HOUSTON—The prognosis for older patients with acute myeloid leukemia (AML) has remained dismal, even after treatment with a hypomethylating agent.
Standard curative treatment for AML, which is primarily a disease of older adults with a median age of 68 years at diagnosis, involves intensive induction chemotherapy followed by consolidation chemotherapy, allogeneic stem-cell transplantation or both. The problem is that, because of advanced age, coexisting conditions and a high incidence of unfavorable genomic features, older patients often are ineligible for or have disease that is refractory to standard chemotherapy. That is especially discouraging at the VA, which treats many older veterans with high comorbidity rates.
The result is that those patients often receive less-intensive regimens, including hypomethylating agents (azacitidine or decitabine) and low-dose cytarabine. That appears to have little effect on survival, with untreated patients with AML who are at least 65 years of age having an incidence of remission of 30% or less and survival of less than a year with azacytidine monotherapy, according to a recent report in the New England Journal of Medicine.1
Background information in that article pointed out that B-cell lymphoma 2 (BCL2) family proteins play an important role in the disease and the effectiveness of chemotherapy and subsequent survival. “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,” wrote the University of Texas MD Anderson Cancer Center-led authors, who added that single-agent venetoclax has had modest activity in AML.
The confirmatory trial (VIALE-A) was designed to evaluate the efficacy and safety of the azacitidine-venetoclax combination regimen as compared with a control regimen of azacitidine and placebo in previously untreated patients with AML who were ineligible for intensive induction therapy.
“In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer, and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone,” the study concluded. “The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group.”
Because of research advances similar to that, recently updated guidelines from NCCN for Acute Myeloid Leukemia make some changes in advice for patients 60 or older who are not candidates for intensive remission induction therapy, decline the therapy or had it previously and have relapsed, including the use of ivosidenib (IDH1 mutated AML) certain circumstances.
The guidelines also upgraded venetoclax plus azacitidine to a Category 1 preferred regimen for patients without actionable mutations, as well as for patients across all actionable mutations (IDH 1, IDH 2 and FLT 3). Venetoclax plus decitabine was retained as a Category 2A preferred regimen for patients without actionable mutations and for patients across all actionable mutation subsets (IDH 1, IDH 2, and venetoclax plus LDAC was retained at a Category 2A designation and was included as other recommended regimen for patients without actionable mutations and for patients across all actionable mutation subsets.
- DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, et. Al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 13;383(7):617-629. doi: 10.1056/NEJMoa2012971. PMID: 32786187