [8], posttransplant cyclophosphamide (PTCy) [9], TCR alpha/beta cell depletion [10]. No studies have been published on risk factors of GVHD with these novel approaches. In the present study, we searched for risk factors in two large cohorts of patients, one with conventional prophylaxis based on calcineurin inhibitors (CNIs) with MTX/mycophenolate mofetil (MMF) and other, with PTCy prophylaxis. Th e purpose of this study was to evaluate whether GVHD prophylaxis does change the pattern of risk
factors.

Patients and methods

One thousand thirteen adult patients transplanted at the First State I. Pavlov Medical University from 2006 to 2017 were included into the study. All the patients were graft ed either from matched related donor (32%) or unrelated donor (68%). In this group, 470 patients received prophylaxis with PTCy, and 543 were subjected to conventional prophylaxis (Table 1). Only patients who successfully engraft ed were included in the analysis.
GVHD prophylaxis under conventional regimen included tacrolimus with target concentration of 5 to 15 ng/ml, starting from day-1 until day+120, or cyclosporine A with target concentrations of 150 to 350 ng/ml, starting from day-1 until day+120. Th e second agent was either MMF 30 mg/kg (day -1 to day+30), or methotrexate 15 mg/m2 (day+1, 10 mg/m2; day +3, 6). Th e recipients of unrelated graft s did also receive ATG (ATGAM, Pfi zer, Inc.), at 20 mg/kg from day -3 until day -1. In the PTCy group, the prophylaxis consisted of single-agent cyclophosphamide (50 mg/kg) on days +3,+4 for matched related or unrelated bone marrow. In recipients of PBSCs, we used cyclophosphamide (50 mg/kg) on days +3,+4 followed by tacrolimus and MMF (30mg/kg) starting on day +5. In the mismatched graft s, the dose of MMF was increased to 45 mg/kg. Myeloablative conditioning (MAC) in conventional prophylaxis group was performed with oral busulfan (16 mg/kg), and cyclophosphamide (120 mg/kg). In the PTCy group, the majority of patients received MAC containing fl udarabine 180 mg/m2 and busulfan 14 mg/kg. Reduced-intensity conditioning (RIC) was performed with oral busulfan (8 mg/kg) and fl udarabine (180 mg/m2). Minority of patients received conditioning with melphalan (140 mg/m2) and fl udarabine (150 mg/m2. RIC was performed in patients, who were either older than 40 years, had HSCT-specifi c co-morbidity index (HCT-CI)≥2, or exhibited, at least, grade 3 hepatotoxicity during the induction therapy. Supportive care did not diff er for the two prophylaxis arms.

Statistical analysis

Th e Consensus Conference criteria were used for acute GVHD grading [11] and National Institutes of Health criteria were used for chronic GVHD grading [12]. Diagnosis of skin GVHD was established either clinically or histologically, the diagnosis of liver GVHD was assessed clinically, whereas gastrointestinal GVHD was specifi ed by pathological examination. Incidence of acute and chronic GVHD was evaluated with cumulative incidence estimates. Time frame for acute GVHD was 125 days, for chronic GVHD, 2 years. Evaluation of risk factors was performed by means of Gray test. Early discontinuation of immunosuppression due to relapse or minimal residual disease was considered a competing risk for aGVHD. Donor lymphocyte infusion was considered a competing risk for cGVHD. Multivariate evaluation and analysis of continuous variables were done using Fine and Grey regression. Th e variables were selected for the multivariate analysis in case of signifi cance <0.15 obtained in the univariate mode. Th e cutoff levels for continuous variables were determined in ROC analysis with maximal sum of sensitivity and specifi city as a criterion. Th e analyses were conducted in SAS 9.3 (SAS Institute, Inc.).

Results

The conventional prophylaxis group comprised 199 recipients of matched related graft s and 344 subjects were transplanted from unrelated donors. The PTCy group consisted of 104 matched related transplants, and 27 matched unrelated HSCTs, with single-agent PTCy prophylaxis. 338 patients received combined prophylaxis with PTCy, tacrolimus and MMF. Among the evaluated patients, 93.4% has engraft ed. Among the engraft ed patients, 436 received PTCy prophylaxis and 485, conventional GVHD prophylaxis, with a fi veyear survival of 47%. Incidence of acute GVHD in the whole group was 43.9%. Of them, 18.6% had grade I; 9.8%, grade II; 12.6%, grade III, and 3% had grade IV GVHD. Th e incidence of chronic GVHD was 31.6%, including 12.6% with mild; 9%, moderate degree, and 10% showed severe GVHD according to NIH criteria. Th e most common organs involved in chronic GVHD were skin, mucosa, eyes, gastrointestinal tract (GIT) and liver (Fig. 1). Incidence of acute GVHD in the PTCy group was 35%; grade II-IV acute GVHD, 15%; chronic GVHD, 29%. Moderate and severe chronic GVHD was registered in 18% of the cases. Similar incidence rates (resp., 53%, 35%, 35% and 30%) were noted for conventional prophylaxis.

Table 1. Patients’ characteristics in the study group

AML= acute myeloblastic leukemia; ALL =acute lymphoblastic leukemia; CML= chronic myeloid leukemia; HL= Hodgkin lymphoma; MDS= myelodysplastic syndrome; АА=aplastic anemia; NHL=non-Hodgkin lymphoma MF=myelofi brosis; MPN=myeloproliferative neoplasm; CLL=chronic lymphoid leukemia; MAC=myeloablative regimen; RIC =reduced-intensity conditioning.

Figure 1. The incidence and severity of acute (A) and chronic GVHD (B). The incidence of organ involvement is calculated only for the patients who developed GVHD

Figure 2. Risk factors of acute GVHD grade II-IV after conventional prophylaxis (A) and posttransplant cyclophosphamide (B). Number of CD34+ cells in the graft, age and BMI are continuous variables, all the others are logistic

For the conventional prophylaxis group, the following factors were revealed in the univariate analysis with signifi cance >0.15 for acute GVHD grade II-IV development: unrelated donor (p<0.0001), salvage group (p=0.0014), number of HSCT (p=0.1064), ABO incompatibility (p=0.0709), cytomegalovirus (CMV) serostatus (p=0.1487), graft source (p=0.0004 conditioning intensity (p=0.0003), alkylating agents in the conditioning (0.1377), age of the recipient (0.0002), CD34 cell number in the graft (p<0.0001), engraft - ment time (p<0.0001), diagnosis (p=0.0379), body mass index (BMI) (p=0.0220). Th ese parameters were included into the multivariate model where only unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96-0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and engraft ment before day +15 (HR 1.55, 95%CI 1.08-2.22) signifi cantly affected the incidence of acute GVHD grade II-IV (Figure 2A). Th e BMI cut-off value was 28 kg/m2 indicating that obese patients had less acute GVHD. Despite common risk factor of graft source, the fast engraft ment was more signifi cant than the graft source factor (p=0.48), despite the fact that fast engraft ment occurred more oft en in the PBSC recipients (32% vs 17%, p<0.0001).
In the univariate analysis of PTCy group, only unrelated donor (p=0.0170), HLA matching (p=0.0347), number of HSCT (p=0.0592), recipient gender (p=0.0592), CMV serostatus (p=0.0592), female donor for male recipient (p=0.0706), time of engraft ment (p=0.0037), and time from diagnosis to transplant were shown to be signifi cant factors (p<0.0001). Since the recipient gender was signifi cant because of female-male combination, only that factor was included in the multivariate analysis. Also in ROC analysis, the cut-off for engraft ment time was diff erent: 20 days instead of 15. Th ese parameters were added to the multivariate model where CMV serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Th e highest incidence was in the -/- pair of donor / recipient (32%), lower in the +/- pair (20%) and the lowest in the CMV-positive recipients (13% with +/+ pair vs 15% with -/+ pair). Th e univariate analysis in conventional prophylaxis group revealed unrelated donor (p=0.0002), salvage group (p=0.0635), cytomegalovirus serostatus (p=0.0248), graft source (p<0.0001), age (p=0.1360), number of CD34 cells in the graft (p=0.0047), engraft ment at <15 days (p=0.0013), time from diagnosis to transplantation (p=0.1151), diagnosis (p=0.0205) and previous acute GVHD (p<.0001) as signifi cant factors for moderate and severe chronic GVHD. In the PTCy group, the univariate analysis revealed unrelated donor (p=0.0980), donor gender (p=0.0138), graft source (p=0.0805), male recipient with female donor (p=0.1082), number of CD34+ cells in the graft (p=0.0272), time to engraft ment (p=0.0302) and previous acute GVHD (p=0.0929), as predisposing factors for chronic GVHD. In the multivariate model with conventional GVHD prophylaxis, only PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37) were signifi cant risk factors for moderate and severe chronic GVHD (Figure 3A).

Figure 3. Risk factors for moderate and severe chronic GVHD with conventional prophylaxis (A) and posttransplantation cyclophosphamide (B)

Modeling in the PTCy group demonstrated only a weak statistical signifi cance for previous acute GVHD (HR 1.59, 95%CI 0.99-2.54), while all the other factors were non-significant (Figure 3B).
Regarding mild acute GVHD (grade I-II) which is usually favorable for prognosis in the conventional prophylaxis group, only the CD34 cell dose increased the probability of this condition (HR 1.08, 95%CI 1.01-1.150, р=0.0133). The other variables were not signifi cantly different. With PTCy prophylaxis, the unrelated donorship was associated with increased probability of grade I-II acute GVHD (HR 3.26, 95%CI 1.26-8.39, p=0.0145). Also a combination of a female donor/ male recipient had week statistical signifi cance (HR 1.87, 0.94-3.72, p=0.0761). No predictors were determined for mild chronic GVHD in conventional prophylaxis patients, whereas, with PTCy, the CMV-positive recipient serostatus was protective against this condition (HR 0.675, 0.496-0.918, p=0.0123). Mild chronic GVHD was lowest in +/+ CMV positive donor/ recipient (6%), being highest in -/+ (15%) and +/- (19%) combinations. In the both CMV-negative pairs, mild chronic GVHD rate was also substantial (14%).

Discussion

In this relatively large study, we have confi rmed that the novel prophylaxis regimens may dramatically change the landscape of risk factors which was not demonstrated before. Previous registry studies mostly documented only evolutional changes in the risk factors due to other aspects of HSCT. In the era of only BM transplantation from matched siblings with cyclosporine and methotrexate as prophylaxis, the predominant risk factors were female donor for male recipient, pregnancy history and older recipient age [13]. Th e subsequent CIBMTR study identifi ed the risk factors of PBSC use, ethnicity, TBI versus busulfan-based conditioning, and positive CMV serostatus [7]. Aft er broad introduction of unrelated transplants, it became obvious that GVHD incidence is higher than aft er sibling transplants [14]. Additional risks of GVHD are associated with partial HLA mismatches [15] and non-HLA allele mismatches [16]. Furthermore, the donor age was also identifi ed as risk factor in unrelated HSCT [17]. Nonetheless the recent mathematical analysis indicates that the predictive potential of clinical parameters is relatively low [18]. Thus, the risk factors of GVHD were slowly evolving, due to implementation of novel cell sources and donor types. We, however, confi rm that the use of PTCy completely abolished the previously signifi cant risk factors. It has been previously published that HLA matching is not a signifi cant factor with PTCy prophylaxis [19], and this was confirmed in the current study. Nonetheless, the diff erence between matched sibling and unrelated donor had a tendency to signifi cance, which was also confirmed in our group of patients. What was not established earlier is the preventive
role of CMV-positive serology in recipient, despite a weak statistical trend in the EBMT study [20]. Th e probable reason for that is diff erent prevalence of CMV seropositivity in Russia, Europe and the USA. In Russia, the CMV seroprevalence is above 85% [21, 22, 23]. Th e CMV seropositivity is unlikely to represent the reason for diff erences, but, rather, it may be a consequence of changes in immune system that, probably, led to decreased GVHD incidence. It was demonstrated that CMV causes expansion of T-regulatory cells [24] and upregulation of IL-33 pathway, which protects against lethal GVHD in animal models [25, 26]. Th e signifi cance of this factor with no such evidence for conventional prophylaxis [7] indicates the presence of different immunological mechanisms behind PTCy prophylaxis that still should be elucidated.
The risk factors identifi ed for moderate and severe chronic GVHD with conventional prophylaxis were similar to the ones previously reported [27, 28]. Th e history of severe acute GVHD was the most predominant risk factor. However, no risk factors were identifi ed for PTCy, probably due to low incidence of this complication and low incidence of preceding acute GVHD in the study cohort. Contrary to this data, the European Registry Study defi ned recipient age, use of PBSC and combination prophylaxis as the risk factors [20]. Th e diff erences might be due to diff erent PTCy schedule (day +3, +5), use of cyclosporine instead of tacrolimus, duration
of immunosuppression [29]. Th e absence of diff erences between PBSC and BM is explained by single-agent PTCy prophylaxis in the matched bone marrow group and combination with tacrolimus and MMF in the PBSC group, which alleviated the diff erences.
In conclusion, this study identified the changing pattern of GVHD risk factors with introduction of novel prophylaxis regimens in related and unrelated HSCT graft s. Further studies are required to elucidate the biological mechanisms behind these changes.

Conflicts of interest

No conflicts of interest are reported by the authors.

References

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Introduction

Graft -versus-host disease (GVHD) is one the most life-threatening complications in allogeneic stem cell transplantation (HSCT). With more the 40000 transplants per year, more than 10 thousand patients have this complication [1, 2]. Clinically signifi cant forms of GVHD occur in 20-50% of HSCT recipients, and it is associated with signifi cant mortality and morbidity reaching 30% in severe cases [3, 4]. Only a few large studies have been published with analysis of GVHD risk factors.
Flowers et al. in the cohort of 2941 related and unrelated graft recipients has demonstrated that unrelated donor, HLA mismatch, female donor in male recipient and donor age were the risk factors for both acute and chronic GVHD, while intensity of the conditioning was a predictor of acute GVHD, whereas patient age and peripheral blood stem cell (PBSC) graft ing were the predictors of the chronic GVHD. Also GVHD was less frequent in CML than in acute leukemia. Th e GVHD prophylaxis with antithymocyte immunoglobulin (ATG) did not reach statistical signifi cance [5]. High cellularity of the graft and high prevalence of CD3-positive cells in the graft was another predictor of acute GVHD with conventional prophylaxis, especially in PBSC recipients [6]. In another large study, the use of PBSC compared to bone marrow (BM) was the risk factor for both acute and chronic GVHD [7].
The Center for International Blood and Marrow Transplant Research (CIBMTR) study with data from 226 centers has identifi ed total body irradiation PBSC, ethnicity, poor performance study and positive cytomegalovirus status of donor and recipient as the signifi cant risk factors of acute GVHD [7]. Th e study also showed that ABO incompatibility was not a signifi cant factor, and the incidence of GVHD in CML is higher probably due to transplantation techniques.
The abovementioned studies were conducted relatively long ago, and were based on population of patients receiving predominantly cyclosporine and methotrexate (MTX) as prophylaxis, and ATG in unrelated donors. However, transplantation technologies have signifi cantly evolved over time. Novel prophylaxis regimens have been introduced, like mTOR inhibitors [8], posttransplant cyclophosphamide (PTCy) [9], TCR alpha/beta cell depletion [10]. No studies have been published on risk factors of GVHD with these novel approaches. In the present study, we searched for risk factors in two large cohorts of patients, one with conventional prophylaxis based on calcineurin inhibitors (CNIs) with MTX/mycophenolate mofetil (MMF) and other, with PTCy prophylaxis. Th e purpose of this study was to evaluate whether GVHD prophylaxis does change the pattern of risk
factors.

Patients and methods

One thousand thirteen adult patients transplanted at the First State I. Pavlov Medical University from 2006 to 2017 were included into the study. All the patients were graft ed either from matched related donor (32%) or unrelated donor (68%). In this group, 470 patients received prophylaxis with PTCy, and 543 were subjected to conventional prophylaxis (Table 1). Only patients who successfully engraft ed were included in the analysis.
GVHD prophylaxis under conventional regimen included tacrolimus with target concentration of 5 to 15 ng/ml, starting from day-1 until day+120, or cyclosporine A with target concentrations of 150 to 350 ng/ml, starting from day-1 until day+120. Th e second agent was either MMF 30 mg/kg (day -1 to day+30), or methotrexate 15 mg/m2 (day+1, 10 mg/m2; day +3, 6). Th e recipients of unrelated graft s did also receive ATG (ATGAM, Pfi zer, Inc.), at 20 mg/kg from day -3 until day -1. In the PTCy group, the prophylaxis consisted of single-agent cyclophosphamide (50 mg/kg) on days +3,+4 for matched related or unrelated bone marrow. In recipients of PBSCs, we used cyclophosphamide (50 mg/kg) on days +3,+4 followed by tacrolimus and MMF (30mg/kg) starting on day +5. In the mismatched graft s, the dose of MMF was increased to 45 mg/kg. Myeloablative conditioning (MAC) in conventional prophylaxis group was performed with oral busulfan (16 mg/kg), and cyclophosphamide (120 mg/kg). In the PTCy group, the majority of patients received MAC containing fl udarabine 180 mg/m2 and busulfan 14 mg/kg. Reduced-intensity conditioning (RIC) was performed with oral busulfan (8 mg/kg) and fl udarabine (180 mg/m2). Minority of patients received conditioning with melphalan (140 mg/m2) and fl udarabine (150 mg/m2. RIC was performed in patients, who were either older than 40 years, had HSCT-specifi c co-morbidity index (HCT-CI)≥2, or exhibited, at least, grade 3 hepatotoxicity during the induction therapy. Supportive care did not diff er for the two prophylaxis arms.

Statistical analysis

Th e Consensus Conference criteria were used for acute GVHD grading [11] and National Institutes of Health criteria were used for chronic GVHD grading [12]. Diagnosis of skin GVHD was established either clinically or histologically, the diagnosis of liver GVHD was assessed clinically, whereas gastrointestinal GVHD was specifi ed by pathological examination. Incidence of acute and chronic GVHD was evaluated with cumulative incidence estimates. Time frame for acute GVHD was 125 days, for chronic GVHD, 2 years. Evaluation of risk factors was performed by means of Gray test. Early discontinuation of immunosuppression due to relapse or minimal residual disease was considered a competing risk for aGVHD. Donor lymphocyte infusion was considered a competing risk for cGVHD. Multivariate evaluation and analysis of continuous variables were done using Fine and Grey regression. Th e variables were selected for the multivariate analysis in case of signifi cance <0.15 obtained in the univariate mode. Th e cutoff levels for continuous variables were determined in ROC analysis with maximal sum of sensitivity and specifi city as a criterion. Th e analyses were conducted in SAS 9.3 (SAS Institute, Inc.).

Results

The conventional prophylaxis group comprised 199 recipients of matched related graft s and 344 subjects were transplanted from unrelated donors. The PTCy group consisted of 104 matched related transplants, and 27 matched unrelated HSCTs, with single-agent PTCy prophylaxis. 338 patients received combined prophylaxis with PTCy, tacrolimus and MMF. Among the evaluated patients, 93.4% has engraft ed. Among the engraft ed patients, 436 received PTCy prophylaxis and 485, conventional GVHD prophylaxis, with a fi veyear survival of 47%. Incidence of acute GVHD in the whole group was 43.9%. Of them, 18.6% had grade I; 9.8%, grade II; 12.6%, grade III, and 3% had grade IV GVHD. Th e incidence of chronic GVHD was 31.6%, including 12.6% with mild; 9%, moderate degree, and 10% showed severe GVHD according to NIH criteria. Th e most common organs involved in chronic GVHD were skin, mucosa, eyes, gastrointestinal tract (GIT) and liver (Fig. 1). Incidence of acute GVHD in the PTCy group was 35%; grade II-IV acute GVHD, 15%; chronic GVHD, 29%. Moderate and severe chronic GVHD was registered in 18% of the cases. Similar incidence rates (resp., 53%, 35%, 35% and 30%) were noted for conventional prophylaxis.

Table 1. Patients’ characteristics in the study group

AML= acute myeloblastic leukemia; ALL =acute lymphoblastic leukemia; CML= chronic myeloid leukemia; HL= Hodgkin lymphoma; MDS= myelodysplastic syndrome; АА=aplastic anemia; NHL=non-Hodgkin lymphoma MF=myelofi brosis; MPN=myeloproliferative neoplasm; CLL=chronic lymphoid leukemia; MAC=myeloablative regimen; RIC =reduced-intensity conditioning.

Figure 1. The incidence and severity of acute (A) and chronic GVHD (B). The incidence of organ involvement is calculated only for the patients who developed GVHD

Figure 2. Risk factors of acute GVHD grade II-IV after conventional prophylaxis (A) and posttransplant cyclophosphamide (B). Number of CD34+ cells in the graft, age and BMI are continuous variables, all the others are logistic

For the conventional prophylaxis group, the following factors were revealed in the univariate analysis with signifi cance >0.15 for acute GVHD grade II-IV development: unrelated donor (p<0.0001), salvage group (p=0.0014), number of HSCT (p=0.1064), ABO incompatibility (p=0.0709), cytomegalovirus (CMV) serostatus (p=0.1487), graft source (p=0.0004 conditioning intensity (p=0.0003), alkylating agents in the conditioning (0.1377), age of the recipient (0.0002), CD34 cell number in the graft (p<0.0001), engraft - ment time (p<0.0001), diagnosis (p=0.0379), body mass index (BMI) (p=0.0220). Th ese parameters were included into the multivariate model where only unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96-0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and engraft ment before day +15 (HR 1.55, 95%CI 1.08-2.22) signifi cantly affected the incidence of acute GVHD grade II-IV (Figure 2A). Th e BMI cut-off value was 28 kg/m2 indicating that obese patients had less acute GVHD. Despite common risk factor of graft source, the fast engraft ment was more signifi cant than the graft source factor (p=0.48), despite the fact that fast engraft ment occurred more oft en in the PBSC recipients (32% vs 17%, p<0.0001).
In the univariate analysis of PTCy group, only unrelated donor (p=0.0170), HLA matching (p=0.0347), number of HSCT (p=0.0592), recipient gender (p=0.0592), CMV serostatus (p=0.0592), female donor for male recipient (p=0.0706), time of engraft ment (p=0.0037), and time from diagnosis to transplant were shown to be signifi cant factors (p<0.0001). Since the recipient gender was signifi cant because of female-male combination, only that factor was included in the multivariate analysis. Also in ROC analysis, the cut-off for engraft ment time was diff erent: 20 days instead of 15. Th ese parameters were added to the multivariate model where CMV serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Th e highest incidence was in the -/- pair of donor / recipient (32%), lower in the +/- pair (20%) and the lowest in the CMV-positive recipients (13% with +/+ pair vs 15% with -/+ pair). Th e univariate analysis in conventional prophylaxis group revealed unrelated donor (p=0.0002), salvage group (p=0.0635), cytomegalovirus serostatus (p=0.0248), graft source (p<0.0001), age (p=0.1360), number of CD34 cells in the graft (p=0.0047), engraft ment at <15 days (p=0.0013), time from diagnosis to transplantation (p=0.1151), diagnosis (p=0.0205) and previous acute GVHD (p<.0001) as signifi cant factors for moderate and severe chronic GVHD. In the PTCy group, the univariate analysis revealed unrelated donor (p=0.0980), donor gender (p=0.0138), graft source (p=0.0805), male recipient with female donor (p=0.1082), number of CD34+ cells in the graft (p=0.0272), time to engraft ment (p=0.0302) and previous acute GVHD (p=0.0929), as predisposing factors for chronic GVHD. In the multivariate model with conventional GVHD prophylaxis, only PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37) were signifi cant risk factors for moderate and severe chronic GVHD (Figure 3A).

Figure 3. Risk factors for moderate and severe chronic GVHD with conventional prophylaxis (A) and posttransplantation cyclophosphamide (B)

Modeling in the PTCy group demonstrated only a weak statistical signifi cance for previous acute GVHD (HR 1.59, 95%CI 0.99-2.54), while all the other factors were non-significant (Figure 3B).
Regarding mild acute GVHD (grade I-II) which is usually favorable for prognosis in the conventional prophylaxis group, only the CD34 cell dose increased the probability of this condition (HR 1.08, 95%CI 1.01-1.150, р=0.0133). The other variables were not signifi cantly different. With PTCy prophylaxis, the unrelated donorship was associated with increased probability of grade I-II acute GVHD (HR 3.26, 95%CI 1.26-8.39, p=0.0145). Also a combination of a female donor/ male recipient had week statistical signifi cance (HR 1.87, 0.94-3.72, p=0.0761). No predictors were determined for mild chronic GVHD in conventional prophylaxis patients, whereas, with PTCy, the CMV-positive recipient serostatus was protective against this condition (HR 0.675, 0.496-0.918, p=0.0123). Mild chronic GVHD was lowest in +/+ CMV positive donor/ recipient (6%), being highest in -/+ (15%) and +/- (19%) combinations. In the both CMV-negative pairs, mild chronic GVHD rate was also substantial (14%).

Discussion

In this relatively large study, we have confi rmed that the novel prophylaxis regimens may dramatically change the landscape of risk factors which was not demonstrated before. Previous registry studies mostly documented only evolutional changes in the risk factors due to other aspects of HSCT. In the era of only BM transplantation from matched siblings with cyclosporine and methotrexate as prophylaxis, the predominant risk factors were female donor for male recipient, pregnancy history and older recipient age [13]. Th e subsequent CIBMTR study identifi ed the risk factors of PBSC use, ethnicity, TBI versus busulfan-based conditioning, and positive CMV serostatus [7]. Aft er broad introduction of unrelated transplants, it became obvious that GVHD incidence is higher than aft er sibling transplants [14]. Additional risks of GVHD are associated with partial HLA mismatches [15] and non-HLA allele mismatches [16]. Furthermore, the donor age was also identifi ed as risk factor in unrelated HSCT [17]. Nonetheless the recent mathematical analysis indicates that the predictive potential of clinical parameters is relatively low [18]. Thus, the risk factors of GVHD were slowly evolving, due to implementation of novel cell sources and donor types. We, however, confi rm that the use of PTCy completely abolished the previously signifi cant risk factors. It has been previously published that HLA matching is not a signifi cant factor with PTCy prophylaxis [19], and this was confirmed in the current study. Nonetheless, the diff erence between matched sibling and unrelated donor had a tendency to signifi cance, which was also confirmed in our group of patients. What was not established earlier is the preventive
role of CMV-positive serology in recipient, despite a weak statistical trend in the EBMT study [20]. Th e probable reason for that is diff erent prevalence of CMV seropositivity in Russia, Europe and the USA. In Russia, the CMV seroprevalence is above 85% [21, 22, 23]. Th e CMV seropositivity is unlikely to represent the reason for diff erences, but, rather, it may be a consequence of changes in immune system that, probably, led to decreased GVHD incidence. It was demonstrated that CMV causes expansion of T-regulatory cells [24] and upregulation of IL-33 pathway, which protects against lethal GVHD in animal models [25, 26]. Th e signifi cance of this factor with no such evidence for conventional prophylaxis [7] indicates the presence of different immunological mechanisms behind PTCy prophylaxis that still should be elucidated.
The risk factors identifi ed for moderate and severe chronic GVHD with conventional prophylaxis were similar to the ones previously reported [27, 28]. Th e history of severe acute GVHD was the most predominant risk factor. However, no risk factors were identifi ed for PTCy, probably due to low incidence of this complication and low incidence of preceding acute GVHD in the study cohort. Contrary to this data, the European Registry Study defi ned recipient age, use of PBSC and combination prophylaxis as the risk factors [20]. Th e diff erences might be due to diff erent PTCy schedule (day +3, +5), use of cyclosporine instead of tacrolimus, duration
of immunosuppression [29]. Th e absence of diff erences between PBSC and BM is explained by single-agent PTCy prophylaxis in the matched bone marrow group and combination with tacrolimus and MMF in the PBSC group, which alleviated the diff erences.
In conclusion, this study identified the changing pattern of GVHD risk factors with introduction of novel prophylaxis regimens in related and unrelated HSCT graft s. Further studies are required to elucidate the biological mechanisms behind these changes.

Conflicts of interest

No conflicts of interest are reported by the authors.

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В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(405) "Различия факторов риска острой и хронической реакции «трансплантат против хозяина» при классической профилактике и использовании посттрансплантационного циклофосфана при родственных и неродственных трансплантациях" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(405) "Различия факторов риска острой и хронической реакции «трансплантат против хозяина» при классической профилактике и использовании посттрансплантационного циклофосфана при родственных и неродственных трансплантациях" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(405) "Различия факторов риска острой и хронической реакции «трансплантат против хозяина» при классической профилактике и использовании посттрансплантационного циклофосфана при родственных и неродственных трансплантациях" ["SECTION_META_TITLE"]=> string(405) "Различия факторов риска острой и хронической реакции «трансплантат против хозяина» при классической профилактике и использовании посттрансплантационного циклофосфана при родственных и неродственных трансплантациях" ["SECTION_META_KEYWORDS"]=> string(405) "Различия факторов риска острой и хронической реакции «трансплантат против хозяина» при классической профилактике и использовании посттрансплантационного циклофосфана при родственных и неродственных трансплантациях" ["SECTION_META_DESCRIPTION"]=> string(405) "Различия факторов риска острой и хронической реакции «трансплантат против хозяина» при классической профилактике и использовании посттрансплантационного циклофосфана при родственных и неродственных трансплантациях" ["SECTION_PICTURE_FILE_ALT"]=> string(405) "Различия факторов риска острой и хронической реакции «трансплантат против хозяина» при классической профилактике и использовании посттрансплантационного циклофосфана при родственных и неродственных трансплантациях" ["SECTION_PICTURE_FILE_TITLE"]=> string(405) "Различия факторов риска острой и хронической реакции «трансплантат против хозяина» при классической профилактике и использовании посттрансплантационного циклофосфана при родственных и неродственных трансплантациях" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "razlichiya-faktorov-riska-ostroy-i-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-pri-klassich" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(405) "Различия факторов риска острой и хронической реакции «трансплантат против хозяина» при классической профилактике и использовании посттрансплантационного циклофосфана при родственных и неродственных трансплантациях" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(405) "Различия факторов риска острой и хронической реакции «трансплантат против хозяина» при классической профилактике и использовании посттрансплантационного циклофосфана при родственных и неродственных трансплантациях" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "razlichiya-faktorov-riska-ostroy-i-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-pri-klassich" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "razlichiya-faktorov-riska-ostroy-i-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-pri-klassich" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "razlichiya-faktorov-riska-ostroy-i-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-pri-klassich" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "115" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> 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array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20866" ["VALUE"]=> array(2) { ["TEXT"]=> string(309) "Иван С. Моисеев, Елена И. Дарская, Татьяна А. Быкова, Александр Л. Алянский, Елена В. Бабенко, Елена В. Морозова, Сергей Н. Бондаренко, Инна В. Маркова, Борис В. Афанасьев<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(303) "Иван С. Моисеев, Елена И. Дарская, Татьяна А. Быкова, Александр Л. Алянский, Елена В. Бабенко, Елена В. Морозова, Сергей Н. Бондаренко, Инна В. Маркова, Борис В. Афанасьев
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20867" ["VALUE"]=> array(2) { ["TEXT"]=> string(348) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(342) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный 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(5) "20868" ["VALUE"]=> array(2) { ["TEXT"]=> string(4047) "<p style="text-align: justify;"> Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3981) "

Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий.

Ключевые слова

Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан.

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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20872" ["VALUE"]=> array(2) { ["TEXT"]=> string(2158) "<p style="text-align: justify;"> Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2092) "

Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations.

Keywords

Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide.

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Moiseev, Elena I. Darskaya, Tatyana A. Bykova, Elena V. Morozova, Alexander L. Alyanskiy, Elena V. Babenko, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(177) "Ivan S. Moiseev, Elena I. Darskaya, Tatyana A. Bykova, Elena V. Morozova, Alexander L. Alyanskiy, Elena V. Babenko, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev
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Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations.

Keywords

Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide.

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Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations.

Keywords

Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide.

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Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий.

Ключевые слова

Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан.

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Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий.

Ключевые слова

Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан.

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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is eff ective method of treatment for malignancies, some solid tumors and hereditary diseases in children and adults [1]. Th e main success factors are dependent on the underlying disease status at the time of therapy initiation, and the level of HLA-match between recipient and donor of hematopoietic stem cells which is a key factor to increase the chance for engraft ment, and to reduce development of acute and chronic graft -versus-host disease (GvHD) [2].

Since the beginning of allo-HSCT implementation as a treatment method from the middle of the XX century, there is a great progress in accessibility and safety of this treatment approach. However, ABO- and Rhesus-incompatibility between patient and donor in allo-HSCT are shown in 30-50% of cases, thus leading to additional complications and erythrocyte recovery delay [3, 4]. The presence of ABO-incompatibility requires higher level of immunological security measures while providing replacement transfusion therapy: compliance with ABO-compatibility rules, depending on the level of posttransplant chimerism; X- or γ-irradiation of erythrocyte and platelet-containing blood products before transfusion, leukofi ltration technology [5].

There are three ABO-incompatibility types – minor (20-25% of all cases), major (20-25%) and bidirectional (5%) (Table 1) [6].

ABO-incompatibility may predispose for some severe complications, such as acute and delayed hemolysis, pure red cell aplasia (PRCA) [7], GvHD [8], graft failure [9], autoimmune hemolytic anemia [10], which negatively aff ect the eff ectiveness of HSCT by increasing mortality [11]. At the same time, there are studies which yield confl icting results and do not reveal distinct impact of ABO mismatch upon the treatment outcomes [8, 12, 13]. Data ambivalence of ABO- and Rhesus-incompatibility impact in allo-HSCT, determined a rationale of a large cohort study, which would allow of creating more homogeneous comparison groups by the main parameters, and, therefore, increase the signifi cance of results. The aim of our study was to specify the role of ABO-incompatibility in allo-HSCT for a well-characterized cohort of patients.

Patients and methods

From 1999 to 2015, 1132 patients with malignancies and hereditary diseases undergone 1482 allo-HSCT at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation (Tab. 2). 149 patients have received second graft , 13 of them – triple (in most cases, from the same donor).

Patients with acute myeloid leukemia (n=568), acute lymphoblastic leukemia (n=475), chronic myeloid leukemia (n=94), myelodysplastic syndrome (n=76), severe aplastic anemia (n=57) represented the dominant clinical group. Over recent years, an increased allo-HSCT activity has been registered for orphan diseases (n=49) and solid tumors in children (n=9).

The choice of conditioning regimen was determined by diagnosis, disease status and patient somatic state. Myeloablative conditioning regimen (MAC) was used in 431 patients (29.5%), non-myeloablative regimens (RIC), were applied in 1030 cases (70.5%). Busulfan + cyclophosphamide drug combination (n=301) was the most frequently used protocol (69.8% of total MAC-treated group). RIC regimens, i.e., busulfan+ fl udarabine, or melphalan+ fludarabine were used, respectively, in 515 (50%) and 21% (n=217).

GvHD prophylaxis was carried out in accordance with European Group for Bone Marrow Transplantation (EBMT) Recommendations, R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation policies, and include cyclophosphamide alone or combinations of immunosuppressive drugs: cyclosporine A, tacrolimus, sirolimus, with their pharmacokinetic control in serum; also combined with methotrexate, mycophenolate mofetil, antithymocyte globulin (ATG).

Evaluation engraft ment and staging of posttransplant complications were made according to standard defi nitions and classifi cations [14-17], and EBMT 2012 Recommendations. Th e fi rst detection of donor RBC in two or more consecutive peripheral blood tests by serological methods was considered to be the beginning of donor chimerism [18].

Standard laboratory techniques for ABO, Rh (D, C, c, E, e, K, Cw) and Cellano (Kell) evaluation were used: cross-method with monoclonal antibodies and micro-typing system (IDcard, Bio Rad). Direct antiglobulin test was made by standard gel method (ID Liss Coombs, DC-Screening I, Bio Rad Laboratories).

In order to reduce the risk of immune transfusion reactions in case of ABO-incompatibility, graft manipulation technologies were used: in case of major ABO-incompatibility, removal of incompatible donor erythrocytes (sedimentation with 6% hydroxyethyl starch); in case of minor incompatibility, donor plasma was removed by centrifugation procedure; in case of bidirectional mismatch, a combination of the methods was used.

Table 1. Different types of donor/recipient ABO incompatibility in allogeneic HSCT [6]

Table 2. Allo-HSCT recipient’s characteristics

If necessary, blood transfusion therapy was carried out according to ABO-status and general recommendations [6]. Statistical analysis was performed using IBM SPSS Statistics version 13.0 by the rules and international recommendations for processing and providing the results of HSCT [19] and include following statistical methods: descriptive statistics for quantitative variables, parametric statistics, description of nominal variables (ABO-incompatibility impact assessment on the development of GvHD); overall survival (OS) analysis was performed by Kaplan-Mayer method using logrank test. To reveal the factors associated with engraft ment terms, a logarithmic utility function (logworth) was used. Th e role of various factors infl uencing posttransplant period and chimerism development was assessed by multivariate analysis (Cox regression). The difference between individual indicators was considered statistically signifi cant at p<0.05.

Results

Impact of ABO blood groups and Rhesus factor on the allo-HSCT effectiveness

In the present study, comprehensive analysis on the impact of ABO- and Rhesus-incompatibility on allo-HSCT effi ciency and risk of complications was performed. Patient's ABO blood group, as an independent parameter, did not aff ect 1-year OS in patients with malignant diseases in allo-HSCT (n=1366), p=0.48. At the same time, negative (n=186) or positive (n=1180) Rhesus factor in the patients proved to be a valuable predictive marker, since its negative status aff ected 1-year OS in allo-HSCT – 48%, with respective average value of 8.1 months, (HR 0.324; 95% CI 7.553 – 8.822), and 59% (average – 8.8 months, HR 0.126; 95% CI 8.605 – 9.101), being signifi cantly diff erent at p=0.01 (Fig. 1).
Rhesus system antigens have a much lower degree of immunogenicity compared to potential eff ects of ABO system, but it can contribute to allo-sensibilisation and promotion of hemolytic complications, thereby reducing the effi ciency of allo-HSCT, which was confi rmed in this study. When comparing pre-transplant RBC phenotypes in the patients with malignancies (n=1175), the following combinations have been found to aff ect the one-year OS (Fig. 2):
- DCCee (n=197) vs ddccee (n=157), 65% (mean, 9.5 months; HR 0.283; 95% CI 8.945-10.056) and 50% (median, 11.4 months; HR 0.348; 95% CI 7.706-9.069), respectively, p=0.006;
- Dccee (n=450) vs ddccee (n=157), 63% (mean – 9 months, HR 0.198; 95% CI 8.672-9.45) and 50%, respectively, p=0.025.
Studying clinical eff ects and outcomes depending on the Rh antigen status of the donor (n=998) confi rm the assumption of a more pronounced negative eff ects of homozygous and D-negative Rh phenotypes upon overall patient survival (Fig. 3):
- DCcEe (n=124) vs DCcee (n=389), 67% and 58%, respectively, (χ2 – 5.454) p=0.019;
- DCcEe (n=124) vs ddccee (n=158), 67% and 53%, respectively, (χ2 – 5.985) p=0.014.
Thus, presence of negative Rhesus factor in the patients (p=0.01) corresponding to the ddccee phenotype (p=0.006), and negative Rhesus factor in graft donor (ddccee phenotype, p=0.014), is associated with a decrease in 1-year OS in patients with malignant diseases, compared with patient’s positive Rhesus and phenotypes DCCee, Dccee and graft donor’s phenotype DCcEe, respectively.

Figure 1. One-year OS in patients with malignant diseases after allo-HSCT depending on the patient’s Rh status

Figure 2. One-year OS in patients with malignant diseases after allo-HSCT, depending on the patient’s erythrocytes Rh phenotype

Figure 3. One-year OS in patients after allo-HSCT, depending on graft donor’s erythrocyte phenotype

The impact of ABO-mismatches on OS and the risk of GvHD development in allo-HSCT

In our study, ABO-incompatibility (n=1428) was documented in 54.6% of allo-HSCT cases (n=780), with major or minor mismatch shown, respectively in 37.8% (n=295), and 45.4% of the cases (n=354); and bidirectional incompatibility having been registered in 16.8% of the cohort (n=131), which is slightly more frequent compared to the worldwide data [4], due to specifi c variability of the gene polymorphisms in the multinational population of Russian Federation, and a significant number of graft s from the foreign unrelated donors used at our HSCT Center.
Th e authors opinion and literature data on the impact of ABO-incompatibility on OS are contradictory since most of them did not prove a negative infl uence upon HSCT outcome. However, the 10-year experience of French BMT group (n=1108) indicate to a negative impact of minor ABO-incompatibility in allo-HSCT patients treated with RIC combination with fl udarabine and low-dose total body irradiation or fl udarabine and busulfan with rabbit ATG, along with absence of remission, and inclusion of ATG>10mg/kg into the GvHD prophylaxys schemes [20].
According to our data, minor ABO-incompatibility in patients with leukemia in remission (n=600) was associated with reduced D+100 OS rates when compared with ABO-compatible allo-HSCT, p=0.05 (Fig. 4): in ABO-compatible patient/donor HSCT, 91% (n=262, a mean of 95 days, HR 0.998; 95% CI 93.32-97.23); for major ABO-incompatibility, 85% (n=117, a mean of 92 days, HR 1.809; 95% CI 89.088-96.179); for minor ABO mismatches, 85% (n=163, an average value of 92 days, HR 1.527; 95% CI 89.324-95.309), and for bidirectional incoompatibility, 93% (n=58, average level of 95 days, HR 1.703; 95% CI 93.207-99.883), respectively. Further analysis was performed according to the type of ABO-incompatibility in combination with conditioning regimens, GvHD prophylaxis, taking into account diff erent degree of myeloablation, mechanisms of immunosuppression and possible risk potentiation for immune complications. A combination of MAC and major ABO-incompatibility in patients with leukemia in remission (n=215) was found to be associated with a decreased OS at 100-days aft er allo- HSCT, if compared with ABO-compatible allo-HSCT, p=0.025 (Fig. 5) which should be taken into account when choosing the conditioning treatment mode. I.e., the OS value for ABO-compatible patients (n=103) was 91% (average of 95 days, HR 1.598; 95% CI 91.885-98.148), in the pairs with major ABO-incompatibility (n=37), the OS value was 76% (average, 88 days, HR 3.765; 95% CI 80.95-95.709). The 100-d OS in cases of minor ABO mismatch (n=56) was 82% (average, 91 days, HR 2.762; 95% CI 86.039-96.868); for bidirectional incompatibility, (n=19), the OS was 89% (average, 93 days, HR 4.364; 95% CI 84.831-101.937).

Figure 4. OS rates for the D+100, depending on the type of ABO-incompatibility in patients with leukemia in remission with allo-HSCT

Figure 5. OS rates on D+100 depending on the type of ABO-incompatibility and MAC in patients with leukemia in remission

Discussion

A high risk for ABO-incompatibility is an additional factor potentiating immunological reactivity, thus increasing risk  of GvHD and possible hemolytic complications remains controversial.  A number of publications noted higher frequency  of acute GvHD grade III-IV in the case of major and minor  ABO-incompatibility [21]. On the other hand, a group of  scientists from Seattle presented data from the large US National  Bone Marrow Donor Program showing no signifi cant  diff erence in the development of acute GvHD depending on  the ABO-incompatibility type [22].

Results of our study indicate that the type of ABO-incompatibility: major (n=123), minor (n=167) or bidirectional  (n=61) did not increase either severity, or incidence of acute  GvHD (grade I-IV) in patients with leukemia transplanted  in remission (n=626), compared to ABO-compatible HSCT  (n=275), p=0.85. Acute GvHD developed in ABO-compatible  HSCT in 52% of cases (n=143), in major ABO-incompatibility,  48.8% (n=60), in minor ABO-mismatch, 50.9%  (n=85), in bidirectional mismatch, 55.7% (n=34), respectively.

Likewise, the type of ABO-incompatibility: major (n=123),  minor (n=167), bidirectional (n=61); did not increase the  risk of chronic GvHD in patients with leukemia treated in  remission (n=626) compared to ABO-compatible HSCT  (n=275), p=0.21. Chronic GvHD developed in ABO-compatible  HSCT in 26.5% of cases (n=73); in major ABO-incompatibility,  24.4% of cases (n=30); in minor, 24% of cases  (n=40); in bidirectional, 37.7% (n=23), respectively.

The impact of ABO-incompatibility on engraftment

According to the results of our study, in general cohort of patients with allo-HSCT, the leukocyte recovery >1.0x109/l was  observed on day 18 (mean ± standard deviation – 20±10.4);  neutrophil recovery >0.5x109/l – on day 17 (20.5±13.6);  platelet recovery >20x109/l – on day 14 (21±17.8); platelet  recovery >50x109/l – on day 16 (23.2±15). Th e most significant  factors which determined time of engraft ment were  as follows: HLA–match (logworth, 15.1), graft source (logworth,  7.05), type of allo-HSCT (logworth 6.4), conditioning  regimen (logworth, 4.05). Th e factors which increased  the engraft ment time were as follows: 9/10 HLA-match,  MAC regimen, bone marrow as a source of transplant. In  turn, ABO- and Rhesus-incompatibility had a much smaller  impact on neutrophils and platelets engraft ment timeline:  ABO-incompatibility (logworth of 0.87), blood group of  the donor (logworth, 0.34), patient’s erythrocyte phenotype  (logworth, 0.33), donor’s Rhesus factor (logworth, 0.27), donor’s  erythrocyte phenotype (logworth, 0.001).
However, as exemplifi ed by 240 recipients of allo-HSCT, the  diff erences in recovery time of erythrocyte counts on D+50  proved to be dependent on ABO-incompatibility, i.e., the patients  from ABO-compatible donor/patient pairs achieved  RBC recovery in 23.8% of cases, and those with ABO-incompatibility,  in 10% (p=0.01).
Th e results of this study suggest that the 100% donor chimerism  for ABO blood groups was reached in 159 of 240  patients (17 to 229 days, a median of 84 days). In 81 patients,  the results could not be assessed due to their death in early  posttransplant period (n=50); inability to identify diff erences,  due to identity for ABO-, Rhesus-system (D, C, c, E, e) and Kell markers (n=7); lack of laboratory data due to incomplete patient's data obtained posttransplant (n=24).  Primary diagnosis (p=0.87), disease status (p=0.69), allo- HSCT type (p=0.26), graft source (p=0.28), degree of  HLA match (p=0.62) and conditioning regimens (p=0.39) did not have a negative impact on blood group conversion  terms. ABO-incompatibility was the only identifi ed factor  increasing chimerism time development (p=0.0001).
For ABO-compatible allo-HSCT with Rh incompatibility (n=52), the time to achieve 100% chimerism was 95±44 days (31-226 days, HR 6,106; 95% CI 82.9-107.4), with major ABO-incompatibility (n=29) – 109±51 days (27-229 days, HR 9.642; 95% CI 89.9-129.4), with minor (n=57) – 67±22 days (17-109 days, HR 3,032; 95% CI 61-73,1), with bidirectional mismatches (n=21) – 72±16 days (48-117 days, HR
3,515; 95% CI 65,3-80). 

Negative effect of ABO-incompatibility type on erythroid time recovery, is refl ected in posttransplant transfusion therapy intensiveness (p=0,003). Th e average number of transfusions of blood components was 25 units in major ABO-incompatibility (p=0.001); 16.5, in minor mismatch (p=0.006); 13.6, in bidirectional (p=0.005); 15.1, in ABO-compatible  allo-HSCT (p=0.001), respectively.

HSCT complications associated with ABO-incompatibility

Additional attention is paid to the development of specifi c complications associated with ABO-incompatibility. Clinical manifestations in this case may be due to localization of ABO system antigens, which are represented not only on erythrocytes, but also on other cells and tissues: platelets, lymphocytes, endothelium of blood vessels and organs (kidneys, liver, heart) circulating in plasma [23].

According to our data, the risk of immune complications in allo-HCT (n=1158) is 2.8% (n=33) versus 4.1% in the presence of ABO-incompatibility (n=638, p=0.02), as seen from Table 3. A low number of cases and mortality (n=3) may indicate adequate prevention, timely and eff ective treatment.

Design of OS predictive models in allo-HSCT

One of the main objectives in multivariate analysis was to identify factors and their combinations that aff ect OS in allo-HSCT, and to create a mathematical model for predicting the probability of potential complications, which will allow for timely prophylaxis and treatment. The study was based on Cox regression with preliminary exploratory analysis for patients with malignant diseases, which was performed  as a Kaplan-Meier test for nominal variables-factors aff ecting the outcome of treatment [24]. As a result of the analysis, the following predictors aff ecting OS were identified: degree of HLA-match, presence of acute GvHD, major ABO-incompatibility, allo-HSCT type, status of the underlying disease, and use of ATG for GvHD prophylaxis (Fig. 6).

Our valid predictive model of 100-day OS may serve such an example, which included patients with leukaemia (n=140) from 9/10 HLA-matched related and unrelated donor, in case of engraft ment up to D+31 (Fig. 7).

Figure 6. OS predictors in allo-HSCT patients with malignant diseases

Figure 7. 100-day OS predictive model in patients with allo-HSCT with 9/10 HLA-match with engraftment up to D+31

Note: Profile 1: MAC, major ABO-incompatibility, GvHD prophylaxis – cyclophosphamide containing schemes; Profi le 2: MAC, major ABO-incompatibility, GvHD prophylaxis «cyclosporine A + methotrexate» or « tacrolimus + methotrexate». Table 3. Development of immune complications in allo-HSCT depending on the ABO-incompatibility type

Table 3. Development of immune complications in allo-HSCT depending on the ABO-incompatibility type

Conclusion

The data presented in this study suggest that ABO-incompatibility may be a negative factor reducing eff ectiveness of treatment in allo-HSCT, especially in the early posttransplantation period and during the fi rst year posttransplant. Adverse eff ects of ABO-incompatibility are realized through allosensitization, increasing the frequency of hemolytic complications and delaying erythroid recovery.
It seems that the main tool for minimizing the ABO-incompatibility consequences is the donor graft preparation based on ABO-incompatibility type, which allows achieving low frequency and severity of possible hemolytic complications.
The next factor of important value is the replacement transfusion therapy, which should be based on red blood cells chimerism level and comply with the principles to use the most leukocyte depleted blood components, which can improve the efficiency of blood transfusions and reduce the risk of posttransfusion reactions and complications.
Thus, when choosing an allogeneic bone marrow donor, giving priority to a higher degree of HLA-match and CMV-status in "recipient-donor" pair, it is also optimal to choose, if possible, an ABO- and Rhesus compatible donor.

Conflict of interests

The authors have noconflict of interest to declare.

References

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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is eff ective method of treatment for malignancies, some solid tumors and hereditary diseases in children and adults [1]. Th e main success factors are dependent on the underlying disease status at the time of therapy initiation, and the level of HLA-match between recipient and donor of hematopoietic stem cells which is a key factor to increase the chance for engraft ment, and to reduce development of acute and chronic graft -versus-host disease (GvHD) [2].

Since the beginning of allo-HSCT implementation as a treatment method from the middle of the XX century, there is a great progress in accessibility and safety of this treatment approach. However, ABO- and Rhesus-incompatibility between patient and donor in allo-HSCT are shown in 30-50% of cases, thus leading to additional complications and erythrocyte recovery delay [3, 4]. The presence of ABO-incompatibility requires higher level of immunological security measures while providing replacement transfusion therapy: compliance with ABO-compatibility rules, depending on the level of posttransplant chimerism; X- or γ-irradiation of erythrocyte and platelet-containing blood products before transfusion, leukofi ltration technology [5].

There are three ABO-incompatibility types – minor (20-25% of all cases), major (20-25%) and bidirectional (5%) (Table 1) [6].

ABO-incompatibility may predispose for some severe complications, such as acute and delayed hemolysis, pure red cell aplasia (PRCA) [7], GvHD [8], graft failure [9], autoimmune hemolytic anemia [10], which negatively aff ect the eff ectiveness of HSCT by increasing mortality [11]. At the same time, there are studies which yield confl icting results and do not reveal distinct impact of ABO mismatch upon the treatment outcomes [8, 12, 13]. Data ambivalence of ABO- and Rhesus-incompatibility impact in allo-HSCT, determined a rationale of a large cohort study, which would allow of creating more homogeneous comparison groups by the main parameters, and, therefore, increase the signifi cance of results. The aim of our study was to specify the role of ABO-incompatibility in allo-HSCT for a well-characterized cohort of patients.

Patients and methods

From 1999 to 2015, 1132 patients with malignancies and hereditary diseases undergone 1482 allo-HSCT at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation (Tab. 2). 149 patients have received second graft , 13 of them – triple (in most cases, from the same donor).

Patients with acute myeloid leukemia (n=568), acute lymphoblastic leukemia (n=475), chronic myeloid leukemia (n=94), myelodysplastic syndrome (n=76), severe aplastic anemia (n=57) represented the dominant clinical group. Over recent years, an increased allo-HSCT activity has been registered for orphan diseases (n=49) and solid tumors in children (n=9).

The choice of conditioning regimen was determined by diagnosis, disease status and patient somatic state. Myeloablative conditioning regimen (MAC) was used in 431 patients (29.5%), non-myeloablative regimens (RIC), were applied in 1030 cases (70.5%). Busulfan + cyclophosphamide drug combination (n=301) was the most frequently used protocol (69.8% of total MAC-treated group). RIC regimens, i.e., busulfan+ fl udarabine, or melphalan+ fludarabine were used, respectively, in 515 (50%) and 21% (n=217).

GvHD prophylaxis was carried out in accordance with European Group for Bone Marrow Transplantation (EBMT) Recommendations, R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation policies, and include cyclophosphamide alone or combinations of immunosuppressive drugs: cyclosporine A, tacrolimus, sirolimus, with their pharmacokinetic control in serum; also combined with methotrexate, mycophenolate mofetil, antithymocyte globulin (ATG).

Evaluation engraft ment and staging of posttransplant complications were made according to standard defi nitions and classifi cations [14-17], and EBMT 2012 Recommendations. Th e fi rst detection of donor RBC in two or more consecutive peripheral blood tests by serological methods was considered to be the beginning of donor chimerism [18].

Standard laboratory techniques for ABO, Rh (D, C, c, E, e, K, Cw) and Cellano (Kell) evaluation were used: cross-method with monoclonal antibodies and micro-typing system (IDcard, Bio Rad). Direct antiglobulin test was made by standard gel method (ID Liss Coombs, DC-Screening I, Bio Rad Laboratories).

In order to reduce the risk of immune transfusion reactions in case of ABO-incompatibility, graft manipulation technologies were used: in case of major ABO-incompatibility, removal of incompatible donor erythrocytes (sedimentation with 6% hydroxyethyl starch); in case of minor incompatibility, donor plasma was removed by centrifugation procedure; in case of bidirectional mismatch, a combination of the methods was used.

Table 1. Different types of donor/recipient ABO incompatibility in allogeneic HSCT [6]

Table 2. Allo-HSCT recipient’s characteristics

If necessary, blood transfusion therapy was carried out according to ABO-status and general recommendations [6]. Statistical analysis was performed using IBM SPSS Statistics version 13.0 by the rules and international recommendations for processing and providing the results of HSCT [19] and include following statistical methods: descriptive statistics for quantitative variables, parametric statistics, description of nominal variables (ABO-incompatibility impact assessment on the development of GvHD); overall survival (OS) analysis was performed by Kaplan-Mayer method using logrank test. To reveal the factors associated with engraft ment terms, a logarithmic utility function (logworth) was used. Th e role of various factors infl uencing posttransplant period and chimerism development was assessed by multivariate analysis (Cox regression). The difference between individual indicators was considered statistically signifi cant at p<0.05.

Results

Impact of ABO blood groups and Rhesus factor on the allo-HSCT effectiveness

In the present study, comprehensive analysis on the impact of ABO- and Rhesus-incompatibility on allo-HSCT effi ciency and risk of complications was performed. Patient's ABO blood group, as an independent parameter, did not aff ect 1-year OS in patients with malignant diseases in allo-HSCT (n=1366), p=0.48. At the same time, negative (n=186) or positive (n=1180) Rhesus factor in the patients proved to be a valuable predictive marker, since its negative status aff ected 1-year OS in allo-HSCT – 48%, with respective average value of 8.1 months, (HR 0.324; 95% CI 7.553 – 8.822), and 59% (average – 8.8 months, HR 0.126; 95% CI 8.605 – 9.101), being signifi cantly diff erent at p=0.01 (Fig. 1).
Rhesus system antigens have a much lower degree of immunogenicity compared to potential eff ects of ABO system, but it can contribute to allo-sensibilisation and promotion of hemolytic complications, thereby reducing the effi ciency of allo-HSCT, which was confi rmed in this study. When comparing pre-transplant RBC phenotypes in the patients with malignancies (n=1175), the following combinations have been found to aff ect the one-year OS (Fig. 2):
- DCCee (n=197) vs ddccee (n=157), 65% (mean, 9.5 months; HR 0.283; 95% CI 8.945-10.056) and 50% (median, 11.4 months; HR 0.348; 95% CI 7.706-9.069), respectively, p=0.006;
- Dccee (n=450) vs ddccee (n=157), 63% (mean – 9 months, HR 0.198; 95% CI 8.672-9.45) and 50%, respectively, p=0.025.
Studying clinical eff ects and outcomes depending on the Rh antigen status of the donor (n=998) confi rm the assumption of a more pronounced negative eff ects of homozygous and D-negative Rh phenotypes upon overall patient survival (Fig. 3):
- DCcEe (n=124) vs DCcee (n=389), 67% and 58%, respectively, (χ2 – 5.454) p=0.019;
- DCcEe (n=124) vs ddccee (n=158), 67% and 53%, respectively, (χ2 – 5.985) p=0.014.
Thus, presence of negative Rhesus factor in the patients (p=0.01) corresponding to the ddccee phenotype (p=0.006), and negative Rhesus factor in graft donor (ddccee phenotype, p=0.014), is associated with a decrease in 1-year OS in patients with malignant diseases, compared with patient’s positive Rhesus and phenotypes DCCee, Dccee and graft donor’s phenotype DCcEe, respectively.

Figure 1. One-year OS in patients with malignant diseases after allo-HSCT depending on the patient’s Rh status

Figure 2. One-year OS in patients with malignant diseases after allo-HSCT, depending on the patient’s erythrocytes Rh phenotype

Figure 3. One-year OS in patients after allo-HSCT, depending on graft donor’s erythrocyte phenotype

The impact of ABO-mismatches on OS and the risk of GvHD development in allo-HSCT

In our study, ABO-incompatibility (n=1428) was documented in 54.6% of allo-HSCT cases (n=780), with major or minor mismatch shown, respectively in 37.8% (n=295), and 45.4% of the cases (n=354); and bidirectional incompatibility having been registered in 16.8% of the cohort (n=131), which is slightly more frequent compared to the worldwide data [4], due to specifi c variability of the gene polymorphisms in the multinational population of Russian Federation, and a significant number of graft s from the foreign unrelated donors used at our HSCT Center.
Th e authors opinion and literature data on the impact of ABO-incompatibility on OS are contradictory since most of them did not prove a negative infl uence upon HSCT outcome. However, the 10-year experience of French BMT group (n=1108) indicate to a negative impact of minor ABO-incompatibility in allo-HSCT patients treated with RIC combination with fl udarabine and low-dose total body irradiation or fl udarabine and busulfan with rabbit ATG, along with absence of remission, and inclusion of ATG>10mg/kg into the GvHD prophylaxys schemes [20].
According to our data, minor ABO-incompatibility in patients with leukemia in remission (n=600) was associated with reduced D+100 OS rates when compared with ABO-compatible allo-HSCT, p=0.05 (Fig. 4): in ABO-compatible patient/donor HSCT, 91% (n=262, a mean of 95 days, HR 0.998; 95% CI 93.32-97.23); for major ABO-incompatibility, 85% (n=117, a mean of 92 days, HR 1.809; 95% CI 89.088-96.179); for minor ABO mismatches, 85% (n=163, an average value of 92 days, HR 1.527; 95% CI 89.324-95.309), and for bidirectional incoompatibility, 93% (n=58, average level of 95 days, HR 1.703; 95% CI 93.207-99.883), respectively. Further analysis was performed according to the type of ABO-incompatibility in combination with conditioning regimens, GvHD prophylaxis, taking into account diff erent degree of myeloablation, mechanisms of immunosuppression and possible risk potentiation for immune complications. A combination of MAC and major ABO-incompatibility in patients with leukemia in remission (n=215) was found to be associated with a decreased OS at 100-days aft er allo- HSCT, if compared with ABO-compatible allo-HSCT, p=0.025 (Fig. 5) which should be taken into account when choosing the conditioning treatment mode. I.e., the OS value for ABO-compatible patients (n=103) was 91% (average of 95 days, HR 1.598; 95% CI 91.885-98.148), in the pairs with major ABO-incompatibility (n=37), the OS value was 76% (average, 88 days, HR 3.765; 95% CI 80.95-95.709). The 100-d OS in cases of minor ABO mismatch (n=56) was 82% (average, 91 days, HR 2.762; 95% CI 86.039-96.868); for bidirectional incompatibility, (n=19), the OS was 89% (average, 93 days, HR 4.364; 95% CI 84.831-101.937).

Figure 4. OS rates for the D+100, depending on the type of ABO-incompatibility in patients with leukemia in remission with allo-HSCT

Figure 5. OS rates on D+100 depending on the type of ABO-incompatibility and MAC in patients with leukemia in remission

Discussion

A high risk for ABO-incompatibility is an additional factor potentiating immunological reactivity, thus increasing risk  of GvHD and possible hemolytic complications remains controversial.  A number of publications noted higher frequency  of acute GvHD grade III-IV in the case of major and minor  ABO-incompatibility [21]. On the other hand, a group of  scientists from Seattle presented data from the large US National  Bone Marrow Donor Program showing no signifi cant  diff erence in the development of acute GvHD depending on  the ABO-incompatibility type [22].

Results of our study indicate that the type of ABO-incompatibility: major (n=123), minor (n=167) or bidirectional  (n=61) did not increase either severity, or incidence of acute  GvHD (grade I-IV) in patients with leukemia transplanted  in remission (n=626), compared to ABO-compatible HSCT  (n=275), p=0.85. Acute GvHD developed in ABO-compatible  HSCT in 52% of cases (n=143), in major ABO-incompatibility,  48.8% (n=60), in minor ABO-mismatch, 50.9%  (n=85), in bidirectional mismatch, 55.7% (n=34), respectively.

Likewise, the type of ABO-incompatibility: major (n=123),  minor (n=167), bidirectional (n=61); did not increase the  risk of chronic GvHD in patients with leukemia treated in  remission (n=626) compared to ABO-compatible HSCT  (n=275), p=0.21. Chronic GvHD developed in ABO-compatible  HSCT in 26.5% of cases (n=73); in major ABO-incompatibility,  24.4% of cases (n=30); in minor, 24% of cases  (n=40); in bidirectional, 37.7% (n=23), respectively.

The impact of ABO-incompatibility on engraftment

According to the results of our study, in general cohort of patients with allo-HSCT, the leukocyte recovery >1.0x109/l was  observed on day 18 (mean ± standard deviation – 20±10.4);  neutrophil recovery >0.5x109/l – on day 17 (20.5±13.6);  platelet recovery >20x109/l – on day 14 (21±17.8); platelet  recovery >50x109/l – on day 16 (23.2±15). Th e most significant  factors which determined time of engraft ment were  as follows: HLA–match (logworth, 15.1), graft source (logworth,  7.05), type of allo-HSCT (logworth 6.4), conditioning  regimen (logworth, 4.05). Th e factors which increased  the engraft ment time were as follows: 9/10 HLA-match,  MAC regimen, bone marrow as a source of transplant. In  turn, ABO- and Rhesus-incompatibility had a much smaller  impact on neutrophils and platelets engraft ment timeline:  ABO-incompatibility (logworth of 0.87), blood group of  the donor (logworth, 0.34), patient’s erythrocyte phenotype  (logworth, 0.33), donor’s Rhesus factor (logworth, 0.27), donor’s  erythrocyte phenotype (logworth, 0.001).
However, as exemplifi ed by 240 recipients of allo-HSCT, the  diff erences in recovery time of erythrocyte counts on D+50  proved to be dependent on ABO-incompatibility, i.e., the patients  from ABO-compatible donor/patient pairs achieved  RBC recovery in 23.8% of cases, and those with ABO-incompatibility,  in 10% (p=0.01).
Th e results of this study suggest that the 100% donor chimerism  for ABO blood groups was reached in 159 of 240  patients (17 to 229 days, a median of 84 days). In 81 patients,  the results could not be assessed due to their death in early  posttransplant period (n=50); inability to identify diff erences,  due to identity for ABO-, Rhesus-system (D, C, c, E, e) and Kell markers (n=7); lack of laboratory data due to incomplete patient's data obtained posttransplant (n=24).  Primary diagnosis (p=0.87), disease status (p=0.69), allo- HSCT type (p=0.26), graft source (p=0.28), degree of  HLA match (p=0.62) and conditioning regimens (p=0.39) did not have a negative impact on blood group conversion  terms. ABO-incompatibility was the only identifi ed factor  increasing chimerism time development (p=0.0001).
For ABO-compatible allo-HSCT with Rh incompatibility (n=52), the time to achieve 100% chimerism was 95±44 days (31-226 days, HR 6,106; 95% CI 82.9-107.4), with major ABO-incompatibility (n=29) – 109±51 days (27-229 days, HR 9.642; 95% CI 89.9-129.4), with minor (n=57) – 67±22 days (17-109 days, HR 3,032; 95% CI 61-73,1), with bidirectional mismatches (n=21) – 72±16 days (48-117 days, HR
3,515; 95% CI 65,3-80). 

Negative effect of ABO-incompatibility type on erythroid time recovery, is refl ected in posttransplant transfusion therapy intensiveness (p=0,003). Th e average number of transfusions of blood components was 25 units in major ABO-incompatibility (p=0.001); 16.5, in minor mismatch (p=0.006); 13.6, in bidirectional (p=0.005); 15.1, in ABO-compatible  allo-HSCT (p=0.001), respectively.

HSCT complications associated with ABO-incompatibility

Additional attention is paid to the development of specifi c complications associated with ABO-incompatibility. Clinical manifestations in this case may be due to localization of ABO system antigens, which are represented not only on erythrocytes, but also on other cells and tissues: platelets, lymphocytes, endothelium of blood vessels and organs (kidneys, liver, heart) circulating in plasma [23].

According to our data, the risk of immune complications in allo-HCT (n=1158) is 2.8% (n=33) versus 4.1% in the presence of ABO-incompatibility (n=638, p=0.02), as seen from Table 3. A low number of cases and mortality (n=3) may indicate adequate prevention, timely and eff ective treatment.

Design of OS predictive models in allo-HSCT

One of the main objectives in multivariate analysis was to identify factors and their combinations that aff ect OS in allo-HSCT, and to create a mathematical model for predicting the probability of potential complications, which will allow for timely prophylaxis and treatment. The study was based on Cox regression with preliminary exploratory analysis for patients with malignant diseases, which was performed  as a Kaplan-Meier test for nominal variables-factors aff ecting the outcome of treatment [24]. As a result of the analysis, the following predictors aff ecting OS were identified: degree of HLA-match, presence of acute GvHD, major ABO-incompatibility, allo-HSCT type, status of the underlying disease, and use of ATG for GvHD prophylaxis (Fig. 6).

Our valid predictive model of 100-day OS may serve such an example, which included patients with leukaemia (n=140) from 9/10 HLA-matched related and unrelated donor, in case of engraft ment up to D+31 (Fig. 7).

Figure 6. OS predictors in allo-HSCT patients with malignant diseases

Figure 7. 100-day OS predictive model in patients with allo-HSCT with 9/10 HLA-match with engraftment up to D+31

Note: Profile 1: MAC, major ABO-incompatibility, GvHD prophylaxis – cyclophosphamide containing schemes; Profi le 2: MAC, major ABO-incompatibility, GvHD prophylaxis «cyclosporine A + methotrexate» or « tacrolimus + methotrexate». Table 3. Development of immune complications in allo-HSCT depending on the ABO-incompatibility type

Table 3. Development of immune complications in allo-HSCT depending on the ABO-incompatibility type

Conclusion

The data presented in this study suggest that ABO-incompatibility may be a negative factor reducing eff ectiveness of treatment in allo-HSCT, especially in the early posttransplantation period and during the fi rst year posttransplant. Adverse eff ects of ABO-incompatibility are realized through allosensitization, increasing the frequency of hemolytic complications and delaying erythroid recovery.
It seems that the main tool for minimizing the ABO-incompatibility consequences is the donor graft preparation based on ABO-incompatibility type, which allows achieving low frequency and severity of possible hemolytic complications.
The next factor of important value is the replacement transfusion therapy, which should be based on red blood cells chimerism level and comply with the principles to use the most leukocyte depleted blood components, which can improve the efficiency of blood transfusions and reduce the risk of posttransfusion reactions and complications.
Thus, when choosing an allogeneic bone marrow donor, giving priority to a higher degree of HLA-match and CMV-status in "recipient-donor" pair, it is also optimal to choose, if possible, an ABO- and Rhesus compatible donor.

Conflict of interests

The authors have noconflict of interest to declare.

References

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Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК. </p> <h2 style="text-align: justify;">Пациенты и методы</h2> <p style="text-align: justify;"> В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ). </p> <h2 style="text-align: justify;">Результаты</h2> <p style="text-align: justify;"> АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. 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["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> 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["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(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) 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["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20876" ["VALUE"]=> array(2) { ["TEXT"]=> string(682) "Mаксим A. Кучер ¹, Дмитрий Э. Певцов ¹, Полина С. Куга ¹, Борис И. Смирнов ¹, ², Александр Л. Алянский ¹, Наталья Е. Иванова ¹, Мария А. Эстрина ¹, Елена В. Бабенко ¹, Бурхонидин Б. Баховадинов ¹, Людмила С. Зубаровская ¹, Борис В. Афанасьев ¹" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(538) "Mаксим A. Кучер ¹, Дмитрий Э. Певцов ¹, Полина С. Куга ¹, Борис И. Смирнов ¹, ², Александр Л. Алянский ¹, Наталья Е. Иванова ¹, Мария А. Эстрина ¹, Елена В. Бабенко ¹, Бурхонидин Б. Баховадинов ¹, Людмила С. Зубаровская ¹, Борис В. Афанасьев ¹" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20877" ["VALUE"]=> array(2) { ["TEXT"]=> string(651) "¹ НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова» Министерства здравоохранения России<br> ² Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(615) "¹ НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова» Министерства здравоохранения России
² Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20878" ["VALUE"]=> array(2) { ["TEXT"]=> string(4105) "<p style="text-align: justify;"> В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК. </p> <h2 style="text-align: justify;">Пациенты и методы</h2> <p style="text-align: justify;"> В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ). </p> <h2 style="text-align: justify;">Результаты</h2> <p style="text-align: justify;"> АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85. </p> <h2 style="text-align: justify;">Заключение</h2> <p style="text-align: justify;"> АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что<br> требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3901) "

В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК.

Пациенты и методы

В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ).

Результаты

АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85.

Заключение

АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что
требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения.

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² St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia
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Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients.

Patients and methods

From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created.

Results

ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85.

Conclusion

ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of
ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications.

Keywords

Hematopoietic stem cell transplantation, ABО-incompatibility, complications.

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Kucher ¹, Dmitrii E. Pevtcov ¹, Polina S. Kuga ¹, Boris I. Smirnov ¹,², Alexander L. Alyanskiy ¹, Natalia E. Ivanova 1, Maria A. Estrina ¹, Elena V. Babenko ¹, Burkhonidin B. Bakhovadinov ¹, Ludmila S. Zubarovskaya ¹, Boris V. Afanasyev ¹<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(372) "Maxim A. Kucher ¹, Dmitrii E. Pevtcov ¹, Polina S. Kuga ¹, Boris I. Smirnov ¹,², Alexander L. Alyanskiy ¹, Natalia E. Ivanova 1, Maria A. Estrina ¹, Elena V. Babenko ¹, Burkhonidin B. Bakhovadinov ¹, Ludmila S. Zubarovskaya ¹, Boris V. Afanasyev ¹
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" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20882" ["VALUE"]=> array(2) { ["TEXT"]=> string(2841) "<p style="text-align: justify;"> Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients. </p> <h2 style="text-align: justify;">Patients and methods</h2> <p style="text-align: justify;"> From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created. </p> <h2 style="text-align: justify;">Results</h2> <p style="text-align: justify;"> ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85. </p> <h2 style="text-align: justify;">Conclusion</h2> <p style="text-align: justify;"> ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of<br> ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, ABО-incompatibility, complications. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2637) "

Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients.

Patients and methods

From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created.

Results

ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85.

Conclusion

ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of
ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications.

Keywords

Hematopoietic stem cell transplantation, ABО-incompatibility, complications.

" ["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(2637) "

Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients.

Patients and methods

From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created.

Results

ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85.

Conclusion

ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of
ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications.

Keywords

Hematopoietic stem cell transplantation, ABО-incompatibility, complications.

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² St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia
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² St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia
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Кучер ¹, Дмитрий Э. Певцов ¹, Полина С. Куга ¹, Борис И. Смирнов ¹, ², Александр Л. Алянский ¹, Наталья Е. Иванова ¹, Мария А. Эстрина ¹, Елена В. Бабенко ¹, Бурхонидин Б. Баховадинов ¹, Людмила С. Зубаровская ¹, Борис В. Афанасьев ¹" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(538) "Mаксим A. Кучер ¹, Дмитрий Э. Певцов ¹, Полина С. Куга ¹, Борис И. Смирнов ¹, ², Александр Л. Алянский ¹, Наталья Е. Иванова ¹, Мария А. Эстрина ¹, Елена В. Бабенко ¹, Бурхонидин Б. Баховадинов ¹, Людмила С. Зубаровская ¹, Борис В. Афанасьев ¹" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(538) "Mаксим A. Кучер ¹, Дмитрий Э. Певцов ¹, Полина С. Куга ¹, Борис И. Смирнов ¹, ², Александр Л. Алянский ¹, Наталья Е. Иванова ¹, Мария А. Эстрина ¹, Елена В. Бабенко ¹, Бурхонидин Б. Баховадинов ¹, Людмила С. Зубаровская ¹, Борис В. Афанасьев ¹" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20878" ["VALUE"]=> array(2) { ["TEXT"]=> string(4105) "<p style="text-align: justify;"> В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК. </p> <h2 style="text-align: justify;">Пациенты и методы</h2> <p style="text-align: justify;"> В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ). </p> <h2 style="text-align: justify;">Результаты</h2> <p style="text-align: justify;"> АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85. </p> <h2 style="text-align: justify;">Заключение</h2> <p style="text-align: justify;"> АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что<br> требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3901) "

В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК.

Пациенты и методы

В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ).

Результаты

АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85.

Заключение

АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что
требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения.

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В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК.

Пациенты и методы

В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ).

Результаты

АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85.

Заключение

АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что
требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения.

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Introduction

Allo-HSCT is a well-defined treatment mode for high-risk acute lymphoblastic leukemia (ALL) [1]. However, relapse still remains the major cause of treatment failure in children with ALL, even among patients who received transplantation during hematologic remission [2-4]. High risk of relapses aft er allo-HSCT arises, mostly, due to selection of the patients with signs of poor clinical prognosis (refractory to chemotherapy, unfavorable cytogenetic or molecular genetic alterations) [5, 6], whereas the patients with more favorable prognosis undergo standard chemotherapy treatment [1, 7]. Th e relapses occur in 30-35% of patients with ALL and it is one of the most common causes of mortality aft er allo-HSCT [2, 3, 8]. Survival of patients who experienced relapse is about 3-19% depending on the time between allo-HSCT and relapse [9]. In the case of clinical posttransplant relapse further treatment options are limited and often ineffective [10, 11]. For example, a second allo-HSCT can give a chance to cure such patients, but it is associated with high  orbidity and mortality. Donor lymphocyte infusion (DLI) has a limited success if it is started during hematological relapse [12]. At the same time, immunotherapy at the stage of early relapse (before hematological manifestation), when the leukemia clone is still small, is more eff ective than relapse treatment [12-15]. Therefore, the study of early signs of disease recurrence is particularly important.
The early signs of impending ALL relapse aft er allo-HSCT are usually detected by MRD monitoring using the following means: 1) fl ow cytometry of leukemia-associated immunophenotype, or quantitative real-time PCR of chimeric oncogenes, or clonal rearrangements of immunoglobulin molecules, or T-cell receptor genes (Ig/TCR-PCR) [16-18]; 2) donor chimerism monitoring [19, 20].
A clone of ALL cells originating from a single primary-transformed cell carries identical Ig/TCR rearrangements in all the malignant cells. Th erefore, the rearrangements detected in ALL samples at diagnosis could serve as specifi c molecular markers for MRD monitoring. Ig/TCR rearrangements allow MRD monitoring in the vast majority of ALL patients, and comparing the results aft er allo-HSCT [21].
MRD monitoring in pediatric ALL by Ig/TCR rearrangements has widely been accepted as a reliable prognostic factor of relapse during chemotherapy and before allo-HSCT [1]. However, its application aft er allo-HSCT has been less clearly defi ned and still controversial. Th e signifi cance of precise quantifi cation of MRD aft er transplantation is not completely established. Th e aim of the study was to evaluate the impact of quantitative MRD on outcomes of allo-HSCT.

Patients and methods

Our study included 45 patients with ALL or biphenotypic AL who underwent the fi rst allo-HSCT at the Center for Pediatric Oncology, Hematology and Immunology from 2010 to 2017. Initial screening for Ig/TCR clonal rearrangements was performed in all the patients. MRD monitoring using Ig/TCR targets was performed in 35 of them (eight patients had no target markers, 1 had no primary engraft ment, no sample material was obtained aft er 1 alloHSCT). Basic characteristics of 35 patients with ALL/biphenotypic AL enrolled in the posttransplant MRD studies are listed in Table 1. The recipient age at the time of transplantation was 2-25 (median 11) years. All parents or guardians signed the informed consent. All the patients received myeloablative conditioning (MAC), except of one with Nijmegen syndrome/ALL who underwent a reduced-intensity conditioning regimen (RIC).
For MRD assays, bone marrow (BM) and peripheral blood (PB) samples were collected on days +30, +60, +100, +180, +365 aft er alloHSCT, and every six months thereaft er. Mononuclear BM cells were isolated in the Histopaque density gradient (Sigma-Aldrich, USA). DNA extraction was carried out by phenol-chloroform method. DNA quality and concentration was evaluated with a NanoDrop 2000c spectrophotometer (Th ermoFisher Scientifi c, USA).
Genomic DNA samples at diagnosis were screened by PCR for clonal IgH, IgK immunoglobulin and rearrangements of TCRD, TCRG, TCRB genes. DNA amplifi cation was performed with primers, recommended by BIOMED-1 Concerted Action [22] for IgK and TCRG genes, and a report by Chim et al. for IgH gene [23]. The TCRD gene was amplified according to Taube et al. [24], and TCRB by BIOMED-2 Concerted Action [21]. Further on, the specifi c PCR products were evaluated by heteroduplex analysis by polyacrylamide gel technique, then being cut from the gels, purifi ed and sequenced in the ABI PRISM 3130 Genetic Analyzer (Applied Biosystems, USA) in both directions. Detailed description of the detection procedure of diff erent Ig/TCR rearrangements in ALL was reported in our previous publications [25, 26]. Allele-specifi c oligonucleotides (ASO) primers were selected to cover the N region of rearrangement, specifi cally, for the 3’ end of primer. Secondary structures were avoided. At least two different ASO-primers were designed for each rearrangement point and tested, in order to choose the best system for MRD quantification.

Table 1. Characteristics of patients with ALL and biphenotypic AL (n= 35) included in the MRD study after allo-HSCT

ASO-primers and germline TaqMan probe approach were applied for RQ-PCR analysis in CFX96 machine (Bio-Rad, USA). PCR amplifi cation was performed in 20μL reaction mix with TaqMan Universal PCR Master Mix (Applied Biosystems, USA), 500 ng of genomic DNA, 500 ng of each primer and 150 ng of fl uorescent TaqMan probe labeled with 3’FAM, 5’BHQ. Th e panel of germline primers and probes was published elsewhere [27]. For MRD quantifi cation, we prepared serial ten-fold dilutions of diagnostic DNA in polyclonal controls to make a standard curve construction. To normalize the individual results, the same samples were amplifi ed with primers for albumin reference gene [28]. A standard curve for the albumin gene was plotted with diagnostic DNA serially diluted in water. Standard Quantity (SQ, mean of triplicate) was automatically generated by CFX96 based on standard curve for both albumin and target. Interpretation of MRD analysis results was performed in accordance with the guidelines published by the European Study Group on MRD detection [29].
RNA was isolated from the BM mononuclear cells with TRIzol reagent (Th ermo Fisher Scientifi c, USA). MRD monitoring based on measuring expression of chimeric oncogenes TEL-AML1, BCR-ABL1, MLL1-AF4 was performed by quantitative real-time PCR of the cDNA. Th e real-time PCR was performed in 25-μl volume containing 2x TaqMan Universal PCR Master Mix (Applied Biosystems, USA), 300 nM primers, 200 nM TaqMan probes and 5 μl of cDNA or standards. Commercial standards (Qiagen, Germany) were used for calibration of absolute gene copy numbers. The PCR conditions were as follows: 2 min, 50°C; 10 min, 95°C; 50 cycles (95°C, 15 sec; 60°C, 60 sec).
MRD detection was also performed by multiparametric fl ow cytometry (FC) of mononuclear cell suspensions (1 million cells/mL, 100 μl). A panel of monoclonal antibodies conjugated with fl uorescent labels FITC, PE, PC5, PC7 (Beckman Coulter, USA). In addition, we used reagents for fi xation and permeabilization (Becton Dickinson, USA) for detection of intracellular antigens. Following incubation and staining, the cells were washed once in phosphate buff er saline with subsequent fi xation in 1% paraformaldehyde. FC-analysis was carried out with the Navios fl ow cytofl uorimeter (Beckman Coulter, USA) using the CXP program.
Donor chimerism was determined by real-time PCR of InDel markers and multiplex PCR of short tandem repeats (STR) in BM and/or PB on +30, +45, +60, + 80, +100, +140, +180, +245, + 365 days aft er allo-HSCT and, thereaft er, every six months. In case of mixed chimerism (MC), the studies were conducted more oft en. AmpFlSTR® SGM Plus® PCR Amplification Kit (ABI, UK) was used for amplifi cation of STR markers, PCR products were separated by capillary electrophoresis using 3130 Genetic Analyzer (Applied Biosystems, USA). Distinct alleles were identifi ed by means of GeneMapper soft ware (Applied Biosystems, USA). InDel-PCR was performed as previously described [30-32]. Full donor chimerism (FDC) was defi ned as >99% donor cells, and mixed chimerism was accepted at 5-99% donor cells.
Statistical evaluation was performed by non-parametric methods using the STATISTICA approach. Overall survival was defi ned as the time period between allo-HSCT and death, or to the last observation date. Treatment-related mortality (TRM) was defi ned as a death in complete remission state (CR) without preceding relapse, from any causes associated with HSCT procedure. Event-free survival (EFS) was determined as survival without TRM, relapse, rejection, or secondary tumor. Th e time to clinical events (relapse, TRM, GVHD) was measured from the date of alloHSCT. Kaplan-Meier estimates were performed to predict probabilities for overall survival and EFS [33]. Th e log-rank test was used for comparisons. Cumulative incidence (CI) curves were calculated to assess incidence of relapse (CIR) and TRM [34]. Gray’s test was used for comparisons of CIs [35]. Fisher’s exact test was applied in order to compare the patients’ categorical data. Th e results of statistical evaluation were considered signifi cant at p<0.05.

Results

Survival of patients with different MRD status after allo-HSCT

Ig/TCR clonal rearrangements were identifi ed for 37 of 45 patients (82.2%). Chimeric oncogenes were determined only in 10 (22%) of 45 patients: 5 (11.1%) with MLL-AF4; 4 BCR-ABL1-positive cases (8.9%); one patient (2.2%) with TEL-AML1. MRD monitoring by Ig/TCR rearrangements was performed aft er 35 allo-HSCT that were included into the analysis. Th e median follow-up of the patients surviving aft er allo-HSCT was 3.6 years.
MRD status according to Ig/TCR target was negative in 21 (60%) patients, and only two of them (9.5%) relapsed. Positive MRD was detected in 14 (40%) patients, 7 (50%) of them had isolated bone marrow relapse. Th e three-year CI of relapse was higher in the patients with positive MRD at
any time aft er allo-HSCT (58.3±16.2%) as compared to the patients with negative MRD (10.7±7.4%), p=0.0042 (Fig. 1). Overall survival and EFS were signifi cantly lower in cases of positive MRD (33.2± 14.4% vs 83.6± 8.8%, p=0.008, and 18.9± 11.7% vs 66.6± 11.4%, p=0.002).
In all six patients who reached high MRD levels (>10-3), we observed recurrence of the disease. Only one (16.7%) patient relapsed of six children with intermediate MRD levels (10-4-10-3). Two patients with MDR level <10-4 retained their CR state. Generally, in cases of positive MRD, the patients with relapse showed higher levels of preceding MRD (1.6*10-1-2.7*10-4), than the relapse-free patients (<10-5-10-3), as seen from Table 2. The three-year cumulative incidence (CI) of relapse for the patients with non-detectable MRD, with MRD ≤10-3, and >10-3 was, respectively, 10.7±7.4% vs 14.6±14.6% vs 100% (p<0.0001). Overall survival rates (OS) were 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), and EFS rates were 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012), respectively (Fig. 2).
In two patients, positive MRD was not found in BM cells before relapse. One patient had extramedullary relapse (EMR) in the central nervous system (CNS). In the second patient, a loss of Ig/TCR target was observed in hematological BM relapse.
MRD monitoring with Ig/TCR rearrangements in BM, along with PB, was performed in 10 patients. In seven cases (70%), positive MRD was detected before relapse in both BM and PB. In three patients, MRD was detected in BM only, one of them relapsed. In this patient, MRD was still not detected in PB at the time of relapse.

Figure 1. Probability (CI) of relapse (A), OS (B) and EFS values (C) in the patients with ALL/biphenotypic AL according to MRD status after allo-HSCT

Figure 2. Probability (CI) of relapse (A), OS (B), and EFS (C) in patients with ALL/biphenotypic AL according to MRD levels after alloHSCT. Curves are designated black (MRD –); green (MRD >10-3); or red (MRD <10-3)

Comparison of MRD results obtained by different targets/methods

In nine patients, MRD was monitored by Ig/TCR rearrangements, as well as expression of BCR-ABL1 (n=4), MLL-AF4 (n=4), TEL-AML1 (n=1). In only one case, the results were discordant, i.e., the abovementioned patient who was negative by Ig/TCR target (loss of the target), but he was positive for MLL-AF4. In four patients, MRD was not detected, either by expression of BCR-ABL1 (n=2), MLL-AF4 (n=2), or Ig/TCR targets. Positive MRD was detected by both methods in four patients. Paired points for comparison were available in two patients. In one case, positive MRD was detectable by both approaches (MLL-AF4 and Ig/TCR markers). In another case (patient №12), we observed earlier appearance of MRD in BM as detected by TEL-AML expression (on day +98), than by Ig/TCR marker (detected at the next point of D+124). Hence, the fi rst method seems to be more sensitive (Fig. 3).

Table 2. Time dynamics of MDR in patients with ALL

Figure 3. MRD time course in Patient #12, according to TEL-AML expression and Ig/TCR rearrangement (Igk). Abscissa, gene copy number (log10); ordinate, terms posttransplant

MRD measured by immunophenotyping and Ig/TCR rearrangements was monitored in four patients in parallel (at the same time points aft er HSCT). Negative MRD was detected by both methods in one patient. In three patients, we received discordant results: there were positive MRD values of <10-3 detected by Ig/TCR gene rearrangements, however, being negative by immunophenotyping technique. Nevertheless, negative results were observed in some cases by both methods.

Comparison of MRD data obtained by Ig/TCR and chimerism markers

Donor chimerism monitoring was performed in all 35 patients.
1) Full donor chimerism (FDC) and negative MRD state were detected in 19 patients, only 2 of them have relapsed (Table 3). In one patient with loss of Ig/TCR target, a relapse was diagnosed more than 2 months aft er last chimerism monitoring in BM cells (D+377, late isolated BM relapse). Th e second patient with extramedullary CNS relapse had negative MRD and FDC in PB and BM cells, even at the time of relapse.
2) Mixed chimerism (MC) and negative MRD were detectable in 2 cases. One patient had negative MRD and MC (98.9%) in BM on D +30. Th is patient reached FDC (since +60 day), but died with infectious complications on D +542. Th e second patient showed FDC conversion to increasing MC accompanied by infection, and died on D +78.
3) FDC and positive MRD (up to 1.6*10-1) was observed in 7 patients, two of them have relapsed. Th e patient №12 had BM relapse on D +522, with last testing point at D +347, when full donor chimerism and MRD of 5*10-5 were determined. In the second patient (№13), a BM relapse was diagnosed by the D+226. Slightly decreased chimerism level of 99.1% was registered in blood leukocytes, along with increased MRD level to 15% at the last term before the relapse (D+197). In three patients with FDC, we observed MRD clearance, the rest of them retained their MRD positivity at the last examination.

Table 3. Comparison of MRD and chimerism monitoring data in ALL patients

4) MC and positive MRD was traced in seven patients, five of them had the disease recurrence. Before relapse, an increase of MC and MRD up to 2.2*10-2 was observed in four patients (the fi ft h patient had an early relapse, and only one monitoring point before relapse). Patient №5 with increasing MC has shown graft rejection on D +74 with subsequent autorecovery without ALL reoccurrence, with MRD levels in BM of <10-4 on days +27 to +39, then becoming negative at later terms. Patient №1 had an MC state (98.5% on D+30 in BM and PC) with FDC state achieved by the D +60; this patient is now alive, being in complete remission.
Thus, we have revealed suffi cient concordance between MRD and donor chimerism in 26 (74.3%) out of 35 cases. Th =e most favorable group comprised a subgroup with negative MRD and FDC, an intermediate group consisted of patients with positive MRD and FDC, and the most unfavorable group included the patients with positive MRD and increasing MC. Th e respective 3-year CI of relapse for these groups were as follows: 11.9 ± 8.2% vs 41.7 ± 29.5% vs 80.0 ± 23.9% (p<0.0008); the OS values were 94.4 ± 5.4% vs 44.4 ± 22.2% vs 20.0 ± 17.9% (p=0.0029); EFS probability was 75.0 ± 11.0% vs 25.0 ± 20.4% vs 0% (p<0.0001), respectively (Fig. 4).

Dependence of survival upon MRD and GVHD association

Grade I-IV acute GvHD (aGvHD) was observed in 17 (48.6%) of 35 patients, and six of them were diagnosed with severe aGvHD (grade III-IV). MRD-negative state was registered more oft en in the patients with aGvHD (in 13 of 17 cases), as compared to the GvHD-free cases (8 of 18 patients, p=0.085).
1) Among 13 patients with negative MRD and aGvHD, only 1 (7.7%) patient had relapse in CNS.
2) Among eight patients with negative MRD without aGvHD, nobody has relapsed.
3) None of the four patients with positive MRD and aGvHD relapsed. MRD clearance occurred in 4 patients (40%) on the days +100–+150.
4) In seven (70%) of 10 patients with positive MRD without aGvHD disease reoccurred. Four of these 10 patients received DLI, 2 of them experienced relapse despite GvHD signs observed aft er IDL.
Clinical outcomes of the patients with negative MRD without aGvHD, patients with negative MRD with aGvHD, and patients with positive MRD and aGvHD were nearly similar, being defi nitely better than in the group of aGvHD-free patients with positive MRD. Th e three-year CI of relapse rates were as follows: 20.0±20.0% vs 7.7±7.7% vs 0% vs 80.0±20.2% (p=0.008).Th e respective, overall survival probability was 80.0±17.9% vs 84.6±10.0% vs 66.7±27.2% vs 18.0±15.1% (p=0.026). Th e EFS values for these subgroups were: 60.1±21.9% vs 67.3±13.6% vs 66.7±27.2% vs 0% (p=0.0004), respectively (Fig. 5).

Figure 4. Probability of relapse (A), OS (B) and EFS (C) in patients with ALL/biphenotypic AL according to MRD and chimerism after allo-HSCT. Curves are designated black (MRD+/FDC); green (MRD+/FDC); or red (MRD-/ mixed chimerism increase)

Discussion

The MRD monitoring can help to identify presence of tumor cells that survived aft er the conditioning. However, this assay is applicable only for patients with a defi ned marker (chimeric oncogenes, mutations, Ig/TCR rearrangements or leukemia-associated immunophenotype). Identifi cation of tumor-specifi c mutations is the most accurate diagnostic approach showing high specifi city. However, the structure of these mutations should be suitable for MRD monitoring, with a sensitivity of, at least, 10-4 [36]. In ALL monitoring, quantitative real-time PCR (qPCR) allows to determine MRD by specifi c chimeric oncogenes/transcripts, point mutations and other rearrangements, such as BCR-ABL1, PML/ RARa, RUNX1-RUNX1T1 (AML1-ETO), CBFB-MYH11, MLL translocations, at a high sensitivity of 10-5-10-6 [37]. Chimeric oncogenes are detected only in a small number of patients with ALL [36, 38]. In our study, they were found only in 11% of transplantation patients. Th ere exists another alternative to chimeric oncogenes and mutations in ALL, i.e., clonal rearrangements of Ig and TCR genes, which are an attractive marker for MRD monitoring, being detectable in vast majority of ALL patients (up to 90-95% [36, 37], 82% of our patients).
Analytical sensitivity is an important aspect of MRD assay, since an arising leukemic clone posttransplant is regarded as an unfavorable event. MRD monitoring with Ig/TCR has a good sensitivity up to 10-4-10-5. Measurement of chimeric oncogene expression may be an even more sensitive approach in some cases, since a single malignant cell may contain several dozens or even thousands copies of chimeric oncogenes. It increases sensitivity up to 1 lg10, thus allowing earlier detection of tumor cells aft er allo-HSCT than with DNA-targets. However, the predictive value of individual methods and expression markers is not well defi ned. By contrast, MRD monitoring procedure with Ig/TCR rearrangements has been standardized and provides comparable results obtained from diff erent patients, which makes it possible to assess not only the presence of MDR aft er alloHSCT, but also takes its levels into account [4, 36, 37, 39]. Immunophenotyping using fl ow cytometry has a lower sensitivity (up to 10-4) than PCR-based methods. Its application for MRD monitoring aft er allo-HSCT is limited due to diffi culties with interpretation of results [40]. Bone marrow regeneration after allo-HSCT makes it diffi cult to identify leukemic cells on the background of normal lymphoid precursors [1].
It is also necessary to consider the stability of various MRD markers [36]. In rare cases, the Ig/TCR target can be lost due to somatic mutations accumulating in tumor cells [41, 42], what we have found in one case (2.9% of total group). RQ-PCR measuring of Ig/TCR rearrangements provides suitable sensitivity and specifi city, being, however, complicated by high costs of the assay, delayed purchasing of ASO, and loss of a gene target in rare cases. However, this method has been accepted in Europe as a standard approach to MRD monitoring [1].
Chimerism assays are used for assessing donor cell engraftment, but they also can be applied for relapse prediction. The study of chimerism by InDel-PCR has a sensitivity of 10-4 [30, 32], but up to 1% of the recipient cells, even after myeloablative conditioning, may be normally present in BM and PB aft er allo-HSCT [43, 44]. Th erefore, the sensitivity of donor chimerism for prediction of relapses is limited to 10^-2.

Figure 5. Probability of relapse (A), OS (B) and EFS (C) in patients with ALL/biphenotypic AL according to MRD and chimerism after allo-HSCT. Curves are designated black (MRD-/no GVHD); blue (MRD-/aGVHD); red (MRD+/ no aGVHD); or green (MRD+/aGVHD)

In addition, the chimerism monitoring is a non-specific method, since the persistent residual cells of recipient origin can be either normal hematopoietic or malignant cells, or both.
MRD monitoring allows identifying the ALL patients being at high risk for relapses aft er alloHSCT. It was shown in ALL patients that the level of MRD before transplantation significantly aff ects the result of posttransplant outcome [4, 40, 45-52]. Not all patients with negative MRD pre-transplant remain relapse-free at later terms, as well as not all patients with positive MRD relapse aft er HSCT. Th erefore, the measurement of MRD post-HSCT is another powerful tool, with a potential for more precise relapse prediction. A limited number of trials has explored the role of MRD assays in the post-HSCT period [1]. Post-HSCT positive MRD strongly associated with high risk of relapse and low survival in childhood ALL [4, 40, 50, 52–55]. Th e presence of detectable MRD aft er transplant was independent of other factors, including pre-HCT MRD and aGVHD status [40].
In our study, the presence of MRD aft er allo-HSCT significantly increased the probability of disease recurrence and led to poor overall and event-free survival. We showed that the risk of relapse was increased only in the patients with high MRD levels (>10-3, CI of relapse is 100%), whereas risk of relapse did not diff er for the patients with MRD ≤10-3 and with negative MRD, (CI of relapse 11% and 15% accordingly). Similarly, Balduzzi et al. have shown that the patients who had high MRD >10-3 at any time point post-HSCT, did relapse, despite any attempts to prevent the recurrence of disease [54]. Most patients relapsed with MRD level of >10-3, but the patients with MRD <10-3-10-4 were more likely to clear their leukemia cells [52, 54, 56]. By contrast, the study of Bader et al. [53] has shown that any level of MRD aft er allo-HSCT did increase risk of relapse, even MRD <10-4 , if compared to MRD-free patients on D+60, +90 and +180, but not on +30 days, and the same results were reported by Zhao group [55]. However, our data and results from other authors [52-54, 56] suggest that the patients with low posttransplant MRD levels <10-3-10-4 do not necessarily relapse, and additional risk stratifi cation is needed.
Despite recommendations on monitoring of MRD and chimerism for relapse prediction of ALL aft er alloHSCT, there are only few studies comparing these two methods [20, 56, 57], and the results of these studies do not give a complete answer as to how a combination of these approaches can improve relapse prediction. We have obtained concordant results between MRD and chimerism in 74% cases. Standard methods for determining MPD are of >1lg10 more sensitive, than the methods for chimerism detection. Th e main diff erence between these two approaches is that MRD monitoring directly determines the residual tumor cells and the chimerism analysis gives only information about the persistence/ recoverye of autologous hematopoiesis. Reappearance of recipient cells may indicate the establishment of immunological tolerance thus potentially leading to a weaker immunological surveillance of malignant cells and the development of relapse [58]. Rarely, stable mixed chimerism in some patients with malignant diseases may persist for up to 20 years after alloHSCT, and it does not lead to relapse or rejection [59], although this is rather an exception to the rules. In the majority of cases, the onset of increasing mixed chimerism precedes disease recurrence [19, 20, 32, 60-62].
In our study, a combination of these two diagnostic approaches makes it possible to stratify patients into groups of high, intermediate and low risk of relapse with a very high accuracy. Th e most favorable group was presented by the patients with negative MRD and FDC with a good OS (94%) and EFS (75%), and a low incidence of relapse (12%). Th e presence of MRD combined with increasing MC led to the development of relapses in almost all patients (CI relapse 80%) and signifi cantly worse OS (20%) and EFS (0%). In the presence of FDC, some patients showed MRD clearance and became MRD-negative, but this group of patients still had relatively high risk of relapse (CI relapses 42%) and intermediate OS (44%) and EFS values (25%). Patients couldclear their MRD by an immunologic graft -versus-leukemia (GvL) eff ect, but MRD must be cleared until the establishment of graft tolerance towards the recipient; otherwise, uncontrolled proliferation of residual leukemia cell fi nally results in hematological relapse [54]. Th e patients with positive MRD in late posttransplant period are shown to relapse more readily, when compared to patients with MRD positivity over the fi rst 1-2 months [53-56]. During the initial phase aft er allo-HSCT (within the fi rst 2 months), immunologic reconstruction is incomplete, and GvL eff ect is not fully exhibited [55]. Our study also confi rms the theory of immunological tolerance, because MRD clearance was more often observed in patients with FDC and GvHD, or after DLI. None of the patients with positive MRD developed bone marrow relapse in the presence of GvHD, in contrast to patients with no GVHD (CI relapse 80%). The role of the GvL eff ect is supported by studies showing that the ALL patients who experience GvHD have a lower risk of relapse [40, 49, 56]. As a rule, these three parameters (MRD, GVHD and chimerism) are interrelated. Detection of MC was oft en combined with positive MRD and lack of GVHD. Absence or reduction of MRD was observed in the patients with FDC and GVHD development.
We have shown that the combination of MRD and chimerism monitoring allows stratifi cation of ALL patients into the groups of relapse risk. In contrast to previous studies [54, 56], we were able to fi nd out prognostic value of increasing MC due to application of sensitive PCR-based method of chimerism detection and testing of BM samples, along with PB cells. Our study demonstrates the combined eff ect of MRD, chimerism and GVHD on the outcomes in allo-HSCT patients. A serious issue is associated with development of extramedullary relapses which are underdiagnosed because they can manifest with no detectable MRD and in FDC state in the presence of GVHD, even in relapse burden [56, 63]. Th ere is also a risk to miss early signs of relapse, if the monitoring intervals for the marrow chimerism and MRD exceed 2 months. We recommend monitoring BM at least once or twice a month over fi rst 6-12 months aft er alloHSCT, when the risk of relapse is high, especially for the patients with previous positive MRD and/or MC, and absence of GVHD signs.
Like other workers, we observed that, in patients with MRD level of <10-3, the clearance of malignant clone can be achieved with preventive immunotherapy [54, 64]. In view of these considerations, MRD combined with chimerism could be used as a tool to guide posttransplant pre-emptive immunomodulation or immunotherapy, in order to prevent a disease relapse.

Conclusion

The presence of positive MRD aft er allo-HSCT is known to be an unfavorable prognostic factor associated with relapses, poor overall and decreased event-free survival. In patients with ALL, the presence of MRD aft er allo-HSCT is not always associated with development of relapses. The manifestation of the GvL eff ect can be observed in patients with FDC and GvHD or aft er DLI. Th e patients of a high-risk group for relapse include those with high MRD level >10-3, as well as the patients in whom the presence of MRD is combined with increasing mixed chimerism and/or absence of GVHD. Monitoring of MRD in bone marrow does not always allow
us to detect extramedullary relapses.

Acknowledgements

The authors report no confl icts of interest.

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Introduction

Allo-HSCT is a well-defined treatment mode for high-risk acute lymphoblastic leukemia (ALL) [1]. However, relapse still remains the major cause of treatment failure in children with ALL, even among patients who received transplantation during hematologic remission [2-4]. High risk of relapses aft er allo-HSCT arises, mostly, due to selection of the patients with signs of poor clinical prognosis (refractory to chemotherapy, unfavorable cytogenetic or molecular genetic alterations) [5, 6], whereas the patients with more favorable prognosis undergo standard chemotherapy treatment [1, 7]. Th e relapses occur in 30-35% of patients with ALL and it is one of the most common causes of mortality aft er allo-HSCT [2, 3, 8]. Survival of patients who experienced relapse is about 3-19% depending on the time between allo-HSCT and relapse [9]. In the case of clinical posttransplant relapse further treatment options are limited and often ineffective [10, 11]. For example, a second allo-HSCT can give a chance to cure such patients, but it is associated with high  orbidity and mortality. Donor lymphocyte infusion (DLI) has a limited success if it is started during hematological relapse [12]. At the same time, immunotherapy at the stage of early relapse (before hematological manifestation), when the leukemia clone is still small, is more eff ective than relapse treatment [12-15]. Therefore, the study of early signs of disease recurrence is particularly important.
The early signs of impending ALL relapse aft er allo-HSCT are usually detected by MRD monitoring using the following means: 1) fl ow cytometry of leukemia-associated immunophenotype, or quantitative real-time PCR of chimeric oncogenes, or clonal rearrangements of immunoglobulin molecules, or T-cell receptor genes (Ig/TCR-PCR) [16-18]; 2) donor chimerism monitoring [19, 20].
A clone of ALL cells originating from a single primary-transformed cell carries identical Ig/TCR rearrangements in all the malignant cells. Th erefore, the rearrangements detected in ALL samples at diagnosis could serve as specifi c molecular markers for MRD monitoring. Ig/TCR rearrangements allow MRD monitoring in the vast majority of ALL patients, and comparing the results aft er allo-HSCT [21].
MRD monitoring in pediatric ALL by Ig/TCR rearrangements has widely been accepted as a reliable prognostic factor of relapse during chemotherapy and before allo-HSCT [1]. However, its application aft er allo-HSCT has been less clearly defi ned and still controversial. Th e signifi cance of precise quantifi cation of MRD aft er transplantation is not completely established. Th e aim of the study was to evaluate the impact of quantitative MRD on outcomes of allo-HSCT.

Patients and methods

Our study included 45 patients with ALL or biphenotypic AL who underwent the fi rst allo-HSCT at the Center for Pediatric Oncology, Hematology and Immunology from 2010 to 2017. Initial screening for Ig/TCR clonal rearrangements was performed in all the patients. MRD monitoring using Ig/TCR targets was performed in 35 of them (eight patients had no target markers, 1 had no primary engraft ment, no sample material was obtained aft er 1 alloHSCT). Basic characteristics of 35 patients with ALL/biphenotypic AL enrolled in the posttransplant MRD studies are listed in Table 1. The recipient age at the time of transplantation was 2-25 (median 11) years. All parents or guardians signed the informed consent. All the patients received myeloablative conditioning (MAC), except of one with Nijmegen syndrome/ALL who underwent a reduced-intensity conditioning regimen (RIC).
For MRD assays, bone marrow (BM) and peripheral blood (PB) samples were collected on days +30, +60, +100, +180, +365 aft er alloHSCT, and every six months thereaft er. Mononuclear BM cells were isolated in the Histopaque density gradient (Sigma-Aldrich, USA). DNA extraction was carried out by phenol-chloroform method. DNA quality and concentration was evaluated with a NanoDrop 2000c spectrophotometer (Th ermoFisher Scientifi c, USA).
Genomic DNA samples at diagnosis were screened by PCR for clonal IgH, IgK immunoglobulin and rearrangements of TCRD, TCRG, TCRB genes. DNA amplifi cation was performed with primers, recommended by BIOMED-1 Concerted Action [22] for IgK and TCRG genes, and a report by Chim et al. for IgH gene [23]. The TCRD gene was amplified according to Taube et al. [24], and TCRB by BIOMED-2 Concerted Action [21]. Further on, the specifi c PCR products were evaluated by heteroduplex analysis by polyacrylamide gel technique, then being cut from the gels, purifi ed and sequenced in the ABI PRISM 3130 Genetic Analyzer (Applied Biosystems, USA) in both directions. Detailed description of the detection procedure of diff erent Ig/TCR rearrangements in ALL was reported in our previous publications [25, 26]. Allele-specifi c oligonucleotides (ASO) primers were selected to cover the N region of rearrangement, specifi cally, for the 3’ end of primer. Secondary structures were avoided. At least two different ASO-primers were designed for each rearrangement point and tested, in order to choose the best system for MRD quantification.

Table 1. Characteristics of patients with ALL and biphenotypic AL (n= 35) included in the MRD study after allo-HSCT

ASO-primers and germline TaqMan probe approach were applied for RQ-PCR analysis in CFX96 machine (Bio-Rad, USA). PCR amplifi cation was performed in 20μL reaction mix with TaqMan Universal PCR Master Mix (Applied Biosystems, USA), 500 ng of genomic DNA, 500 ng of each primer and 150 ng of fl uorescent TaqMan probe labeled with 3’FAM, 5’BHQ. Th e panel of germline primers and probes was published elsewhere [27]. For MRD quantifi cation, we prepared serial ten-fold dilutions of diagnostic DNA in polyclonal controls to make a standard curve construction. To normalize the individual results, the same samples were amplifi ed with primers for albumin reference gene [28]. A standard curve for the albumin gene was plotted with diagnostic DNA serially diluted in water. Standard Quantity (SQ, mean of triplicate) was automatically generated by CFX96 based on standard curve for both albumin and target. Interpretation of MRD analysis results was performed in accordance with the guidelines published by the European Study Group on MRD detection [29].
RNA was isolated from the BM mononuclear cells with TRIzol reagent (Th ermo Fisher Scientifi c, USA). MRD monitoring based on measuring expression of chimeric oncogenes TEL-AML1, BCR-ABL1, MLL1-AF4 was performed by quantitative real-time PCR of the cDNA. Th e real-time PCR was performed in 25-μl volume containing 2x TaqMan Universal PCR Master Mix (Applied Biosystems, USA), 300 nM primers, 200 nM TaqMan probes and 5 μl of cDNA or standards. Commercial standards (Qiagen, Germany) were used for calibration of absolute gene copy numbers. The PCR conditions were as follows: 2 min, 50°C; 10 min, 95°C; 50 cycles (95°C, 15 sec; 60°C, 60 sec).
MRD detection was also performed by multiparametric fl ow cytometry (FC) of mononuclear cell suspensions (1 million cells/mL, 100 μl). A panel of monoclonal antibodies conjugated with fl uorescent labels FITC, PE, PC5, PC7 (Beckman Coulter, USA). In addition, we used reagents for fi xation and permeabilization (Becton Dickinson, USA) for detection of intracellular antigens. Following incubation and staining, the cells were washed once in phosphate buff er saline with subsequent fi xation in 1% paraformaldehyde. FC-analysis was carried out with the Navios fl ow cytofl uorimeter (Beckman Coulter, USA) using the CXP program.
Donor chimerism was determined by real-time PCR of InDel markers and multiplex PCR of short tandem repeats (STR) in BM and/or PB on +30, +45, +60, + 80, +100, +140, +180, +245, + 365 days aft er allo-HSCT and, thereaft er, every six months. In case of mixed chimerism (MC), the studies were conducted more oft en. AmpFlSTR® SGM Plus® PCR Amplification Kit (ABI, UK) was used for amplifi cation of STR markers, PCR products were separated by capillary electrophoresis using 3130 Genetic Analyzer (Applied Biosystems, USA). Distinct alleles were identifi ed by means of GeneMapper soft ware (Applied Biosystems, USA). InDel-PCR was performed as previously described [30-32]. Full donor chimerism (FDC) was defi ned as >99% donor cells, and mixed chimerism was accepted at 5-99% donor cells.
Statistical evaluation was performed by non-parametric methods using the STATISTICA approach. Overall survival was defi ned as the time period between allo-HSCT and death, or to the last observation date. Treatment-related mortality (TRM) was defi ned as a death in complete remission state (CR) without preceding relapse, from any causes associated with HSCT procedure. Event-free survival (EFS) was determined as survival without TRM, relapse, rejection, or secondary tumor. Th e time to clinical events (relapse, TRM, GVHD) was measured from the date of alloHSCT. Kaplan-Meier estimates were performed to predict probabilities for overall survival and EFS [33]. Th e log-rank test was used for comparisons. Cumulative incidence (CI) curves were calculated to assess incidence of relapse (CIR) and TRM [34]. Gray’s test was used for comparisons of CIs [35]. Fisher’s exact test was applied in order to compare the patients’ categorical data. Th e results of statistical evaluation were considered signifi cant at p<0.05.

Results

Survival of patients with different MRD status after allo-HSCT

Ig/TCR clonal rearrangements were identifi ed for 37 of 45 patients (82.2%). Chimeric oncogenes were determined only in 10 (22%) of 45 patients: 5 (11.1%) with MLL-AF4; 4 BCR-ABL1-positive cases (8.9%); one patient (2.2%) with TEL-AML1. MRD monitoring by Ig/TCR rearrangements was performed aft er 35 allo-HSCT that were included into the analysis. Th e median follow-up of the patients surviving aft er allo-HSCT was 3.6 years.
MRD status according to Ig/TCR target was negative in 21 (60%) patients, and only two of them (9.5%) relapsed. Positive MRD was detected in 14 (40%) patients, 7 (50%) of them had isolated bone marrow relapse. Th e three-year CI of relapse was higher in the patients with positive MRD at
any time aft er allo-HSCT (58.3±16.2%) as compared to the patients with negative MRD (10.7±7.4%), p=0.0042 (Fig. 1). Overall survival and EFS were signifi cantly lower in cases of positive MRD (33.2± 14.4% vs 83.6± 8.8%, p=0.008, and 18.9± 11.7% vs 66.6± 11.4%, p=0.002).
In all six patients who reached high MRD levels (>10-3), we observed recurrence of the disease. Only one (16.7%) patient relapsed of six children with intermediate MRD levels (10-4-10-3). Two patients with MDR level <10-4 retained their CR state. Generally, in cases of positive MRD, the patients with relapse showed higher levels of preceding MRD (1.6*10-1-2.7*10-4), than the relapse-free patients (<10-5-10-3), as seen from Table 2. The three-year cumulative incidence (CI) of relapse for the patients with non-detectable MRD, with MRD ≤10-3, and >10-3 was, respectively, 10.7±7.4% vs 14.6±14.6% vs 100% (p<0.0001). Overall survival rates (OS) were 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), and EFS rates were 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012), respectively (Fig. 2).
In two patients, positive MRD was not found in BM cells before relapse. One patient had extramedullary relapse (EMR) in the central nervous system (CNS). In the second patient, a loss of Ig/TCR target was observed in hematological BM relapse.
MRD monitoring with Ig/TCR rearrangements in BM, along with PB, was performed in 10 patients. In seven cases (70%), positive MRD was detected before relapse in both BM and PB. In three patients, MRD was detected in BM only, one of them relapsed. In this patient, MRD was still not detected in PB at the time of relapse.

Figure 1. Probability (CI) of relapse (A), OS (B) and EFS values (C) in the patients with ALL/biphenotypic AL according to MRD status after allo-HSCT

Figure 2. Probability (CI) of relapse (A), OS (B), and EFS (C) in patients with ALL/biphenotypic AL according to MRD levels after alloHSCT. Curves are designated black (MRD –); green (MRD >10-3); or red (MRD <10-3)

Comparison of MRD results obtained by different targets/methods

In nine patients, MRD was monitored by Ig/TCR rearrangements, as well as expression of BCR-ABL1 (n=4), MLL-AF4 (n=4), TEL-AML1 (n=1). In only one case, the results were discordant, i.e., the abovementioned patient who was negative by Ig/TCR target (loss of the target), but he was positive for MLL-AF4. In four patients, MRD was not detected, either by expression of BCR-ABL1 (n=2), MLL-AF4 (n=2), or Ig/TCR targets. Positive MRD was detected by both methods in four patients. Paired points for comparison were available in two patients. In one case, positive MRD was detectable by both approaches (MLL-AF4 and Ig/TCR markers). In another case (patient №12), we observed earlier appearance of MRD in BM as detected by TEL-AML expression (on day +98), than by Ig/TCR marker (detected at the next point of D+124). Hence, the fi rst method seems to be more sensitive (Fig. 3).

Table 2. Time dynamics of MDR in patients with ALL

Figure 3. MRD time course in Patient #12, according to TEL-AML expression and Ig/TCR rearrangement (Igk). Abscissa, gene copy number (log10); ordinate, terms posttransplant

MRD measured by immunophenotyping and Ig/TCR rearrangements was monitored in four patients in parallel (at the same time points aft er HSCT). Negative MRD was detected by both methods in one patient. In three patients, we received discordant results: there were positive MRD values of <10-3 detected by Ig/TCR gene rearrangements, however, being negative by immunophenotyping technique. Nevertheless, negative results were observed in some cases by both methods.

Comparison of MRD data obtained by Ig/TCR and chimerism markers

Donor chimerism monitoring was performed in all 35 patients.
1) Full donor chimerism (FDC) and negative MRD state were detected in 19 patients, only 2 of them have relapsed (Table 3). In one patient with loss of Ig/TCR target, a relapse was diagnosed more than 2 months aft er last chimerism monitoring in BM cells (D+377, late isolated BM relapse). Th e second patient with extramedullary CNS relapse had negative MRD and FDC in PB and BM cells, even at the time of relapse.
2) Mixed chimerism (MC) and negative MRD were detectable in 2 cases. One patient had negative MRD and MC (98.9%) in BM on D +30. Th is patient reached FDC (since +60 day), but died with infectious complications on D +542. Th e second patient showed FDC conversion to increasing MC accompanied by infection, and died on D +78.
3) FDC and positive MRD (up to 1.6*10-1) was observed in 7 patients, two of them have relapsed. Th e patient №12 had BM relapse on D +522, with last testing point at D +347, when full donor chimerism and MRD of 5*10-5 were determined. In the second patient (№13), a BM relapse was diagnosed by the D+226. Slightly decreased chimerism level of 99.1% was registered in blood leukocytes, along with increased MRD level to 15% at the last term before the relapse (D+197). In three patients with FDC, we observed MRD clearance, the rest of them retained their MRD positivity at the last examination.

Table 3. Comparison of MRD and chimerism monitoring data in ALL patients

4) MC and positive MRD was traced in seven patients, five of them had the disease recurrence. Before relapse, an increase of MC and MRD up to 2.2*10-2 was observed in four patients (the fi ft h patient had an early relapse, and only one monitoring point before relapse). Patient №5 with increasing MC has shown graft rejection on D +74 with subsequent autorecovery without ALL reoccurrence, with MRD levels in BM of <10-4 on days +27 to +39, then becoming negative at later terms. Patient №1 had an MC state (98.5% on D+30 in BM and PC) with FDC state achieved by the D +60; this patient is now alive, being in complete remission.
Thus, we have revealed suffi cient concordance between MRD and donor chimerism in 26 (74.3%) out of 35 cases. Th =e most favorable group comprised a subgroup with negative MRD and FDC, an intermediate group consisted of patients with positive MRD and FDC, and the most unfavorable group included the patients with positive MRD and increasing MC. Th e respective 3-year CI of relapse for these groups were as follows: 11.9 ± 8.2% vs 41.7 ± 29.5% vs 80.0 ± 23.9% (p<0.0008); the OS values were 94.4 ± 5.4% vs 44.4 ± 22.2% vs 20.0 ± 17.9% (p=0.0029); EFS probability was 75.0 ± 11.0% vs 25.0 ± 20.4% vs 0% (p<0.0001), respectively (Fig. 4).

Dependence of survival upon MRD and GVHD association

Grade I-IV acute GvHD (aGvHD) was observed in 17 (48.6%) of 35 patients, and six of them were diagnosed with severe aGvHD (grade III-IV). MRD-negative state was registered more oft en in the patients with aGvHD (in 13 of 17 cases), as compared to the GvHD-free cases (8 of 18 patients, p=0.085).
1) Among 13 patients with negative MRD and aGvHD, only 1 (7.7%) patient had relapse in CNS.
2) Among eight patients with negative MRD without aGvHD, nobody has relapsed.
3) None of the four patients with positive MRD and aGvHD relapsed. MRD clearance occurred in 4 patients (40%) on the days +100–+150.
4) In seven (70%) of 10 patients with positive MRD without aGvHD disease reoccurred. Four of these 10 patients received DLI, 2 of them experienced relapse despite GvHD signs observed aft er IDL.
Clinical outcomes of the patients with negative MRD without aGvHD, patients with negative MRD with aGvHD, and patients with positive MRD and aGvHD were nearly similar, being defi nitely better than in the group of aGvHD-free patients with positive MRD. Th e three-year CI of relapse rates were as follows: 20.0±20.0% vs 7.7±7.7% vs 0% vs 80.0±20.2% (p=0.008).Th e respective, overall survival probability was 80.0±17.9% vs 84.6±10.0% vs 66.7±27.2% vs 18.0±15.1% (p=0.026). Th e EFS values for these subgroups were: 60.1±21.9% vs 67.3±13.6% vs 66.7±27.2% vs 0% (p=0.0004), respectively (Fig. 5).

Figure 4. Probability of relapse (A), OS (B) and EFS (C) in patients with ALL/biphenotypic AL according to MRD and chimerism after allo-HSCT. Curves are designated black (MRD+/FDC); green (MRD+/FDC); or red (MRD-/ mixed chimerism increase)

Discussion

The MRD monitoring can help to identify presence of tumor cells that survived aft er the conditioning. However, this assay is applicable only for patients with a defi ned marker (chimeric oncogenes, mutations, Ig/TCR rearrangements or leukemia-associated immunophenotype). Identifi cation of tumor-specifi c mutations is the most accurate diagnostic approach showing high specifi city. However, the structure of these mutations should be suitable for MRD monitoring, with a sensitivity of, at least, 10-4 [36]. In ALL monitoring, quantitative real-time PCR (qPCR) allows to determine MRD by specifi c chimeric oncogenes/transcripts, point mutations and other rearrangements, such as BCR-ABL1, PML/ RARa, RUNX1-RUNX1T1 (AML1-ETO), CBFB-MYH11, MLL translocations, at a high sensitivity of 10-5-10-6 [37]. Chimeric oncogenes are detected only in a small number of patients with ALL [36, 38]. In our study, they were found only in 11% of transplantation patients. Th ere exists another alternative to chimeric oncogenes and mutations in ALL, i.e., clonal rearrangements of Ig and TCR genes, which are an attractive marker for MRD monitoring, being detectable in vast majority of ALL patients (up to 90-95% [36, 37], 82% of our patients).
Analytical sensitivity is an important aspect of MRD assay, since an arising leukemic clone posttransplant is regarded as an unfavorable event. MRD monitoring with Ig/TCR has a good sensitivity up to 10-4-10-5. Measurement of chimeric oncogene expression may be an even more sensitive approach in some cases, since a single malignant cell may contain several dozens or even thousands copies of chimeric oncogenes. It increases sensitivity up to 1 lg10, thus allowing earlier detection of tumor cells aft er allo-HSCT than with DNA-targets. However, the predictive value of individual methods and expression markers is not well defi ned. By contrast, MRD monitoring procedure with Ig/TCR rearrangements has been standardized and provides comparable results obtained from diff erent patients, which makes it possible to assess not only the presence of MDR aft er alloHSCT, but also takes its levels into account [4, 36, 37, 39]. Immunophenotyping using fl ow cytometry has a lower sensitivity (up to 10-4) than PCR-based methods. Its application for MRD monitoring aft er allo-HSCT is limited due to diffi culties with interpretation of results [40]. Bone marrow regeneration after allo-HSCT makes it diffi cult to identify leukemic cells on the background of normal lymphoid precursors [1].
It is also necessary to consider the stability of various MRD markers [36]. In rare cases, the Ig/TCR target can be lost due to somatic mutations accumulating in tumor cells [41, 42], what we have found in one case (2.9% of total group). RQ-PCR measuring of Ig/TCR rearrangements provides suitable sensitivity and specifi city, being, however, complicated by high costs of the assay, delayed purchasing of ASO, and loss of a gene target in rare cases. However, this method has been accepted in Europe as a standard approach to MRD monitoring [1].
Chimerism assays are used for assessing donor cell engraftment, but they also can be applied for relapse prediction. The study of chimerism by InDel-PCR has a sensitivity of 10-4 [30, 32], but up to 1% of the recipient cells, even after myeloablative conditioning, may be normally present in BM and PB aft er allo-HSCT [43, 44]. Th erefore, the sensitivity of donor chimerism for prediction of relapses is limited to 10^-2.

Figure 5. Probability of relapse (A), OS (B) and EFS (C) in patients with ALL/biphenotypic AL according to MRD and chimerism after allo-HSCT. Curves are designated black (MRD-/no GVHD); blue (MRD-/aGVHD); red (MRD+/ no aGVHD); or green (MRD+/aGVHD)

In addition, the chimerism monitoring is a non-specific method, since the persistent residual cells of recipient origin can be either normal hematopoietic or malignant cells, or both.
MRD monitoring allows identifying the ALL patients being at high risk for relapses aft er alloHSCT. It was shown in ALL patients that the level of MRD before transplantation significantly aff ects the result of posttransplant outcome [4, 40, 45-52]. Not all patients with negative MRD pre-transplant remain relapse-free at later terms, as well as not all patients with positive MRD relapse aft er HSCT. Th erefore, the measurement of MRD post-HSCT is another powerful tool, with a potential for more precise relapse prediction. A limited number of trials has explored the role of MRD assays in the post-HSCT period [1]. Post-HSCT positive MRD strongly associated with high risk of relapse and low survival in childhood ALL [4, 40, 50, 52–55]. Th e presence of detectable MRD aft er transplant was independent of other factors, including pre-HCT MRD and aGVHD status [40].
In our study, the presence of MRD aft er allo-HSCT significantly increased the probability of disease recurrence and led to poor overall and event-free survival. We showed that the risk of relapse was increased only in the patients with high MRD levels (>10-3, CI of relapse is 100%), whereas risk of relapse did not diff er for the patients with MRD ≤10-3 and with negative MRD, (CI of relapse 11% and 15% accordingly). Similarly, Balduzzi et al. have shown that the patients who had high MRD >10-3 at any time point post-HSCT, did relapse, despite any attempts to prevent the recurrence of disease [54]. Most patients relapsed with MRD level of >10-3, but the patients with MRD <10-3-10-4 were more likely to clear their leukemia cells [52, 54, 56]. By contrast, the study of Bader et al. [53] has shown that any level of MRD aft er allo-HSCT did increase risk of relapse, even MRD <10-4 , if compared to MRD-free patients on D+60, +90 and +180, but not on +30 days, and the same results were reported by Zhao group [55]. However, our data and results from other authors [52-54, 56] suggest that the patients with low posttransplant MRD levels <10-3-10-4 do not necessarily relapse, and additional risk stratifi cation is needed.
Despite recommendations on monitoring of MRD and chimerism for relapse prediction of ALL aft er alloHSCT, there are only few studies comparing these two methods [20, 56, 57], and the results of these studies do not give a complete answer as to how a combination of these approaches can improve relapse prediction. We have obtained concordant results between MRD and chimerism in 74% cases. Standard methods for determining MPD are of >1lg10 more sensitive, than the methods for chimerism detection. Th e main diff erence between these two approaches is that MRD monitoring directly determines the residual tumor cells and the chimerism analysis gives only information about the persistence/ recoverye of autologous hematopoiesis. Reappearance of recipient cells may indicate the establishment of immunological tolerance thus potentially leading to a weaker immunological surveillance of malignant cells and the development of relapse [58]. Rarely, stable mixed chimerism in some patients with malignant diseases may persist for up to 20 years after alloHSCT, and it does not lead to relapse or rejection [59], although this is rather an exception to the rules. In the majority of cases, the onset of increasing mixed chimerism precedes disease recurrence [19, 20, 32, 60-62].
In our study, a combination of these two diagnostic approaches makes it possible to stratify patients into groups of high, intermediate and low risk of relapse with a very high accuracy. Th e most favorable group was presented by the patients with negative MRD and FDC with a good OS (94%) and EFS (75%), and a low incidence of relapse (12%). Th e presence of MRD combined with increasing MC led to the development of relapses in almost all patients (CI relapse 80%) and signifi cantly worse OS (20%) and EFS (0%). In the presence of FDC, some patients showed MRD clearance and became MRD-negative, but this group of patients still had relatively high risk of relapse (CI relapses 42%) and intermediate OS (44%) and EFS values (25%). Patients couldclear their MRD by an immunologic graft -versus-leukemia (GvL) eff ect, but MRD must be cleared until the establishment of graft tolerance towards the recipient; otherwise, uncontrolled proliferation of residual leukemia cell fi nally results in hematological relapse [54]. Th e patients with positive MRD in late posttransplant period are shown to relapse more readily, when compared to patients with MRD positivity over the fi rst 1-2 months [53-56]. During the initial phase aft er allo-HSCT (within the fi rst 2 months), immunologic reconstruction is incomplete, and GvL eff ect is not fully exhibited [55]. Our study also confi rms the theory of immunological tolerance, because MRD clearance was more often observed in patients with FDC and GvHD, or after DLI. None of the patients with positive MRD developed bone marrow relapse in the presence of GvHD, in contrast to patients with no GVHD (CI relapse 80%). The role of the GvL eff ect is supported by studies showing that the ALL patients who experience GvHD have a lower risk of relapse [40, 49, 56]. As a rule, these three parameters (MRD, GVHD and chimerism) are interrelated. Detection of MC was oft en combined with positive MRD and lack of GVHD. Absence or reduction of MRD was observed in the patients with FDC and GVHD development.
We have shown that the combination of MRD and chimerism monitoring allows stratifi cation of ALL patients into the groups of relapse risk. In contrast to previous studies [54, 56], we were able to fi nd out prognostic value of increasing MC due to application of sensitive PCR-based method of chimerism detection and testing of BM samples, along with PB cells. Our study demonstrates the combined eff ect of MRD, chimerism and GVHD on the outcomes in allo-HSCT patients. A serious issue is associated with development of extramedullary relapses which are underdiagnosed because they can manifest with no detectable MRD and in FDC state in the presence of GVHD, even in relapse burden [56, 63]. Th ere is also a risk to miss early signs of relapse, if the monitoring intervals for the marrow chimerism and MRD exceed 2 months. We recommend monitoring BM at least once or twice a month over fi rst 6-12 months aft er alloHSCT, when the risk of relapse is high, especially for the patients with previous positive MRD and/or MC, and absence of GVHD signs.
Like other workers, we observed that, in patients with MRD level of <10-3, the clearance of malignant clone can be achieved with preventive immunotherapy [54, 64]. In view of these considerations, MRD combined with chimerism could be used as a tool to guide posttransplant pre-emptive immunomodulation or immunotherapy, in order to prevent a disease relapse.

Conclusion

The presence of positive MRD aft er allo-HSCT is known to be an unfavorable prognostic factor associated with relapses, poor overall and decreased event-free survival. In patients with ALL, the presence of MRD aft er allo-HSCT is not always associated with development of relapses. The manifestation of the GvL eff ect can be observed in patients with FDC and GvHD or aft er DLI. Th e patients of a high-risk group for relapse include those with high MRD level >10-3, as well as the patients in whom the presence of MRD is combined with increasing mixed chimerism and/or absence of GVHD. Monitoring of MRD in bone marrow does not always allow
us to detect extramedullary relapses.

Acknowledgements

The authors report no confl icts of interest.

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К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК. </p> <h2 style="text-align: justify;">Пациенты и методы</h2> <p style="text-align: justify;"> Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и &gt;10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p&lt;0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и &gt;10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов. </p> <h2 style="text-align: justify;">Выводы</h2> <p style="text-align: justify;"> Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. 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Лавриненко ¹, Александр Н. Мелешко ¹, Дмитрий В. Луцкович ¹, Юлия Е. Марейко ¹, Дмитрий В. Прудников ¹, Михаил В. Белевцев ¹, Ольга В. Алейникова ¹, Ильдар М. Бархатов ², Борис В. Афанасьев ²<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(448) "Виктория А. Лавриненко ¹, Александр Н. Мелешко ¹, Дмитрий В. Луцкович ¹, Юлия Е. Марейко ¹, Дмитрий В. Прудников ¹, Михаил В. Белевцев ¹, Ольга В. Алейникова ¹, Ильдар М. Бархатов ², Борис В. Афанасьев ²
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² НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Российская Федерация
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Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК.

Пациенты и методы

Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и >10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p<0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и >10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов.

Выводы

Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3.

Ключевые слова

Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов.

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² R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian Federation" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20892" ["VALUE"]=> array(2) { ["TEXT"]=> string(2321) "<p style="text-align: justify;"> At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes<br> aft er allo-HSCT. </p> <h2 style="text-align: justify;">Patients and methods</h2> <p style="text-align: justify;"> The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and &gt;10-3 proved to  be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p&lt;0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and &gt;10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion. </p> <h2 style="text-align: justify;">Conclusion</h2> <p style="text-align: justify;"> Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD&gt;10-3. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2145) "

At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes
aft er allo-HSCT.

Patients and methods

The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to  be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion.

Conclusion

Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3.

Keywords

Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk.

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Lavrinenko ¹, Alexandr N. Meleshko ¹, Dmitry V. Lutskovich ¹, Yulia E. Mareiko ¹, Dmitriy V. Prudnikov ¹, Mikhail V. Belevtsev ¹, Olga V. Aleynikova ¹, Ildar M. Barkhatov ², Boris V. Afanasyev ²<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(309) "Victoria A. Lavrinenko ¹, Alexandr N. Meleshko ¹, Dmitry V. Lutskovich ¹, Yulia E. Mareiko ¹, Dmitriy V. Prudnikov ¹, Mikhail V. Belevtsev ¹, Olga V. Aleynikova ¹, Ildar M. Barkhatov ², Boris V. Afanasyev ²
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" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20892" ["VALUE"]=> array(2) { ["TEXT"]=> string(2321) "<p style="text-align: justify;"> At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes<br> aft er allo-HSCT. </p> <h2 style="text-align: justify;">Patients and methods</h2> <p style="text-align: justify;"> The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and &gt;10-3 proved to  be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p&lt;0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and &gt;10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion. </p> <h2 style="text-align: justify;">Conclusion</h2> <p style="text-align: justify;"> Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD&gt;10-3. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2145) "

At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes
aft er allo-HSCT.

Patients and methods

The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to  be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion.

Conclusion

Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3.

Keywords

Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk.

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At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes
aft er allo-HSCT.

Patients and methods

The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to  be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion.

Conclusion

Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3.

Keywords

Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk.

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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(448) "Виктория А. Лавриненко ¹, Александр Н. Мелешко ¹, Дмитрий В. Луцкович ¹, Юлия Е. Марейко ¹, Дмитрий В. Прудников ¹, Михаил В. Белевцев ¹, Ольга В. Алейникова ¹, Ильдар М. Бархатов ², Борис В. Афанасьев ²
" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20888" ["VALUE"]=> array(2) { ["TEXT"]=> string(3918) "<p style="text-align: justify;"> Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК. </p> <h2 style="text-align: justify;">Пациенты и методы</h2> <p style="text-align: justify;"> Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и &gt;10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p&lt;0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и &gt;10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов. </p> <h2 style="text-align: justify;">Выводы</h2> <p style="text-align: justify;"> Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3752) "

Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК.

Пациенты и методы

Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и >10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p<0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и >10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов.

Выводы

Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3.

Ключевые слова

Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов.

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Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК.

Пациенты и методы

Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и >10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p<0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и >10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов.

Выводы

Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3.

Ключевые слова

Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов.

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² НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Российская Федерация
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² НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Российская Федерация
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	 Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
	 Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан.
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	 Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий.

Ключевые слова

	 Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан.

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	 Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations.
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<h2 style="text-align: justify;">Keywords</h2>
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	 Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide.
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	 Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations.

Keywords

	 Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide.

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                    [TEXT] => <sup>1</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова» Министерства здравоохранения России<br>
 <sup>2</sup> Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия<br>
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 2 Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия

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	 В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК.
</p>
<h2 style="text-align: justify;">Пациенты и методы</h2>
<p style="text-align: justify;">
	 В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ).
</p>
<h2 style="text-align: justify;">Результаты</h2>
<p style="text-align: justify;">
	 АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85.
</p>
<h2 style="text-align: justify;">Заключение</h2>
<p style="text-align: justify;">
	 АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что<br>
	 требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
	 Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения.
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	 В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК.

Пациенты и методы

	 В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ).

Результаты

	 АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85.

Заключение

	 АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что

	 требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови.

Ключевые слова

	 Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения.

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                    [TEXT] => <sup>1</sup> R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation; Chair of Hematology, Transfusiology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St.P etersburg, Russia<br>
 <sup>2</sup> St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia<br>
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 2 St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia

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	 Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients.
</p>
<h2 style="text-align: justify;">Patients and methods</h2>
<p style="text-align: justify;">
	 From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created.
</p>
<h2 style="text-align: justify;">Results</h2>
<p style="text-align: justify;">
	 ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85.
</p>
<h2 style="text-align: justify;">Conclusion</h2>
<p style="text-align: justify;">
	 ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of<br>
	 ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications.
</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
	 Hematopoietic stem cell transplantation, ABО-incompatibility, complications.
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	 Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients.

Patients and methods

	 From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created.

Results

	 ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85.

Conclusion

	 ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of

	 ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications.

Keywords

	 Hematopoietic stem cell transplantation, ABО-incompatibility, complications.

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                    [TEXT] => <sup>1</sup> Республиканский научно-практический центр детской онкологии, гематологии и иммунологии, Минск, Республика Беларусь<br>
 <sup>2</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Российская Федерация<br>
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 2 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Российская Федерация

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	 Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК.
</p>
<h2 style="text-align: justify;">Пациенты и методы</h2>
<p style="text-align: justify;">
	 Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и &gt;10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p&lt;0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и &gt;10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов.
</p>
<h2 style="text-align: justify;">Выводы</h2>
<p style="text-align: justify;">
	 Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
	 Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов.
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	 Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК.

Пациенты и методы

	 Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и >10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p<0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и >10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов.

Выводы

	 Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3.

Ключевые слова

	 Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов.

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 <sup>2</sup> R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian Federation
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 2 R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian Federation
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	 At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes<br>
	 aft er allo-HSCT.
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<h2 style="text-align: justify;">Patients and methods</h2>
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	 The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and &gt;10-3 proved to  be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p&lt;0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and &gt;10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion.
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<h2 style="text-align: justify;">Conclusion</h2>
<p style="text-align: justify;">
	 Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD&gt;10-3.
</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
	 Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk.
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	 At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes

	 aft er allo-HSCT.

Patients and methods

	 The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to  be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion.

Conclusion

	 Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3.

Keywords

	 Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk.

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