Results from a Phase II Study of Crenolanib in Patients With FLT3-Positive Acute Myeloid Leukemia

CHICAGO–The next-generation tyrosine kinase inhibitor (TKI) crenolanib besylate showed “encouraging” activity and safety as a single agent in patients with relapsed/refractory FLT3-positive acute myeloid leukemia (AML), a patient group with poor prognosis, according to results from a phase II study presented at the 2016 ASCO Annual Meeting.

Crenolanib is an orally bio-available benzamidazole that selectively and potently inhibits signaling of wild-type and mutant isoforms of class III receptor FLT3, PDGFR α, and PDGFR β.

In this trial, Jorge E. Cortes, MD, from the University of Texas MD Anderson Cancer Center in Houston, Texas, and authors evaluated the clinical activity, pharmacokinetics, safety, and resistance mechanisms of crenolanib in 69 patients with relapsed/refractory FLT3-positive AML. Patients had the following FLT3 activating mutations: ITD (n=29), D835 (n=11), and ITD + D835 (n=29).

Patients received crenolanib at one of two dosing schedules: 100 mg three times daily (n=42) or 200 mg/m2 per day in three divided doses (n=27).

Sixty-five patients were evaluable and were followed from August 2012 to May 2015, and were split into three cohorts for analysis:

  • Cohort A –Patients who had not received prior FLT3 inhibitors (n=18), including:
    • D835 = 6
    • ITD = 9
    • ITD+D835 = 3
  • Cohort B – Patients receiving crenolanib who had progressed after prior TKIs (n=36), including:
    • sorafenib (n=28)
    • quizartinib (n=11)
    • pexidartinib (n=4)
    • midostaurin (n=3)
    • gilteritinib (n=2)
    • FLX-925 (n=1)
  • Cohort C – Patients who developed FLT3-positive AML after prior myelodysplastic syndrome (n=8), myelofibrosis (n=1), polycythemia vera (n=1), or systemic mastocytosis (n=1)

In cohort A, 39 percent of patients achieved a complete remission with incomplete blood count recovery (CRi), and 11 percent achieved a partial response (PR). Median overall survival (OS) was 234 days: 238 days in patients who had received ≤2 prior therapies versus 133 days in those who had received ≥3 prior therapies.

Among the different mutation types in this cohort, patients with the FLT3­-ITD mutation had the highest median OS (238 days) compared with 183 days for FLT3-TKD and 128 days for FLT3-ITD+TKD. Younger patients (<60 years) also had higher median OS than older patients (234 days vs. 183 days).

In cohort B, 10 patients received two or more prior TKIs, and 25 patients acquired FLT3-TKD mutations following TKI exposure:

  • Dual mutations with FLT3-ITD (n=19)
  • FLT3-D835 (n=17; ITD=15; D835=2)

The overall response rate in cohort B was 31 percent, with 6 CRis and 5 PRs. Median OS was 94 days: 158 days for those with FLT3-ITD and 63 days for those with dual FLT3-ITD+D835 mutations.

In cohort C, the OS was 55 days, with the authors noting that “these patients had only transient benefit from crenolanib.”

Pharmacokinetic analysis showed that crenolanib had “predictable” pharmacokinetics (tmax = 2 hours, thalf = 7.5 hours), with no accumulation seen with repeated dosing.

The most common treatment-related adverse events (AEs; mostly grade 1-2) included nausea and vomiting, transaminitis, and fluid retention. Two patients discontinued crenolanib treatment due to AEs. Among patients who relapsed following crenolanib therapy, none acquired secondary FLT3 mutations, the authors noted.

“Encouraging single-agent activity, safety, and pharmacokinetics were observed with crenolanib in multiple patients with relapsed FLT3-positive AML (including 40 patients with FLT3 D835 mutations),” Dr. Cortes and colleagues concluded. “Crenolanib is being assessed in combination with standard chemotherapy in newly diagnosed and relapsed/refractory AML.”


Cortes JE, Kantarjian HM, Kadia TM, et al. Crenolanib besylate, a type I pan-FLT3 inhibitor, to demonstrate clinical activity in multiply relapsed FLT3-ITD and D835 AML. Abstract #7008. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 4, 2016.