Author(s): ,
Roland B. Walter
Clinical Research Division,Fred Hutchinson Cancer Research Center,Seattle, WA,United States
Robert H. Collins
University of Texas Southwestern Medical Center,Dallas, TX,United States
Richard M. Stone
Dana-Farber Cancer Institute,Boston, MA,United States
Martin S. Tallman
Division of Hematologic Oncology, Leukemia Service,Memorial Sloan Kettering Cancer Center,New York, NY,United States
Chatchada Karanes
Gehr Family Center for Leukemia Research,City of Hope,Duarte, CA,United States
Carlos E. Vigil
Division of Hematology, Oncology, and Blood & Marrow Transplantation,The University of Iowa,Iowa City, IA,United States
John R. Eckardt
AROG Pharmaceuticals, Inc.,Dallas, TX,United States
Eunice S. Wang
Roswell Park Comprehensive Cancer Center,Buffalo, NY,United States
EHA Library. B. Walter R. 06/15/18; 214713; PF227
Dr. Roland B. Walter
Dr. Roland B. Walter

Abstract: PF227

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

The multikinase inhibitor midostaurin was recently approved in combination with chemotherapy based on the RATIFY trial of younger patients with treatment-naïve FLT3-mutant AML demonstrating a survival benefit (2yr OS: 60% midostaurin vs 51% placebo). We hypothesized that a more selective FLT3-targeted agent such as crenolanib, a potent and specific FLT3 tyrosine kinase inhibitor (TKI) which inhibits both FLT3­ITD and FLT3­TKD mutations, would further improve patient outcomes when combined with chemotherapy. We here report an analysis of patients treated with crenolanib combined with chemotherapy similar to the population studied in the RATIFY trial.

To assess the outcomes of a sub-group of newly diagnosed FLT3-mutant AML patients treated with crenolanib and standard chemotherapy to be targeted in a pivotal phase III trial comparing crenolanib with midostaurin.

Twenty-seven of 29 consecutive patients ≤ 60 years old enrolled in a phase II study of crenolanib combined with chemotherapy in newly diagnosed FLT3-mutant AML (NCT02283177) were included in this analysis. Two patients were excluded due to 1) prior treatment for a myeloproliferative disorder and 2) pre-existing liver cirrhosis. Patients received 7+3 induction with cytarabine 100 mg/m2 for 7 days and either daunorubicin 90 mg/m2 (n=16) or idarubicin 12 mg/m2 (n=11) for 3 days. Crenolanib 100 mg TID was administered continuously starting 24 hours after chemotherapy until 72 hours prior to the next chemotherapy cycle.

Consolidation consisted of up to four cycles of high-dose cytarabine (HiDAC: 3 g/mfor < 60 years and 1 g/m2 for 60 years) q12 hours on days 1, 3, and 5 with crenolanib starting 24 hours after the final HiDAC dose in each cycle. Eligible patients proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Maintenance crenolanib at 100mg TID was started after HiDAC or 30-90 days after HSCT for a maximum of 12 cycles.

Patients included in the analysis were generally older (median 51 vs. 47 years for RATIFY) and most patients (85%) had FLT3-ITD mutations. Six patients had concurrent NPM1 and DNMT3A mutations, a constellation associated with poor prognosis. Only 4 (15%) patients had more favorable FLT3-TKD mutations compared with 23% in the RATIFY study.

As of February 2018, 22/27 (81%) patients are alive with a median follow-up of 20.8 months. Median overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) have not been reached. Fourteen patients received HSCT of which 11 are alive free of disease. Seven patients were consolidated with HiDAC and did not undergo HSCT. Only one of these seven patients has relapsed and the other six remain alive free of disease, suggesting that standard chemotherapy plus crenolanib can provide durable remissions without HSCT. 4/6 (67%) patients with high-risk concomitant mutations in FLT3-ITD, DNMT3A and NPM1 are alive free of disease. Overall, only 3/21 patients have relapsed, none of whom received > 1 week of crenolanib maintenance.

This analysis suggests that outcomes in younger patients with newly diagnosed FLT3-mutant AML may be improved by adding a potent pan-FLT3 inhibitor to chemotherapy. A phase III randomized multicenter trial has been initiated to compare the efficacy of crenolanib versus midostaurin combined with standard chemotherapy for newly diagnosed patients with FLT3-mutant AML (NCT03258931).

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute Myeloid Leukemia, FLT3, Tyrosine kinase inhibitor

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