Quizartinib Combination Highly Active in Myeloid Leukemias

December 21, 2017

A combination of the FLT3 kinase inhibitor quizartinib with 5-azacitidine or low-dose cytarabine is active in patients with FLT3-ITD mutated myeloid leukemias, according to a new study.

A combination of the FLT3 kinase inhibitor quizartinib with 5-azacitidine (AZA) or low-dose cytarabine (LDAC) is active in patients with FLT3-ITD mutated myeloid leukemias, according to a new study.

FLT3 is overexpressed in the majority of cases of acute myeloid leukemia (AML). Quizartinib inhibits FLT3 kinase activity and induced about a 50% composite response rate among patients with FLT3-ITD mutations in phase I and II studies, said lead author Mahesh Swaminathan, MD of the University of Texas MD Anderson Cancer Center in Houston.

He reported on a phase I/II study (abstract 723) of a combination of quizartinib with either AZA or LDAC at the American Society of Hematology (ASH) Annual Meeting and Exposition, held December 9–12 in Atlanta.

The phase I portion included 12 patients with relapsed/refractory high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or AML, irrespective of FLT3 mutation and salvage status. The phase II portion enrolled 49 patients with untreated MDS/CMML/AML of any age receiving first salvage treatment for AML with a FLT3-ITD mutation.

The 28-day treatment cycle included AZA 75 mg/m2 subcutaneously or intravenously for 7 days per cycle, or cytarabine 20 mg subcutaneously twice daily for 10 days per cycle along with quizartinib at two planned dose levels: 60 mg (dose level 1) or 90 mg orally daily (dose level 2), uninterrupted.

Of the 61 patients (median age 68 years), 38 received AZA and 23 received LDAC; 59 patients were evaluable for response. The overall response rate was 73%, including 67% in the LDAC arm and 76% in the AZA arm; 5 of 43 (12%) patients are minimal residual disease (MRD)-negative.

Eleven of 12 patients who were previously untreated have responded, he noted. The median overall survival for previously untreated patients was 18.6 months. Overall response rate among the 47 previously treated was 68%, and the median overall survival was 11.25 months. 

Among the 55 patients with FLT3-ITD mutations, the overall response rate was 75%, and 5 (9%) patients had no detectable MRD (4 AZA, 1 LDAC). Four of five patients (80%) with prior FLT3 inhibitor exposure responded.

At a median follow-up of 20 months, 11 of the 43 responders remain in complete response. Six patients had stem cell transplant, four are continuing study therapy, and one discontinued due to insurance issues.

For the total study group, median overall survival was 20 months: 13.4 months in AZA arm and 6.7 months in LDAC arm. “Fourteen (33%) patients have maintained response for more than 1 year,” said Swaminathan.

Grade 3/4 toxicities included hypokalemia (19), hyperkalemia (2), hypotension (9), hypophosphatemia (9), hyponatremia (9), hypocalcemia (5), hyperbilirubinemia (7), elevated ALT (8), elevated AST (4), abdominal pain (3), intra cerebral hemorrhage (2), hypernatremia (2), hypermagnesemia (4), diarrhea (8), dehydration (2), respiratory failure (6), hyperglycemia (1), QTc derived from Fridericia’s formula (QTcF) prolongation (3), sinus tachycardia (1), atrial fibrillation (4), and pericardial effusion (1).

In conclusion, Swaminathan said: “The combination of quizartinib and AZA or LDAC is active among patients with FLT3-ITD mutations. Response rates and remission duration appear higher than expected with either agent alone. The safety profile of both combinations is favorable. Clinically significant QTcF prolongation is infrequent.”