-
1.
Eltrombopag improves platelet engraftment after haploidentical bone marrow transplantation: Results of a Phase II study
Ahmed, S., Bashir, Q., Bassett, R. L., Jr., Ullah, F., Aung, F., Valdez, B. C., Alousi, A. M., Hosing, C., Kebriaei, P., Khouri, I., et al
American journal of hematology. 2024
-
-
-
-
Editor's Choice
Abstract
Slow platelet recovery frequently occurs after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with bone marrow graft and post-transplant cyclophosphamide (PCy)-based graft-versus-host disease (GVHD) prophylaxis. Improved platelet recovery may reduce the need for transfusions and improve outcomes. We investigated the safety and efficacy of eltrombopag, a thrombopoietin receptor agonist, at enhancing platelet recovery post-haplo-HSCT. The prospective study included patients ≥18 years of age who received haplo-HSCT with bone marrow graft and PCy. Patients received eltrombopag 300 mg/day starting on Day +5. The primary objective was to estimate platelet engraftment (>50 000/μL by Day 60). In a post hoc analysis, they were compared to a contemporary matched control group who did not receive eltrombopag. One hundred ten patients were included in the analysis (30 eltrombopag and 80 control). Seventy-three percent and 50% of patients in the eltrombopag group and control group, respectively, attained >50 000/μL platelet count by Day 60 (p = .043). No eltrombopag-related grade ≥4 adverse events were observed. Median time to platelet recovery (>20 000/μL) was 29 days with eltrombopag and 31 days for controls (p = .022), while its cumulative incidence was 90% (95% confidence interval [CI]: 78%-100%) with eltrombopag versus 67.5% (95% CI: 57%-78%) for controls (p = .014). Number of platelet transfusions received, overall survival, progression-free survival, GVHD rate, relapse rate, and non-relapse mortality were similar between groups. Overall, eltrombopag is safe and improves platelet recovery in patients undergoing haplo-HSCT with bone marrow graft and PCy.
PICO Summary
Population
Adults underoing haploidentical transplant with bone marrow graft and post-transplant cyclophosphamide from a single centre in USA (n=110)
Intervention
Eltrombopag 300 mg/day starting on Day +5 (n=30)
Comparison
contemporary matched control group who did not receive eltrombopag (n=80)
Outcome
Seventy-three percent and 50% of patients in the eltrombopag group and control group, respectively, attained >50 000/μL platelet count by Day 60. No eltrombopag-related grade ≥4 adverse events were observed. Median time to platelet recovery (>20 000/μL) was 29 days with eltrombopag and 31 days for controls, while its cumulative incidence was 90% (95% confidence interval [CI]: 78%-100%) with eltrombopag versus 67.5% (95% CI: 57%-78%) for controls. Number of platelet transfusions received, overall survival, progression-free survival, GVHD rate, relapse rate, and non-relapse mortality were similar between groups.
-
2.
Single-agent lenalidomide maintenance after upfront autologous stem cell transplant for newly diagnosed multiple myeloma: The MD Anderson experience
Pasvolsky, O., Milton, D. R., Masood, A., Sami, S. S., Tanner, M. R., Bashir, Q., Srour, S., Saini, N., Lin, P., Ramdial, J., et al
American journal of hematology. 2023
Abstract
The optimal duration of lenalidomide (Len) maintenance for patients with multiple myeloma (MM) after autologous stem cell transplantation (autoHCT) is unknown. We conducted a retrospective single-center analysis of adult MM patients that received upfront autoHCT between 2005 and 2021, followed by single-agent Len maintenance. A total of 1167 patients were included with a median age of 61.4 (range 25.4-82.3) years, and high-risk chromosomal abnormalities in 19%. Median duration of maintenance was 22.3 (range 0.03-139.6) months. After a median follow-up of 47.9 (range 2.9-171.7) months, median PFS and OS for the entire cohort were 56.6 (95% CI 48.2-61.4) months and 111.3 (95% CI 101.7-121.5) months, respectively. In MVA, high-risk cytogenetics was associated with a worse PFS (HR 1.91) and OS (HR 1.73) (p < .001 for both). Use of KRD induction and achievement of MRD-negative ≥ VGPR before autoHCT were associated with an improved PFS (HR 0.53 and HR 0.57, respectively; p < .001 for both). Longer maintenance duration, even with a 5-year cutoff, was associated with superior PFS and OS (HR 0.17 and 0.12, respectively; p < .001 for both). A total of 106 patients (9%) developed a second primary malignancy (SPM), mostly solid tumors (39%) and myeloid malignancies (30%). Longer maintenance duration was associated with a higher risk of SPM, reaching statistical significance after >2 years (odds ratio 2.25; p < .001). In conclusion, outcomes with Len maintenance were comparable to those reported in large clinical trials. Longer duration of maintenance, even beyond 5 years, was associated with improved survival.
-
3.
Lenalidomide-Based Maintenance After Autologous Hematopoietic Stem Cell Transplant for Patients with High-Risk Multiple Myeloma
Pasvolsky, O., Milton, D. R., Rauf, M., Tanner, M. R., Bashir, Q., Srour, S., Tang, G., Saini, N., Ramdial, J., Masood, A., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Maintenance therapy with single-agent lenalidomide (Len) after autologous hematopoietic stem cell transplantation (autoHCT) for multiple myeloma (MM) is associated with improved progression-free survival (PFS). However, MM patients with high-risk chromosomal abnormalities (HRMM) may need a more intense regimen. OBJECTIVE We hypothesized that adding another anti-myeloma drug to Len maintenance would lead to improved outcomes. STUDY DESIGN We conducted a retrospective single-center chart review analysis of adult HRMM patients who received autoHCT between 2008-2018, followed by Len-based maintenance therapy. High-risk cytogenetics were defined as del(17p), t(4;14), t(14;16), 1q21 gain or amplification by fluorescence in situ hybridization (FISH). We divided patients into those who received either single-agent Len maintenance (Len-only) or Len-based combinations (Len-combo). We compared non-relapse mortality (NRM), day 100 and best post-transplant responses, minimal residual disease (MRD) status, PFS, and overall survival (OS) between the two groups. We also performed sensitivity analyses using inverse probability weights to correct for potential bias due to nonrandomization of the two groups. RESULTS A total of 231 patients with HRMM were included in our analysis, with a median age of 62.4 (range 33.5-79.9) years, and 55% were male. There were 153 patients in the Len-only group and 78 in the Len-combo group. Len-combo regimens were either doublets (Len with dexamethasone [dex: n=10], elotuzumab [n=28] or ixazomib [n=14]) or triplets (Len with bortezomib/dex [n=10], ixazomib/dex [n=10] or carfilzomib/dex [n=6]). More patients in the Len-combo group had ≥2 high-risk cytogenetic abnormalities compared to the Len-only group (32% vs. 12%: p<0.001). Median follow-up was 40.7 and 37.0 months in the Len-only and Len-combo groups, respectively. Median PFS and OS for all patients were 25.5 and 82.6 months, respectively. There was no significant difference in PFS (hazard ratio [95% CI]: 1.01 [0.71-1.44], p=0.94) or OS (0.84 [0.49-1.43], p=0.52) between the Len-only and the Len-combo groups, respectively. However, for patients with high-risk cytogenetic abnormalities other than 1q+, there was a trend towards better PFS in the Len-combo group (0.59 [0.32-1.09], p=0.09), but no difference in OS (0.79 [0.37-1.65], p=0.53). CONCLUSIONS In this single center retrospective analysis, use of Len-based combinations for post-transplant maintenance did not show improvements in HRMM patient outcomes. However, there was a trend towards improved PFS in patients with high-risk abnormalities other than 1q+.
-
4.
Blinatumomab Maintenance After Allogeneic Hematopoietic Cell Transplantation for B-lineage Acute Lymphoblastic Leukemia
Gaballa, M. R., Banerjee, P. P., Milton, D. R., Jiang, X., Ganesh, C., Khazal, S. J., Nandivada, V., Islam, S., Kaplan, M., Daher, M., et al
Blood. 2021
Abstract
Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single center phase II study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least one cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44-105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute GVHD grades 2-4 and 3-4 were 33% and 5%, respectively; two cases of mild (10%) and one case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival, progression-free survival, and non-relapse mortality rates were 85%, 71%, and 0%, respectively. In a matched-analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab's efficacy. Correlative studies of baseline and post-treatment samples identified patients with specific T-cell profiles as "responders" or "non-responders" to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Non-responders were T-cell deficient and expressed more inhibitory checkpoint molecules, including TIM3. We found that blinatumomab post-allogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment.
-
5.
A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients
Oran, B., de Lima, M., Garcia-Manero, G., Thall, P. F., Lin, R., Popat, U., Alousi, A. M., Hosing, C., Giralt, S., Rondon, G., et al
Blood advances. 2020;4(21):5580-5588
-
-
-
Free full text
-
-
Editor's Choice
Abstract
This study investigated the efficacy and safety of azacitidine maintenance in the posttransplant setting based on the encouraging phase 1/2 reports for azacitidine maintenance in patients with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Between 2009 and 2017, a total of 187 patients aged 18 to 75 years were entered into a randomized controlled study of posttransplant azacitidine if they were in complete remission. Patients randomized to the treatment arm (n = 93) were scheduled to receive azacitidine, given as 32 mg/m2 per day subcutaneously for 5 days every 28 days for 12 cycles. The control arm (n = 94) had no intervention. Eighty-seven of the 93 patients started azacitidine maintenance. The median number of cycles received was 4; a total of 29 patients relapsed on study, and 23 patients withdrew from the study due to toxicity, patient's preference, or logistical reasons. Median relapse-free survival (RFS) was 2.07 years in the azacitidine group vs 1.28 years in the control group (P = .19). There was also no significant difference for overall survival, with a median of 2.52 years vs 3.56 years in the azacitidine and control groups (P = .43), respectively. Cox regression analysis revealed no improvement in RFS or overall survival with the use of azacitidine as maintenance compared with the control group (hazard ratios of 0.86 [95% confidence interval, 0.59-1.3; P = .43] and 0.84 [95% confidence interval, 0.55-1.29; P = .43]). This randomized trial with azacitidine maintenance showed that a prospective trial in the posttransplant setting was feasible and safe but challenging. Although RFS was comparable between the 2 arms, we believe the strategy of maintenance therapy merits further study with a goal to reduce the risk of relapse in patients with AML/MDS. This trial was registered at www.clinicaltrials.gov as #NCT00887068.
PICO Summary
Population
Adults who underwent allogeneic transplantation for high-risk acute myeloid leukaemia enrolled in a randomised trial (n=187)
Intervention
Azacitidine maintenance, given as 32 mg/m2 per day subcutaneously for 5 days every 28 days for 12 cycles (n=93)
Comparison
Control, no intervention (n=94)
Outcome
87 of the 93 patients started azacitidine maintenance. The median number of cycles received was 4; a total of 29 patients relapsed on study, and 23 patients withdrew from the study due to toxicity, patient's preference, or logistical reasons. Median relapse-free survival (RFS) was 2.07 years in the azacitidine group vs 1.28 years in the control group. There was also no significant difference for overall survival, with a median of 2.52 years vs 3.56 years in the azacitidine and control groups, respectively. Cox regression analysis revealed no improvement in RFS or overall survival with the use of azacitidine as maintenance compared with the control group (hazard ratios of 0.86 and 0.84)
-
6.
CC-486 Maintenance After Stem Cell Transplantation in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes
de Lima, M., Oran, B., Champlin, R. E., Papadopoulos, E. B., Giralt, S. A., Scott, B. L., William, B. M., Hetzer, J., Laille, E., Hubbell, B., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
-
-
Free full text
-
Editor's Choice
Abstract
BACKGROUND Relapse is the main cause of treatment failure after allogeneic stem cell transplant (alloSCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Injectable azacitidine can improve posttransplant outcomes but presents challenges with exposure and compliance. Oral CC-486 allows extended dosing to prolong azacitidine activity. We investigated use of CC-486 maintenance therapy post-alloSCT. METHODS Adults with MDS or AML in morphological complete remission at CC-486 initiation (42-84 days post-alloSCT) were included. Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles. Endpoints included safety, pharmacokinetics, graft-vs-host disease (GvHD) incidence, relapse/progression rate, and survival. ClinicalTrials.gov NCT01835587. RESULTS Of 30 patients, 7 received CC-486 once-daily for 7 days/cycle (200-mg n=3, 300-mg n=4); and 23 for 14 days/cycle (150-mg n=4, 200-mg n=19 [expansion cohort]). Grade 3-4 adverse events were infrequent and occurred with similar frequency across regimens. Standard concomitant medications did not alter CC-486 pharmacokinetic parameters. Three patients (10%) experienced grade 3 acute GvHD and 9 experienced chronic GvHD. Of 28 evaluable patients, 6 (21%) relapsed or had progressive disease: 3/7 patients (43%) receiving 7-day dosing and 3/23 (13%) receiving 14-day dosing. Transplant-related mortality was 3%. At 19 months of follow-up, median overall survival was not reached. Estimated 1-year survival was 86% and 81% in the 7-day and 14-day dosing cohorts, respectively. CONCLUSIONS CC-486 maintenance was generally well-tolerated, with low rates of relapse, disease progression, and GvHD. CC-486 maintenance may permit epigenetic manipulation of the alloreactive response post-allograft. Findings require confirmation in randomized trials.
-
7.
Prolonged survival with a longer duration of maintenance lenalidomide after autologous hematopoietic stem cell transplantation for multiple myeloma
Mian, I., Milton, D. R., Shah, N., Nieto, Y., Popat, U. R., Kebriaei, P., Parmar, S., Oran, B., Shah, J. J., Manasanch, E. E., et al
Cancer. 2016;122(24):3831-3837
Abstract
BACKGROUND Although lenalidomide maintenance therapy has demonstrated improved outcomes after autologous hematopoietic stem cell transplantation (auto-HCT) for patients with multiple myeloma (MM), the impact of the duration of this therapy is not clearly known. METHODS This study retrospectively analyzed all MM patients who were placed on maintenance lenalidomide after auto-HCT between January 2007 and December 2013. Progression-free survival (PFS) and overall survival (OS) were analyzed in multivariate Cox proportional hazards regression models that included the duration of maintenance as a time-dependent covariate. RESULTS Of the 464 patients identified, 46% initiated therapy early (<4 months after auto-HCT). The median PFS and OS were 38 and 78 months, respectively. Improvements in PFS (hazard ratio [HR], 0.13; 95% confidence interval [CI], 0.04-0.38; P<.001) and OS (HR, 0.09; 95% CI, 0.03-0.26; P<.001) were seen for those on maintenance for >2 years versus those on maintenance for <2 years. For those on maintenance for >3 versus those on maintenance for <3 years, this trend continued with improvements seen in PFS (HR, 0.02; 95% CI, 0.00-0.44; P=.012) and OS (HR, 0.05; 95% CI, 0.00-0.83; P=.037). The incidence of second primary malignancies (SPMs) in the entire cohort was 3%. No differences were seen in survival between early and late initiators of maintenance lenalidomide. CONCLUSIONS A longer duration of maintenance therapy was associated with longer survival. The incidence of SPMs was low, and they were not associated with the duration of maintenance. The timing of the initiation of maintenance had no effect on survival. Cancer 2016;122:3831-3837. © 2016 American Cancer Society. Copyright © 2016 American Cancer Society.