Venetoclax Plus Gilteritinib for -Mutated Relapsed/Refractory Acute Myeloid Leukemia.
Naval Daver, Alexander E Perl, Joseph Maly, Mark Levis, Ellen Ritchie, Mark Litzow, James McCloskey, Catherine C Smith, Gary Schiller, Terrence Bradley, Ramon V Tiu, Kiran Naqvi, Monique Dail, Deanna Brackman, Satya Siddani, Jing Wang, Brenda Chyla, Paul Lee, Jessica K Altman
Author Information
Naval Daver: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX. ORCID
Alexander E Perl: Division of Hematology/Oncology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA. ORCID
Joseph Maly: Department of Hematologic Malignancies and Cellular Therapy, Norton Cancer Institute, Louisville, KY.
Mark Levis: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
Ellen Ritchie: Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY.
Mark Litzow: Division of Hematology, Mayo Clinic, Rochester, MN. ORCID
James McCloskey: Department of Leukemia, John Theurer Cancer Center at Hackensack Meridian Health, Hackensack, NJ.
Catherine C Smith: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA. ORCID
Gary Schiller: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Terrence Bradley: Department of Medicine, University of Miami, Miami, FL.
Ramon V Tiu: Astellas Pharma US, Northbrook, IL.
Kiran Naqvi: Genentech, South San Francisco, CA.
Monique Dail: Genentech, South San Francisco, CA. ORCID
Deanna Brackman: AbbVie Inc, North Chicago, IL.
Satya Siddani: AbbVie Inc, North Chicago, IL.
Jing Wang: AbbVie Inc, North Chicago, IL.
Brenda Chyla: AbbVie Inc, North Chicago, IL. ORCID
Paul Lee: AbbVie Inc, North Chicago, IL.
Jessica K Altman: Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL. ORCID
PURPOSE: The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory -mutated () acute myeloid leukemia (AML) but seldom reduces burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of AML. METHODS: This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with wild-type and (escalation) or (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III-defined response criteria. RESULTS: Sixty-one patients were enrolled (n = 56 ); 64% (n = 36 of 56) of patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). molecular response (< 10) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for patients was 10.0 months. CONCLUSION: The combination of venetoclax and gilteritinib was associated with high mCRc and molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.
