Phase I study of quizartinib as post-transplant maintenance therapy in FLT3-ITD mutated AML

On 1st November 2017,  in American Journal of Hematology, Brenda M. Sandmaier from the Fred Hutchinson Cancer Research Center, Seattle, WA, US, and colleagues published results from their phase I, multi-center, sequential-group, dose escalation study (NCT01468467), which aimed to evaluate the safety and tolerability of quizartinib, a selective and highly potent Fms Like Tyrosine Kinase 3 (FLT3) inhibitor, when administered as maintenance therapy in patients with FLT3-Internal Tandem duplication (FLT3-ITD)-mutated Acute Myeloid Leukemia (AML) who underwent Allogenic Hematopoietic Cell Transplant (allo-HCT).

In total, 13 patients with FLT3-ITD-mutated AML (median age = 43 years) in morphological remission following Human Leukocyte Antigen (HLA)-matched allo-HCT were administered either 40 mg (n = 7) or 60 mg (n = 6) oral quizartinib in 28-day cycles for up to 24 cycles. The primary outcomes of the study were to determine the Dose Limiting Toxicities (DLTs) of quziartinib, Maximum Tolerated Dose (MTD) and evaluation of the safety and tolerability of quizartinib.

Key findings of the study were:
  • Safety
    • At dose level 1 (40 mg) and 2 (60 mg), DLT occurred in one patient each due to grade 3 hemorrhage and anemia respectively
    • All patients discontinued treatment due to completion of therapy (n = 5), serious adverse events (n = 4), investigators discretion (n = 2), disease progression (n = 1) and unspecified (n = 1)
    • Most common grade 3–4 hematological adverse events occurred including neutropenia (23%), leukopenia (15%), anemia (15%), thrombocytopenia (15%) and lymphopenia (15%) 
    • MTD = not reached
  • Efficacy
    • Ten patients received quizartinib for > 1 year
    • Relapse occurred in one patient
    • Death occurred due to disease progression (n = 1), peritoneal hemorrhage (n = 1) and unknown causes (n = 1)
    • Nine patients survived ≥ 50 weeks
    • Four patients survived ≥ 104 weeks

In summary, maintenance therapy with quizartinib in FLT3-ITD mutated AML patients demonstrated an acceptable tolerability and reduced relapse rate following allo-HCT, which the authors noted compared favorably to historical cohorts. Additionally, while MTD was not identified in this study, 60 mg daily was selected as the MTD for continuous daily administration based on the strong efficacy data from previous quizartinib studies.

Key limitations of this study includes the small sample size and the absence of a control arm. Additionally, the authors noted that the study was terminated early, which limited the planned readouts on safety, efficacy and pharmacodynamics of quizartinib for maintenance therapy in FLT3-ITD mutated AML.


FLT3-ITD–mutated acute myeloid leukemia (AML) has very high risk of relapse and is associated with poor outcome following allogeneic hematopoietic-cell transplant (allo-HCT). This two-part, phase 1, multicenter, open-label, sequential-group, dose-escalation study aimed to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and safety/tolerability of quizartinib, a selective and highly potent FLT3 inhibitor, when administered as maintenance therapy after allo-HCT. Thirteen subjects with documented FLT3-ITD–mutated AML in morphological remission following allo-HCT received one of two quizartinib dihydrochloride dose levels (DL): 40 mg/d (DL1; n=7) and 60 mg/d (DL2; n=6), administered orally in 28-day cycles for up to 24 cycles. Median age of participants was 43 years. All subjects received human leukocyte antigen (HLA)-matched allo-HCT. One subject treated at DL1 and 1 treated at DL2 had DLTs that required drug interruption (grade 3 gastric hemorrhage and grade 3 anemia, respectively). Ten subjects (77%) received quizartinib for >1 year; 5 (38%) completed 24 cycles. Four subjects (31%) discontinued quizartinib due to adverse events. One subject (8%) experienced relapse during cycle 1 and discontinued treatment. Most common (≥20%) grade 3/4 adverse events were neutropenia (23%), anemia (15%), leukopenia (15%), lymphopenia (15%), and eye disorders (15%). This study demonstrated acceptable tolerability and early evidence of reduced relapse rate following allo-HCT with quizartinib maintenance compared to historical cohorts. No MTD was identified, but 60 mg daily was selected as highest dose for continuous daily administration based on randomized comparison of daily 30 and 60 mg doses in relapsed/refractory AML.

  1. Sandmaier B. M. et al. Results of a Phase 1 Study of Quizartinib as Maintenance Therapy in Subjects With Acute Myeloid Leukemia in Remission Following Allogeneic Hematopoietic Stem Cell Transplant. Am J Hematol. 2017 Nov 1. DOI: 10.1002/ajh.24959. [Epub ahead of print].
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