Impact of Age and Midostaurin-Dose on Response and Outcome in Acute Myeloid Leukemia with FLT3-ITD: Interim-Analyses of the AMLSG 16-10 Trial

Background: Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in roughly 25% of younger adult patients (pts) with acute myeloid leukemia (AML). The multi-targeted kinase inhibitor midostaurin combined with intensive chemotherapy has shown activity against AML with FLT3 mutations. However, toxicity and potential drug-drug interactions with strong CYP3A4 inhibitors such as posaconazole may necessitate dose reduction.

Aims: To evaluate the impact of age and midostaurin dose-adaptation after intensive induction chemotherapy on response and outcome in AML with FLT3-ITD within the AMLSG 16-10 trial (NCT01477606).

Methods: The study included adult pts (age 18-70 years (yrs)) with newly diagnosed FLT3-ITD positive AML enrolled in the ongoing single-arm phase-II AMLSG 16-10 trial. Pts with acute promyelocytic leukemia were not eligible. The presence of FLT3-ITD was analyzed within our diagnostic study AMLSG-BiO (NCT01252485) by Genescan-based DNA fragment-length analysis. Induction therapy consisted of daunorubicin (60 mg/m², d1-3) and cytarabine (200 mg/m², continuously, d1-7); midostaurin 50 mg bid was applied from day 8 until 48h before start of the next treatment cycle. A second cycle was allowed in case of partial remission (PR). For consolidation therapy, pts proceeded to allogeneic hematopoietic-cell transplantation (HCT) as first priority; if alloHCT was not feasible, pts received three cycles of age-adapted high-dose cytarabine (HDAC) in combination with midostaurin starting on day 6. In all pts one-year maintenance therapy with midostaurin was intended. The first patient entered the study in June 2012 and in April 2014, after recruitment of n=147 pts, the study was amended including a sample size increase to 284 pts and a dose reduction to 12.5% of the initial dose of midostaurin in case of co-medication with strong CYP3A4 inhibitors (e.g. posaconazole). This report focuses on age and the comparison between the first (n=147) and the second cohort (n=137) of the study in terms midostaurin dose-adaptation.

Results: Patient characteristics were as follows: median age 54 yrs (range, 18-70; younger, 68% < 60 yrs; older, 32% ≥ 60 yrs); median white cell count 44.7G/l (range 1.1-1543 G/l); karyotype, n=161 normal, n=16 high-risk according to ELN recommendations; mutated NPM1 n=174 (59%). Data on response to first induction therapy were available in 277 pts; complete remission (CR) including CR with incomplete hematological recovery (CRi) 60%, PR 20%, refractory disease (RD) 15%, and death 5%. A second induction cycle was given in 54 pts. Overall response (CR/CRi) after induction therapy was 76% (76%, younger; 76%, older) and death 6% (4%, younger; 10% older). The dose of midostaurin during first induction therapy was reduced in 53% and 71% of patients in cohort-1 and cohort-2, respectively. Reasons for dose reduction were in 58% and 49% toxicity, and in 9% and 23% co-medication in cohort-1 and cohort-2, respectively. No difference in response to induction therapy was noted between cohorts (p=0.81). Median follow-up was 18 months. Overall 146 pts received an alloHCT, 128 in first CR (n=94 younger, n=34 older; n=92 from a matched unrelated and n=36 from a matched related donor). In pts receiving an alloHCT within the protocol in median two chemotherapy cycles were applied before transplant (range 1-4). The cumulative incidence of relapse (CIR) and death after transplant were 13% (SE 3.2%) and 16% (SE 3.5%) without differences (p=0.97, p=0.41, respectively) between younger and older patients. So far maintenance therapy was started in 86 pts, 61 pts after alloHCT and 25 pts after HDAC. Fifty-five adverse events 3°/4° were reported being attributed to midostaurin; cytopenias after alloHCT were the most frequent (29%). CIR in patients starting maintenance therapy was 20% one year after start of maintenance without difference between alloHCT and HiDAC (p=0.99). In addition, no difference in CIR was identified in patients after consolidation with alloHCT or HDAC according to dose reduction of midostaurin during first induction therapy (p=0.43, p=0.98, respectively). Median overall survival was 25 months (younger, 26 months; older 23 months; p=0.15).

Conclusions: The addition of midostaurin to intensive induction therapy and as maintenance after alloHCT or HDAC is feasible and effective without an impact of age and dose adaptation on outcome.