Low Relapse Rate in Younger Patients ≤ 60 Years Old with Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia (AML) Treated with Crenolanib and Cytarabine/Anthracycline Chemotherapy

Background:While midostaurin, a pan-kinase inhibitor, represents an advance in the treatment of newly diagnosed patients <age 60 with FLT3-mutated AML, numerous challenges remain. In the RATIFY trial, approximately 40% patients relapsed after achieving a complete remission (CR) with chemotherapy plus midostaurin (Stone et al., NEJM 2017). Crenolanib is a potent type I FLT3 specific inhibitor, which can be safely administered at maximal doses in combination with 7+3 induction and high dose cytarabine (HiDAC) consolidation. We report the CR and relapse rates of patients <60 years old with FLT3-mutated AML who were treated with crenolanib combined with standard induction chemotherapy.

Methods: Results from 29 patients in the trial (n=44) who were ≤60 years old with newly diagnosed FLT3-mutated AML are included. Patients received standard 7+3 induction with cytarabine 100 mg/m² for 7d and either daunorubicin 90 mg/m² (n=16) or idarubicin 12 mg/m² (n=13) for 3d. Crenolanib 100 mg TID was administered continuously starting 24h after chemotherapy until 72h prior to the next chemo cycle. Re-induction was allowed in case of morphological evidence of residual leukemia. Consolidation cycles (up to 4) consisted of six doses of HiDAC q12h on days 1,3,5, (dosed at 3g/m² for <60 yrs and 1g/m² for 60 yrs) with crenolanib starting 24h 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 months.

Results: 21 of 29 (72%) patients achieved a CR after one cycle of induction with cytarabine/anthracycline/crenolanib. An additional 3 patients achieved a CR either after re-induction (1 patient) or after treatment with HiDAC or HSCT (1 patient each).

Of these 24 patients with complete remission, 18 received HiDAC consolidation (range 1-4 cycles). Sixteen underwent HSCT, including: matched unrelated (n=9), matched related (n=2) or haploidentical donor (n=2). One patient underwent a cord blood transplant. 8 patients did not receive a transplant (7 due to lack of donor, social issues or other comorbidities and 1 too early). The demographics of these 24 patients are presented in Table 1.

23/24 patients in complete remission are currently in follow up (median follow-up of 14 months, range 5-26 months). One patient died in CR due to post-transplant complications. Two patients have relapsed. Of these two, one had a bone-marrow relapse 71 days after undergoing a haplo HSCT as his only consolidation therapy. The second patient's blasts harbored four mutations (FLT3-ITD, IDH1, TET2, MLL) with a WBC count of 181,000/µL at presentation. He had a CNS relapse 7 months after a haplo HSCT following one cycle of HiDAC. The overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) curves are shown below.

Conclusion: In patients aged ≤ 60 yrs with FLT3 mutated AML, induction treatment with cytarabine/anthracycline/crenolanib resulted in a CR in 24/29 (83%) patients. With a median follow up of 14 months, only one systemic and one isolated CNS relapse have occurred in these 24 patients who achieved a CR. These data suggest that adding crenolanib, a potent FLT3 inhibitor, to standard induction chemotherapy in younger patients with FLT3-mutated AML may be associated with a low relapse rate, especially if HSCT is routinely used. A phase 3 trial of crenolanib in combination with 7+3 vs midostaurin in combination with 7+3 is being initiated.

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