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Efficacy of a Type I FLT3 Inhibitor, Crenolanib, with Idarubicin and High-Dose Ara-C in Multiply Relapsed/Refractory FLT3+ AML

Maro Ohanian, Hagop M. Kantarjian, Gautam Borthakur, Tapan M. Kadia, Marina Konopleva, Guillermo Garcia-Manero, Zeev Estrov, Alessandra Ferrajoli, Koichi Takahashi, Elias J. Jabbour, Naval Daver, Steven M. Kornblau, William G. Wierda, Jan A. Burger, Kiran Naqvi, Christopher B. Benton, Prithviraj Bose, John R. Eckardt, Farhad Ravandi and Jorge E. Cortes

Abstract

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Background: Crenolanib is a novel, type I, oral pan-FLT3 inhibitor with in vitro activity against FLT3-ITD and FLT3-tyrosine kinase domain (TKD) mutations. Crenolanib has a half-life of 6-8 hrs and does not accumulate after chronic dosing. As a single agent, an overall response rate (ORR) of 30% (CR/CRi 19%, PR 12%) has been reported among patients (pts) with multiply relapsed/refractory (R/R) AML pts with FLT3 mutations despite sixty-five percent of the patients having prior exposure to FLT3 inhibitors. We report data from the first 13 pts with R/R FLT3+ AML treated with salvage idarubicin (Ida) and high-dose ara-C (HiDAC) followed by crenolanib.

Design: Pts received Ida (12 mg/m2 for 3d) with HiDAC (1.5 g/m2/d over 3 hrs for 4d or for 3d if >60y), followed by crenolanib starting on d5 and continued until 72 hrs. prior to next chemotherapy regimen. Standard rolling-6 design was implemented with dose escalation of crenolanib as follows: 60 mg TID (dose level 1), 80 mg TID (dose level 2), and 100 mg TID (dose level 3). Responding pts were eligible to proceed to allogeneic stem cell transplant (allo-SCT) or receive consolidation with ara-C (750 mg/m2 for 3d) and Ida (8 mg/m2 for 2d) followed by crenolanib at the same dose received during induction. Patients could then continue on maintenance with crenolanib. Post-SCT crenolanib maintenance therapy was not allowed.

Results: To date, all 3 dose escalation cohorts have been completed, which included 13 pts (11 males, 2 female) with a median age of 51 yrs (range 19-73). All pts had R/R FLT3+ AML. 6/13 pts had relapsed after 1 or 2 prior AML therapies, with the remaining 7 pts having 3-8 prior AML therapies (allo-SCT in 3). Nine pts had received prior FLT3 inhibitors including sorafenib (n=7), quizartinib (n=2), and E6201 (n=2). Nine pts had a FLT3-D835 kinase domain mutation, of which 4 pts also had FLT3-ITD; the remaining 4 pts had FLT3-ITD alone. Conventional cytogenetic testing included: normal karyotype (n=4; 31%), miscellaneous (n=5; 36%), and complex (n=4; 31%). Besides FLT3, multiple other leukemia-associated mutations were present at baseline: NPM1 (36%), DNMT3A (36%), NRAS/KRAS (27%), WT1 (18%), TET2 (18%), RUNX1 (18%), IDH1 (9%), IDH2 (9%), and ASXL1 (9%).

No dose-limiting toxicities were observed at any of the dose levels explored and there were no dose reductions required. Non-hematologic adverse events assessed as possibly or probably related to crenolanib were all grade 1 in severity, including: nausea (n=2), vomiting (n=2), diarrhea (n=1), and abdominal pain (n=1). No deaths were attributed to crenolanib.

The ORR in 11 pts evaluable for response was 36% (1 CR, 3 CRi; 2 not evaluable because of early discontinuation of therapy). Among 6 pts who received ≤2 prior AML therapies, 4 pts (67%) achieved a CR/CRi (including 2 pts with prior exposure to FLT3 inhibitors). These remissions occurred in pts with FLT3-ITD (n=2), FLT3-D835 (n=1) and FLT3-ITD+FLT3-D835 (n=1) (Table 1). No CRs were seen in the 5 pts who had 3 or more prior therapies (including 3/5 who had received prior FLT3 inhibitors) before coming on study.

Three CRi pts have undergone allo-SCT: 1 pt (43/F) achieved CRi (with persistent FLT3-ITD) after 1 cycle and maintained remission with FLT3-ITD negativity for 6 months post allo-SCT, 1 pt (67/M) achieved CRi with FLT3-D835 negativity after 2 cycles and maintained remission for 3 months post allo-SCT, and 1 pt (58/M) achieved CRi after 1 cycle and relapsed 1.5 months post allo-SCT. One pt (73/M) achieved a full CR with FLT3 negativity and count recovery and is currently receiving crenolanib maintenance.

The median OS for all patients was 259d; median OS by prior therapies was 259d for pts with ≤ 2 prior therapies, and 53d for pts with ≥ 3 prior therapies (Figure 1).

Conclusions: Full doses of crenolanib (100 mg TID) can be safely combined with idarubicin and HiDAC in multiply relapsed/refractory FLT3+ AML. There is suggestion of clinical efficacy particularly among pts with only 1-2 prior therapies. This trial is being expanded to allow combination of full dose crenolanib with other standard salvage chemotherapies, including MEC (mitoxantrone, etoposide, cytarabine) and FLA(G)-IDA (fludarabine, cytarabine, idarubicin w/ or w/o G-CSF).

Disclosures Konopleva: Calithera: Research Funding; Cellectis: Research Funding. Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver: Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding. Wierda: Acerta: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Burger: Pharmacyclics: Research Funding. Eckardt: Arog: Employment, Equity Ownership. Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

  • * Asterisk with author names denotes non-ASH members.

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