Clinical Pearls & Morning Reports
Published August 12, 2020
Acute myeloid leukemia (AML) is primarily a disease of older adults, with a median age of 68 years at diagnosis. DiNardo et al. conducted a phase 3 trial that evaluated azacitidine plus venetoclax as compared with azacitidine alone in previously untreated patients with AML who were ineligible for intensive induction therapy. Read the NEJM Original Article here.
Q: What are the shortcomings of currently available therapies for older patients with AML?
A: Standard curative treatment for AML consists of intensive induction chemotherapy followed by consolidation chemotherapy, allogeneic stem-cell transplantation, or both. However, because of advanced age, coexisting conditions, and a high incidence of unfavorable genomic features, older patients are frequently ineligible for or have disease that is refractory to standard chemotherapy. Instead, such patients often receive less intensive regimens, including hypomethylating agents (azacitidine or decitabine) and low-dose cytarabine. Among untreated patients with AML who are at least 65 years of age, azacitidine monotherapy has been associated with an incidence of remission of 30% or less and survival of less than 1 year.
Q: What is venetoclax?
A: B-cell lymphoma 2 (BCL2) family proteins play an important role in the intrinsic mitochondrial apoptotic response. Increased expression of BCL2 family proteins in AML blasts has been reported, and a majority of AML stem cells express aberrantly high levels of BCL2 and are dependent on BCL2 for survival. Furthermore, high expression of BCL2 has been associated with an inferior response to chemotherapy and poor survival among patients with AML. Venetoclax, a selective small-molecule BCL2 inhibitor, has been shown in preclinical studies to induce apoptosis in malignant cells that are dependent on BCL2 for survival. Single-agent venetoclax has had modest activity in AML.
A: In this phase 3 trial involving patients with AML who had not received treatment previously and who were either elderly or otherwise ineligible to receive intensive chemotherapy, combination treatment with azacitidine plus venetoclax was superior to azacitidine alone. The median overall survival among patients who were randomly assigned to azacitidine plus venetoclax was 14.7 months, as compared with 9.6 months with azacitidine alone (hazard ratio for death, 0.66; P<0.001). The incidence of composite complete remission (complete remission or complete remission with incomplete hematologic recovery) was 66.4% among the patients who received azacitidine plus venetoclax; this incidence was more than twice as high as that among those who received azacitidine alone. This higher incidence of remission resulted in significant increases in the incidence of transfusion independence. Responses were both rapid and durable. No differences were observed between the two treatment groups with respect to quality-of-life measures.
A: The most frequently reported hematologic adverse events of grade 3 or higher in the azacitidine–venetoclax and control (azacitidine alone) groups included thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), febrile neutropenia (in 42% and 19%), anemia (in 26% and 20%), and leukopenia (in 21% and 12%). Gastrointestinal adverse events of any grade were common and predominantly included nausea (in 44% of the patients in the azacitidine–venetoclax group and 35% of those in the control group), constipation (in 43% and 39%, respectively), diarrhea (in 42% and 33%), and vomiting (in 30% and 23%). Notable serious adverse events (grade ≥3) were febrile neutropenia (in 30% of the patients in the azacitidine–venetoclax group and 10% of those in the control group) and pneumonia (in 16% and 22%).