Safety Study of Salvage Chemotherapy High-Dose Ara-C/Mitoxantrone (HAM) and Type I FLT3-TKI Crenolanib in First Relapsed/Primary Refractory AML

• Published in: Blood 2016-12, Vol.128 (22), p.3983-3983
• Main Authors: Iyer, Swaminathan P., Jethava, Yogesh, Karanes, Chatchada, Eckardt, John R., Collins, Robert
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V128.22.3983.3983

Background: High-dose cytarabine and mitoxantrone (HAM) have been used as salvage chemotherapy in patients (pts) with relapsed/refractory AML. Mitoxantrone is less cardiotoxic than other anthracyclines and can be tolerated in older pts. Crenolanib is a novel, type I, oral pan-FLT3 inhibitor with promising single-agent activity in multiply relapsed/refractory FLT3+ve AML. Crenolanib has a half-life of 6-8 hrs and does not accumulate after chronic dosing. We here report data from the first 8 pts with primary relapsed or refractory AML treated with HAM followed by crenolanib. Design: Pts with AML and/or prior MDS regardless of FLT3 status (wild-type or mutant) were enrolled in this study. Eligible pts must have progressed on or be refractory to their first line AML therapy. Pts were treated with HAM (cytarabine 1.0 g/m2/d for d1-6 and mitoxantrone 10 mg/m2 for d1-3) followed by crenolanib 100 mg TID, starting from d8 continuously for a maximum of 49d per cycle (2 cycles of treatment were allowed). Older pts (≥60 yr) or pts who had prior SCT or who required a second induction cycle received lower dose of HAM (cytarabine 0.5 g/m2/d for d1-6 and mitoxantrone 8 mg/m2 for d1-3). Pts in remission following salvage induction were eligible to proceed to allo SCT. Results: 8 pts (4 males, 4 females) with first relapsed or primary refractory AML have been enrolled and received HAM followed by crenolanib. The median age on study was 64 (range 36-78) with 6/8 pts ≥ 60yr and 3 pts older than 70yr. 3/8 pts came on study with FLT3 activating mutations, including ITD (2 pts) and D835 (1 pt). 7/8 pts had de novo AML, and 1 had prior-MDS after receiving prior chemotherapy for ovarian cancer. 3/8 pts were primary refractory to first line therapy with the remaining 5 pts having relapsed following response to first line therapy. Pt demographics are summarized in Table 1. 8 pts received 1 cycle of salvage treatment with HAM followed by continuous daily crenolanib (100 mg TID). 6 pts were evaluable for responses with a complete remission rate of 67% (2 CR, 2 CRi), including 2 pts who were refractory to front line chemotherapy. 2 of 3 pts with FLT3 activating mutations (1 with ITD and 1 with D835) achieved complete remission with complete count recovery; the third pt (FLT3-ITD) had 10% residual blasts after 1 cycle of induction, and is currently planned for transplant. Crenolanib with salvage chemotherapy was well-tolerated in all 8 pts administered full dose crenolanib (100 mg TID)