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Efficacy analysis of different FLT3 inhibitors in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

ABSTRACT: Several FLT3 inhibitors(i) are available to treat relapsed/refractory (R/R) FLT3-internal tandem duplicated acute myeloid leukemia (AML). This study analyzes the efficacies of various FLT3i (types 1 and 2) tested in clinical trials in treating R/R AML and high-risk myelodysplastic syndromes (HR-MDS). PubMed and EMBASE databases were searched for single/double-arm phase I/II/III R/R AML or HR-MDS clinical trials published between 1/1/2000 and 6/1/2021. The outcomes studied were composite response rate (CRc) and overall response rate (ORR). Toxicities were compared based on the organ system. The 28 studies analyzed had 1927 patients. The pooled ORR and (CRc) for all FLT3i were 53% (95% CI, 43%-63%) and 34% (95% CI, 26%-44%). Pooled ORR and CRc were 37% (95% CI, 25%-51%) and 35% (95% CI, 21%-52%) for type 1 and 58% (95% CI, 43%-71%) and 38% (95% CI, 27%-50%) for type 2, respectively. Gastrointestinal (GI) and hematological toxicity occurred in 22% (95% CI, 19%-25.4%) and 74.6% (95% CI, 70%-79%) with type 1 and 13.9% (95% CI, 12%-16%) and 57.7% (95% CI, 54.6%-60.8%) with type 2 FLT3i. QTc prolongation occurred in 2.06% (95% CI, 1.03%-3.65%) with type 1 and 7% (95% CI, 5.3%-9%) with type 2 FLT3i. Type 2 FLT3i had less GI toxicity but more QTc prolongation. Prospective studies are needed to compare the efficacy of type 1 and 2 FLT3i.

SUBMITTER: Swaminathan M

PROVIDER: S-EPMC9928788 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Efficacy analysis of different FLT3 inhibitors in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

Swaminathan Mahesh M Aly Mai M MM Khan Abdul Moiz AM Share Bayan Al BA Dhillon Vikram V Lalo Enxhi E Ramos Harry H Akers Katherine G KG Kim Seongho S Balasubramanian Suresh S

EJHaem 20221121 1

Several FLT3 inhibitors(i) are available to treat relapsed/refractory (R/R) <i>FLT3</i>-internal tandem duplicated acute myeloid leukemia (AML). This study analyzes the efficacies of various FLT3i (types 1 and 2) tested in clinical trials in treating R/R AML and high-risk myelodysplastic syndromes (HR-MDS). PubMed and EMBASE databases were searched for single/double-arm phase I/II/III R/R AML or HR-MDS clinical trials published between 1/1/2000 and 6/1/2021. The outcomes studied were composite r ...[more]

PMID: 36819163

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Project description:PurposeThe FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but seldom reduces FLT3mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3mut AML.MethodsThis phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with FLT3 wild-type and FLT3mut (escalation) or FLT3mut (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.ResultsSixty-one patients were enrolled (n = 56 FLT3mut); 64% (n = 36 of 56) of FLT3mut 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 FLT3mut 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 FLT3mut patients was 10.0 months.ConclusionThe 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.

Dataset Information

Efficacy analysis of different FLT3 inhibitors in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

Publications

Efficacy analysis of different FLT3 inhibitors in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

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