Crenolanib Plus Intensive Chemo Demonstrates Efficacy for Patients With Newly Diagnosed FLT3-Mutant AML

Crenolanib, a second-generation tyrosine kinase inhibitor, plus intensive chemotherapy demonstrated high rates of deep responses and long-term survival among patients with newly diagnosed FMS‐like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), according to findings from a trial published in the Journal of Clinical Oncology. 

Eunice S. Wang, MD, Roswell Park Comprehensive Cancer Center, Buffalo, New York, and coauthors stated that although the current standard of care treatments for patients with FLT3-mutant AML are approved and regularly used, “there remains a high unmet need, as reflected by a 2-year relapse rate approaching 40%” with these therapies.

In this study, Wang et al aimed to determine whether adding crenolanib to intensive chemotherapy improves outcomes among patients with newly diagnosed FLT3-mutant AML. The primary end point was safety and tolerability, and the secondary end point was efficacy, determined by overall response rate, event-free survival, and overall survival. Pharmacokinetic studies, as well as exploratory end points consisting of measurable residual disease and mutational programming, were also evaluated. 

Patients with FLT3-mutant AML, including FLT3-ITD (n = 36) and FLT3-TKD (n = 11), were enrolled in this trial. Induction therapy was made up of cytarabine continuous infusion at 100 mg/m2 on days 1 through 7 and anthracycline (daunorubicin at 60 to 90 mg/m2 or idarubicin 12 mg/m2, once daily) on days 1 through 3. Consolidation followed, which consisted of high-dose cytarabine at 1 to 3 g/m2 twice daily on days 1, 3, and 5, and/or allogeneic transplant. Patients received crenolanib at 100 mg twice a day from day 9 until 72 hours before the next cycle, post-consolidation, and for 12 months post-consolidation or transplant. 

Results indicated that disease risk, as measured by European LeukemiaNet 2017, was favorable in 34% of patients, intermediate in 30%, and adverse in 36%. The overall response rate was 86%, with a complete remission (CR) rate of 77% and a CR with incomplete count recovery (CRi) of 9%. The measurable residual disease-negative CR rate was 89%, and the measurable residual disease-negative CRi rate was 45%. At a follow-up of 45 months, the median overall survival was not reached, and the median event-free survival was 44.7 months. Younger patients had an estimated 3-year survival of 71.4% with 15% cumulative incidence of relapse. 

In terms of safety, the study authors noted that treatment-related serious adverse events consisted of febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL during induction was 29 days, and the absolute neutrophil count ≥1,000/µL during induction was 32 days. There were no additional FLT3-mutant clones found at relapse among patients completing consolidation. 

Notably, Charles F. Craddock, MD, the Journal of Clinical Oncology associate editor, stated, “Over two thirds of younger patients age ≤60 years were alive after 3 years.”

Wang et al concluded, “Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity.”

“A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing,” they added. 

Source: 

Wang ES, Goldberg AD, Tallman M, et al. Crenolanib and intensive chemotherapy in adults with newly-diagnosed FLT3-mutated AML. J Clin Oncol. Published online: February 7, 2024. doi: 10.1200/JCO.23.01061