Midostaurin Plus Chemotherapy Is Well Tolerated in Adults With FLT3-Mutated AML, Irrespective of Age

Midostaurin in combination with intensive chemotherapy is well tolerated with high response rates in fit adult patients, irrespective of age, with FLT3-mutated newly diagnosed acute myeloid leukemia (FLT3^mut ND-AML), according to research published in Blood Advances.

“The pivotal RATIFY study demonstrated midostaurin (50 mg twice daily) with standard chemotherapy significantly reduced mortality in adult patients (<60 years) with [FLT3^mut ND-AML],” the authors wrote in their report. “However, given that older patients constitute the majority of AML cases and often respond poorly to standard therapy, limited information is available about patients ≥60 years of age.”

The investigators conducted an open-label, multicenter phase 3b trial to further evaluate the safety and efficacy of midostaurin plus chemotherapy in induction, consolidation, and maintenance monotherapy in young (≤60 years) and older (>60 years) patients with FLT3^mut ND-AML (ClinicalTrials.gov Identifier: NCT03379727). 

Compared with RATIFY (ClinicalTrials.gov Identifier: NCT00651261), the open-label study extended midostaurin treatment from 14 days to 21 days, substituted anthracyclines (idarubicin or daunorubicin), and allowed variation in standard combination chemotherapy dosing (“7+3” or “5+2” in more fragile patients). 

Between February 2018 and January 2020, the study enrolled 301 patients with  FLT3^mut ND-AML and an Eastern Cooperative Oncology Group performance status of ≤2. Patients had a median age of 59 years (range, 19-85 years; >60 years, 47.2%) upon entering the induction phase. Most patient (82.7%) had a FLT3-ITD mutation, while 17.6% had a FLT3-TKD mutation.

Nearly all patients (98.0%) had at least 1 adverse event (AE), and 84.4% had a grade ≥3 AE. Grade ≥3 serious AEs occurred in 44.5%; these included febrile neutropenia (10.6%), sepsis (4.7%), pneumonia (4.0%), septic shock (3.7%), and respiratory failure (2.3%). 

For the entire treatment duration, no difference in AE frequency was observed between age groups. However, patients with older age had a higher frequency of grade ≥3 AEs (90.1% vs 79.2%), SAEs (54.2% vs 37.7%), and AEs leading to treatment discontinuation (16.9% vs 10.1%) than patients with younger age. 

Overall, 65.3% of patients had a complete remission (CR), and 15.3% had a

CR with incomplete hematologic recovery. The resulting CR + CRi rate of 80.7% (95% CI, 75.74-84.98%) was comparable between age groups (≤60 years, 83.5%; >60 to ≤70 years, 82.5%; in patients >70 years, 64.1%) and irrespective of the anthracyclines used. The CR + CRi rate was lower in males (76.4%) than females (84.4%). 

“In this study, midostaurin in combination with intensive chemotherapy provided high response rates, irrespective of patient age, induction regimen (“7+3” or “5+2”), or the type of anthracycline used (daunorubicin or idarubicin) during the induction therapy,” the authors concluded. “These response rates support the results observed in the RATIFY study, in which 59% of patients who received midostaurin achieved CR.”

Limitations of the study included lack of a placebo arm and lack of patient follow up after treatment discontinuation and survival analyses, given the primary end point was safety.

Disclosure: This research was supported by Novartis. Please see the original reference for a full list of disclosures.

This article originally appeared on Hematology Advisor