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Post-transplant сyclophosphamide after matched donor hematopoietic stem cell transplantation in children with acute leukemia
Borovkova, A. S., Paina, O. V., Semenova, E. V., Bykova, T. A., Osipova, A. A., Slesarchuk, O. A., Kozhokar, P. V., Tsvetkova, L. A., Rakhmanova, Z. Z., Kozlov, A. V., et al
Clinical transplantation. 2023;:e15181
Abstract
INTRODUCTION The data on post-transplant cyclophosphamide (PTCy) in pediatric acute leukemia after matched allo-HSCT are limited to case series. The present study aimed to assess the results of PTCy-based GVHD prophylaxis in a large cohort of children with acute leukemia after matched allo-HSCT. METHODS A retrospective analysis of 190 pediatric patients with acute leukemia who had a first allograft between 2008 and 2020 from a matched sibling donor (MSD) or matched unrelated donor (MUD) was carried out. In the MSD setting, GVHD prophylaxis consisted of PTCy alone (n = 28) for the study group, and calcineurin inhibitor (CNI) ± antimetabolite (n = 30) for the control group. In MUD setting, most patients in the study group received GVHD prophylaxis with PTCy+CNI+mycophenolate mofetil (n = 42, 66.7%) or PTCy+CNI+sirolimus (n = 12, 19%). All patients (n = 69) in the control group received ATG+CNI+antimetabolite. RESULTS After MUD allo-HSCT, the incidences of acute GVHD grade III-IV and moderate/severe chronic GVHD were significantly lower in the PTCy group compared to control (6.6% vs. 35.0% and 12.7% vs. 47.1%, respectively, p < .0001). Five-year GVHD-free, relapse-free survival (GRFS) after MUD allo-HSCT was higher in the PTCy group compared to control (35.1% vs. 7.3%, p < .0001). At the same time, there was no significant difference between both groups after MSD allo-HSCT. CONCLUSIONS In pediatric acute leukemia, PTCy-based GVHD prophylaxis for MUD allo-HSCT is a feasible and effective option that results in a low incidence of GVHD. Compared to the ATG-based approach, PTCy provides better control of GVHD in children. In pediatric allo-HSCT from MSD, PTCy demonstrates comparable effectiveness to conventional GVHD prophylaxis.
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A pilot study of implication of machine learning for relapse prediction after allogeneic stem cell transplantation in adults with Ph-positive acute lymphoblastic leukemia
Afanaseva, K. S., Bakin, E. A., Smirnova, A. G., Barkhatov, I. M., Gindina, T. L., Moiseev, I. S., Bondarenko, S. N.
Scientific reports. 2023;13(1):16790
Abstract
The posttransplant relapse in Ph-positive ALL increases the risk of death. There is an unmet need for instruments to predict the risk of relapse and plan prophylaxis. In this study, we analyzed posttransplant data by machine learning algorithms. Seventy-four Ph-positive ALL patients with a median age of 30 (range 18-55) years who previously underwent allo-HSCT, were retrospectively enrolled. Ninety-three percent of patients received prophylactic/preemptive TKIs after allo-HSCT. The values of the BCR::ABL1 level at serial assessments and over variables were collected in specified intervals after allo-HSCT. They were used to model relapse risk with several machine-learning approaches. GBM proved superior to the other algorithms and provided a maximal AUC score of 0.91. BCR::ABL1 level before and after allo-HSCT, prediction moment, and chronic GvHD had the highest value in the model. It was shown that after Day + 100, both error rates do not exceed 22%, while before D + 100, the model fails to make accurate predictions. As a result, we determined BCR::ABL1 levels at which the relapse risk remains low. Thus, the current BCR::ABL1 level less than 0.06% in patients with chronic GvHD predicts low risk of relapse. At the same time, patients without chronic GVHD after allo-HSCT should be classified as high risk with any level of BCR::ABL1. GBM model with posttransplant laboratory values of BCR::ABL1 provides a high prediction of relapse after allo-HSCT in the era of TKIs prophylaxis. Validation of this approach is warranted.
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Graft-versus-host disease prophylaxis with posttransplantation bendamustine (PTB) in patients with refractory acute leukemia: a dose-ranging study: Category of manuscript: Regular Manuscript
Moiseeev, I. S., Bondarenko, S. N., Morozova, E. V., Vlasova, Y. Y., Dotsenko, A. A., Epifanovskaya, O. S., Babenko, E. V., Botina, A. V., Baykov, V. V., Surkova, E. A., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND The prognosis of acute leukemia refractory to induction chemotherapy or immunotherapy is dismal. Salvage allogeneic hematopoietic stem cell transplantation (HSCT) is widely used option for these patients, but only 10-15% of patients are cured by the procedure. Preclinical studies indicate that substitution of posttransplantation cyclophosphomide (PTCY) with bendamustine (PTB) in a prophylaxis regimen may be associated with augmented graft-versus-leukemia (GVL) reaction. OBJECTIVE establish the optimal dose of PTB and evaluate the anti-leukemic effect of HSCT with this type of graft-versus-host disease (GVHD) prophylaxis. STUDY DESIGN In the prospective trial (NCT02799147) PTB was administered in doses 140, 100 and 70 mg/m2 on days +3,+4. Myeloablative conditioning with fludarabine and oral busulfan was performed in all patients. First 12 patients received single-agent PTB and subsequent- combination with tacrolimus and MMF. Inclusion criteria were acute myeloblstic (AML) or lymphoblstic leukemia (ALL) refractory to at least on induction course of chemotherapy or target therapy and =5% clonal blasts in the bone marrow. Seven patients were enrolled in the 140 mg/m2 cohort (due to stopping rule), 10 in 100 mg/m2 and 10 in 70 mg/m2 group, including 22 with AML and 5 with ALL. Primary refractory disease was documented in 41% of patients and secondary refractory - in 59%. Median blast count in the bone marrow at the start of the conditioning was 18% (range 6-97%). Matched sibling transplantation was performed in 5 patients, matched or mismatched unrelated in 15, and haploidentical in 7. RESULTS Engraftment was documented in 93% of patients, including 89% with complete remission (CR) and 63% without measurable residual disease (MRD). After PTB prophylaxis we observed an unusual complication, a cytokine release syndrome (CRS), in 70% of the patients, including grade 3-5 in 44% of patients. Most often clinical symptoms included high fever in 67% of patients, abnormal liver function tests in 67%, pancreatitis in 63%, skin vasculitis in 56%, enterocolitis in 48%, inflammation of oral mucosa in 37%, disseminated intravascular coagulation (DIC) in 37%, CNS toxicity in 26%. Development of CRS was associated with HLA-mismatched donor (75% vs 20%, p= 0.0043). Classical acute GVHD was documented in 44% of patients. Grade II-IV acute GVHD was associated with grade 3-5 CRS (67% vs 25%, p=0.031). Moderate and severe chronic GVHD in the 100-day survivors was more often observed after single-agent PTB than after the combination immunosuppression (100% vs 18%, p=0.002). Relatively low relapse incidence was observed for this patient population. Three-year overall survival was 28% (95% CI 13-46%), event-free-survival 29% (95% CI 13-46%). NRM was 46% (95% CI 25-64%), CIR was 26% (95%CI 11-44). No relapses were documented after day+100. There was no statistical differences between the dose groups (p=0.3481), however the survival was higher in the 100 mg/kg group. The survival was higher in AML than ALL (35% vs 0%, p=0.0157). CONCLUSION PTB represents a promising option to augment GVL effect in refractory AML, however high CRS-associated mortality requires additional studies to reduce the risk of this complication. Thus, routine clinical application of PTB cannot be currently recommended. Combination immunosuppression with tacrolimus and MMF partially ameliorates these complications at least in the setting of HLA-matched allografts. Biological mechanisms of CRS and GVL after PTB require further elucidation.
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Graft-versus-Host Disease Prophylaxis in Unrelated Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil
Moiseev, I. S., Pirogova, O. V., Alyanski, A. L., Babenko, E. V., Gindina, T. L., Darskaya, E. I., Slesarchuk, O. A., Bondarenko, S. N., Afanasyev, B. V.
Biology of Blood & Marrow Transplantation. 2016;22(6):1037-42
Abstract
Clinical efficacy of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has been demonstrated in haploidentical and HLA-matched bone marrow but not in unrelated peripheral blood stem cell (PBSC) transplantations. Also, no direct comparisons have been published with current standard of care, combination of antithymocyte globulin (ATG), calcineurin inhibitors, and either methotrexate or mycophenolate mofetil (MMF). Eighty-six adult patients (median age 34 years; range, 18 to 59) with acute myeloblastic and lymphoblastic leukemia underwent unrelated PBSC transplantation with PTCy, tacrolimus, and MMF as GVHD prophylaxis in the single-center trial (clinicaltrial.govNCT02294552). The control group comprised 125 consecutive historical control patients who received ATG, tacrolimus, and methotrexate or MMF. Cumulative incidences of grades II to IV acute (19% versus 45%, P = .0003), grades III to IV acute (4% versus 27%, P < .0001), and chronic GVHD (16% versus 65%, P < .0001) were significantly lower in the PTCy compared with the ATG group. PTCy-based prophylaxis was associated with reduced incidence of nonrelapse mortality (16% versus 36%, P = .005; HR, .55; 95% CI, .34 to .89) and improved overall survival (69% versus 40%, P = .0007; HR, .43; 95% CI, .26 to .70), event-free survival (65% versus 38%, P = .0006; HR, .49; 95% CI, .31 to .78), and GVHD relapse-free survival (52% versus 12%, P < .0001). PTCy-based prophylaxis also had a better safety profile compared with ATG with reduced incidence of veno-occlusive disease, cytomegalovirus reactivation, invasive mycosis, and reduced severity of mucositis. In this study we demonstrated that PTCy in combination with tacrolimus and MMF is a safe and effective GVHD prophylaxis for unrelated PBSC transplantation. Although there are several limitations of the historical control approach, this study suggests the superiority of a PTCy-based approach over an ATG-based prophylaxis. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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[Acute Ph-negative lymphoblastic leukemias in adults: Risk factors in the use of the ALL-2009 protocol]. [Russian]
Parovichnikova, E. N., Sokolov, A. N., Troitskaya, V. V., Klyasova, G. A., Rusinov, M. A., Akhmerzaeva, ZKh, Kuz'mina, L. A., Bondarenko, S. N., Baranova, O. Y., Kaporskaya, T. S., et al
Terapevticheskii Arkhiv. 2016;88(7):15-24
Abstract
AIM: to analyze well-known risk factors (RFs), such as age, immunophenotype, baseline leukocytosis, enhanced lactate dehydrogenase (LDH) activity, time to achieve complete remission, a risk group, and cytogenetic abnormalities) in patients with acute lymphoblastic leukemia (ALL) in the use of the ALL-2009 protocol. SUBJECTS AND METHODS The protocol covered 298 patients (137 women (including 13 pregnant women) and 161 men) aged 15 to 55 years (median age 28 years) with Ph-negative ALL. The phenotype was unknown in 6 patients. Three (1%) were ascertained to have a biphenotypic variant. 182 (62.4%) patients were found to have B-cell ALL (early pre-B ALL (n=51); common ALL (n=92), and pre-B ALL (n=39); 107 (36.6%) patients had T-cell ALL (early T-ALL (n=56); thymic T-ALL (n=41), and mature T-ALL (n=10). According to the baseline clinical and laboratory parameters (leukocytosis of 30.109/l and more for B-ALL; and that of 100.109/l and more for T-ALL; phenotype B-I for B-ALL, phenotype T-I-II-IV for T-ALL; LDH activity was more than twice the normal values; the presence of translocation t(4;11)), the high-risk group included most patients with B-ALL (n=110 (72.8%)) and T-ALL (n=76 (76%)). Thirty-five patients with T-ALL underwent autologous bone marrow transplantation (BMT). Allogeneic BMT was performed in 18 (7%) of the 258 patients who had undergone an induction phase. RESULTS Five-year overall survival for all the patients included in the investigation was 59%; relapse-free survival was 65%, which was significantly different in the patients with B-ALL and in those with T-ALL: the overall survival rates were 53.3 and 67.5% (p=0.1); the relapse-free survival was 56 and 79% (p=0.005), respectively. Multivariate analysis including the well-known RFs demonstrated that the latter for T-ALL were of no independent prognostic value and only the patient's age was identified for B-ALL (p=0.013). CONCLUSION A lower chemotherapeutic load and a small number of allogeneic BMTs did not affect total positive treatment results in adult patients with ALL, by complying with the principle achieving the continuity of cytostatic effects and by preserving the total cytostatic loading dose. The results of the Russian investigation casts some doubt on the necessity of using very intensive consolidation cycles and performing a large number of allogeneic BMTs in adult patients with ALL.