A new regimen of FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib and venetoclax was tolerable at standard doses and produced high response rates for advanced, FLT3-mutated acute myeloid leukemia (AML) in a multicenter Phase 1 study.

“The results were encouraging. We saw high rates of marrow response and promising overall survival for this high-risk group of patients,” said Joseph J. Maly, M.D., a hematologist/oncologist at Norton Cancer Institute and co-author of the study.

The combination of gilteritinib and venetoclax had not been studied clinically before this Phase 1 study. The primary objectives were safety and identification of the recommended Phase 2 dose.

The regimen “potentially improves response frequency and depth over existing standards in a high-risk, mutation-defined group of patients with AML” the study’s authors wrote in the Journal of Clinical Oncology.

In the Phase 1 study, a total of 61 patients with a median age of 63 were enrolled. Two-thirds were relapsed, a third were refractory.

The modified composite response rate was 75% in FLT3-mutated patients treated at any dose (56 of those enrolled). This modified rate combined those with complete response, plus complete response with incomplete blood count recovery, plus complete response with incomplete platelet recovery, plus morphologic leukemia-free state.

The median time to response was just under a month, and the median remission duration was 4.7 months. The median follow-up was 17.5 months.

Relapsed or refractory AML has a median overall survival rate of four to seven months with standard chemotherapy treatment. The overall survival in the study was 10 months for all FLT3-mutated patients.

The major toxicity found in the study was myelosuppression, which was successfully managed with dosing modifications. Early mortality was similar to gilteritinib monotherapy.

AML  is one of the most common types of leukemia in adults, but it is still rare, accounting for only about 1% of cancers overall. The average age at diagnosis is 68.   of those who receive standard induction chemotherapy go into remission.

Until recently, treatment options for relapsed or refractory AML were limited to reinduction regimens that were available only to younger, healthier patients.

In 2017, the Food and Drug Administration approved three new agents: the IDH inhibitor enasidenib, the BCL-2 inhibitor venetoclax, and the FLT3 inhibitors midostaurin and gilteritinib.

Taken alone, gilteritinib improved survival. Venetoclax added to DNA hypomethylating agents and low-dose cytarabine improved outcomes for newly diagnosed, older patients. As a single agent, the efficacy of venetoclax has been modest, but it appears to work synergistically in combination with other agents.

Other participants in the study included:

• The University of Texas MD Anderson Cancer Center
• Abramson Cancer Center, University of Pennsylvania
• Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
• Weill Cornell Medical College
• Mayo Clinic
• John Theurer Cancer Center at Hackensack Meridian Health
• Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
• David Geffen School of Medicine at UCLA
• University of Miami Sylvester Comprehensive Cancer Center