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Quizartinib Combinations Show High Activity in Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation

TON - March 2018, Vol 11, No 1 - Conference Correspondent, Drug Updates
Wayne Kuznar

 

Quizartinib Combinations Show High Activity in Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation

Atlanta, GA—The combination of the investigational drug quizartinib plus azacitidine (Vidaza) or low-dose cytarabine has substantial activity in patients with myeloid leukemias and FLT3 mutations.

The composite complete response (CRc) with the combinations was approximately 83% in previously untreated patients and 59% in patients with relapsed disease in an interim report of a phase 1/2 clinical trial presented by Mahesh Swaminathan, MD, Leukemia Fellow, M.D. Anderson Cancer Center, Houston, at ASH 2017. The response rates and the duration of remission were higher than expected with each agent alone, “although this needs to be confirmed in more patients in a randomized trial,” he said.

FLT3 is expressed in hematopoietic progenitor cells. Activating mutations are present in 25% to 40% of patients with acute myeloid leukemia (AML), and are associated with poor prognosis.

Quizartinib, an oral FLT3 receptor tyrosine kinase inhibitor, inhibits wild-type FLT3 and FLT3-ITD. Single-­agent quizartinib induced CRs in approximately 50% of patients with AML and FLT3-ITD mutations in phase 1 and 2 studies. Doses as low as 30 mg and 60 mg have shown activity, with higher response rates and overall survival (OS) with the 60-mg dose. Based on these results, quizartinib 60 mg was combined with either azacitidine or low-dose cytarabine in the phase 1/2 clinical trial of 61 patients with myelodysplastic syndrome, chronic myelomonocytic leukemia, or AML.

Quizartinib was administered daily in 28-day cycles, uninterrupted, with azaci­tidine 75 mg/m2 for 7 days per cycle, or with cytarabine 20 mg twice daily for 10 days per cycle. In all, 8% of patients in the azacitidine arm and 25% in the low-dose cytarabine arm had previous exposure to FLT3 inhibitors.

Approximately 24% and 13% of patients in the azacitidine and low-dose cytarabine arms, respectively, had not received previous therapy. Overall, >90% of patients had FLT3-ITD mutations at baseline. The total CRc rate was 64%, with 68% in the azacitidine arm and 58% in the low-dose cytarabine arm.

“The treatment was associated with a low rate of early deaths, with a 60-day mortality rate of only 5% in the azacitidine arm and 0% in the low-dose cytarabine arm,” said Dr Swaminathan. The median OS was 14.8 months and 7.4 months, respectively; the median relapse-free survival rates were 6.93 months and 4.37 months, respectively.

Among the newly diagnosed patients, the median OS was 21 months in the azacitidine arm, and was not reached in the low-dose cytarabine arm; the median relapse-free survival was 17.7 months and was not reached, respectively. The CRc rates were 78% and 100%, respectively. “These results remain unchanged when you consider patients who have not been previously exposed to FLT3 inhibitors,” Dr Swaminathan said.

In the 12 patients who received stem-cell transplant, the median OS was 5.12 months in the azacitidine arm and was not reached in the low-dose cytarabine arm.

QTc prolongation was reported in 9 patients. The most common grade 3/4 toxicities were infections, gastrointestinal hemorrhage, hypokalemia, and hyponatremia.

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Last modified: April 27, 2020