Azacitidine + Venetoclax Combo Benefits Older Patients With AML

Nancy A. Melville

August 12, 2020

For older patients with acute myeloid leukemia (AML) who are not eligible for chemotherapy, adding venetoclax (Venclexta, Venclyxto) to azacitidine significantly improved overall survival, complete remission, and other outcomes when compared with azacitidine alone.

These results come from the phase 3 VIALE-A trial, published this week in The New England Journal of Medicine.

AML primarily affects older adults (median age at diagnosis, 68 years). These patients are often ineligible for standard chemotherapy, owing to their age or coexisting conditions, or their disease is refractory to treatment, the authors explain. The authors note that "the prognosis in older patients with AML who are ineligible to receive intensive chemotherapy has been dismal.

"The combination of azacitidine plus venetoclax in this challenging patient population in this trial was an effective treatment regimen that led to significant improvements in the incidence of composite complete remission and overall survival," they report.

At a median follow-up of 20.5 months, for patients who were randomly assigned to undergo treatment with azacitidine plus venetoclax, the median overall survival was 14.7 months, compared with 9.6 months for those treated with azacitidine plus a placebo (hazard ratio for death, 0.66; P < .001).

This study demonstrates that "noteworthy synergism is associated with the combination of azacitidine and venetoclax, with meaningfully higher responses than those with azacitidine alone," commented Charles A. Schiffer, MD, of Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, writing in an accompanying editorial.

Given the frustration experienced in the treatment of older patients with AML, the VIALE-A trial findings "are welcome," he added.

Venetoclax is a targeted agent that acts as a selective inhibitor of B-cell lymphoma 2 (BCL2) family proteins. It is already approved for use in chronic lymphocytic leukemia and small lymphocytc leukemia and is approved for use in AML in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of adults (≥75 years) who are newly diagnosed or who have comorbidities that preclude use of intensive induction chemotherapy.


The VIALE-A trial, which was supported by the manufacturers of venetoclax, was led by Courtney D. DiNardo, MD, of the Division of Cancer Medicine, Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas.

It enrolled patients with AML who had not previously been treated and who were ineligible for standard induction therapy because of coexisting conditions, being older than 75, or both.

The median age of the patients was 76 years (range, 49 – 91). All patients were treated with a standard dose of azacitidine (75 mg/m2 body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle) combined with either venetoclax (target dose, 400 mg) or a matching placebo administered orally once daily in 28-day cycles.

The intention-to-treat population included 286 patients in the azacitidine-venetoclax group and 145 in the azacitidine-placebo group. In addition to higher overall survival rates at a median follow-up of 20.5 months, the incidence of complete remission was higher in the combination therapy group (36.7% vs 17.9%; P < .001).

The rate for a composite of complete remission or complete remission with incomplete hematologic recovery was more than twice as high among patients in the azacytidine plus venetoclax group (66.4% vs 28.3%; P < .001).

"This higher incidence of remission resulted in significant increases in the incidence of transfusion independence," the authors note.

The responses were rapid, with 43% of those in the azacitidine plus venetoclax group having a first response (either complete remission or complete remission with incomplete hematologic recovery) prior to the initiation of cycle 2. The median duration of remission was 17.5 months.

In addition, improvements in incidence of composite complete remission were observed across all AML genomic risk groups, including those patients with adverse cytogenetic risk, secondary AML, and high-risk molecular mutations.

Among patient with FLT3 mutations, 72% had a response, and among those with IDH1 or IDH2 mutations, 75% had a response.

The improved responses translated into increased overall survival in many of the evaluated subgroups, including patients with either de novo or secondary AML, intermediate cytogenetic risk, and IDH1 or IDH2 mutations, the authors note.

However, "interpretation of these findings should be tempered by the fact that the number of patients in each of these subgroups was not large," they caution.

Adverse events were consistent with findings in previous studies. Rates were higher in the azacitidine plus venetoclax group compared to the azacitidine plus placebo group for nausea of any grade (44% vs 35%), thrombocytopenia of grade 3 or higher (45% vs 38%), neutropenia (42% vs 29%), and febrile neutropenia (42% vs 19%).

Infections of any grade occurred in 85% of patients in the azacitidine-venetoclax group, vs 67% in the control group. Serious adverse events occurred in 83% and 73%, respectively.

"Ongoing Attentiveness" Is Key

The authors suggest that early bone marrow assessments to determine response with the combination therapy, most importantly after the completion of cycle 1, allow for appropriate interruptions in venetoclax between treatment cycles to augment hematologic recovery.

They note that for most patients in the azacitidine-venetoclax group (53%), modifications were made to the duration of venetoclax therapy; 32% also received granulocyte colony–stimulating factor during remission.

Supportive care, including the incorporation of prophylactic antimicrobial agents, such as antibiotic, antiviral, and antifungal therapy, is recommended for patients treated with azacitidine plus venetoclax.

"Unlike monitoring of patients who receive azacitidine alone, ongoing attentiveness to the monitoring and management of myelosuppression is key for patient safety with this combination therapy," the authors underscore.

In his editorial, Schiffer notes that in trying to understand the best therapeutic approaches for AML, "evaluation of the mechanisms of drug sensitivity rather than drug resistance, building on the new lessons learned from pharmacologic manipulation of the complex BCL2 pathway, might be very informative."

The study received support from AbbVie and Genentech.

New Engl J Med. Published August 13, 2020. Abstract, Editorial

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