Emerging Real-World Midostaurin Treatment Patterns and Outcomes in FLT3-Mutated Acute Myeloid Leukemia at a Comprehensive Cancer Center
Authors: Willis Connor , Menon Jyothi , Unni Sudhir , Au Trang , Ndife Briana , Joseph George J , Bonifacio Gaetano J , Stein Eytan M. , Tantravahi Srinivas K. , Shami Paul J , Kovacsovics Tibor , Brixner Diana , Stenehjem David Dean 
Published: October 2019

Abstract
Introduction: Fms-like tyrosine kinase 3 (FLT3) gene mutation occurs in approximately 25-30% of acute myeloid leukemia (AML) cases and is associated with poor prognosis. Decreased overall survival is reported in FLT3-mutated vs. FLT3-wildtype. Midostaurin, a pan-targeted kinase inhibitor that inhibits activated FLT3 received FDA approval in April 2017 for adult patients with newly diagnosed FLT3-mutated AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. We report descriptive US clinical treatment patterns and outcomes in FLT3-mutated early midostaurin-users, historical FLT3-mutated patients prior to midostaurin approval, and historical FLT3-wildtype AML patients all treated with 7+3 induction therapy at an academic cancer specialty hospital to support the development of a larger database across several comprehensive cancer centers.
Methods: This retrospective, observational study utilized ICD codes, tumor registry data, and pharmacy records from the Huntsman Cancer Institute (HCI) to identify AML patients treated with 7+3 induction chemotherapy from 2007 to July 2018. FLT3-mutated midostaurin-users treated with 7+3 induction including midostaurin from May 2017 to July 2018 comprise Group 1. Historical FLT3-mutated patients prior to midostaurin approval (non-users) and FLT3-wildtype patients comprise Groups 2 and 3, respectively. Complete response (CR), relapse rates, overall survival and treatment patterns were described.
Results: A total of 105 patients met eligibility for inclusion in the study. Groups 1, 2, and 3 included five, 39 and 61 patients, respectively. Off-label midostaurin use in Group 1 after induction therapy was observed in one patient with post-consolidation monotherapy and salvage therapy in combination with ATRA (tretinoin) and CLAG (cladribine, cytarabine, and filgrastim). Following midostaurin approval, two FLT3-mutated patients received induction therapy without midostaurin due to enrollment in clinical trials that excluded midostaurin use for induction and consolidation therapy. These two patients were excluded from the study. Descriptive results of the comparative groups are summarized in Table 1. CR rate from induction therapy was 100% for Group 1, 90% for Group 2, and 77% for Group 3. The proportion of patients who received consolidation therapy was 60%, 74%, and 67%, and patients who maintained CR during consolidation therapy was 100%, 83%, and 49% for Groups 1, 2, and 3, respectively. Sixty-six percent of eligible Group 1 patients, 74% of Group 2 patients, and 54% of Group 3 patients received transplant. Median time from diagnosis to transplant was 81, 99, and 145 days for Groups 1, 2, and 3, respectively. The proportion of patients who received salvage therapy in Groups 1, 2, and 3 was 20%, 38%, and 56% respectively. Median follow-up was 6 months for Group 1, 14 months for Group 2, and 24 months for Group 3. After CR, 20% of Group 1, 49% of Group 2, and 59% of Group 3 relapsed. All Group 1 patients were alive at time of analysis while four Group 2, and eight Group 3 patients died during the study period.
Discussion: Similar CR and relapse rates were observed between the comparative groups, although early use observations indicate improved response rates of induction therapy and consolidation therapy in a limited Group 1 sample. Patients in Group 1 and Group 2 underwent transplant earlier and more frequently than patients in Group 3, which may explain the higher relapse rate in Group 3. As this data resource is expanded across similar institutions, statistical comparisons of FLT3-mutated AML patients treated with and without midostaurin can be made.
Sponsorship: Funding for this study was provided by Novartis Pharmaceuticals.

Disclosures
Unni: Novartis: Research Funding. Ndife:Novartis: Employment. Joseph:Novartis Pharmaceuticals Corporation: Employment; Amgen: Equity Ownership; Pfizer: Equity Ownership; Express Scripts: Equity Ownership. Bonifacio:Novartis: Employment. Stein:Novartis: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Pfizer: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees. Kovacsovics:Amgen: Honoraria, Research Funding; Abbvie: Research Funding. Brixner:BD: Consultancy; Abbott: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Millcreek Outcomes Group: Equity Ownership; University of Utah: Research Funding. Stenehjem:Novartis: Research Funding.