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1.
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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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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A Prospective Pilot Study of Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide and Ruxolitinib in Patients with Myelofibrosis
Morozova, E. V., Barabanshikova, M. V., Moiseev, I. S., Shakirova, A. I., Barhatov, I. M., Ushal, I. E., Rodionov, G. G., Moiseev, S. I., Surkova, E. A., Lapin, S. V., et al
Acta haematologica. 2020;:1-8
Abstract
INTRODUCTION This prospective study evaluated a calcineurin inhibitor-free graft-versus-host disease (GVHD) prophylaxis regimen of ruxolitinib in combination with post-transplant cyclophosphamide (PTCy). Patents and Methods: Twenty patients with primary or secondary myelofibrosis were prospectively enrolled. Reduced intensity conditioning was performed, followed by allogeneic stem cell transplantation from related (n = 7) or unrelated (n = 13) donors. GVHD prophylaxis included only PTCy and ruxolitinib (45 mg) from day-7 to day-2, and 15 mg from day+5 to day+100. This trial was registered at www.clinicaltrials.gov as #NCT02806375. RESULTS Primary engraftment was documented in 17 patients. One patient experienced primary graft failure and 2 died before engraftment. Eleven patients demonstrated severe poor graft function (SPGF), which required ruxolitinib dose reduction. The regimen was well tolerated, with grade 3-4 non-haematological toxicity in 30%, viral reactivation in 45%, and severe sepsis in 15% of patients. The incidence of acute GVHD grade II-IV was 25%, grade III-IV GVHD was 15%, and moderate chronic GVHD was 20%, with no severe cases. Only 2 patients required systemic steroids. Haematological relapse was documented in 1 patient. Two-year non-relapse mortality was 15%, 2-year overall survival was 85%, and 2-year event-free survival was 72%. CONCLUSION GVHD prophylaxis with PTCy and ruxolitinib is associated with low toxicity, good acute and chronic GVHD control, and low relapse incidence. However, the relatively high rate of SPGF should be taken into account. SPGF could possibly be mitigated by ruxolitinib dose reduction.
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4.
Risk-adapted GVHD prophylaxis with post-transplantation cyclophosphamide in adults after related, unrelated, and haploidentical transplantations
Moiseev, I. S., Pirogova, O. V., Alyanski, A. L., Babenko, E. V., Gindina, T. L., Darskaya, E. I., Slesarchuk, O. A., Bykova, T. A., Chukhlovin, A. B., Pevtcov, D. E., et al
European journal of haematology. 2018;100(5):395-402
Abstract
INTRODUCTION Although a number of studies were published on the efficacy of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis, no large studies prospectively evaluated this strategy in related, unrelated, and haploidentical grafts. METHODS In this study, GVHD prophylaxis for 57 matched bone marrow (MBM) grafts consisted of single-agent PTCy, for 88 matched PBSC grafts (MPBSC) consisted of PTCy, tacrolimus, and mycophenolate mofetil (MMF) 30 mg/kg, and for 55 mismatched grafts (MMGs) consisted of PTCy, tacrolimus and MMF 45 mg/kg. RESULTS The study met the primary endpoint to demonstrate equivalent rates of acute GVHD grade II-IV (11%, 17%,19%, P = .46), III-IV (7%, 2%, 6%, P = .41), and moderate and severe chronic GVHD (22%, 11%, 15%, P = .23). There was also no differences in non-relapse mortality (11% vs 15% vs 17%, P = .75), overall survival (63% vs 71% vs 56%, P = .72), event-free-survival (51% vs 66% vs 48%, P = .32) for MBM, MPBSC, and MMG groups, respectively. Toxicity was comparable between groups except higher incidence of nephrotoxicity in combination arms (P = .0005) and higher incidence of graft failures in MMG group (P = .004). CONCLUSION The suggested risk-adapted PTCy-based prophylaxis is feasible and is associated with low GVHD incidence and mortality in all types of grafts. The study was registered on clinicaltrials.gov (NCT02294552).
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Profiles of pro-inflammatory cytokines in allogenic stem cell transplantation with post-transplant cyclophosphamide
Pirogova, O. V., Moiseev, I. S., Surkova, E. A., Lapin, S. V., Bondarenko, S. N., Kulagin, A. D., Afanasyev, B. V.
Cytokine. 2017;99:148-153
Abstract
Large number of studies was published about predictive value of cytokines for graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Recently, there has been a growing interest in GVHD prophylaxis with post-transplant cyclophosphamide (PTCy). Clinical data on the dynamics of proinflammatory cytokines with this prophylaxis is lacking. In this study, we have measured the levels of IL-17, IL-6, IL-8, IFN-gamma and TNF-alpha in plasma on days -7, 0, +7, +14 and after engraftment in 20 patients with acute GVHD and 40 matched control patients with PTCy-based prophylaxis. Low levels of IL-8 (p=0.04) on day +7 and IFN-gamma (p=0.03) after engraftment were associated with grade II-IV acute GVHD. The same pattern was observed for severe acute GVHD. Low IFN-gamma after engraftment was also associated with increased non-relapse mortality (p=0.014). No impact of cytokine levels on overall survival and relapse incidence was observed (p>0.05). In conclusion, the dynamics of IL-8 and IFN-gamma in GVHD patients after PTCy was different from previously reported after conventional prophylaxis. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Pharmacokinetic comparison of cyclosporin A and tacrolimus in graft-versus-host disease prophylaxis
Moiseev, I. S., Burmina, E. A., Muslimov, A. R., Pirogova, O. V., Bondarenko, S. N., Darskaya, E. I., Tarakanova, Y. A., Senina, N. G., Afanasyev, B. V.
Annals of Hematology. 2017;96(6):935-942
Abstract
A number of studies were published with contradictory results comparing tacrolimus (Tac) and cyclosporine A (CsA) for graft-versus-host disease (GVHD) prophylaxis, but there are only few that accounted for pharmacokinetic (PK) parameters. In this study, we created a model based on median concentrations, variability of concentrations, and failures to maintain target levels that distinguished patients with low, intermediate, and high risks of acute GVHD (hazard ratios (HR) 1.77, 95%CI 1.36-2.32, p < 0.0001). This model was used to compare 95 patients with CsA and 239 with Tac GVHD prophylaxis. In the multivariate analysis, incorporating PK risk, no differences were observed for grade II-IV acute GVHD (HR 0.73, 95%CI 0.48-1.10, p = 0.13), but grade III-IV acute GVHD was lower in the Tac group (HR 0.47, 95%CI 0.28-0.78, p = 0.004). The observed difference was due to patients with high PK risk (HR 0.377, 95%CI 0.19-0.75, p = 0.005), but not with low and intermediate PK risk (p > 0.05). Patients in the Tac group had better GVHD relapse-free survival (HR = 0.659, p = 0.01) and comparable overall survival (p > 0.05). In conclusion, PK risk should be accounted for in comparisons of GVHD prophylaxis regimens with calcineurin inhibitors, and Tac was superior to CsA in patients with high, but not intermediate and low PK risk.
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7.
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.