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1.
Isatuximab plus Carfilzomib and Dexamethasone vs Carfilzomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: IKEMA Subgroup Analysis by Prior Transplantation
Martin, T. G., Capra, M., Mohty, M., Suzuki, K., Quach, H., Cavo, M., Moreau, P., Dimopoulos, M., Yong, K., Tekle, C., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND In the era of highly active novel agents for multiple myeloma (MM), the role, ideal timing, and impact of transplant on further therapy after relapse remains a matter of debate. The impact of prior transplant on treatment benefit from monoclonal antibodies in patients with relapsed/refractory MM (RRMM) is largely unknown. Few Phase 3 studies of monoclonal antibody combinations with proteasome inhibitors or immunomodulatory agents have reported outcomes according to transplant status. OBJECTIVE This subgroup analysis examined efficacy and safety in patients from the Phase 3 IKEMA study with and without previous transplant. STUDY DESIGN IKEMA (NCT03275285) was a randomized, open-label, multinational, parallel-group Phase 3 study that investigated isatuximab (Isa), an anti-CD38 monoclonal antibody, combined with carfilzomib and dexamethasone (Isa-Kd; experimental group) vs Kd (control group) in 302 patients with RRMM and 1-3 prior lines of therapy. Patients were randomized in a 3:2 ratio to either Isa-Kd or Kd, with stratification by number of prior lines (1 vs more than 1) and R-ISS stage (I or II vs III vs not classified). Treatment was given until progressive disease, unacceptable adverse events, or patient choice. RESULTS Of the 302 randomized patients in IKEMA, 185 (61.3%) had received a prior transplant, comprising 116 of 179 (64.8%) patients in the Isa-Kd arm and 69 of 123 (56.1%) patients in the Kd arm. After a median follow-up of 20.6 months, median progression-free survival (PFS) in patients with prior transplant was not reached with Isa-Kd vs 19.15 months with Kd (HR 0.60; 99% CI: 0.31-1.16). After a median follow-up of 20.8 months, median PFS in patients without prior transplant was not reached with Isa-Kd vs 18.99 months with Kd (HR 0.44; 99% CI: 0.18-1.05). The overall response rate in patients with prior transplant was 87.9% (Isa-Kd) vs 85.5% (Kd). More patients in the Isa-Kd arm achieved a complete response or better compared with the Kd arm (43.1% vs 29.0%). The overall response rate in patients without prior transplant was 84.1% (Isa-Kd) vs 79.6% (Kd). More patients in the Isa-Kd arm achieved a complete response or better compared with the Kd arm (33.3% vs 25.9%). The MRD negativity rate was higher with Isa-Kd vs Kd in patients with (31.9% vs 13.0%) and without prior transplant (25.4% vs 13.0%). In patients with prior transplant, Grade 3 or higher treatment-emergent adverse events (TEAEs) were more common with Isa-Kd; however, no increases in serious TEAEs or definitive treatment discontinuations were seen vs Kd. Among patients without prior transplant, serious treatment-related TEAEs were similar and there were fewer TEAEs leading to definitive discontinuation with Isa-Kd. The most common Grade 3 or higher TEAEs in patients with and without prior transplant were hypertension and pneumonia. CONCLUSION For patients who underwent prior transplant, Isa-Kd is an effective treatment option. Overall, these data demonstrate that Isa-Kd represents a standard of care for patients with RRMM, regardless of prior transplant status.
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2.
Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European Society for Blood and Marrow Transplantation (EBMT)
Polverelli, N., Mauff, K., Kröger, N., Robin, M., Beelen, D., Beauvais, D., Chevallier, P., Mohty, M., Passweg, J., Rubio, M. T., et al
American Journal of Hematology. 2021;96(1):69-79
Abstract
The role of spleen size and splenectomy for the prediction of post-allogeneic hematopoietic stem cell transplant (allo-HCT) outcome in myelofibrosis remains under debate. In EBMT registry, we identified a cohort of 1195 myelofibrosis patients transplanted between 2000-2017 after either fludarabine-busulfan or fludarabine-melphalan regimens. Overall, splenectomy was performed in 202 (16.9%) patients and its use decreased over time (28.3% in 2000-2009 vs 14.1% in 2010-2017 period). By multivariate analysis, splenectomy was associated with less NRM (HR 0.64, 95% CI 0.44-0.93, P = .018) but increased risk of relapse (HR 1.43, 95% CI 1.01-2.02, P = .042), with no significant impact on OS (HR 0.86, 95% CI 0.67-1.12, P = .274). However, in subset analysis comparing the impact of splenectomy vs specific spleen sizes, for patients with progressive disease, an improved survival was seen in splenectomised subjects compared to those patients with a palpable spleen length ≥ 15 cm (HR 0.44, 95% CI 0.28-0.69, P < .001), caused by a significant reduction in NRM (HR 0.26, 95% CI 0.14-0.49, P < .001), without significantly increased relapse risk (HR 1.47, 95% CI 0.87-2.49, P = .147). Overall, despite the possible biases typical of retrospective cohorts, this study highlights the potential detrimental effect of massive splenomegaly in transplant outcome and supports the role of splenectomy for myelofibrosis patients with progressive disease and large splenomegaly.
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3.
Allogeneic Stem Cell Transplantation for FLT3-Mutated Acute Myeloid Leukemia: In vivo T-Cell Depletion and Posttransplant Sorafenib Maintenance Improve Survival. A Retrospective Acute Leukemia Working Party-European Society for Blood and Marrow Transplant Study
Bazarbachi, A., Labopin, M., Battipaglia, G., Djabali, A., Forcade, E., Arcese, W., Socié, G., Blaise, D., Halter, J., Gerull, S., et al
Clinical hematology international. 2019;1(1):58-74
Abstract
Acute myeloid leukemia (AML) with FLT3-mutation carries a poor prognosis, and allogeneic stem cell transplantation (allo-SCT) is recommended at first complete remission (CR1). We assessed 462 adults (median age 50 years) with FLT3-mutated AML allografted between 2010 and 2015 from a matched related (40%), unrelated (49%), or haploidentical donor (11%). The median follow-up of alive patients was 39 months. Day-100 acute graft versus host disease (GVHD) grades II-IV and III-IV were encountered in 26% and 9%, whereas the 2-year incidence of chronic and extensive chronic GVHD were 34% and 16%, respectively. The 2-year incidences of relapse and nonrelapse mortality were 34% and 15%, respectively. The 2-year leukemia-free survival, overall survival (OS), and GVHD relapse-free survival (GRFS) were 51%, 59%, and 38%, respectively. In multivariate analysis, NPM1-mutation, transplantation in CR1, in vivo T-cell depletion, and posttransplant sorafenib improved OS, whereas more than one induction (late CR1) negatively affected OS. Similarly, NPM1-mutation, a haploidentical donor, T-cell depletion, and sorafenib maintenance improved GRFS, whereas late CR1 or persistent disease negatively affected it. In conclusion, FLT3-mutated AML remains a challenge even following allo-SCT. In vivo T-cell depletion and posttransplant sorafenib significantly improve OS and GRFS, and may be considered as standard of care.
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4.
Tolerability and Efficacy of Treatment With Azacytidine as Prophylactic or Preemptive Therapy for Myeloid Neoplasms After Allogeneic Stem Cell Transplantation
Marini, C., Brissot, E., Bazarbachi, A., Dulery, R., Sestili, S., Battipaglia, G., Mediavilla, C., Paviglianiti, A., Belhocine, R., Isnard, F., et al
Clinical lymphoma, myeloma & leukemia. 2019
Abstract
INTRODUCTION/BACKGROUND Azacytidine (AZA) has been used as a promising treatment for relapse after allogeneic transplantation. A clear benefit has been demonstrated when treating patients with a reduced disease burden, thus a prophylactic and preemptive approach to these patients has emerged. MATERIALS AND METHODS We retrospectively analyzed patients with myeloid malignancies treated with azacytidine in the posttransplantation setting between September 2013 and April 2018 in a single tertiary care hospital. Of 32 patients analyzed, 21 were treated for prophylactic use and 11 preemptively, with a median follow-up of 20 months. Prophylactic treatment consisted of AZA at 32 mg/m(2) for 5 days every 28 days, and preemptive treatment of AZA 75 mg/m(2) for 5 or 7 days per cycle. In addition, 10 patients received one or more donor lymphocyte infusions (DLIs). Two patients presented with infectious complications demanding hospitalization, and 13 patients (10 in the prophylactic group and 3 in the preemptive group) presented graft-versus-host disease (GvHD). Of patients who had GvHD, 3 needed treatment discontinuation. Overall, 12 patients suspended treatment, 8 for disease progression and 1 due to patient request. RESULTS In the prophylactic group, all patients are alive at 1 year with an event-free survival (EFS) of 95%, as only 1 patient relapsed. In the preemptive group, 1-year EFS was 54% and 1-year overall survival was 82%. CONCLUSION Low-dose AZA in posttransplantation patients with myeloid neoplasms is a well-tolerated therapy with the potential to prevent relapse and maintain stable remissions. Randomized prospective trials are needed to determine patient selection and dosage, timing, and duration of treatment.
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5.
Bone marrow versus mobilized peripheral blood stem cells in haploidentical transplants using posttransplantation cyclophosphamide
Ruggeri, A., Labopin, M., Bacigalupo, A., Gülbas, Z., Koc, Y., Blaise, D., Bruno, B., Irrera, G., Tischer, J., Diez-Martin, J. L., et al
Cancer. 2018;124(7):1428-1437
Abstract
BACKGROUND Incidence of graft-versus-host disease (GVHD) in haploidentical bone marrow (BM) transplants using posttransplantion cyclophosphamide (PT-Cy) is low, whereas GVHD using mobilized peripheral blood stem cells (PBSC) ranges between 30% and 40%. METHODS To evaluate the effect of stem cell source in haploidentical transplantation with PT-Cy, we analyzed 451 patients transplanted for acute myeloid leukemia or acute lymphoblastic leukemia reported to the European Society for Blood and Marrow Transplantation. RESULTS BM was used in 260 patients, and PBSC were used in 191 patients. The median follow-up was 21 months. Engraftment was lower in BM (92% vs 95%, P < 0.001). BM was associated with a lower incidence of stage II-IV and stage III-IV acute GVHD (21% vs 38%, P ≤ .01; and 4% vs 14%, P < .01, respectively). No difference in chronic GVHD, relapse, or nonrelapse mortality were found for PBSC or BM. The 2-year overall survival (OS) was 55% versus 56% (P = .57) and leukemia-free survival (LFS) was 49% versus 54% (P = .74) for BM and PBSC, respectively. On multivariate analysis, PBSC were associated with an increased risk of stage II-IV (hazard ratio [HR], 2.1; P < .001) and stage III-IV acute GVHD (HR, 3.8; P < .001). For LFS and OS, reduced intensity conditioning was the only factor associated with treatment failure (LFS: HR, 1.40; P = .04) and relapse (HR, 1.62; P = .02). CONCLUSION In patients with acute leukemia in first or second remission receiving haploidentical transplantation with PT-Cy, the use of PBSC increases the risk of acute GVHD, whereas survival outcomes are comparable. Cancer 2018;124:1428-37. © 2018 American Cancer Society.
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6.
Medication adherence among allogeneic hematopoietic stem cell transplant recipients: a pilot single-center study
Lehrer, J., Brissot, E., Ruggeri, A., Dulery, R., Vekhoff, A., Battipaglia, G., Giannotti, F., Fernandez, C., Mohty, M., Antignac, M.
Bone marrow transplantation. 2018;53(2):231-233
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7.
Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia
Craddock, C., Labopin, M., Robin, M., Finke, J., Chevallier, P., Yakoub-Agha, I., Bourhis, J. H., Sengelov, H., Blaise, D., Luft, T., et al
Haematologica. 2016;101(7):879-83
Abstract
Disease relapse is the most common cause of treatment failure after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes, yet treatment options for such patients remain extremely limited. Azacitidine is an important new therapy in high-risk myelodysplastic syndromes and acute myeloid leukemia but its role in patients who relapse post allograft has not been defined. We studied the tolerability and activity of azacitidine in 181 patients who relapsed after an allograft for acute myeloid leukemia (n=116) or myelodysplastic syndromes (n=65). Sixty-nine patients received additional donor lymphocyte infusions. Forty-six of 157 (25%) assessable patients responded to azacitidine therapy: 24 (15%) achieved a complete remission and 22 a partial remission. Response rates were higher in patients transplanted in complete remission (P=0.04) and those transplanted for myelodysplastic syndromes (P=0.023). In patients who achieved a complete remission, the 2-year overall survival was 48% versus 12% for the whole population. Overall survival was determined by time to relapse post transplant more than six months (P=0.001) and percentage of blasts in the bone marrow at time of relapse (P=0.01). The concurrent administration of donor lymphocyte infusion did not improve either response rates or overall survival in patients treated with azacitidine. An azacitidine relapse prognostic score was developed which predicted 2-year overall survival ranging from 3%-37% (P=0.00001). We conclude that azacitidine represents an important new therapy in selected patients with acute myeloid leukemia/myelodysplastic syndromes who relapse after allogeneic stem cell transplantation. Prospective studies to confirm optimal treatment options in this challenging patient population are required.