General AML,   FLT3

ASH 2017 | Combination of quizartinib with azacitidine or LDAC in patients with FLT3-ITD mutated AML

During the 59th American Society of Hematology (ASH) Annual Meeting, Atlanta, GA, on Monday 11th December 2017, Mahesh Swaminathan, from The University of Texas MD Anderson Cancer Center, Houston, TX, presented interim data from a phase I/II study (NCT01892371) of quizartinib, a Fms Like Tyrosine Kinase 3 (FLT3) inhibitor, combined with azacitidine or Low-Dose cytarabine (LDAC) in patients with Acute Myeloid Leukemia (AML).

The phase I portion of this study aims to identify the MTD of quizartinib with either AZA or LDAC and the associated DLT in patients with R/R AML or high-risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) were enrolled irrespective of their FLT3 mutations status. The phase II portion of the study aims to determine the efficacy of quizartinib with either AZA or LDAC in untreated patients with AML, MDS or CMML who are FLT3-Internal Tandem Duplication (FLT3-ITD) mutated.

In total, 61 patients were enrolled in the phase I (n = 12) and II (n = 49) portions of the study. Patients were administered oral quizartinib at either 60 or 80 mg daily plus AZA (75 mg/m2 subcutaneously [SQ] or intravenously for 7 Days per cycle [AZA arm, n = 37]) or LDAC (cytarabine 20 mg SQ twice daily for 10 Days per cycle [LDAC arm, n = 24]).

Key Findings:
  • Recommended phase II dose for both the AZA and LDAC arm; quizrtinib 60 mg daily
  • ORR in both arms; 69%
    • AZA arm; 70%
    • LDAC arm; 67%
  • Survival in the AZA and LDAC arm respectively
    • Median OS; 14.8 vs 7.4 months, P = 0.390
    • Median RFS in responders; 6.93 vs 4.37 months, P = 0.963
    • Median OS in patients censored for SCT; 13.4 vs 6.0 months, P = 0.111
  • 60-day mortality rate in the AZA and LDAC arms; 5% vs 0% respectively
  • MRD was assessed in 31 patients in the AZA (n = 17) and LDAC arm (n = 14)
    • Of these 31 patients, four (24%) and two (14%) were MRD negative in the AZA and LDAC arm respectively
    • CR occurred in three and one patient in the AZA and LDAC arm respectively
  • Among previously untreated patients in the AZA (n = 9) and LDAC (n = 3) arm respectively
    • ORR: 89% vs 100%
    • Median survival; 21.1 months vs NR
  • Among relapsed patients in the AZA (n = 28) and LDAC (n = 21) arm respectively
    • ORR: 64% vs 62%
    • Median survival; 12 vs 7.4 months
  • Among patients with no prior FLT3 treatment in the AZA (n = 25) and LDAC (n = 15) arm respectively
    • ORR: 68% vs 60%
    • Median survival; 12 vs 7.4 months
  • Most frequent grade 3– 4 hematologic AEs in both arms include febrile neutropenia, thrombocytopenia, leukopenia, and anemia
  • A total of five deaths occurred as a result of sepsis, multi-organ failure, intra-cerebal hemorrhage and unknown

The speaker concluded by stating that the combination of quizartinib and AZA or LDAC was highly active among patients with FLT3-ITD mutation. Additionally, the ORR observed in this study was higher than the one seen with single agent quizartinib. He added that accrual to this phase I/II study is still ongoing. 

In an interview with the AML Global Portal, Assoc. Prof. Tapan Kadia from The University of Texas MD Anderson Cancer Center commented on the findings of this phase I/II study. He noted that combination of quizartinib and AZA or LDAC showed a “high response rate and excellent tolerability" in older AML patients.

  1. Swaminathan M. et al. The Combination of Quizartinib with Azacitidine or Low Dose Cytarabine Is Highly Active in Patients (Pts) with FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial. Oral Abstract #723: 59th ASH Annual Meeting and Exposition, Atlanta, GA.
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