Abstract
Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) patients may be improved by a single-agent tyrosine kinase inhibitor (TKI) (i.e., quizartinib or gilteritinib). In the current study, we retrospectively investigated the characteristics and real-world outcomes of R/R FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with FLT3-ITD AML that received intensive chemotherapy as a first-line treatment. The rate of complete remission (CR) or CR without hematological recovery (CRi) was 75.2%, and 160 patients were R/R after a first-line TKI-free treatment (n = 294). Within the subgroup of R/R patients that fulfilled the main criteria of the QUANTUM-R study, 48.9% received an intensive salvage regimen; none received hypomethylating agents or low-dose cytarabine. Among the R/R FLT3-ITD AML patients with CR1 durations < 6 months who received intensive TKI-free treatment, the rate of CR or CRi after salvage chemotherapy was 52.8%, and these results allowed a bridge to be transplanted in 39.6% of cases. Finally, in this QUANTUM-R standard arm-matched cohort, the median overall survival (OS) was 7.0 months and 1-, 3- and 5-year OS were 30.2%, 23.7% and 21.4%, respectively. To conclude, these real-world data show that the intensity of the second-line treatment likely affects response and transplantation rates. Furthermore, the results indicate that including patients with low-intensity regimens, such as low-dose cytarabine or hypomethylating agents, in the control arm of a phase 3 trial may be counterproductive and could compromise the results of the study.
Highlights
Internal tandem duplication (ITD) in the FLT3 gene is one of the most frequent mutations found in acute myeloid leukemia (AML) [1]
Among 3290 newly diagnosed AML patients included in the DATAML registry between 2000 and 2017, 1500 did not have the information for FLT3 mutation and 358 did not receive intensive treatment
AML patients unable to achieve complete remission (CR) or CR without hematological recovery (CRi) after standard induction chemotherapy, or whose disease relapses after achieving remission, are likely to die from their disease
Summary
Internal tandem duplication (ITD) in the FLT3 gene is one of the most frequent mutations found in acute myeloid leukemia (AML) [1]. FLT3 tyrosine kinase inhibitors (TKI), developed as ATP-competitive inhibitors, are currently the focus of new development strategies in FLT3-mutated AML, both as single agents at relapse and in combination with intensive chemotherapy or as first-line maintenance therapy. Type I inhibitors, including midostaurin, gilteritinib, and crenolanib, have activity against FLT3-ITD and tyrosine kinase domain (TKD) mutations [5]. Type II inhibitors, including sorafenib and quizartinib, do not have activity against FLT3-TKD mutations [5]. First-generation FLT3 TKI, such as midostaurin [6] and sorafenib [7], have marginal single-agent activity in an active disease, they have recently shown promising activity as maintenance therapies [8,9], notably after allogeneic hematopoietic stem cell transplantation (HSCT) [10].
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