Venetoclax Makes Inroads Into More Hematologic Setting

Courtney D. DiNardo, MD, MCSE

Expanding beyond the chronic lymphocytic leukemia/ small lymphocytic lymphoma space, the BCL2 inhibitor venetoclax (Venclexta) garnered attention in 2020 for positive reports from phase 3 clinical trials exploring its use in acute myeloid leukemia (AML) and multiple myeloma.

“A large [number] of patients with AML, including those [75 years or older] or those who have medical comorbidities, cannot tolerate existing treatment strategies, and the patients with AML who are ineligible for intensive chemotherapy often experience poor prognoses,” Courtney D. DiNardo, MD, MCSE, lead investigator and an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, said in a news release.⁴ “We launched the VIALE-A trial to evaluate whether we could safely use a combination therapy to treat this critical patient population.”

The trial met its primary end point of overall survival (OS) superiority with venetoclax. The median OS was 14.7 months for the venetoclax group and 9.6 months with placebo, which represents a 34% reduction in the risk of death (HR, 0.66; 95% CI, 0.52-0.85; P < .001). The benefit of the combination by median OS was observed across most patient subgroups, including those with secondary AML (HR, 0.56; 95% CI, 0.35-0.91), intermediate cytogenetic risk (HR, 0.57; 95% CI, 0.41-0.79), and IDH1/2 mutations (HR, 0.34; 95% CI, 0.20-0.60).

Venetoclax also improved complete remission (CR) rates, which represented a key secondary end point. Corresponding rates of CR were 36.7% versus 17.9% (P < .001); the corresponding composite CR rates (CR + CR with incomplete hematologic recovery) were 66.4% and 28.3% (P < .001).³

Notable hematologic adverse events with venetoclax included thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia. Discontinuation rates were similar in the venetoclax and placebo arms (24% vs 20%). Dose interruptions to allow for hematologic recovery occurred more frequently with venetoclax (TABLE 1³).

“Key management guidelines include dosing interruptions between cycles to allow for count recovery in the setting of a leukemia-free marrow and the use of granulocyte colony-stimulating factor as an adjunct to improve neutrophil count once a patient is in remission,” DiNardo said.

Supportive care for patients receiving the venetoclax regimen, such as prophylactic antimicrobial agents, was recommend by the investigators. It was noted that there were no differences in quality-of-life measures between the 2 groups.

Myeloma Combinations With Venetoclax In BELLINI, patients with relapsed/refractory multiple myeloma who had received 1 to 3 prior therapies were randomly assigned to bortezomib and dexamethasone plus either placebo (n = 97) or venetoclax (n = 194).²

Median progression-free survival (PFS), the trial’s primary end point, was significantly improved with venetoclax at 22.4 months versus 11.5 months with placebo (HR, 0.63; 95% CI, 0.44-0.90; P = .01).

Despite the positive efficacy findings, troubling treatment-related mortality data emerged. Eight (4%) treatment-emergent fatal infections were reported with venetoclax, and 3 deaths were concluded to be related to treatment. However, neither event was noted in the placebo group. These concerning findings elevated the importance of identifying patient subsets who derive the greatest benefit from this therapy regimen.

Subgroup analyses identified patient groups with distinct efficacy outcome improvement. Response rates were better in patients who had high BCL2 expression or t(11;14) translocation (TABLE 2² ), and these responses were some of the best and most durable ever reported in phase 3 trials examining triplet therapies for multiple myeloma, the investigators said.

Shaji K. Kumar, MD

Considerations for Care

Looking at the composite results of these trials, the evidence suggest that venetoclax may be a valuable tool in the broader precision medicine paradigm in specific hematologic cancer population subsets.

Notably, the investigators on BELLINI reviewed why the agent was particularly effective in patients with a specific cytogenetic profile. “Most of the existing therapies for multiple myeloma target cellular mechanisms that are crucial to plasma cells broadly, rather than targeting changes unique to malignant myeloma cells,” wrote the investigators led by Shaji K. Kumar, MD, of Mayo Clinic in Rochester, Minnesota. “Venetoclax, by virtue of its mechanism of action, is more effective against multiple myeloma cells that are more dependent on BCL2 for survival. BCL2 dependency varies between patients and is affected by BCL2 protein family member expression and the presence of genetic abnormalities, such as t(11;14) translocation, thus offering the opportunity to develop a personalized treatment strategy in multiple myeloma.”

Another phase 1/2 study (NCT01794520), which was reported at the 2019 American Society of Hematology Annual Meeting & Exposition, showed similarly positive results with the combination of venetoclax and dexamethasone in patients with multiple myeloma and translocation t(11;14), where 35% of patients had a very good partial response or better. These results were recorded in a cohort that included a majority of patients who were refractory to daratumumab (Darzalex).⁵

The phase 3 CANOVA trial (NCT03539744) is examining venetoclax and dexamethasone in patients with relapsed/refractory myeloma, this time with a comparator arm of pomalidomide (Pomalyst) and dexamethasone.

In AML, the placement of venetoclax in the frontline setting offers an optimal treatment option to those who formerly had few options, but this treatment approach is still evolving.

“While this combination represents a key advance in AML therapy, improving both remission and survival rates in newly diagnosed patients with AML, many unfortunately will still relapse,” DiNardo said. “Our next steps include an evaluation of azacitidine and venetoclax as a backbone to which additional novel therapeutics are being evaluated in particularly high-risk populations.”

_References:

_{1. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. FDA. October 16, 2020. Accessed November 16, 2020. https:// bit.ly/3nqxYNl}

_{2. Kumar SK, Harrison SJ, Cavo M, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. Published online October 29, 2020. doi:10.1016/S1470-2045(20)30525-8}

_{3. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/ NEJMoa2012971}

_{4. Combination therapy significantly improves survival outcomes for patients with acute myeloid leukemia. News release. The University of Texas MD Anderson Cancer Center. August 12, 2020. Accessed November 16, 2020. https://bit.ly/3pwJ6dj}

_{5. Kaufman JL, Gasparetto C, Schjesvold FH, et al. Phase I/II study evaluating the safety and efficacy of venetoclax in combination with dexamethasone as targeted therapy for patients with t(11;14) relapsed/refractory multiple myeloma. Blood. 2019;134(suppl 1):926. doi:10.1182/blood-2019-125871}