Journal Article

FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML

Taussig, David, Potter, Nicola, Freeman, Sylvie D, Mohite, Unmesh, Rider, Tom, Roberts, Wing, McMullin, Mary Frances, Jain, Manish, O’Nions, Jenny, Ngu, Loretta, Khan, Anjum, Gilkes, Amanda, Mokretar, Katya, Othman, Jad, Taylor, Tom, Latif, Anne-Louise, Furness, Caroline, Patrick, Katharine, Knapper, Steven, Ingram, Wendy, Craddock, Charles, Krishnamurthy, Pramila, Amer, Mariam, Russell, Nigel H, Severinsen, Marianne Tang, Cahalin, Paul, Culligan, Dominic, Storrar, Neill, King, Andrew, Aries, James, Kottaridis, Panagiotis, Belsham, Edward, Conneally, Eibhlin, Hodgson, Katherine, Dennis, Mike, Duncan, Caroline, Dillon, Richard, Gkreka, Paraskevi

2023

Overview

Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure. This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated. We identified 56 patients treated with FLT3i at molecular failure. The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69–93) and molecular event-free survival 56% (95%CI 44–72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies.

• Publisher: Nature Publishing Group
• Subject: Allografts / Chemotherapy / Drug dosages / Failure / Hematology / Inhibitor drugs / Inhibitors / Kinases / Leukemia / Lymphocytes / Mutation / Neutropenia / Next-generation sequencing / Survival / Teaching hospitals / Toxicity