Follow-up of patients with R/R FLT3-mutation–positive AML treated with gilteritinib in the phase 3 ADMIRAL trial

Abstract

The phase 3 ADMIRAL trial demonstrated superior overall survival (OS) in relapsed/refractory FLT3-mutation-positive acute myeloid leukemia patients randomized 2:1 to the oral FLT3 inhibitor, gilteritinib, versus those randomized to salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203/247 and 97/124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-arm patients remained on treatment. The median OS for gilteritinib and SC arms was 9.3 and 5.6 months, respectively (HR=0.665; 95% CI: 0.518, 0.853; two-sided P=0.0013); 2-year estimated survival rates were 20.6% (95% CI: 15.8, 26.0) and 14.2% (95% CI: 8.3, 21.6), respectively. The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49/247 patients in the gilteritinib arm and 14/124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-arm patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (HSCT) and 16 restarted gilteritinib as post-HSCT maintenance therapy. Most common adverse events (AEs) of interest during Years 1 and 2 of gilteritinib therapy were increased liver transaminases; AE incidence decreased in Year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival versus SC. www.clinicaltrials.gov NCT02997202

Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy

“…19 Estimated survival rates after 5 2 years were 20.6% for gilteritinib monotherapy and 14.2% for chemotherapy. 21 In preclinical studies, gilteritinib plus AZA (GIL+AZA) impeded cell growth and induced apoptosis and differentiation of FLT3-ITD AML cell lines. 22 In xenografted mouse models, combining GIL+AZA appeared synergistic and demonstrated superior antitumor efficacy versus gilteritinib or AZA.…”

Therapeutic Management of Patients with FLT3 + Acute Myeloid Leukemia: Case Reports and Focus on Gilteritinib Monotherapy

“…These data confirm the higher efficacy of gilteritinib versus the standard therapy in terms of sustained disease remission and survival. 19 …”

“FLipping” the Story: FLT3-Mutated Acute Myeloid Leukemia and the Evolving Role of FLT3 Inhibitors

“…Response rates and remission duration were similar irrespective of FLT3 mutations (e.g., TKD or ITD) and, in both cases, were superior to chemotherapy. Subsequently, study results have been updated and continue to show similar overall results, persisting to at least 2 years following completion of therapy [ 100 ].…”

“…Prolonged QT interval was observed in 4.9% of patients, but only 0.4% (one patient) had a QT greater than 500 msec. Long-term follow-up data did not reveal any additional safety signals [ 100 ].…”

“…* Midostaurin [80][81][82][83] Lestaurtinib [84,85] Sunitinib [86] Sorafenib [87][88][89][90] Pexidartinib [91] Ponatinib [92][93][94][95] Second Generation FLT3 Inhibitors ** Gilteritinib [96][97][98][99][100][101] Crenolanib [67,[102][103][104][105] MRX-2843 [106][107][108] Quizartinib [109,110] * Midostaurin is FDA-approved for adult patients with newly diagnosed FLT3-mutated AML, in combination with cytarabine plus daunorubicin induction and cytarabine consolidation. ** Gilteritinib is FDA-approved for adult patients with relapsed/refractory FLT3-mutated AML.…”