Abstract
Background: Patients with R/R AML have poor prognosis. FLT3 mutations worsened the prognosis but offer a targeted therapy. FLT3 inhibitors have demonstrated efficacy as monotherapy in FLT3-positive R/R AML. Aims: The objective of the present study was to analyze the efficacy and safety of Gilteritinib and Quizartinib in R/R FLT3-mutated AML in real-life context. Methods: Between December 2016 and April 2021, 22 patients were treated with Gilteritinib and 5 patients with Quizartinib in 13 centers of the Spanish PETHEMA and CETLAM groups. Results: The median age was 62 years (range 25; 81) and 56% were women. Most patients presented ITD FLT3 (80%), 56% were refractory and 44% were relapsed (CR1 duration ≥6 months in 60%). The 1st line therapy was intensive chemotherapy (78%, 38% with midostaurin) or HMA (22%). A total of 13/27 patients (48%) had previously received a FLT3 inhibitor (midostaurin=6, sorafenib=2, quizartinib=2, midostaurin + crenolanib vs placebo=2 and midostaurin + quizartinib=1). Seventy percent of the patients received >1 line of treatment prior to Gilteritinib/Quizartinib (the most frequent was FLAG-IDA). Compared with diagnosis, patients in R/R had poorer functional status (ECOG<2 88% vs. 73%) but lower leukocyte counts, LDH level and FLT3 ITD ratio (21.5 x109/L vs 4.7x109/L, 563 U/L vs 330 U/L and 0.60 vs 0.42, respectively). Three patients displayed clonal evolution in R/R with acquisition of cytogenetic alterations in patients with altered karyotype at diagnosis and appearance of alterations in patients with normal karyotype. The ORR was 63% (21% CR, 21% CRi and 21% PR) and the median OS was 5.8 (95%CI, 3.8; 7.9) months. Time to achieve better response was 1.8 months (range 0.9;4.1). Eight patients received the FLT3 inhibitor as a bridge to SCT, and six of them were finally transplanted. Gilteritinib dose was 120mg/day, increasing to 200mg/d in 41% of patients (due to lack of response after 28 days). Toxicity was observed in 69% of patients (g3/4 in 30%). Febrile neutropenia was the most frequent toxicity (35%) followed by hepatotoxicity (28%) and QTc prolongation (16%). One patient died of toxicity attributed to Gilteritinib (febrile neutropenia). Summary/Conclusion: Treatment with Gilteritinib and Quizartinib as monotherapy is an effective and tolerable option for patients with R/R FLT3-mutated AML in real-life, with similar response rates and toxicity to those reported in Phase 3 trials, despite the fact that the study population from our series was more heterogeneous.
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