Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML

Abstract

Purpose: Crenolanib is a second-generation tyrosine kinase inhibitor with activity against FLT3-ITD- and TKD-mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML.

Methods: Eligible patients were 18 years and older. Induction chemotherapy consisted of cytarabine (100 mg/m²) continuous infusion on days 1-7 and anthracycline (daunorubicin 60-90 mg/m² or idarubicin 12 mg/m², once daily) on days 1-3 followed by consolidation with high-dose cytarabine (1-3 g/m² twice daily on days 1, 3, 5) and/or allogeneic transplant. Crenolanib (100 mg thrice a day) was given from day 9 until 72 hours before the next cycle, after consolidation, and for 12 months after consolidation or transplant.

Results: Forty-four patients (median age, 57; range, 19-75 years) were enrolled. Thirty-six had FLT3-ITD, and 11 had FLT3-TKD mutations. European LeukemiaNet 2017 disease risk was favorable in 34%, intermediate in 30%, and adverse in 36%. The overall response rate was 86% (complete remission [CR], 77%; CR with incomplete count recovery [CRi], 9%): 90% in patients 60 years and younger and 80% in older patients. Measurable residual disease-negative CR/CRi rates were 89% and 45%, respectively. With a 45-month follow-up, median overall survival has not been reached and the median event-free survival was 44.7 months. Among younger patients, the estimated 3-year survival was 71.4% with 15% cumulative incidence of relapse. Treatment-related serious adverse events included febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL and absolute neutrophil count ≥1,000/µL during induction was 29 and 32 days, respectively. No new FLT3-mutant clones were detected at relapse in patients completing consolidation.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT02283177.

FIG 1.

CONSORT diagram. Twelve patients who did not meet inclusion criteria were screened and excluded as screen failures. HSCT, hematopoietic stem cell transplant; HIDAC, high-dose cytarabine.

FIG 2.

OS and EFS. (A) OS for all patients and by age (60 years and younger and older than 60 years; n = 44). (B) Median OS of patients by age and estimated 1-, 2-, and 3-year OS percentages (95% CI) after initiation of therapy. (C) Subgroup analyses of patients with newly diagnosed FLT3-mutant AML. Influence of disease characteristics on patient outcomes is presented as estimated 3-year OS rate (95% CI) in each category. (D) EFS for all patients and by age (60 years and younger and older than 60 years; n = 44). EFS, event-free survival; ELN, European LeukemiaNet; NE, not estimable; OS, overall survival.

FIG 3.

CIR and OS of patients achieving CR/CI after therapy. (A) CIR of all patients (n = 36) age 18-75 years who achieved CR/CRi on therapy; (B) CIR of responding patients by age 60 years and younger (n = 26) versus older than 60 years (n = 12); (C) CIR and (D) median OS of all responding patients who underwent subsequent transplant (HSCT) versus no transplant; (E) CIR and (F) median OS of all responding patients who received crenolanib maintenance therapy versus no crenolanib maintenance therapy after up-front therapy. CIR, cumulative incidence of relapse; CR, complete remission; CRi, CR with incomplete count recovery; HSCT, hematopoietic stem-cell transplant; NE, Not estimable; OS, overall survival.

FIG 4.

Responses, MRD status at CR/CRi, and FLT3 status throughout protocol therapy. Shown here are the diagnostic FLT3 mutation type, best response at any time, MRD status (when available as determined by local multiparameter flow cytometry and/or FLT3 mutation testing), relapse status, and FLT3 status at the time of relapse (if occurred). Data for (A) younger patients (60 years and younger; n = 18) and (B) older patients (older than 60 years; n = 12) are presented. CR, complete remission; CRi, CR with incomplete count recovery; MRD, measurable residual disease.