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Non-Myeloablative Allogeneic Transplantation with Post-Transplant Cyclophosphamide after Immune Checkpoint Inhibition for Classic Hodgkin Lymphoma: a Retrospective Cohort Study
Paul, S., Zahurak, M., Luznik, L., Ambinder, R. F., Fuchs, E. J., Bolanos-Meade, J., Wagner-Johnston, N., Swinnen, L. J., Schoch, L., Varadhan, R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are approved in relapsed classic Hodgkin lymphoma (cHL). The safety and effectiveness of allogeneic blood or marrow transplantation (alloBMT) in ICI pre-treated cHL patients remain unclear. The aim of this study is to assess outcomes of cHL patients receiving ICIs before alloBMT using post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis. METHODS We performed a retrospective study of relapsed/refractory cHL patients undergoing alloBMT with PTCy at Johns Hopkins between Nov 2004 and Sept 2019. Engraftment, GVHD incidence, non-relapse mortality (NRM), progression free survival (PFS) and overall survival (OS) were compared between patients receiving pre-alloBMT ICI or standard salvage chemotherapy. FINDINGS We identified 105 consecutive relapsed/refractory cHL patients, of which 37 (35.2%) received ICIs and 68 (64.7%) received chemotherapy without ICIs (no-ICI) before alloBMT. ICI and no-ICI patients experienced a 3-year estimated OS of 94% versus 78%, [hazard ratio (HR) 0.35 (95% CI: 0.08-1.56), P=0.17) and a 3-year estimated PFS of 90% and 65% [HR 0.3 (95 % CI: 0.09-1), P=0.05], respectively. We observed no statically significant difference in the 12-month cumulative incidence of acute grade II-IV GVHD or in the 24-month incidence of chronic GVHD. INTERPRETATION ICIs do not increase acute or chronic GVHD incidence compared to salvage chemotherapy. cHL patients receiving ICIs prior to alloBMT experienced outstanding PFS and OS. Thus ICI therapy is safe in cHL patients when undergoing alloBMT with PTCy and may improve post-alloBMT disease progression and survival. FUNDING National Institutes of Health, National Cancer Institute grants.
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Myeloablative haploidentical BMT with posttransplant cyclophosphamide for hematologic malignancies in children and adults
Symons, H. J., Zahurak, M., Cao, Y., Chen, A., Cooke, K., Gamper, C., Klein, O., Llosa, N., Zambidis, E. T., Ambinder, R., et al
Blood advances. 2020;4(16):3913-3925
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Abstract
Promising results have been reported for patients with high-risk hematologic malignancies undergoing HLA-haploidentical bone marrow transplantation (haploBMT) with posttransplantation cyclophosphamide (PTCy), but there are few data on outcomes with myeloablative conditioning in this context. We report the results of a single-institution, prospective phase 2 trial of myeloablative haploBMT using busulfan-based or total body irradiation-based conditioning in 96 children or adults (median age, 42 years; range, 1-65 years) with high-risk hematologic malignancies. Recovery of neutrophils and platelets occurred at a median of 24 and 29 days. Engraftment of donor cells with chimerism >95% was achieved in 91%. The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and grades III to IV at day 100 was 11% and 4%, and of chronic GVHD at 6 and 12 months was 4% and 15%, with 6% moderate to severe. The cumulative incidence of nonrelapse mortality was 6% at 100 days and 11% at 1 year (19% in those aged >55 years). The cumulative incidence of relapse at 1 year was 35%; at 3 years, it was 43%. In multivariable analysis, relapse was associated with increased age (P = .02 for age 20-55 years and P = .02 for age >55 years) and with minimal residual disease before transplantation (P = .05). The overall survival at 1 and 3 years is 73% and 54%, and event-free survival at 1 and 3 years is 57% and 49%. We show that haploBMT with PTCy after myeloablative conditioning is safe and efficacious for adult and pediatric patients with hematologic malignancies. Careful consideration must be given to using myeloablative conditioning in patients age >55 years. This trial was registered at www.clinicaltrials.gov as #NCT00796562.
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A prospective study of peri-transplant sorafenib for FLT3-ITD AML patients undergoing allogeneic transplantation
Pratz, K. W., Rudek, M. A., Smith, B. D., Karp, J., Gojo, I., Dezern, A., Jones, R. J., Greer, J., Gocke, C., Baer, M. R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
FLT3-ITD mutated acute myeloid leukemia (AML) remains a therapeutic challenge. FLT3 inhibition in the setting of minimal residual disease and a new immune system via allogeneic transplantation offers a promise of improved survival for these patients. We performed a prospective study of patients with FLT3-ITD AML undergoing allogeneic transplant was conducted to evaluate the safety, tolerability, and outcome of sorafenib administered peri-transplant. Sorafenib dosing was individualized, starting at 200 mg BID, and titrated based on tolerability or toxicities until a tolerable dose was identified. Forty-four patients, with a median age of 52, undergoing allogeneic transplant were started on sorafenib in the peri-transplant period (21 pre-transplant). The median duration of post-transplant follow up is 27.6 months (range, 5.2-60.4). Overall survival was 76% at both 24 and 36 months. Event-free survival at 24 and 36 months was 74% and 64%, respectively. Ten patients died in the post-transplant period, with six deaths due to relapsed leukemia and four from transplant-associated toxicity. Tolerable doses ranged from 200 mg QOD to 400 mg BID with similar exposure. Correlative studies evaluating FLT3 inhibition via a plasma inhibitory activity assay showed consistent inhibition of FLT3 at all tolerability-determined dosing levels. Sorafenib is well tolerated in the peri-transplant setting irrespective of the conditioning intensity or the donor source. Our findings indicate that sorafenib dosing can be individualized in the post-transplantation setting according to patient tolerability. This approach results in effective in vivo FLT3 inhibition and yields encouraging survival results.
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Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide Using Non-First-Degree Related Donors
Elmariah, H., Kasamon, Y. L., Zahurak, M., Macfarlane, K. W., Tucker, N., Rosner, G. L., Bolanos-Meade, J., Fuchs, E. J., Wagner-Johnston, N., Swinnen, L. J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Outcomes of nonmyeloablative (NMA) haploidentical (haplo) blood or marrow transplant (BMT) with post-transplantation cyclophosphamide (PTCy) using non-first-degree relatives are unknown. We evaluated 33 consecutive adult patients (median age 56 years) with hematologic malignancies who underwent NMA haplo T-cell replete BMT with PTCy at Johns Hopkins using second- or third-degree related donors. Donors consisted of 10 nieces (30%), 9 nephews (27%), 7 first cousins (21%), 5 grandchildren (15%), and 2 uncles (6%). Thirty-one patients (94%) reached full donor chimerism by day 60. The estimated cumulative incidence (CuI) of grade II-IV acute GVHD (aGVHD) at day 180 was 24% (90% CI: 9-38%). Only 1 patient experienced grade III-IV aGVHD. At 1 year, the CuI of chronic GVHD was 10% (90% CI: 0-21%). The CuI of nonrelapse mortality at 1 year was 5% (90% CI: 0-14%). At 1 year, the probability of relapse was 31% (90% CI: 12-49%), progression-free survival was 64% (90% CI: 48-86%) and overall survival was 95% (90% CI: 87-100%). The 1-year probability of GVHD-free, relapse free survival was 57% (90% CI: 41-79%). NMA haplo BMT with PTCy from non-first-degree relatives is an acceptably safe and effective alternative donor platform, with results similar to those seen with first degree relatives.
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Nonmyeloablative Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide for Pediatric and Young Adult Patients with High-Risk Hematologic Malignancies
Klein, O. R., Buddenbaum, J., Tucker, N., Chen, A. R., Gamper, C. J., Loeb, D., Zambidis, E., Llosa, N. J., Huo, J. S., Robey, N., et al
Biology of Blood & Marrow Transplantation. 2017;23(2):325-332
Abstract
Lower-intensity conditioning regimens for haploidentical blood or marrow transplantation (BMT) are safe and efficacious for adult patients with hematologic malignancies. We report data for pediatric/young adult patients with high-risk hematologic malignancies (n=40) treated with nonmyeloablative haploidentical BMT with post-transplantation cyclophosphamide from 2003 to 2015. Patients received a preparative regimen of fludarabine, cyclophosphamide, and total body irradiation. Post-transplantation immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, and tacrolimus. Donor engraftment occurred in 29 of 32 (91%), with median time to engraftment of neutrophils >500/micro L of 16 days (range, 13 to 22) and for platelets >20,000/micro L without transfusion of 18 days (range, 12 to 62). Cumulative incidences of acute graft-versus-host disease (GVHD) grades II to IV and grades III and IV at day 100 were 33% and 5%, respectively. The cumulative incidence of chronic GVHD was 23%, with 7% moderate-to-severe chronic GVHD, according to National Institutes of Health consensus criteria. Transplantation-related mortality (TRM) at 1 year was 13%. The cumulative incidence of relapse at 2 years was 52%. With a median follow-up of 20 months (range, 3 to 148), 1-year actuarial overall and event-free survival were 56% and 43%, respectively. Thus, we demonstrate excellent rates of engraftment, GVHD, and TRM in pediatric/young adult patients treated with this regimen. This approach is a widely available, safe, and feasible option for pediatric and young adult patients with high-risk hematologic malignancies, including those with a prior history of myeloablative BMT and/or those with comorbidities or organ dysfunction that preclude eligibility for myeloablative BMT.Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.