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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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The timing of post-transplant cyclophosphamide administration in haploidentical transplantation: a comparative study on behalf of the ALWP of the EBMT
Ruggeri, A., Labopin, M., Battipaglia, G., Chiusolo, P., Tischer, J., Diez-Martin, J. L., Bruno, B., Castagna, L., Moiseev, I. S., Vitek, A., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
Timing of immunosuppressive-drugs therapy used in combination with post-transplant cyclophosphamide (PTCY) in haploidentical hematopoietic stem cell transplant (Haplo-HSCT) is not standardized. We evaluated the schedule of immunosuppression therapy after haplo-HSCT in 509 patients with acute leukemia receiving PTCY on day +3 and +4 along with tacrolimus (group 1, n=215) or cyclosporine A (CSA) and mycophenolate -mofetil (MMF) from day+5 (group 2, n=170) or CSA+MMF from day 0 or 1 with PTCY on day +3 and +5 (group 3, n=124). Patients in group 3 were younger (median age 46 years, p=0.02), received bone marrow (77%, p<0.01) and a regimen containing thiotepa, fludarabine and busulfan (84%, p<0.01) more frequently. At 2 years, OS was 44%, 48% and 59% (p=0.15), LFS was 43%, 46%, and 53%, (p=0.05) and refined-GRFS (rGRFS) was 33%, 39% and 36% (p=0.02), in groups 1, 2 and 3, respectively. Grade II-IV acute GVHD was 25%, 39% and 18%, respectively (p<0.01), and chronic GVHD was 25%, 21% and 24% (p=0.50) for the 3 groups, respectively. Relapse incidence was 36%, 37% and 26%, (p=0.02) and NRM was 26%, 20% and 21% (p=0.35) for the 3 groups, respectively. On multivariate analysis, the early start of ISTimmunosuppression therapy at day+1 followed by PTCY was associated with a better LFS (hazard ratio (HR) 0.58, p=0.02) and an improved rGRFS (HR 0.62, p=0.02). In our study, timing of immunosuppression influences outcomes of haplo-HSCT with PTCY. The early starting of CSA+MMF with PTCY administered on day +3 and +5 improves LFS and rGRFS.
PICO Summary
Population
Patients with acute leukaemia undergoing haploidentical transplantation (n=509)
Intervention
Post-transplant cyclophosphamide (PTCY) on day +3 and +4 along with tacrolimus (group 1, n=215)
Comparison
Cyclosporine A (CSA) and mycophenolate -mofetil (MMF) from day+5 (group 2, n=170) or CSA+MMF from day 0 or 1 with PTCY on day +3 and +5 (group 3, n=124)
Outcome
Patients in group 3 were younger (median age 46 years), received bone marrow (77%) and a regimen containing thiotepa, fludarabine and busulfan (84%) more frequently. At 2 years, OS was 44%, 48% and 59%, LFS was 43%, 46%, and 53%, and refined-GRFS (rGRFS) was 33%, 39% and 36%, in groups 1, 2 and 3, respectively. Grade II-IV acute GVHD was 25%, 39% and 18%, respectively, and chronic GVHD was 25%, 21% and 24% for the 3 groups, respectively. Relapse incidence was 36%, 37% and 26%, and NRM was 26%, 20% and 21% for the 3 groups, respectively. On multivariate analysis, the early start of ISTimmunosuppression therapy at day+1 followed by PTCY was associated with a better LFS (hazard ratio (HR) 0.58) and an improved rGRFS (HR 0.62).
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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.