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Targeting of FLT3 AML
continued from the previous page
Crenolanib
Quizartinib
Gilteritinib
Clinical trial
- phase III trial (AROG Pharmac Inc.)
- randomized 1:1,
- arm A (experimental): 7+3
plus crenolanib during induction/consolidation; crenolanib as maintenance
- arm B (standard): TKI: midostaurin
- open label
Status: recruiting
- “Quantum first” trial, phase III (Daiichi Sankyo Inc.)
- randomized 1:1,
- arm A (experimental):
7+3 plus quizartinib during induction/consolidation; quizartinib as maintenance
- arm B: 7+3 plus placebo Status: active, not recruiting
- phase III trial (HOVON/AML-SG)
- randomized 1:1
- arm A (experimental):
7+3 plus gilteritinib during induction/ consolidation; 12 months gilteritinib as maintenance
- arm B (standard): TKI: midostaurin
- open label
Status: recruiting
Patients’ characteristics
- n=510 AML
- FLT3-ITD and/or TKD D835
mutation
- age ≥18y and ≤60y
- n=539
- FLT3-ITD mutation - age ≥18y and ≤75y
- n=768 AML or MDS-EB2
- FLT3-ITD and/or TKD mutation - age ≥18y
Endpoints
Primary: EFS Secondary: OS
Primary: EFS Secondary: OS
Primary: EFS
Secondary: OS, CR rate
Clinical trial register
NCT03258931
NCT02668653
NCT04027309
Main result
Results expected 2025
Results expected 2022
Results expected 2023
AML: acute myeloid leukemia; chemo: chemotherapy; CR: complete remission; CHR: complete hematologic remission; d: day; EFS: event-free survival; FLT3: fms like tyrosine kinase 3; HR: hazard ratio; ITD: internal tandem duplication; n: number; mido: midostaurin; OS: overall survival; RFS: relapse-free survival; SOC: standard of care;TKD: tyrosine kinase domain;TKI: tyrosine kinase inhibitor; y: years.
Chemotherapy, donor lymphocyte infusion or second HCT only achieve long-term outcomes in around 5% of cases.58,59
Intriguingly, sorafenib monotherapy resulted in durable remissions in a small, but nonetheless important propor- tion of FLT3-ITD+ AML patients relapsing after HCT.32,33 This clinical observation implied that sorafenib might prevent AML relapse after HCT by inhibiting FLT3-ITD- driven AML outgrowth, thereby giving the new immune system more time to elicit immune responses against residual AML blasts. In a murine FLT3-ITD AML model, FLT3-ITD inhibition by sorafenib promoted anti-leukemic T-cell immunity by triggering IL-15 secretion.60 On the other hand, sorafenib-induced autocrine IL-15 secretion cannot explain the positive results in the SORAML trial since this study mainly included FLT3-ITD- AML patients. Indeed, in mice, sorafenib aggravates T-cell mediated allo-immunity independently from FLT3-ITD inhibition.61 Taken together, it seems that different mechanisms might
contribute to the beneficial effects of sorafenib observed post HCT. A first placebo-controlled post-HCT mainte- nance therapy trial (the SORMAIN trial) started in 2010 using the multi-kinase and FLT3-TKI sorafenib (see below).
As of today, five randomized controlled clinical trials have investigated whether FLT3 TKI maintenance thera- py post HCT improves outcome (Table 2). Three recent randomized trials addressed the value of FLT3-TKI (crenolanib, quizartinib or gilteritinib) in combination with chemotherapy followed by post-HCT TKI mainte- nance (Table 2), and some of these are ongoing with results expected between 2021 and 2025.
Midostaurin
In the RADIUS trial, Maziarz et al. randomized 60 FLT3-ITD+ AML midostaurin versus standard of care (SOC).62 This was an open label trial and midostaurin treatment was given for 12 months. The primary out-
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