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PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL
Dreger, P., Sureda, A., Ahn, K. W., Eapen, M., Litovich, C., Finel, H., Boumendil, A., Gopal, A., Herrera, A. F., Schmid, C., et al
Blood advances. 2019;3(3):360-369
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Abstract
This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD-) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)-based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD-, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD-. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD-. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.
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Reduced intensity conditioning regimens including alkylating chemotherapy do not alter survival outcomes after allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia compared to low-intensity non-myeloablative conditioning
Andersen, N. S., Bornhauser, M., Gramatzki, M., Dreger, P., Vitek, A., Karas, M., Michallet, M., Moreno, C., van Gelder, M., Henseler, A., et al
Journal of cancer research and clinical oncology. 2019
Abstract
PURPOSE The optimal dose intensity for conditioning prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) for chronic lymphocytic leukemia (CLL) is unknown. METHODS We retrospectively compared outcomes of patients who received a first alloHCST after non-myeloablative (NMA) and reduced intensity conditioning (RIC). Data of 432 patients with a median age of 55 years were included, of which 86 patients underwent NMA and 346 RIC. RESULTS The median follow-up after alloHSCT was 4.3 years. Compared to the RIC group, more NMA patients had purine-analog-sensitive disease, were in complete remission and received matched related donor transplantation. After RIC, the probabilities for 5-year OS, EFS, CIR, and NRM were 46%, 38%, 28%, and 35% and after NMA the respective probabilities were 52%, 43%, 25%, and 32%. In multivariate analysis, remission status prior to conditioning but not RIC versus NMA conditioning had a significant impact on CIR, EFS, and OS. CONCLUSION Presumed higher anti-leukemic activity of RIC versus NMA conditioning did not translate into better outcomes after alloHSCT, but better remission status prior to conditioning did. Effective pathway inhibitor-based salvage therapies combined with NMA conditioning might thus represent the most attractive contemporary approach for alloHSCT for patients with CLL.
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Long-term efficacy of reduced-intensity versus myeloablative conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: retrospective follow-up of an open-label, randomised phase 3 trial
Fasslrinner, F., Schetelig, J., Burchert, A., Kramer, M., Trenschel, R., Hegenbart, U., Stadler, M., Schafer-Eckart, K., Batzel, M., Eich, H., et al
The Lancet. Haematology. 2018
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Abstract
BACKGROUND The impact of the intensity of conditioning before allogeneic haemopoietic cell transplantation (HCT) has been studied in a randomised phase 3 trial comparing reduced-intensity conditioning with myeloablative conditioning in patients with acute myeloid leukaemia in first complete remission. Because of the short follow-up of the original trial, whether reduced-intensity conditioning increases the risk of late relapse compared with myeloablative conditioning remained unclear. To address this question, we present retrospective 10-year follow-up data of this trial and focus on late relapse. METHODS The original randomised phase 3 trial included patients aged 18-60 years, with intermediate-risk or high-risk acute myeloid leukaemia, an adequate organ function, and an available HLA-matched sibling donor or an unrelated donor with at least nine out of ten HLA alleles matched. Patients were randomly assigned (1:1) to 120 mg/m(2) fludarabine combined with four 2 Gy doses of total-body irradiation (reduced-intensity conditioning) or six 2 Gy doses of total-body irradiation and 120 mg/kg cyclophosphamide (myeloablative conditioning). The primary and secondary efficacy endpoints of this trial have been published previously. In this retrospective, long-term follow-up analysis, data were collected from medical reports from individual participating study centres, and from physician and patient interviews. Endpoints included in this analysis were cumulative relapse incidence, overall survival, disease-free survival, and non-relapse mortality in the original study population and in patients alive and relapse-free at 12 months after HCT (landmark analysis). 10-year time to event rates were calculated in the intention-to-treat population and were compared with the Gray test. The trial is registered with ClinicalTrials.gov, number NCT00150878. FINDINGS In the original trial, 195 patients were randomly assigned to receive reduced-intensity conditioning (n=99) or myeloablative conditioning (n=96). For this retrospective analysis, data were collected with a nearly complete follow-up (completeness index 99%). Median follow-up time for surviving patients was 9.9 years (IQR 8.5-11.4), during which the cumulative incidence of relapse in the complete study population was identical in both groups (30% [95% CI 20-39] in the reduced-intensity conditioning group vs 30% [21-40] in the myeloablative conditioning group; Gray test p=0.99). Relapse occurred at a median of 5.0 months (IQR 3.0-8.8) in the reduced-intensity conditioning group versus 9.5 months (4.5-20.5) in the myeloablative conditioning group. 10-year disease-free survival was 55% (95% CI 45-66) in the reduced-intensity conditioning group and 43% (34-55) in the myeloablative conditioning group (hazard ratio [HR] 0.76 [0.51-1.14]; p=0.19). 10-year non-relapse mortality was 16% (95% CI 8-24) in the reduced-intensity conditioning group and 26% (17-36) in the myeloablative conditioning group (subdistribution HR 0.60 [95% CI 0.32-1.11]; Gray test p=0.10). The incidence of long-term toxicities associated with total-body irradiation was comparable; secondary malignancies occurred in six (6%) of 94 patients in the reduced-intensity conditioning group and five (6%) of 90 in the myeloablative conditioning group (p=1.00). INTERPRETATION There is no evidence that reduced-intensity conditioning increases the risk of late relapse compared with myeloablative conditioning. Given that the reduced-intensity conditioning group in the original trial was associated with lower early morbidity and toxicity, reduced-intensity conditioning with moderately reduced total-body irradiation doses could be the preferred conditioning strategy for patients with acute myeloid leukaemia who are younger than 60 years and transplanted in first complete remission. FUNDING None.
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Long-term outcome analysis of reduced-intensity allogeneic stem cell transplantation in patients with mantle cell lymphoma: a retrospective study from the EBMT Lymphoma Working Party
Robinson, S. P., Boumendil, A., Finel, H., Peggs, K. S., Chevallier, P., Sierra, J., Finke, J., Poiré, X., Maillard, N., Milpied, N., et al
Bone marrow transplantation. 2018;53(5):617-624
Abstract
Reduced-intensity allogeneic stem cell transplantation (RIST) is usually reserved for patients with mantle cell lymphoma who relapse after an autoSCT. However, the long-term efficacy of RIST and its curative potential have not been clearly demonstrated. We studied the long-term outcome of patients receiving a RIST for MCL as reported to the EBMT. A total of 324 patients, median age 57 years (range 31-70), underwent a RIST between 2000 and 2008; 43% of the patients had received >3 lines of prior therapy, including an autoSCT in 46%. Non-relapse mortality (NRM) was 10% at 100 days and 24% at 1 year and was lower for patients receiving anti-thymocyte globulin (ATG)/ALG (RR 0.59, p = 0.046). After a median follow-up of 72 months (range 3-159), 118 patients relapsed at a median of 8 months post RIST (range 1-117). The cumulative incidence of relapse was 25% and 40% at 1 and 5 years, respectively, and was associated with chemorefractory disease (HR 0.49, p = 0.01) and the use of CAMPATH (HR 2.59, p = 0.0002). The 4-year progression-free survival rate and overall survival rate was 31 and 40%, respectively. RIST results in long-term disease-free survival in about 30% of the patients, including those patients relapsing after a prior autoSCT.
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Dose-Reduced Versus Standard Conditioning Followed by Allogeneic Stem-Cell Transplantation for Patients With Myelodysplastic Syndrome: A Prospective Randomized Phase III Study of the EBMT (RICMAC Trial)
Kroger, N., Iacobelli, S., Franke, G. N., Platzbecker, U., Uddin, R., Hubel, K., Scheid, C., Weber, T., Robin, M., Stelljes, M., et al
Journal of Clinical Oncology. 2017;35(19):2157-2164
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Abstract
Purpose To compare a reduced-intensity conditioning regimen (RIC) with a myeloablative conditioning regimen (MAC) before allogeneic transplantation in patients with myelodysplastic syndrome (MDS) within a randomized trial. Patients and Methods Within the European Society of Blood and Marrow Transplantation, we conducted a prospective, multicenter, open-label, randomized phase III trial that compared a busulfan-based RIC with MAC in patients with MDS or secondary acute myeloid leukemia. A total of 129 patients were enrolled from 18 centers. Patients were randomly assigned in a 1:1 ratio and were stratified according to donor, age, and blast count. Results Engraftment was comparable between both groups. The CI of acute graft-versus-host disease II to IV was 32.3% after RIC and 37.5% after MAC ( P = .35). The CI of chronic graft-versus-host disease was 61.6% after RIC and 64.7% after MAC ( P = .76). The CI of nonrelapse mortality after 1 year was 17% (95% CI, 8% to 26%) after RIC and 25% (95% CI, 15% to 36%) after MAC ( P = .29). The CI of relapse at 2 years was 17% (95% CI, 8% to 26%) after RIC and 15% (95% CI, 6% to 24%) after MAC ( P = .6), which resulted in a 2-year relapse-free survival and overall survival of 62% (95% CI, 50% to 74%) and 76% (95% CI, 66% to 87%), respectively, after RIC, and 58% (95% CI, 46% to 71%) and 63% (95% CI, 51% to 75%), respectively, after MAC ( P = .58 and P = .08, respectively). Conclusion This prospective, randomized trial of the European Society of Blood and Marrow Transplantation provides evidence that RIC resulted in at least a 2-year relapse-free survival and overall survival similar to MAC in patients with MDS or secondary acute myeloid leukemia.
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Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes
Vrhovac, R., Labopin, M., Ciceri, F., Finke, J., Holler, E., Tischer, J., Lioure, B., Gribben, J., Kanz, L., Blaise, D., et al
Bone Marrow Transplantation. 2016;51(2):186-93
Abstract
Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning haematopoietic stem cell transplantation (RIC1). A retrospective study on European Society for Blood and Marrow Transplantation (EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2) from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5-79) months after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17-28.4), 63.9% (56.7-70.1), 14.6% (8.8-18.5) and 20.5% (14.9-26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia (representing 89.8% of all patients), duration of remission following RIC1 >225 days, presence of CR at RIC2, patient's Karnofsky performance status >80 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients' favourable outcome.