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. 2023 Oct;37(10):2066-2072.
doi: 10.1038/s41375-023-01994-x. Epub 2023 Aug 9.

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

Jad Othman  1   2   3 , Nicola Potter  1 , Katya Mokretar  4 , David Taussig  5 , Anjum Khan  6 , Pramila Krishnamurthy  7 , Anne-Louise Latif  8 , Paul Cahalin  9 , James Aries  10 , Mariam Amer  11 , Edward Belsham  12 , Eibhlin Conneally  13 , Charles Craddock  14 , Dominic Culligan  15 , Mike Dennis  16 , Caroline Duncan  17 , Sylvie D Freeman  18 , Caroline Furness  5 , Amanda Gilkes  19 , Paraskevi Gkreka  20 , Katherine Hodgson  21 , Wendy Ingram  22 , Manish Jain  6 , Andrew King  23 , Steven Knapper  24 , Panagiotis Kottaridis  25 , Mary Frances McMullin  26 , Unmesh Mohite  27 , Loretta Ngu  28 , Jenny O'Nions  25 , Katharine Patrick  29 , Tom Rider  30 , Wing Roberts  31 , Marianne Tang Severinsen  32 , Neill Storrar  33 , Tom Taylor  34 , Nigel H Russell  2 , Richard Dillon  35   36
Affiliations

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

Jad Othman et al. Leukemia. 2023 Oct.

Abstract

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.

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Conflict of interest statement

JO, NP, KM, DT, PC, JA, MA, EB, EC, DC, MD, CD, SDF, CF, AG, PG, KH, WI, P Kottaridis, MFM, UM, LN, KP, TR, WR, MTS and NS have no conflicts to declare. A Khan declares speakers bureau from Astellas. P Krishnamurthy declares honoraria and speakers bureau from Astellas. ALL declares honoraria from Astella. CC declares consultancy from Astellas and Daiichi-Sankyo. A King declares honoraria from Astellas. SK declares speakers bureau from Astellas. NHR declares honoraria from Astellas. RD declares consultancy with Astellas.

Figures

Fig. 1
Fig. 1. Swimmer plot of responses and events.
Top panel—patients without prior FLT3 inhibitor. Bottom panel—patients with prior FLT3 inhibitor.
Fig. 2
Fig. 2. Response rates in patient subgroups.
Molecular response rates by pre-treatment characteristics. Black text - overall molecular response rate. White text - CRMRD- rate. Abbreviations: Pers, molecular persistence; Prog, molecular progression; Rel, molecular relapse.
Fig. 3
Fig. 3. Outcomes in all patients.
Overall survival, relapse-free survival and molecular event-free survival from day of starting therapy.
See this image and copyright information in PMC

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