Crenolanib, a Type I FLT3 TKI, Can be Safely Combined with Cytarabine and Anthracycline Induction Chemotherapy and Results in High Response Rates in Patients with Newly Diagnosed FLT3 Mutant Acute Myeloid Leukemia (AML)
Abstract Background: Crenolanib is a type I oral FLT3 TKI, which inhibits both FLT3-ITD and FLT3-TKD mutations (D835, N841, etc). Crenolanib has a half-life of 6-8 hours and does not accumulate with repeated dosing. Crenolanib does not inhibit c-kit at clinically achievable concentrations, potentially allowing for full count recovery even when combined with myelosuppressive chemotherapy. We report here the first analysis of a phase II trial evaluating the tolerability and efficacy of crenolanib combined with standard induction chemotherapy in patients (pts) with newly diagnosed FLT3 mutant AML. Methods: Pts (≥ 18yrs) (no upper age limit) with newly diagnosed AML characterized by FLT3 (ITD and/or TKD) mutations were enrolled. Pts received standard 7+3 induction with cytarabine 100 mg/m2/d for 7 days and either daunorubicin (<60yrs: 90 mg/m2; ≥60yrs: 60 mg/m2) or idarubicin 12 mg/m2 for 3 days. Crenolanib 100 mg TID was administered starting on day 9 until 72 hrs prior to next chemotherapy. Re-induction was permitted for pts with inadequate leukemia cytoreduction. Up to 4 courses of consolidation consisting of 6 doses of high dose cytarabine (HiDAC) (<60yrs: 3 g/m2; ≥60yrs: 1g/m2) was given, with crenolanib starting on day 7. Eligible pts could proceed to allogeneic stem cell transplant (SCT). Crenolanib maintenance therapy was offered for 1 year after HiDAC or -SCT. Safety and tolerability were assessed as well as anti-leukemic activity. Results: Demographics: Twenty-six pts (14 females, 12 males) with a median age of 55yrs (range 22-74yrs) have received 7+3 followed by crenolanib; nine (35%) pts were ≥ 60yrs. Five pts had initial WBC >100,000/μL (two pts had WBC >200,000). Three pts had AML following antecedent MDS or MPN. Mutational Analysis: Twenty-two pts had either FLT3-ITD (n=19) or FLT3-D835 (n=3) mutations. Genomic sequencing revealed multiple concurrent FLT3 activating mutations in four pts. One pt had a dual-activating kinase domain mutation in trans (D835Y+N841T). Three other pts had FLT3-ITD together with N841 (n=2), I836del (n=2), and V592/593 (n=2). Fifteen (60%) pts had FLT3 and NPM1 mutations, and 11 (52%) had FLT3 and DNMT3A mutations. Five pts (24%) had AML with three mutations (FLT3 + NPM1+ DNMT3A). WIT (WT1, IDH1/2, TET2) mutations were present in 11 (52%) pts. Three pts had trisomy 8; one pt each having monosomy 7, trisomy 4, and t(3;18)del(6q)der(3). Treatment Outcome: Eighteen (69%) pts received induction with cytarabine+daunorubicin (10 pts at 90 mg/m2, 8 pts at 60 mg/m2) and eight pts (31%) received cytarabine+idarubicin. To date, crenolanib has been well-tolerated in combination with chemotherapy. Six pts required crenolanib dose reductions for periorbital edema (n=2), delayed count recovery (n=1), LFT elevation (n=1), nausea (n=1) and rash (n=1). Out of the twenty-five pts evaluable for response, twenty-two (88%) achieved complete remission (CR) with full count recovery after one cycle of induction. Overall CR/CRi rate was 96% (Table 1). Sixteen pts (10 pts< 60yrs; 6 pts≥ 60yrs) have received a total of 26 cycles of consolidation with HiDAC and crenolanib. Twelve pts (46%) have been bridged to allogeneic SCT. With a median follow up of 6 months, only three pts (all > 60yrs) have relapsed. Overall survival is shown in Figure 1. Conclusion: Crenolanib, a type I pan-FLT3 TKI, can be safely combined at full doses with cytarabine/daunorubicin or cytarabine/idarubicin induction and HiDAC consolidation chemotherapy for upfront AML therapy. A high CR rate of 88% with full count recovery was observed after one cycle of induction with an overall CR/CRi rate of 96%. HiDAC consolidation and allo SCT could be administered on schedule. Encouraging anti-leukemic activity has been observed with no relapses in FLT3 mutant AML pts <60yrs. Accrual to this trial continues. Disclosures Stone: Roche: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy. Eckardt:Arog: Employment, Equity Ownership.