Interim data from a phase 3b study evaluating the safety and efficacy of midostaurin, a multikinase inhibitor that directly inhibits FMS-like tyrosine kinase 3, or FLT3, in FLT3-mutated acute myeloid leukemia (AML), are presented here. This study was designed to include enrollment of younger (aged ≤60 years) and older (aged >60 years) patients, as well as variations in chemotherapy regimens, including idarubicin or daunorubicin for 7+3 or 5+2.
This study is an open-label, single-arm, multicenter study in adults with documented FLT3 internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutations who are fit for chemotherapy and have an Eastern Cooperative Oncology Group performance status ≤2. To be eligible, patients are required to start their first induction cycle with 7+3 (cytarabine 100-200 mg/m2 daily on days 1-7 + daunorubicin 60-90 mg/m2 daily or idarubicin 12 mg/m2 daily on days 1-3) or 5+2 (a reduced-dose regimen with these agents) at the discretion of the investigator, and enroll in the study by day 7 of their first induction cycle. Patients are assigned to the 7+3 group if their cytarabine duration is ≥7 days, independent of the duration of administration of daunorubicin/idarubicin. All other cases are assigned to the 5+2 group. Patients are excluded if they switch treatment after being initiated on 7+3 or 5+2. Patients receive cytarabine consolidation, with dosing as determined by the investigator. Midostaurin 50 mg twice daily is administered on days 8 to 28 of each 28-day induction/consolidation cycle and daily for ≤12 cycles of maintenance. Patients are discontinued from the study if they are not in complete remission (CR) or CR with incomplete hematologic recovery (CRi) at the end of induction, relapse during consolidation/maintenance, receive an allogeneic stem-cell transplantation (allo-SCT), or experience unacceptable toxicities. The primary end point is safety outcomes, and the secondary end point is the proportion of patients achieving CR/CRi.
Patients for this study were recruited across Europe with enrollment closing on January 28, 2020. A total of 318 patients were screened, of which 17 failed screening. The safety analysis included 301 patients who received treatment, and the efficacy analyses included 300 patients who met all study criteria. The median age was 59 years (range, 19-85 years), and 47.2% were aged >60 years. The majority (82.7%) of patients had an FLT3-ITD mutation and 17.6% of patients had an FLT3-TKD mutation. Data cutoff was March 31, 2020, at which time 63 patients were still receiving treatment. All patients (N = 301) entered induction, with 69% entering consolidation and 26% entering maintenance; 28.7% underwent allo-SCT. The majority (80.4%) of patients were treated with midostaurin plus 7+3. The remaining (19.6%) patients received midostaurin plus 5+2. For induction, 55.1% of patients received idarubicin and 44.9% received daunorubicin. A total of 242 patients achieved CR/CRi (80.7%; 95% confidence interval, 75.7-85.0). The CR/CRi rates in older versus younger patients, female versus male patients, and patients who received daunorubicin versus idarubicin for induction were similar. Most serious adverse events (SAEs) occurred during induction (75; 24.9%) and consolidation (64; 30.6%). The most common hematologic adverse events (AEs) were neutropenia, thrombocytopenia, and anemia. The most common nonhematologic AEs were febrile neutropenia, nausea, stomatitis, prolonged QT interval, alanine aminotransferase increase, sepsis, increased blood bilirubin, and decreased platelet count. Older patients had a higher frequency of grade ≥3 AEs (90.8% vs 78.6%) and SAEs (51.4% vs 35.8%), AEs leading to dose adjustment/interruption (43% vs 30.2%), treatment-related AEs (78.2% vs 73.6%), treatment-related SAEs (23.9% vs 15.7%), and AEs leading to discontinuation (11.3% vs 6.9%) compared with younger patients. Older patients also had a higher frequency of grade ≥3 AEs, including severe infections (45.1% vs 31.4%), leukopenia (49.3% vs 40.9%), QT prolongation (7.7% vs 3.1%), and pulmonary toxicity (7.7% vs 3.8%) compared with younger patients. Eighteen on-treatment deaths occurred, the majority of which were in older patients. Three treatment-related deaths occurred, all of which were older patients.
In conclusion, midostaurin + chemotherapy resulted in high response rates regardless of patient age, sex, induction drug, or alternative chemotherapy regimen. Regardless of age, most patients received a 7+3 regimen. The safety profile of midostaurin + idarubicin or daunorubicin for induction was generally similar. No new safety signals for midostaurin were identified.
Sierra J, Montesinos P, Thomas X, et al. Phase 3b Study Assessing the Safety and Efficacy of Midostaurin in Younger and Older Patients with Newly Diagnosed, FLT3-Mutated Acute Myeloid Leukemia (AML) Who Are Eligible for 7+3 or 5+2 Chemotherapy. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition, December 5-8, 2020. Abstract 632.