Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia

Abstract

We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18–70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69–96%) in the midostaurin arm and 76% (54–88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12–1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362).

Maintenance therapy for <i>FLT3-ITD</i>-mutated acute myeloid leukemia

“…In the RADIUS trial, Maziarz et al randomized 60 FLT3-ITD + AML midostaurin versus standard of care (SOC). 62 This was an open label trial and midostaurin treatment was given for 12 months. The primary out- AML: acute myeloid leukemia; chemo: chemotherapy; CR: complete remission; CHR: complete hematologic remission; d: day; EFS: event-free survival; FLT3: fms like tyrosine kinase 3; HR: hazard ratio; ITD: internal tandem duplication; n: number; mido: midostaurin; OS: overall survival; RFS: relapse-free survival; SOC: standard of care; TKD: tyrosine kinase domain; TKI: tyrosine kinase inhibitor; y: years.…”

Prognostic and therapeutic implications of measurable residual disease in acute myeloid leukemia

“…Given the broad kinome of sorafenib, which inhibits several non-FLT3 targets, future studies evaluating TKIs with more specificity for FLT3 would be of great interest to determine whether these clinically beneficial effects are due to on-target FLT3 inhibition or more broad inhibition of leukemic and immunologic kinase activity. Studies using other TKIs in the post-HSCT setting, including midostaurin, recently concluded (NCT04027309) [ 103 ], and a study including gilteritinib is underway (NCT02997202).…”

FLT3 Tyrosine Kinase Inhibitors for the Treatment of Fit and Unfit Patients with FLT3-Mutated AML: A Systematic Review

“…Conversely, Midostaurin maintenance following alloHSCT has not proved to improve patient outcomes in the recent phase 2 open-label randomized RADIUS trial of the standard of care (SOC) with or without Midostaurin after alloHSCT for FLT3-mutated AML patients [ 48 ]. In this trial, 60 adults (aged 18–70 years old) patients who received alloHSCT in first complete remission, were randomized to receive standard of care with or without Midostaurin (50 mg twice daily) continuously in 12 four-week cycles.…”