A Phase I/II Study Combining Sunitinib with Standard Ara-C/Daunorubicin Chemotherapy In Patients 60 Years or Older with FLT3 Mutated AML
Authors: Fiedler Walter , Krauter Jürgen , Götze Katharina , Salih Helmut R. , Bokemeyer Carsten , Spaeth Daniela , Döhner Konstanze , Döhner Hartmut , Schlenk Richard F. 
Published: October 2019

Abstract
Abstract 3285
Acute myeloid leukemia (AML) with mutated FLT3 in patients over the age of 60 years is associated with a dismal prognosis despite intensive chemotherapeutic approaches. Analysis of the AMLSG database revealed that for this patient group the CR rate was below 50% and the 5-year event-free (EFS) and overall survival (OS) was less than 5%. Sunitinib is a potent FLT3 inhibitor with a cellular IC50 value of 0.05μM for mutated FLT3 vs. 0.25μM for wild-type (wt) FLT3 and has already shown activity as single agent treatment in refractory AML patients.
In the current phase–I study two schedules of sunitinib were evaluated in conjunction with standard chemotherapy: Either 25 mg daily continuously during the chemotherapy treatment phase (dose level 1) or 25 mg sunitinib days 1–7 during each chemotherapy cycle followed by a break until recovery of blood counts (dose level -1). After consolidation therapy all patients received sunitinib 25mg daily continuously in both groups. Induction chemotherapy consisted of Ara-C 100 mg/m2 by CI days 1–7 and daunorubicin 60 mg/m2 days 1–3 and consolidation therapy of Ara-C 1g/m2 day 1,3,5 for 3 cycles. Dose limiting toxicity (DLT) was defined as time to recovery of blood counts of not later than 35 days after start of treatment and any grade 3 toxicity probably related to sunitinib. Occurrence of a DLT should be observed in no more than 1 of 6 evaluable patients in each dose group according to the modified Fibonacci design.
Twelve patients have been included up to now (2 male and 10 female). Median age was 71 years (range 60–78). Determination of FLT3 status was performed by a central lab within 48 hours. Eight patients had FLT3-ITD and 4 patients FLT3-TKD mutation. Four patients had an additional NPM1 mutation. Eight patients exhibited a normal karyotype and 4 patients additional unfavourable chromosomal aberrations.
In the continuous dosing group 6 patients were entered. Two DLTs in three evaluable patients were noted, 1 patient had prolonged aplasia (>day 35) and the second a hand-leg syndrome. This schedule was therefore abandoned. In the intermittent dosing cohort one DLT (prolonged aplasia) was seen in 4 evaluable patients. Main toxicities of all 12 patients included grade 4 neutropenia (100%) and thrombocytopenia (100%), grade 3 for anemia (33%), febrile neutropenia (58%), infections (42%), diarrhea/colitis (50%), bleeding (25%), hypertension (16%), tachyarrhythmia absoluta (16%), syncope (16%) and mucositis (8%). Three patients died during induction or consolidation therapy due to infectious complications, 2 in the continuous and one in the intermittent dosing group.
Ten patients are evaluable for response. Seven patients achieved a CR/CRi, one patient had a PR and two patients had refractory disease. Three patients with FLT3-TKD mutation obtained a CR and the forth a PR.
In conclusion, addition of sunitinib 25mg (days 1–7) in parallel to induction and consolidation therapy is feasible. Side effects consist mainly of hematotoxicity and infectious complications and are expected in an elderly patient group receiving intensive chemotherapy. No cases of cardiac insufficiency due to sunitinib in conjunction with the administration of anthracyclines were recorded. The response rate of 70% CR/CRi is encouraging. Additional patients will be entered at this schedule to further define tolerability and efficacy.

Disclosures:
Fiedler: Pfizer: Consultancy, Research Funding. Salih:Pfizer: Research Funding. Bokemeyer:Pfizer: Research Funding, Speakers Bureau. Döhner:Pfizer: Research Funding. Schlenk:Pfizer: Research Funding.