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Excellent results for triplet regimen in FLT3-mutated AML 

Presented by
Prof. Nicholas Short, University of Texas, TX, USA
ASH 2022
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 64th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.

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