A phase I/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome

Abstract

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in quizartinib/LDAC. The median OS was 19.2 months for quizartinib/AZA and 8.5 months for quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in quizartinib/AZA and 4 (29%) in quizartinib/LDAC. The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.

Venetoclax in Acute Myeloid Leukemia: Molecular Basis, Evidences for Preclinical and Clinical Efficacy and Strategies to Target Resistance

“…Pre-clinical studies in FLT3 mut cell lines, primary samples, and xenografts have shown a synergy between FLT3i and VEN through downregulation of MCL-1 and BCL-XL [ 81 , 82 , 83 ]. Prior clinical studies have demonstrated the safety and efficacy of the combination of SORA, quizartinib, or GILT with HMA, with an ORR of 65–80% and median OS 8.5–20 months [ 84 , 85 , 86 , 87 ].…”

“…Consistently, clinical studies identified lower response and survival rates in patients with AML and TP53 alterations [ 44 , 46 , 48 ]. A retrospective analysis of 121 patients treated with DEC10-VEN frontline therapy in a phase II trial was performed to specifically assess the role of TP53 mutations [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ...…”

Myelodysplastic Syndromes and Modalities of Treatment: An Updated Literature Review

“…Moreover, the median overall survival was enhanced in the combination therapy cohort. These results give evidence for the effectiveness of quizartinib as a combination therapy, specifically with azacytidine, in patients with FLT3-ITD-mutated AML [ 49 ].…”

Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

“…The corresponding inhibitors (ivosidenib and enasidenib) have shown encouraging results in AML patients and are currently tested in higher-risk MDS setting [155][156][157][158]. Other target therapies for higher-risk MDS, adopted from AML treatment, include the FLT-3 inhibitors (midostaurin, gilteritinib, and quizartinib), which are investigated in phase 2 clinical trials [159][160][161]. Cellular-based immune-therapies are of increasing interest.…”