Venetoclax Makes Inroads Into More Hematologic Setting

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

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 durante acute myeloid leukemia (AML) and multiple myeloma.

“Per 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 durante Houston, said in verso news release. 4 “We launched the Viale-Verso trial esatto evaluate whether we could safely use a combination therapy preciso 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).>

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);>

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%). Ritaglio interruptions onesto allow for hematologic recovery occurred more frequently with venetoclax (TABLE 1 3 ).

“Key vertici guidelines include sugardaddie dosing interruptions between cycles preciso allow for count recovery sopra the setting of a leukemia-free marrow and the use of granulocyte colony-stimulating factor as an adjunct esatto improve neutrophil count once verso 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 niente affatto differences con quality-of-life measures between the 2 groups.

Myeloma Combinations With Venetoclax Per BELLINI, patients with relapsed/refractory multiple myeloma who had received 1 esatto 3 prior therapies were randomly assigned preciso 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 scadenza emerged. Eight (4%) treatment-emergent fatal infections were reported with venetoclax, and 3 deaths were concluded sicuro be related preciso treatment. However, neither event was noted mediante 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 mediante patients who had high BCL2 expression or t(11;14) translocation (TABLE 2 2 ), and these responses were some of the best and most durable ever reported mediante phase 3 trials examining triplet therapies for multiple myeloma, the investigators said.

Considerations for Care

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

Notably, the investigators on BELLINI reviewed why the agent was particularly effective per patients with verso specific cytogenetic profile. “Most of the existing therapies for multiple myeloma target cellular mechanisms that are crucial preciso plasma cells broadly, rather than targeting changes unique sicuro malignant myeloma cells,” wrote the investigators led by Shaji K. Kumar, MD, of Mayo Clinic sopra 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 tau(11;14) translocation, thus offering the opportunity preciso develop verso personalized treatment strategy in multiple myeloma.”

Another phase 1/2 study (NCT01794520), which was reported at the 2019 American Society of Hematology Annual Assemblea & 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 per very good partial response or better. These results were recorded sopra a cohort that included a majority of patients who were refractory to daratumumab (Darzalex). 5

Venetoclax Makes Inroads Into More Hematologic Setting

The phase 3 CAining venetoclax and dexamethasone durante patients with relapsed/refractory myeloma, this time with per comparator arm of pomalidomide (Pomalyst) and dexamethasone.

In AML, the placement of venetoclax durante 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 per key advance con AML therapy, improving both remission and survival rates durante newly diagnosed patients with AML, many unfortunately will still relapse,” DiNardo said. “Our next steps include an evaluation of azacitidine and venetoclax as per backbone esatto which additional novel therapeutics are being evaluated in particularly high-risk populations.”

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

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

_{4. Combination therapy significantly improves survival outcomes for patients with acute myeloid leukemia. News release. The University of Texas MD Anderson Cancer Center. .}

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