Clinical Outcomes in Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated with Gilteritinib Who Received Prior Midostaurin or Sorafenib

Perl, Alexander E.; Altman, Jessica K.; Hosono, Naoko; Montesinos, Pau; Podoltsev, Nikolai A.; Martinelli, Giovanni; Smith, Catherine C.; Levis, Mark J.; Röllig, Christoph; Gross-Langenhoff, Marco; Hasabou, Nahla; Lu, Qiaoyang; Tiu, Ramon V.

doi:10.1182/blood-2020-136395

Cited by 7 publications

(10 citation statements)

References 22 publications

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“…Perl and colleagues investigated whether prior FLT3i therapy influenced outcomes in patients treated with gilteritinib. Regardless of prior FLT3i therapy, gilteritinib-treated patients had CRc rates >40%, however, the median OS with single-agent gilteritinib was 6.5 vs 9.6 months in prior FLT3i exposed ( n = 31) vs naive patients ( n = 216) with FLT3 mut R/R AML 74 . These data suggests that although responses may still be achieved with gilteritinib in patients refractory to prior first-generation FLT3i-based therapies, optimization with doublet or triplet combinations with second-generation FLT3i is likely needed to significantly improve OS with prior TKI exposure.…”

Section: Future Directionmentioning

confidence: 94%

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021

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Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

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Section: Future Directionmentioning

confidence: 94%

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021

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“…23 and , 1024 , respectively (Fig 4A and Data Supplement). The median OS in mCRc patients achieving molecular response (n 5 15; , 10 22 ) was 11.6 months (95% CI, 7.43 to NR) and 8.2 months (95% CI, 1.05 to NR) in those who did not (n 5 10; Fig 4B).…”

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confidence: 95%

Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia

Daver

Perl

Maly

et al. 2022

JCO

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109

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PURPOSE The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated ( FLT3 mut) acute myeloid leukemia (AML) but seldom reduces FLT3 mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3 mut AML. METHODS This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505 ) enrolled patients with FLT3 wild-type and FLT3 mut (escalation) or FLT3 mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III–defined response criteria. RESULTS Sixty-one patients were enrolled (n = 56 FLT3 mut); 64% (n = 36 of 56) of FLT3 mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3 mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10−2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3 mut patients was 10.0 months. CONCLUSION The combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.

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“…This study became the basis for the registration of gilteritinib monotherapy in 2019 in the treatment of R/R AML with FLT3 mutation [21]. There is also evidence confirming the effectiveness of treatment with second-generation FLT3 kinase inhibitors in patients previously treated with midostaurin or sorafenib [22]. The presented case of the first patient previously treated with midostaurin proves the validity of the use of gilteritinib in the treatment of chemoresistant AML FLT3 recurrence.…”

Section: Discussionmentioning

confidence: 58%