Triplet Combo Quizartinib, Decitabine, and Venetoclax Active in Patients with FLT3/ITD-Mutated AML

Take-aways:

• Quizartinib, decitabine, and venetoclax was active in patients with FLT3/ITD-mutated AML.
• Among 23 patients treated with this combination, three achieved complete remission and 15 achieved complete remission with incomplete hematological recovery.
• Among those who responded to treatment, six of 16 and five of 18 patients achieved FLT3-PCR and multicolor flow cytometry negativity, respectively.

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The triplet combination of quizartinib, decitabine, and venetoclax was active in patients with FLT3-internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML), according to results of a phase I/II trial .

Quizartinib is a potent second-generation FLT3 inhibitor that has previously demonstrated synergy with venetoclax in AML cell lines and patient-derived xenograft models.

The study evaluated the safety and efficacy of the triplet therapy quizartinib, decitabine, and venetoclax in patients with newly diagnosed or relapsed/refractory FLT3-ITD-mutated AML.

A total of 28 patients were enrolled and evaluated at the time the presentation. All patients received quizartinib 30 mg/day or 40 mg/day daily throughout the trial, as well as 10 days of decitabine 20 mg/m² during cycle one. In subsequent cycles, decitabine was reduced to five days. Patients also received venetoclax 400 mg/day starting from day one.

At day 14, patients underwent a bone marrow (BM) biopsy; for patients with BM blasts ≤5% or aplasia, venetoclax was put on hold, while those with BM blasts >5% continued venetoclax for 21 days during cycle one.

Among 23 patients with relapsed/refractory AML, three achieved complete remission (CR) and 15 achieved CR with incomplete hematological recovery (CRi), for an overall composite CR (CRc) rate of 78%. The CRc rates were 75% and 72% in patients who received prior gilteritinib and prior hypomethylating agents plus venetoclax, respectively. Among patients who responded to therapy, six of 16 and five of 18 achieved FLT3-polymerase chain reaction (PCR) and multicolor flow cytometry negativity, respectively.

Among the relapsed/refractory cohort, the 60-day mortality rate was 5%, and median overall survival (OS) was 7.6 months, with a median follow-up of 13 months. The median OS fell to 6.3 months for patients previously exposed to gamma-interferon-inducible lysosomal thiol reductase or FLT3 inhibitors.

Among the five patients with newly diagnosed AML (median age, 69 years), all achieved CRc (two CRs and three CRis). Among them, four of five and two of four achieved FLT3-PCR and multicolor flow cytometry negativity, respectively. The 60-day mortality rate was zero.

Quizartinib 30 mg/day was determined to be the recommended phase II dose for the triplet treatment since no patients developed dose-limiting toxicities (DLTs), whereas two patients developed hematologic DLTs (grade 4 neutropenia with a <5% cellular BM lasting ≥42 days) at the quizartinib 40 mg/day dose level.

Less than half of patients (40%) with underlying RAS/MAPK mutations were responsive to the therapy compared to 94% of patients without these mutations, suggesting that RAS/MAPK mutations drive both primary and secondary resistance to the triplet regimen, according to the researchers.

Reference

Yilmaz M, Muftuoglu M, Kantarjian H, et al. Quizartinib with decitabine and venetoclax (triplet) is active in patients with FLT3-ITD mutated acute myeloid leukemia – a phase I/II study. Abstract #S127. Presented at the 2022 European Hematology Association Congress, June 9-12, 2022.