Excellent results for triplet regimen in FLT3-mutated AML 

The triplet combination of azacitidine, venetoclax, and gilteritinib induced high response rates in patients with newly diagnosed or relapsed/refractory FLT3-mutated acute myeloid leukaemia (AML) in a phase 1/2 study.

Azacitidine plus venetoclax is the standard-of-care for older or unfit patients with FLT3-mutated AML. However, the 1-year overall survival (OS) rate is low, at 40–60% [1]. Therefore, researchers tested a regimen of azacitidine, venetoclax, and gilteritinib, an FLT3 inhibitor that improves OS in patients with relapsed/refractory FLT3-mutated AML [2].

Patients with relapsed/refractory FLT3-mutated AML (n=20) or newly diagnosed FLT3-mutated AML, unfit for intensive chemotherapy (n=27), received a regimen of azacitidine, venetoclax, and gilteritinib (80 or 120 mg, once daily) in a phase 1/2 study. After the phase 1 part of the study, 80 mg was selected as the phase 2 expansion dose. The primary endpoint of the phase 2 part of the trial was complete remission (CR)/ complete remission with incomplete count recovery (CRi). Prof. Nicholas Short (University of Texas, TX, USA) presented the results [3].

CR was achieved in 92% of the participants who were treated with the triplet regimen in the frontline. The 2 remaining participants in this cohort achieved CRi and a morphologic leukaemia-free state (MLFS) response, respectively. Correspondingly, 20% of the participants in the relapsed/refractory cohort reached CR, 15% achieved CRi, and 35% had an MLFS response. In addition, 93% of the participants in the frontline cohort were on marrow remission after 14 days or had an aplastic marrow. In the relapsed/refractory cohort, the corresponding rate was 63%. Furthermore, MRD-negativity, assessed through flow cytometry, was achieved in 82% and 43% of the participants in the frontline cohort and relapsed/refractory cohort, respectively. The 1-year OS rate was 85% in the frontline cohort and 30% in the relapsed/refractory cohort.

“In the frontline cohort, the regimen was generally well tolerated, with minimal non-haematological toxicity,” said Prof. Short. Myelosuppression was common but manageable with dose adaptations. One patient died due to an infection in this cohort. “In the relapsed/refractory cohort, most adverse events were related to myelosuppression but mostly manageable with mitigation strategies.” In this cohort, there were 4 unsteady deaths, 2 due to an infection, 1 because of an intracranial haemorrhage, and 1 due to disseminated intravascular coagulation.

1. Konopleva M, et al. Clin Cancer Research. 2022;28(13):2744–2752.
2. Perl AE, et al. N Engl J Med. 2019;381(18):728–740.
3. Short NJ, et al. Updated Results from a Phase I/II Study of the Triplet Combination of Azacitidine, Venetoclax and Gilteritinib for Patients with FLT3-Mutated Acute Myeloid Leukemia. Abstract 831, ASH 64^th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.

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Posted on 20 February 2023