Azacitidine/Quizartinib Combo Showcases Early Activity in MDS, MDS/MPN With FLT3 or CBL Mutations

Article
Pipeline Report: August 2022

The combination of azacitidine and quizartinib produced preliminary responses in patients with myelodysplastic syndrome and myelodysplastic syndrome/myeloproliferative neoplasms whose tumors harbored FLT3 or CBL mutations, according to data from a phase 1/2 trial (NCT04493138).

The combination of azacitidine and quizartinib produced preliminary responses in patients with myelodysplastic syndrome (MDS) and MDS/myeloproliferative neoplasms (MPN) whose tumors harbored FLT3 or CBL mutations, according to data from a phase 1/2 trial (NCT04493138).

At a median follow-up of 13.2 months (95% CI, 4.6-21.7), the combination elicited a 90% overall response rate (ORR; n = 9/10). Among the 10 patients, 60% had a complete response in the marrow (mCR). Additionally, a complete response, a mCR with hematologic improvement (HI), and a HI were observed in 1 patient each. The median number of cycles to best response was 1 (range, 1-6) and the median duration of response (DOR) was 6.3 months (range, 1.6-14.3).

“[The] combination of quizartinib and azacitidine [is] active in MDS and MDS/MPN, [and] no dose-limiting toxicities [DLTs] were [observed] in [the] phase 1 dose-escalation portion [of the trial] up to doses of 60 mg daily [on] days 1 to 28,” study authors from The University of Texas MD Anderson Cancer Center wrote in a poster shared during the 2022 EHA Congress. “[The regimen had an] acceptable toxicity profile.”

Approximately 1% of patients with newly diagnosed MDS harbor FLT3 mutations, although the mutations occur in up to 19% of patients at the time of failure of a hypomethylating agent (HMA). Additionally, approximately 10% of patients with MDS/MPN harbor CBL mutations; these mutations occur in 13% to 15% of those with chronic myelomonocytic leukemia (CMML).

The phase 1/2 trial evaluated the doublet in adult patients aged 18 years of age or older with HMA-naïve MDS or MDS/MPN with intermediate-2/high-risk disease per International Prognostic Scoring System (IPSS) or higher than 5% blasts; or any MDS or MDS/MPN following failure on HMA treatment. All patients were required to have a CBL exon 8 or 9 mutation, or a FLT3-ITD/D835 mutation; they also needed to have an ECOG performance status of 0 to 2.

Patients were excluded from the study if they had a QTcF of more than 450 msec; a history of clinically significant ventricular fibrillation, torsades de pointes, sustained ventricular tachycardia, or long QT syndrome; a known history of second- or third-degree heart block; a complete left bundle branch or bifascicular block; or atrial fibrillation documented within 2 weeks of study entry.

Patients enrolled to the dose-escalation portion of the trial received either 30 mg (n = 3), 40 mg (n = 3), or 60 mg (n = 4) of oral quizartinib per day on days 1 through 28, in combination with 75 mg/m2 of azacitidine daily on days 1 through 5 of each 28-day cycle.

The primary end points of the dose-escalation portion of the trial were to evaluate safety and tolerability, and determine the maximum tolerated dose (MTD) of quizartinib. Secondary end points included ORR per International Working Group 2006 criteria, overall survival (OS), DOR, relapse-free survival, and leukemia-free survival.

At data cutoff, total of 10 patients were enrolled to the trial,; 9 patients were included in the dose-escalation portion of the research and 1 was included in dose-expansion portion. Half of all patients had intermediate-2 risk disease, and the other half had intermediate-1 risk disease per IPSS.

Seven patients presented with CMML, 2 had MDS, and 1 had atypical chronic myeloid leukemia. Six patients harbored FLT3 mutations, and 4 had CBL mutations. Eight patients had normal cytogenetics at baseline, 1 had complex cytogenetics, and 1 had monosomy 7 cytogenetics. The median absolute neutrophil count (ANC) was 10.68 x 109 (range, 0.33-113.8), the median platelet count was 110 x 109 (range, 34-536), the median hemoglobin level was 9.6 g/dL (range, 7-10.3), and the median bone marrow blasts was 8% (range, 2%-15%).

Additional data showed that the combination resulted in a median OS of 17.35 months (95% CI, 6.8-28.3). Platelet recovery to more than 50 x 109/L and more than 100 x 109/L by day 28 of therapy occurred in 67% and 56% of patients, respectively. Furthermore, ANC recovered to 1 x 109/L by day 28 in 9 patients.

At the time of data cutoff, 1 patient remained on study treatment. Reasons for discontinuation included moving to allogeneic stem cell transplant (n = 4), disease relapse (n = 1), disease progression (n = 2), and patient/physician preference (n = 2). Patients received a median of 6 (range, 1-11) cycles of treatment.

No DLTs were reported in the dose-escalation phase of the research. However, 2 patients required dose reductions of quizartinib during cycle 3 or later because of cytopenias. Additionally, 3 patients needed dose reductions of azacitidine due to cytopenias. No early mortality was reported at weeks 4 and 8.

The most frequent grade 1/2 adverse effects reported with the doublet included constipation (n = 6), oral mucositis (n = 3), diarrhea (n = 2), fatigue (n = 2), nausea (n = 2), arthralgia (n = 2), atrial fibrillation (n = 1), hypokalemia (n = 1), injection site reaction (n = 1), and skin infection (n = 1). The most common grade 3 AEs were thrombocytopenia (n = 3), anemia (n = 2), atrial fibrillation (n = 1), hypokalemia (n = 1), chest pain (n = 1), and febrile neutropenia (n = 1).

The dose-escalation phase of the research is ongoing to further evaluate the safety and efficacy of the combination, according to study authors. Additional research on lower dose levels of 40 mg of quizartinib per day are warranted.

Reference

Abuasab T, Jabbour E, Short N, et al. Initial results of phase I/II study of azacitidine in combination with quizartinib for patients with myelodysplastic syndrome and myelodysplastic/myeloproliferative neoplasm with FLT3 or CBL mutation. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P754.

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