Effect of cytarabine/anthracycline/crenolanib induction on minimal residual disease (MRD) in newly diagnosed FLT3 mutant AML.

Abstract

7016 Background: Baseline characteristics such as age >60, WBC>100,000/µL and FLT3/NPM1/DNMT3A+ve are known to be associated with a poor prognosis in AML. Ivey et al. (NEJM 2016) reported that FLT3-ITD+ve patients (pts) who were MRD+ve after 2 cycles of induction chemotherapy were more likely to relapse as compared to those who became MRD-ve (92% vs 35%). Eradication of FLT3+veclones may lead to reduced relapse rates. Crenolanib is a type I FLT3 TKI, which inhibits both FLT3-ITD and TKD mutations. We here report that a single induction cycle of cytarabine/anthracycline/crenolanib leads to MRD negativity by multiparameter flow cytometry (MPF), and low rate of early relapse in pts with newly diagnosed FLT3+veAML. Methods: This abstract includes 29 consecutively treated, newly diagnosed, FLT3+ve AML pts, who achieved CR1 after one course of cytarabine/anthracycline/crenolanib. Pts received 7+3 induction with cytarabine 100 mg/m2/d for 7d and either daunorubicin (<60 y: 90 mg/m2; ≥60 y: 60 mg/m2) or idarubicin 12 mg/m2 for 3d. Crenolanib (100 mg TID) was started on day 9 until 72 h prior to next chemotherapy. Results: 29 pts (15M, 14F), median age 55y (10pts ≥60y) are included. MRD at time of count recovery was assessed by MPF in 25/29 pts. 20/25 (80%) became MRD–ve. With a median follow up of 7mth, 4/25 pts have relapsed (2/5 MRD+ve, 2/20 MRD-ve).Age ≥60 was a risk factor for MRD+ve and relapse. All 4 pts with WBC>100K as well as 5 pts with FLT3/NPM1/DNMT3A+ve AML became MRD-ve after one induction cycle and none have relapsed. Conclusions: These data suggest, in the context of an ongoing trial (NCT02283177), crenolanib in combination with standard induction is associated with a high rate of achieving an MRD negative state by MPF and a low rate of relapse in previously untreated adults with mutant FLT3. Longer follow-up and comparison of MRD data with similar pts treated with standard chemo alone will be necessary to reach more definitive conclusions. Clinical trial information: NCT02283177. [Table: see text]

Which are the most promising targets for minimal residual disease-directed therapy in acute myeloid leukemia prior to allogeneic stem cell transplant?

“…In a single-arm, phase II study (NCT02283177) of crenolanib in combination with standard induction and consolidation chemotherapy followed by crenolanib maintenance for 1 year, 24 out of 29 (83%) patients achieved CR and 20 out of 25 evaluable patients (80%) achieved MRD-negative disease, as determined by multiparameter flow cytometry. 26,27 Similarly, in a phase I study in patients with newly diagnosed FLT3 -mutated AML, gilteritinib in combination with induction and consolidation led to a high CR rate of 77% (n=23/30). 28 A phase I study of quizartinib in combination with induction and consolidation in newly diagnosed AML led to CR in six of nine (67%) patients and a morphological leukemia-free state in two of nine (22%) patients with FLT3 -ITD mutations.…”

FLT3 and IDH1/2 Inhibitors for Acute Myeloid Leukemia: Focused Clinical Narrative Review of Forthcoming Drugs from an Indian Context

“…In a phase 2 study, 29 newly diagnosed FLT3-mutated patients were treated with intensive chemotherapy in combination with crenolanib and demonstrated MRD negativity in 80% of patients at the end of induction. 85 Long-term results of the trial were presented in the 2022 ASCO meeting and included data from 44 patients. With a median follow-up of 45 months, median OS was not reached and median EFS was 45 months.…”

Clinical use of FLT3 inhibitors in acute myeloid leukemia

“… 33 Moreover, this combination has also resulted in minimal residual disease-negative status (measured by flow cytometry) in 80% of patients. 34 A Phase III study of crenolanib vs midostaurin in this setting has been planned (NCT03258931). One of the drawbacks of crenolanib is its short half-life (6–8 hours) without any accumulation after chronic dosing; thus, a thrice-daily dosing regimen is required.…”