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 sopra acute myeloid leukemia and multiple myeloma.
Expanding beyond the chronic lymphocytic leukemia/ small lymphocytic lymphoma space, the BCL2 inhibitor venetoclax (Venclexta) garnered attention con 2020 for positive reports from phase 3 clinical trials exploring its use per 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 con Houston, said in a news release. 4 “We launched the Viale-A trial esatto evaluate whether we could safely use verso combination therapy puro 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, fiacchezza, and leukopenia. Discontinuation rates were similar in the venetoclax and placebo arms (24% vs 20%). Porzione interruptions to allow for hematologic recovery occurred more frequently with venetoclax (TABLE 1 3 ).
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“Key direzione guidelines include dosing interruptions between cycles esatto allow for count recovery in the setting of per leukemia-free marrow and the use of granulocyte colony-stimulating factor as an adjunct to improve neutrophil count once a patient is mediante 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 giammai differences in quality-of-life measures between the 2 groups.
Myeloma Combinations With Venetoclax Per BELLINI, patients with relapsed/refractory multiple myeloma who had received 1 to 3 prior therapies were randomly assigned onesto 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 tempo emerged. Eight (4%) treatment-emergent fatal infections were reported with venetoclax, and 3 deaths were concluded esatto be related esatto 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 con 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 con the broader precision medicine paradigm in specific hematologic cancer population subsets.
Notably, the investigators on BELLINI reviewed why the agent was particularly effective mediante 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 puro 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 tau(11;14) translocation, thus offering the opportunity sicuro develop per personalized treatment strategy mediante 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 sopra 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 mediante verso cohort that included per majority of patients who were refractory preciso daratumumab (Darzalex). 5
Venetoclax Makes Inroads Into More Hematologic Setting
The phase 3 CAining venetoclax and dexamethasone sopra patients with relapsed/refractory myeloma, this time with per comparator arm of pomalidomide (Pomalyst) and dexamethasone.
Per AML, the placement of venetoclax sopra the frontline setting offers an optimal treatment option onesto those who formerly had few options, but this treatment approach is still evolving.
“While this combination represents verso key advance per 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 onesto which additional novel therapeutics are being evaluated mediante particularly high-risk populations.”
2. Kumar SK, Harrison SJ, Sartia M, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone durante patients with relapsed or refractory multiple myeloma (BELLINI): per 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 durante 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 con combination with dexamethasone as targeted therapy for patients with tau(11;14) relapsed/refractory multiple myeloma. Blood. 2019;134(suppl 1):926. doi:/blood-2019-125871