Safety and Efficacy: Clinical Experience of Venetoclax in Combination With Hypomethylating Agents in Both Newly Diagnosed and Relapsed/Refractory Advanced Myeloid Malignancies
Jonathan Feld,
Douglas Tremblay,
Mikaela Dougherty,
Tina Czaplinska,
Gillian Sanchez,
Claudia Brady,
Marina Kremyanskaya,
Michal Bar-Natan,
Alla Keyzner,
Bridget K. Marcellino,
Janice Gabrilove,
Shyamala C. Navada,
Lewis R. Silverman,
Siraj M. El Jamal,
John Mascarenhas,
Alan H. Shih
Affiliations
Jonathan Feld
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Douglas Tremblay
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Mikaela Dougherty
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Tina Czaplinska
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Gillian Sanchez
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Claudia Brady
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Marina Kremyanskaya
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Michal Bar-Natan
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Alla Keyzner
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Bridget K. Marcellino
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Janice Gabrilove
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Shyamala C. Navada
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Lewis R. Silverman
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Siraj M. El Jamal
2 Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
John Mascarenhas
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Alan H. Shih
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Hypomethylating agents (HMAs) in combination with venetoclax have been widely adopted as the standard of care for patients who cannot tolerate induction chemotherapy and for patients who have relapsed/refractory (R/R) acute myeloid leukemia (AML). This study retrospectively analyzed the outcomes of all patients with AML (n = 65) or myelodysplastic syndrome (n = 7) who received the combination of HMA and venetoclax at our institution. Outcomes measured included complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, duration of response (DOR), and overall survival (OS). Patient mutational profiles and transfusion requirements were also assessed. Of 26 newly diagnosed AML patients, the CR/CRi rate was 53.8%. The median DOR and OS were 6.9 months and not reached, respectively. Of 39 R/R AML patients, the CR/CRi rate was 38.5%. The median DOR and OS were both 8.1 months. Responders to HMA and venetoclax were enriched for TET2, IDH1, and IDH2 mutations, while nonresponders were associated with FLT3 and RAS mutations. Adaptive resistance was observed through various mechanisms including acquired RAS pathway mutations. Of transfusion-dependent patients, 12.2% and 15.2% achieved red blood cell (RBC) and platelet transfusion independence, respectively, while 44.8% and 35.1% of RBC and platelet transfusion independent patients, respectively, became transfusion dependent. In total 59.1% of patients developed a ≥grade 3 infection and 46.5% neutropenic fever. HMA + venetoclax can lead to impressive response rates with moderately durable remissions and survival. However, the benefits of this combination are diminished by the significant toxicities from infection, persistent cytopenias, and transfusion requirements.
