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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
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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.
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Three Years Maintenance with VRD in Multiple Myeloma: Results of Total Therapy IIIB with a 15-Year Follow Up
Al Hadidi, S., Ababneh, O., Schinke, C., Thanendrarajan, S., Bailey, C., Smith, R. T., Panozzo, S., Alapat, D. Md, Cottler-Fox, M., Tricot, G. J., et al
Blood advances. 2023
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Editor's Choice
Abstract
The TTIIIB phase II study incorporated bortezomib into tandem melphalan-based hematopoietic stem cell transplantation with dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide for induction/consolidation and bortezomib, lenalidomide, and dexamethasone (VRD) for maintenance in patients with newly diagnosed multiple myeloma (MM). This updated analysis presents a 15.4-year median follow-up. Of 177 patients, 21% patients had gene expression profile (GEP)-defined high-risk MM. 15-year progression free survival (PFS) was 27.9%. Median PFS was better in GEP-defined low-risk patients at 7.8 years and in international stage system stage I patients at 8.7 years. Overall, median OS was 9.1 years, and 15-year overall survival (OS) was 35.9%. GEP-defined low-risk patients' median OS was 11.2 years, and that of GEP-defined high-risk patients was 2.8 years. There was no difference in OS between TT IIIB and TT IIIA. This study includes the longest follow-up of patients treated with maintenance VRD reported to date. In patients with GEP-defined low-risk, nearly half and one-third of patients without ongoing treatment showed no signs of progression at 10 and 15 years, respectively. One-third of patients survived more than 15 years, but 3 years of VRD maintenance did not improve outcomes for patients with GEP-defined high-risk MM.
PICO Summary
Population
Adults from a single centre in USA with newly diagnosed multiple myeloma, enrolled in the Total Therapy (TT) IIIB trial between 2006 and 2008, (n=177)
Intervention
Bortezomib incorporated into tandem melphalan-based hematopoietic stem cell transplantation with dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide for induction/consolidation and bortezomib, lenalidomide, and dexamethasone (VRD) for maintenance. Three years of VRD maintenance (TT IIIB, n=177)
Comparison
Comparison cohort received one year of bortezomib, thalidomide, and dexamethasone followed by two years of thalidomide and dexamethasone (TD) maintenance (TT IIIA group)
Outcome
15-year progression free survival (PFS) in TTIIIB was 27.9%. Median PFS was better in Gene expression profile (GEP)-defined low-risk patients at 7.8 years and in international stage system stage I patients at 8.7 years. Overall, median overall survival (OS) was 9.1 years, and 15-year OS was 35.9%. GEP-defined low-risk patients' median OS was 11.2 years, and that of GEP-defined high-risk patients was 2.8 years. There was no difference in OS between TT IIIB and TT IIIA.
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Azacitidine and lenalidomide combination: a novel relapse prophylaxis regimen after allogeneic hematopoietic stem-cell transplantation in patients with acute myeloid leukemia
Feng, Y., Chen, T., Zhang, Y., Yao, H., Wang, P., Wang, L., Cassady, K., Zou, Z., Liu, Y., Zhao, L., et al
Frontiers in immunology. 2023;14:1182251
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Editor's Choice
Abstract
INTRODUCTION While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be a curative regimen for acute myeloid leukemia (AML), relapse of AML remains a serious risk post-transplantation. Once relapsed, salvage options are limited and management of AML is difficult. Here we designed a prospective study to examine the efficacy and tolerability of maintenance therapy with azacytidine (AZA) plus low-dose lenalidomide (LEN) to prevent relapse after allo-HSCT for AML patients (ChiCTR2200061803). METHODS AML patients post-allo-HSCT were treated with AZA (75 mg/m(2) for 7 days), followed by LEN (5 mg/m(2), day 10-28), and a 4-week resting interval, which was defined as one treatment cycle. A total of 8 cycles was recommended. RESULTS 37 patients were enrolled, 25 patients received at least 5 cycles, and 16 patients finished all 8 cycles. With a median follow-up time of 608 (43-1440) days, the estimated 1-year disease free survival (DFS) was 82%, cumulative incidence of relapse (CIR) was 18%, and overall survival (OS) was 100%. Three patients (8%) had grade 1-2 neutropenia without fever; one patient developed grade 3-4 thrombocytopenia and minor subdural hematoma; 4/37 patients (11%) developed chronic GVHD with a score of 1-2, without requiring systemic treatment; No patient developed acute GVHD. After AZA/LEN prophylaxis, increasing numbers of CD56(+)NK and CD8(+) T, and decreasing of CD19(+) B cells were observed. DISCUSSION Azacitidine combined with low-dose lenalidomide was observed to be an effective relapse prophylaxis option after allo-HSCT in AML patients, and can be administered safely without significantly increasing the risk of GVHD, infection and other AEs. CLINICAL TRIAL REGISTRATION www.chictr.org, identifier ChiCTR2200061803.
PICO Summary
Population
AML patients post-allo-HSCT prospectively recruited from a single centre in China (n=37)
Intervention
Maintenance therapy with azacytidine (AZA) 75 mg/m(2) for 7 days, followed by lenalidomide (LEN) 5 mg/m(2), day 10-28, and a 4-week resting interval, which was defined as one treatment cycle. A total of 8 cycles was recommended.
Comparison
None
Outcome
25 patients received at least 5 cycles, and 16 patients finished all 8 cycles. With a median follow-up time of 608 (43-1440) days, the estimated 1-year disease free survival (DFS) was 82%, cumulative incidence of relapse (CIR) was 18%, and overall survival (OS) was 100%. Three patients (8%) had grade 1-2 neutropenia without fever; one patient developed grade 3-4 thrombocytopenia and minor subdural hematoma; 4/37 patients (11%) developed chronic GVHD with a score of 1-2, without requiring systemic treatment; No patient developed acute GVHD. After AZA/LEN prophylaxis, increasing numbers of CD56(+)NK and CD8(+) T, and decreasing of CD19(+) B cells were observed.
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Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial
Flaadt, T., Ladenstein, R. L., Ebinger, M., Lode, H. N., Arnardóttir, H. B., Poetschger, U., Schwinger, W., Meisel, R., Schuster, F. R., Döring, M., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023;:Jco2201630
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Editor's Choice
Abstract
PURPOSE Patients with relapsed high-risk neuroblastoma (rHR-NB) have a poor prognosis. We hypothesized that graft-versus-neuroblastoma effects could be elicited by transplantation of haploidentical stem cells (haplo-SCT) exploiting cytotoxic functions of natural killer cells and their activation by the anti-GD2 antibody dinutuximab beta (DB). This phase I/II trial assessed safety, feasibility, and outcomes of immunotherapy with DB plus subcutaneous interleukin-2 (scIL2) after haplo-SCT in patients with rHR-NB. METHODS Patients age 1-21 years underwent T-/B-cell-depleted haplo-SCT followed by DB and scIL2. The primary end point 'success of treatment' encompassed patients receiving six cycles, being alive 180 days after end of trial treatment without progressive disease, unacceptable toxicity, acute graft-versus-host-disease (GvHD) ≥grade 3, or extensive chronic GvHD. RESULTS Seventy patients were screened, and 68 were eligible for immunotherapy. Median number of DB cycles was 6 (range, 1-9). Median number of scIL2 cycles was 3 (1-6). The primary end point was met by 37 patients (54.4%). Median observation time was 7.8 years. Five-year event-free survival (EFS) and overall survival from start of trial treatment were 43% (95% CI, 31 to 55) and 53% (95% CI, 41 to 65), respectively. Five-year EFS among patients in complete remission (CR; 52%; 95% CI, 31 to 69) or partial remission (44%; 95% CI, 27 to 60) before immunotherapy were significantly better compared with patients with nonresponse/mixed response/progressive disease (13%; 95% CI, 1 to 42; P = .026). Overall response rate in 43 patients with evidence of disease after haplo-SCT was 51% (22 patients), with 15 achieving CR (35%). Two patients developed GvHD grade 2 and 3 each. No unexpected adverse events occurred. CONCLUSION DB therapy after haplo-SCT in patients with rHR-NB is feasible, with low risk of inducing GvHD, and results in long-term remissions likely attributable to increased antineuroblastoma activity by donor-derived effector cells.
PICO Summary
Population
Patients aged 1-21 with relapsed high-risk neuroblastoma (rHR-NB) from four European centres (n=68)
Intervention
Immunotherapy with dinutximab (DB) plus subcutaneous interleukin-2 (scIL2) after haploidentical transplant
Comparison
None
Outcome
Median number of DB cycles was 6 (range, 1-9). Median number of scIL2 cycles was 3 (1-6). The primary end point was met by 37 patients (54.4%). Median observation time was 7.8 years. Five-year event-free survival (EFS) and overall survival from start of trial treatment were 43% (95% CI, 31 to 55) and 53% (95% CI, 41 to 65), respectively. Five-year EFS among patients in complete remission (CR; 52%; 95% CI, 31 to 69) or partial remission (44%; 95% CI, 27 to 60) before immunotherapy were significantly better compared with patients with nonresponse/mixed response/progressive disease (13%; 95% CI, 1 to 42). Overall response rate in 43 patients with evidence of disease after haplo-SCT was 51% (22 patients), with 15 achieving CR (35%). Two patients developed GvHD grade 2 and 3 each. No unexpected adverse events occurred.
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Venetoclax is safe and tolerable as post-transplant maintenance therapy for AML patients at high risk for relapse
Kent, A., Schwartz, M., McMahon, C., Amaya, M., Smith, C. A., Tobin, J., Marciano, K., Rezac, R., Bosma, G., Pollyea, D. A., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
Relapse is the most common cause of mortality in acute myeloid leukemia (AML) patients after allogeneic stem cell transplant (SCT). Post-SCT maintenance strategies that prevent relapse are desirable but must be well tolerated and convenient to administer. We hypothesized single agent venetoclax (ven) may be an effective maintenance therapy among high relapse risk patients. Between February 2019 and December 2021, we administered post-SCT ven maintenance to 49 AML patients at high-risk for relapse as a prospectively defined off-label practice at our institution. Ven was planned to be administered until 1-year post-SCT. While temporary interruptions were common (67.3% of all patients), of those with >1 year follow up, 22/25 (88%) completed the full year of planned therapy. Cytopenias (40.8%) and gastrointestinal adverse events (34.7%) were the most common toxicities. At 1-year post-SCT, overall survival (OS) and relapse-free survival (RFS) were 70% and 67% respectively. Our experience demonstrates single agent ven is a safe, tolerable, and feasible maintenance therapy that may improve RFS and OS in high relapse risk post-SCT patients.
PICO Summary
Population
Adults with acute myeloid leukaemia at high risk for relapse, and undergoing transplant at a single centre in USA (n=49)
Intervention
Post-transplant venetoclax (ven) maintenance for one year post-SCT
Comparison
None
Outcome
While temporary interruptions were common (67.3% of all patients), of those with >1 year follow up, 22/25 (88%) completed the full year of planned therapy. Cytopenias (40.8%) and gastrointestinal adverse events (34.7%) were the most common toxicities. At 1-year post-SCT, overall survival (OS) and relapse-free survival (RFS) were 70% and 67% respectively.
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Refractory patients with favorable/intermediate-risk acute myeloid leukemia benefit from azacytidine maintenance therapy following allogeneic hematopoietic stem cell transplantation
Cao, Y., Zheng, X., Zhang, H., Wang, M., Guo, W., Chen, X., Zhai, W., Wei, J., Yang, D., Huang, Y., et al
Hematological oncology. 2023
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Editor's Choice
Abstract
Recurrence following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the major cause of treatment failure in patients with myeloid malignancy. Azacytidine (AZA) maintenance is a promising therapy to prevent relapse and improve survival. We conducted a prospective, one-arm study involving 78 patients with myeloid malignancy at a high risk of recurrence who were enrolled between September 2019 and April 2022. Furthermore, 102 matched historical controls were selected using propensity score matching. With a median follow-up time of 19.6 (3.5-91.7) months, AZA maintenance therapy significantly improved relapse-free survival (RFS; log-rank test, p = 0.01). The AZA and control groups had a 1-year RFS of 87.7% (95% confidence interval [CI], 0.80-0.96) and 72.2% (95% CI, 0.64-0.82), respectively, with a hazard ratio (HR) of 0.21 (95% CI, 0.09-0. 47; p < 0.01). There were no grade 4 adverse effects or deaths related to AZA. Refractory patients with favorable/intermediate-risk acute myeloid leukemia (AML) benefited more from AZA maintenance therapy than those with adverse-risk AML according to the European Leukemia Net guidelines (RFS in favorable/intermediate-risk AML, HR = 0.29, 95% CI, 0.11-0.79; RFS in adverse-risk AML, HR = 0.57, 95% CI, 0.21-1.6; p for interaction = 0.03). Our findings suggest that AZA maintenance therapy following allo-HSCT was safe and could reduce the incidence of relapse, particularly for refractory patients with favorable/intermediate-risk AML.
PICO Summary
Population
People aged 15-65 years with myeloid malignancy at a high risk of recurrence, identified from a single centre in China (n=78)
Intervention
Azacytidine (AZA) maintenance therapy (n=78)
Comparison
Propensity-score matched controls who met the inclusion criteria, did not receive maintenance therapy and experienced no death, relapse, delayed engraftment or acute GvHD at grade III or higher (n=102)
Outcome
With a median follow-up time of 19.6 (3.5-91.7) months, AZA maintenance therapy significantly improved relapse-free survival (RFS). The AZA and control groups had a 1-year RFS of 87.7% (95% confidence interval [CI], 0.80-0.96) and 72.2% (95% CI, 0.64-0.82), respectively, with a hazard ratio (HR) of 0.21 (95% CI, 0.09-0. 47). There were no grade 4 adverse effects or deaths related to AZA. Refractory patients with favorable/intermediate-risk acute myeloid leukemia (AML) benefited more from AZA maintenance therapy than those with adverse-risk AML according to the European Leukemia Net guidelines (RFS in favorable/intermediate-risk AML, HR = 0.29, 95% CI, 0.11-0.79; RFS in adverse-risk AML, HR = 0.57, 95% CI, 0.21-1.6;).
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Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial
Xuan, L., Wang, Y., Yang, K., Shao, R., Huang, F., Fan, Z., Chi, P., Xu, Y., Xu, N., Deng, L., et al
The Lancet. Haematology. 2023
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Editor's Choice
Abstract
BACKGROUND Our open-label, multicentre, randomised, phase 3 trial showed that sorafenib maintenance after haematopoietic stem-cell transplantation (HSCT) improved overall survival and reduced relapse for patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic HSCT. Here, we present a post-hoc analysis on the 5-year follow-up data of this trial. METHODS This phase 3 trial, done in seven hospitals in China, included patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT, who were aged 18-60 years, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days after transplantation. Patients were randomly assigned (1:1) to receive sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days after transplantation. Randomisation was done with permuted blocks (block size four) via an interactive web-based system. Investigators and participants were not masked to group assignment. The primary endpoint was the 1-year cumulative incidence of relapse, which was reported previously. For this updated analysis, the 5-year endpoints were overall survival; cumulative incidence of relapse; non-relapse mortality; leukaemia-free survival; graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); cumulative incidence of chronic GVHD; and late effects in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02474290, and is complete. FINDINGS Between June 20, 2015, and July 21, 2018, 202 patients were randomly assigned to sorafenib maintenance (n=100) or non-maintenance (n=102). Median follow-up was 60·4 months (IQR 16·7-73·3). Extended follow-up showed improved overall survival (72·0% [95% CI 62·1-79·7] vs 55·9% [45·7-64·9]; hazard ratio [HR] 0·55, 95% CI 0·34-0·88; p=0·011), leukaemia-free survival (70·0% [60·0-78·0] vs 49·0% [39·0-58·3]; 0·47, 0·30-0·73; p=0·0007), and GRFS (58·0% [47·7-67·0] vs 39·2% [29·8-48·5]; 0·56, 0·38-0·83; p=0·0030), lower cumulative incidence of relapse (15·0% [8·8-22·7] vs 36·3% [27·0-45·6]; 0·33, 0·18-0·60; p=0·0003), and no increase in non-relapse mortality (15·0% [8·8-22·7] vs 14·7% [8·6-22·3]; 0·79, 0·39-1·62; p=0·98) for patients in the sorafenib group compared with those in the control group. The 5-year cumulative incidence of chronic GVHD (54·0% [43·7-63·2] vs 51·0% [40·8-60·3]; 0·82, 0·56-1·19; p=0·73) did not differ significantly between the two groups and we did not find substantial differences in late effects between the two groups. There were no treatment-related deaths. INTERPRETATION With extended follow-up, sorafenib maintenance after transplantation is associated with improved long-term survival and reduced relapse rates compared with non-maintenance, further supporting this strategy as a standard of care for patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT. FUNDING None. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
PICO Summary
Population
Adults up to 60 years with FLT3-ITD acute myeloid leukaemia in composite remission before and after transplantation, recruited from seven centres in China (n=202)
Intervention
Sorafenib (400 mg orally twice daily) maintenance (n=100)
Comparison
Control: Non-maintenance (n=102)
Outcome
Median follow-up was 60·4 months (IQR 16·7-73·3). Extended follow-up showed improved overall survival (72·0% [95% CI 62·1-79·7] vs 55·9% [45·7-64·9]; hazard ratio [HR] 0·55, 95% CI 0·34-0·88), leukaemia-free survival (70·0% [60·0-78·0] vs 49·0% [39·0-58·3]; 0·47, 0·30-0·73), and GvHD-free-relapse-free survival (58·0% [47·7-67·0] vs 39·2% [29·8-48·5]; 0·56, 0·38-0·83), lower cumulative incidence of relapse (15·0% [8·8-22·7] vs 36·3% [27·0-45·6]; 0·33, 0·18-0·60), and no increase in non-relapse mortality (15·0% [8·8-22·7] vs 14·7% [8·6-22·3]; 0·79, 0·39-1·62) for patients in the sorafenib group compared with those in the control group. The 5-year cumulative incidence of chronic GVHD (54·0% [43·7-63·2] vs 51·0% [40·8-60·3]; 0·82, 0·56-1·19) did not differ significantly between the two groups and we did not find substantial differences in late effects between the two groups. There were no treatment-related deaths.
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Brentuximab vedotin plus nivolumab after autologous haematopoietic stem-cell transplantation for adult patients with high-risk classic Hodgkin lymphoma: a multicentre, phase 2 trial
Herrera, A. F., Chen, L., Nieto, Y., Holmberg, L., Johnston, P., Mei, M., Popplewell, L., Armenian, S., Cao, T., Farol, L., et al
The Lancet. Haematology. 2022
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Editor's Choice
Abstract
BACKGROUND After autologous haematopoietic stem-cell transplantation (HSCT), consolidation with brentuximab vedotin in patients with high-risk relapsed or refractory classic Hodgkin lymphoma has been shown to improve progression-free survival compared with placebo. Brentuximab vedotin plus nivolumab is a safe and effective treatment for relapsed or refractory classic Hodgkin lymphoma; therefore, we aimed to evaluate the safety and activity of this drug combination post-autologous HSCT consolidation in patients with high-risk relapsed or refractory classic Hodgkin lymphoma. METHODS We did a multicentre phase 2 trial at five centres in the USA. Eligible patients were aged 18 years or older with high-risk relapsed or refractory classic Hodgkin lymphoma, had an ECOG performance status of 0-2, and had adequate organ and bone marrow function. Enrolled patients received brentuximab vedotin (1·8 mg/kg) and nivolumab (3 mg/kg) intravenously starting 30-60 days after autologous HSCT on day 1 of each 21-day cycle for up to 8 cycles. Nivolumab dose reduction was not allowed. Brentuximab vedotin dose reduction to 1·2 mg/kg was permitted. If one drug was discontinued because of a toxic effect, the other could be continued. The primary endpoint was 18-month progression-free survival in all treated patients. This study is registered with ClinicalTrials.gov, number NCT03057795. FINDINGS Between May 3, 2017, and July 13, 2019, 59 patients were enrolled and received the study therapy. Patients initiated brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT and received a median of 8 cycles (8-8). 34 (58%) of 59 patients were male, 29 (49%) completed 8 cycles of brentuximab vedotin plus nivolumab, and 45 (76%) completed 8 cycles of at least one drug. The median follow-up time was 29·9 months (IQR 24·6-34·8). The 18-month progression-free survival in all 59 patients was 94% (95% CI 84-98). The most common adverse events were sensory peripheral neuropathy (31 [53%] of 59) and neutropenia (25 [42%]), and immune-related adverse events requiring corticosteroids occurred in 17 (29%) of 59 patients. No treatment-related deaths were observed. INTERPRETATION Brentuximab vedotin plus nivolumab was highly active post-autologous HSCT consolidation for patients with high-risk relapsed or refractory classic Hodgkin lymphoma, most of whom had previous exposure to either brentuximab vedotin or PD-1 blockade. Combination immunotherapy in this setting should be further studied in patients with classic Hodgkin lymphoma with further refinement of the regimen to mitigate toxic effects, particularly in high-risk patients in whom more intensive therapy to prevent relapse is warranted. FUNDING Bristol Myers Squibb, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and National Cancer Institute of the National Institutes of Health.
PICO Summary
Population
Adults with high-risk relapsed or refractory Hodgkin lymphoma from five centres in the USA (n=59)
Intervention
Brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT
Comparison
None
Outcome
Patients initiated brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT and received a median of 8 cycles (8-8). 34 (58%) of 59 patients were male, 29 (49%) completed 8 cycles of brentuximab vedotin plus nivolumab, and 45 (76%) completed 8 cycles of at least one drug. The median follow-up time was 29·9 months (IQR 24·6-34·8). The 18-month progression-free survival in all 59 patients was 94% (95% CI 84-98). The most common adverse events were sensory peripheral neuropathy (31 [53%] of 59) and neutropenia (25 [42%]), and immune-related adverse events requiring corticosteroids occurred in 17 (29%) of 59 patients. No treatment-related deaths were observed.
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Multicenter phase II, double-blind placebo-controlled trial of maintenance ixazomib after allogeneic transplantation for high-risk multiple myeloma: Results of the BMT CTN 1302 Trial
Bashir, Q., Nishihori, T., Pasquini, M. C., Martens, M. J., Wu, J., Alsina, M., Anasetti, C., Brunstein, C., Dawson, P., Efebera, Y., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND The role of allogeneic hematopoietic cell transplantation (allo-HCT) followed by maintenance therapy in high-risk multiple myeloma remains controversial. We evaluated the efficacy of ixazomib maintenance therapy after a reduced-intensity allo-HCT from HLA-matched donors in patients with high-risk multiple myeloma. OBJECTIVES The primary endpoint for this study was progression-free survival (PFS) post-randomization, treated as a time to event. Secondary endpoints were grades 2-4 and 3-4 acute graft-versus-host-disease (GVHD), chronic GVHD, best response, disease progression, non-relapse mortality (NRM), overall survival (OS), toxicity, infection, and health-related quality of life (HRQOL). STUDY DESIGN In this phase 2, double-blinded, prospective multicenter trial, we randomized patients with high-risk multiple myeloma (poor-risk cytogenetics, plasma cell leukemia, or relapsing within 24 months after autologous transplant) to ixazomib (3 mg, days 1, 8, 15) or a placebo after allo-HCT. The conditioning regimen included fludarabine/melphalan/bortezomib with tacrolimus plus methotrexate for GVHD. RESULTS Fifty-seven patients were enrolled. 52 (91.2%) received allo-HCT, and 43 (82.7%) were randomized to ixazomib vs. placebo. At 21-month post-randomization, ixazomib vs. placebo groups had similar PFS (55.3% vs. 59.1%, p=1.00) and OS (94.7% vs. 86.4%, p=0.17). Cumulative incidences of grade III-IV acute GVHD at 100 days (9.5% vs. 0%) and chronic GVHD at 12 months (68.6% vs. 63.6%) were similar. The secondary analysis showed that at 24 months post-allo-HCT, PFS and OS were 52% and 82%, respectively, with corresponding non-relapse mortality of 11.7%. CONCLUSIONS These results show the safety and durable disease control with allo-HCT in high-risk myeloma patients. We could not adequately assess the efficacy of ixazomib maintenance as the trial terminated early because of enrollment delays, but there was no signal of an impact on outcomes.
PICO Summary
Population
People with high-risk myeloma from 15 centres in USA (n=57)
Intervention
Allogeneic transplant with ixazomib maintenance therapy (n=21)
Comparison
Allogeneic transplant with placebo (n=22); not randomised (n=14)
Outcome
At 21-month post-randomisation, ixazomib vs. placebo groups had similar PFS (55.3% vs. 59.1%) and OS (94.7% vs. 86.4%). Cumulative incidences of grade III-IV acute GVHD at 100 days (9.5% vs. 0%) and chronic GVHD at 12 months (68.6% vs. 63.6%) were similar. The secondary analysis showed that at 24 months post-allo-HCT, PFS and OS were 52% and 82%, respectively, with corresponding non-relapse mortality of 11.7%.
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10.
Enasidenib as Maintenance following Allogeneic Hematopoietic Cell Transplantation for IDH2-Mutated Myeloid Malignancies
Fathi, A. T., Kim, H. T., Soiffer, R. J., Levis, M. J., Li, S., Kim, A. S., Mims, A. S., DeFilipp, Z., El-Jawahri, A., McAfee, S. L., et al
Blood advances. 2022
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Abstract
IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3x3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100 mg daily. Grade ≥3 toxicities attributable to enasidenib were rare, with the most common being cytopenias. Eight patients stopped maintenance therapy before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft versus host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID-19 infection (n=1). No cases of grade ≥3 acute GVHD were seen, and the 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); only one subject relapsed while receiving maintenance enasidenib. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (950% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at ClinicalTrials.gov (NCT03515512).
PICO Summary
Population
Adults with IDH2-mutated relapsed or refractory AML (n=23)
Intervention
Maintenance enasidenib between days 30 and 90 following HCT and continuing for twelve 28-day cycles (n=19)
Comparison
None
Outcome
No dose limiting toxicities were observed, and the RP2D was established at 100 mg daily. Grade ≥3 toxicities attributable to enasidenib were rare, with the most common being cytopenias. Eight patients stopped maintenance therapy before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft versus host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID-19 infection (n=1). No cases of grade ≥3 acute GVHD were seen, and the 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); only one subject relapsed while receiving maintenance enasidenib. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (950% CI, 44-90%), respectively.