Gilteritinib Is Well Tolerated in Patients With FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia

In the open-label, phase I Chrysalis trial, gilteritinib (a novel oral FLT3/AXL inhibitor) was found to be well tolerated, and potentially efficacious, in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia (AML). Alexander E. Perl, MD, from the University of Pennsylvania-Abramson Comprehensive Cancer Center, in Philadelphia, and researchers presented the findings at the 2016 ASH Annual Meeting.

The Chrysalis trial was a first-in-human phase I/II dose-escalation, dose-expansion study evaluating gilteritinib in adult patients with AML. A total of 252 patients (median age = 62 years; range = 21-90 years) were enrolled between October 2013 and August 2015, and assigned to one of seven dose-escalation cohorts, ranging from once daily doses of 20 to 450 mg of gilteritinib

Confirmed FLT3 mutation was not required; however, each expanded dose level enrolled ≥10 patients who were FLT3-positive, and the 120 mg and 200 mg dose levels further expanded to include ≥40 FLT3-positive patients. “The choice to expand these dose cohorts was based upon FLT3 inhibition in correlative assays and clinical activity seen during dose escalation,” Dr. Perl and researchers explained.

“The study population was heavily pretreated,” the researchers noted. “Seventy percent of patients (n=177) had received two or more prior therapies for AML,” including 29 percent (n=73) who received a hematopoietic cell transplantation, and 25 percent (n=63) who received prior treatment with a tyrosine kinase inhibitor (TKI; sorafenib was most common). Of these patients, 194 had a locally confirmed FLT3 mutation, including ITD (n=159), D835 (n=13), ITD-D835 (n=16), and other (n=6).

Of these, 182 patients discontinued treatment, most commonly due to disease progression (n=75), followed by lack of efficacy (n=44), adverse events (AEs; n=34), and death (n=29). In the dose-escalation cohort, the maximum-tolerated dose was determined to be 300 mg; dose-limiting toxicities in the 450 mg cohort included diarrhea and/or hepatic transaminase elevation. The most common treatment-related AEs included diarrhea (16%) and fatigue (15%).

Seven deaths were deemed possibly and/or probably related to gilteritinib; fatal events included pulmonary embolism, respiratory failure, hemoptysis, intracranial bleeding ventricular fibrillation, septic shock, and neutropenia (n=1 for each).

Pharmacokinetic analysis revealed that gilteritinib concentrations were generally dose-proportional and showed both a long-elimination half-life (range = 45-159 hours) and substantial accumulation (range = 3.2-10 fold) by day 15 of treatment. An exposure-related increase in the inhibition of FLT3 phosphorylation with increasing doses of gilteritinib also was observed.

“Gilteritinib showed strong antileukemic activity in [patients with FLT3 mutations],” for an ORR of 49 percent, the researchers wrote, however, responses were observed less frequently for patients with wild-type FLT3 (ORR=12%).

Among patients with FLT3 mutations, the ORR was 55 percent in patients with ITD, 17 percent with D835, and 62 percent with ITD-D835. Prior treatment with a tyrosine kinase inhibitor appeared to be associated with a lower ORR: 42 percent among FLT3-positive patients treated with prior TKI therapy compared with 56 percent among those who were not.

While complete remission (CR), CR with incomplete platelet recovery (CRp), and CR with incomplete hematologic recovery (CRi) occurred at all doses (TABLE), FLT3-positive patients who had steady-state trough concentrations ≥100 ng/mL, which, the investigators wrote, “correlated with potent FLT3 inhibition in pharmacodynamic assays and corresponded to doses ≥80 mg.”

“The survival of these patients appears better than expected for this patient population when treated with standard therapy,” Dr. Perl noted, with a median overall survival of approximately 31 weeks (range = 1.7-61 weeks), and a median duration of response of 20 weeks (range = 1.1-55 weeks).

“Our data suggest that FLT3 inhibition may improve survival in patients with FLT3-mutated relapsed/refractory AML,” Dr. Perl and researchers concluded. A phase III study of once-daily gilteritinib (120 mg) in patients with relapsed/refractory FLT3-positive AML after frontline therapy is underway.


Perl AE, Altman JK, Cortes JE, et al. Final results of the Chrysalis trial: A first-in-human phase 1/2 dose-escalation, dose-expansion study of gilteritinib (ASP2215) in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Abstract #1069. Presented at the ASH Annual Meeting and Exhibition, December 5, 2016; San Diego, California.

TABLE. Clinical Response to Gilteritinib
  80 mg


120 mg


200 mg


300 mg


450 mg




Complete response 2








0 18


Complete response with incomplete platelet recovery 0 2







0 10


Complete response with incomplete hematologic recovery 3








0 41


Partial response 3












Composite complete response* 5








0 69


Overall response rate 8












*Complete response + complete response with incomplete hematologic recovery = composite complete response