1.
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.
2.
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.