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Risk factors for outcome after allogeneic stem cell transplantation in patients with advanced phase CML
Niederwieser, C., Morozova, E., Zubarovskaya, L., Zabelina, T., Klyuchnikov, E., Janson, D., Wolschke, C., Christopeit, M., Ayuk, F., Moiseev, I., et al
Bone marrow transplantation. 2021
Abstract
Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative option for patients with advanced chronic myeloid leukemia (CML). However, outcome is dismal and of short follow-up. The objective of the study was to determine long-term outcome and risk factors in patients with a history of CML Blast Crisis (BC; n?=?96) or accelerated phase (n?=?51) transplanted between 1990 and 2018. At transplant, patients had a median age of 39 (range 7-76) years and were in =CP2 (n?=?70), in AP (n?=?40) or in BC (n?=?37) with a diagnosis-HSCT interval of median 1.9 (range 0.3-24.4) years. Overall survival (OS) amounted 34% (95% CI 22-46) and progression-free survival (PFS) 26% (95% CI 16-36) at 15 years. Adverse risk factors for OS and PFS were low CD34(+) count in the graft, donor age (>36 years) and BC. Cumulative incidence of Non-Relapse Mortality (NRM) was 28% (95% CI 18-38) and of relapse (RI) 43% (95% CI 33-53) at 15 years. PB-HSCT and HSCT after 2008 were favorable prognostic factors for NRM, while family donor and patient age >39 years were independently associated with higher RI. HSCT resulted in long-term OS in patients with advanced CML. OS was improved in non-BC patients, with donors =36 years and with higher CD34(+) dose in the graft.
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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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High prevalence of CD3, NK, and NKT cells in the graft predicts adverse outcome after matched-related and unrelated transplantations with post transplantation cyclophosphamide
Moiseev, I. S., Babenko, E. V., Epifanovskaya, O. S., Sergeev, V. S., Dotcenko, A. A., Bakin, E. A., Surkova, E. A., Kuznetsova, D. A., Lapin, S. V., Pirogova, O. V., et al
Bone marrow transplantation. 2019
Abstract
The predictive value of graft composition and plasma biomarkers on the outcome of allogeneic HSCT is well known for conventional GVHD prophylaxis based on calcineurin inhibitors with or without antithymocyte globulin. Currently, there is limited data whether these results could be translated to post transplantation cyclophosphamide (PTCy). The prospective extension cohort of NCT02294552 trial enrolled 79 adult patients with acute leukemia in CR. Twenty-six received matched-related bone marrow (BM) grafts with single-agent PTCy and 53 received unrelated peripheral blood stem cell graft (PBSC) with PTCy, tacrolimus, and MMF. The grafts were studied by the flow cytometry, and plasma samples were analyzed by ELISA. In the cluster and major component analysis, we determined that transplantation from donors with high content of CD3, NKT, and CD16-CD56 + subpopulations in the PBSC grafts was associated with poor immunological recovery and compromised event-free survival (50% vs. 80%, HR 2.93, p = 0.015) both due to increased relapse incidence and non-relapse mortality. The significant independent predictor of moderate and severe chronic GVHD was the high prevalence of and iNKT, Vbeta11, and double-positive cells in the PBSC grafts from young donors (HR 2.75, p = 0.0483). No patterns could be identified for BM grafts and for plasma biomarkers.
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Second Hematopoietic Stem Cell Transplantation for Post-Transplant Relapsed Acute Leukemia in Children: a Retrospective EBMT- PDWP Study
Yaniv, I., Krauss, A. C., Beohou, E., Dalissier, A., Corbacioglu, S., Zecca, M., Afanasyev, B. V., Berger, M., Diaz, M. A., Kalwak, K., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Outcome data were collected from the EBMT registry on 373 children from 120 centers with relapsed leukemia (214 ALL, 159 AML) who underwent second allogeneic hematopoietic stem cell transplantation (HSCT) between 2004 and 2013. At 2 and 5 years, respectively, overall survival (OS) was 38% and 29%, and leukemia-free survival (LFS) was 30% and 25%. Median follow-up after second HSCT was 36.4 months in the ALL group and 50.2 months in the AML group. In the ALL group, at 2 and 5 years, respectively, OS was 43% and 33%, and LFS, 34% and 31%; corresponding values in the AML group were OS 32% and 24%, LFS 24% and 17%. Non-relapse mortality rates at 2 years were 22% (ALL) and 18% (AML). Favorable prognostic factors (P <0.05) for OS and LFS included >12 months between transplants and chronic graft-versus-host disease after the first SCT (both groups), complete response before the second HSCT (ALL only), and age >12 years (AML only). Findings were more consistent over time in the ALL group, with no significant differences between 2-year and 5-year rates of relapse, non-relapse mortality, and LFS. Children with relapsed acute leukemias have a substantial chance at long-term survival following second HSCT. Given the many novel targeted and immune-modulation therapies currently under development, it is important to identify specific patient subpopulations that may benefit from a second HSCT versus those better suited to new approaches.
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5.
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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Allogeneic hematopoietic cell transplantation for primary refractory acute lymphoblastic leukemia: A report from the Acute Leukemia Working Party of the EBMT
Pavlu, J., Labopin, M., Zoellner, A. K., Sakellari, I., Stelljes, M., Finke, J., Fanin, R., Stuhler, G., Afanasyev, B. V., Bloor, A. J., et al
Cancer. 2017;123(11):1965-1970
Abstract
BACKGROUND Patients with primary refractory acute lymphoblastic leukemia (PREF ALL) who fail to achieve a complete remission (CR) after >=2 courses of chemotherapy have a dismal prognosis without undergoing allogeneic hematopoietic cell transplantation (HCT). To the authors' knowledge, there currently are no data regarding factors influencing transplantation outcomes. METHODS The authors retrospectively studied outcomes of transplantation for cases of PREF ALL reported to European Society for Blood and Marrow Transplantation registry. Eligibility criteria for the current analysis included adult patients who underwent their first HCT for PREF ALL between 2000 and 2012. PREF disease was defined as the failure to achieve a morphological CR after >=2 courses of induction chemotherapy. RESULTS Data regarding 86 adult patients were analyzed. With a median follow-up of 106 months, the probability of survival was 36% at 2 years and 23% at 5 years. The probability of leukemia-free survival was 28% and 17%, respectively, and the probability of nonrecurrence mortality was 20% and 29%, respectively, at 2 years and 5 years. For 66 patients who achieved a CR (77%), the survival at 2 years and 5 years was 36% and 29%, respectively. In multivariate analysis, use of total body irradiation was found to be associated with improved survival. Total body irradiation and infusion of female hematopoietic cells into male recipients was associated with improved leukemia-free survival. These findings were incorporated into a scoring system that identified 3 groups (those with 2, 1, or no prognostic factors) with survival rates of 57%, 22%, and 8%, respectively. CONCLUSIONS Although overall these patients would clearly benefit from the introduction of novel antileukemic therapies, the data from the current study support the use of allogeneic HCT in selected patients with PREF ALL. Cancer 2017;123:1965-1970. © 2017 American Cancer Society.