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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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Editor's Choice
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.
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Outcomes in Patients With FLT3-Mutated R/R AML Who Underwent Transplantation in the Phase 3 ADMIRAL Trial of Gilteritinib Versus Salvage Chemotherapy
Perl, A. E., Larson, R. A., Podoltsev, N. A., Strickland, S., Wang, E. S., Atallah, E., Schiller, G. J., Martinelli, G., Neubauer, A., Sierra, J., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) in the phase 3 ADMIRAL trial. OBJECTIVES To assess survival and relapse rates among patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received posttransplant gilteritinib maintenance therapy. STUDY DESIGN ADMIRAL was a global, phase 3, randomized controlled trial, which enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or preselected high- or low-intensity salvage chemotherapy (1-2 cycles) as previously described (Perl AE, et al. N Engl J Med. 2019). Gilteritinib-arm patients who proceeded to HSCT could receive posttransplant gilteritinib maintenance therapy if they were within 30 to 90 days posttransplant and had achieved composite complete remission (CRc) with successful engraftment and no posttransplant complications. Adverse events during HSCT were collected in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent adverse events were evaluated in patients who restarted gilteritinib as posttransplant maintenance therapy. RESULTS Gilteritinib-arm patients underwent HSCT more frequently (n=64; 26%) than chemotherapy-arm patients (n=19; 15%). For all transplanted patients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplant CRc, posttransplant survival was comparable across arms. Patients who resumed gilteritinib after HSCT had low relapse rates after pretransplant CRc (20%) or CR (0%). The most common adverse events observed with posttransplant gilteritinib therapy were increased alanine aminotransferase (40%), pyrexia (43%), and diarrhea (40%); grade ≥3 adverse events were primarily related to myelosuppression. Incidences of grade ≥3 graft-versus-host disease and related mortality were low. CONCLUSION Posttransplant survival was similar across the two study arms in ADMIRAL, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as posttransplant maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplant-eligible patients.
PICO Summary
Population
Adults with FLT3-mutated R/R AML who underwent transplantation and were enrolled in the ADMIRAL Trial (n=371; HSCT n=83)
Intervention
Gilteritinib 120 mg/day (n=246; HSCT n=64)
Comparison
Salvage chemotherapy (n=109; HSCT n=19)
Outcome
For all transplanted patients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplant composite complete remission (CRc), posttransplant survival was comparable across arms. Patients who resumed gilteritinib after HSCT had low relapse rates after pretransplant CRc (20%) or complete remission (0%). The most common adverse events observed with posttransplant gilteritinib therapy were increased alanine aminotransferase (40%), pyrexia (43%), and diarrhea (40%); grade ≥3 adverse events were primarily related to myelosuppression. Incidences of grade ≥3 graft-versus-host disease and related mortality were low.
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Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide
Webster, J. A., Luznik, L., Tsai, H. L., Imus, P. H., DeZern, A. E., Pratz, K. W., Levis, M. J., Gojo, I., Showel, M. M., Prince, G., et al
Blood advances. 2020;4(20):5078-5088
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Editor's Choice
Abstract
Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.
PICO Summary
Population
Adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) undergoing allogeneic transplantation (n=76)
Intervention
Myeloablative conditioning in first complete remission (CR1 MAC, n=26); Non-myeloablative conditioning in first complete remission (CR1 NMAC, n=43)
Comparison
Patients in second or subsequent remission (CR2+, n=12)
Outcome
For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%.
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4.
Allogeneic hematopoietic cell transplantation improves outcome of adults with t(6;9) acute myeloid leukemia - results from an international collaborative study
Kayser, S., Hills, R. K., Luskin, M. R., Brunner, A. M., Terre, C., Westermann, J., Menghrajani, K., Shaw, C., Baer, M. R., Elliott, M. A., et al
Haematologica. 2019
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Editor's Choice
Abstract
Acute myeloid leukemia with t(6;9)(p22;q34) is a distinct entity accounting for 1-2% of acute myeloid leukemia cases. A substantial proportion of these patients have a concomitant FLT3-ITD. While outcomes are dismal with intensive chemotherapy, limited evidence suggests allogeneic hematopoietic cell transplantation may improve survival if applied early during first complete remission. We report on a cohort of 178 patients with t(6;9)(p22;q34) within an international, multicenter collaboration. Median age was 46 (range: 16-76) years, acute myeloid leukemia was de novo in 88%, FLT3-ITD was present in 62%, and additional cytogenetic abnormalities in 21%. Complete remission was achieved in 81% (n=144), including 14 patients who received high-dose cytarabine after initial induction failure. With a median follow-up of 5.43 years, estimated overall survival at 5 years was 38% (95%-CI, 31-47%). Allogeneic hematopoietic cell transplantation was performed in 117 (66%) patients, including 89 in first complete remission. Allogeneic hematopoietic cell transplantation in first complete remission was associated with higher 5-year relapse-free and overall survival as compared to consolidation chemotherapy (45% [95%-CI, 35-59%] and 53% [95%-CI, 42-66%], vs. 7% [95%-CI, 3-19%] and 23% [95%-CI, 13-38%]. For patients undergoing allogeneic hematopoietic cell transplantation, overall survival rates at 5 years did not differ whether performed in first (53% [95%-CI, 42-66%]), or second complete remission (58% [95%-CI, 31-100%]; n=10) or with active disease/relapse (54% [95%-CI, 34-84%]; n=18) (P=0.67). Neither FLT3-ITD nor additional chromosomal abnormalities impacted survival. In conclusion, outcomes of t(6;9)(p22;q34) acute myeloid leukemias are poor with chemotherapy, and can be substantially improved with allogeneic hematopoietic cell transplantation.
PICO Summary
Population
Patients with patients with acute myeloid leukaemia and a t(6;9)(p22;q34) mutation (n=178)
Intervention
Allogeneic haematopoietic stem cell transplant (n=144)
Comparison
Consolidation chemotherapy
Outcome
Allogeneic hematopoietic cell transplantation in first complete remission was associated with higher 5-year relapse-free and overall survival as compared to consolidation chemotherapy (45 and 53% vs. 7% and 23%. For patients undergoing allogeneic hematopoietic cell transplantation, overall survival rates at 5 years did not differ whether performed in first or second complete remission or with active disease/relapse. Neither FLT3-ITD nor additional chromosomal abnormalities impacted survival.