Ibrutinib/Venetoclax in Relapsed/Refractory Mantle Cell Lymphoma

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Patients with relapsed or refractory mantle cell lymphoma who received ibrutinib in combination with venetoclax experienced significantly better rates of progression-free survival compared with patients who received ibrutinib and placebo, according to findings from the international phase III Sympatico trial being reported at the 2023 ASH Annual Meeting & Exposition (Abstract LBA-2). Researchers say the findings suggest that ibrutinib and venetoclax, which have different modes of action, work synergistically, resulting in a better response than either drug alone. 

“Ibrutinib plus venetoclax has been shown to be very effective, safe, and well tolerated, and could benefit many patients with relapsed mantle cell lymphoma,” said Michael Wang, MD, Puddin Clarke Endowed Professor at The University of Texas MD Anderson Cancer Center, the study’s lead author and principal investigator. “This combination should be a new standard therapy for relapsed/refractory patients [with mantle cell lymphoma] in countries [where] ibrutinib is approved for mantle cell lymphoma.”

Mantle cell lymphoma is a rare non-Hodgkin lymphoma that is most common in older adults. Patients affected with this cancer often have swollen lymph nodes, an enlarged spleen, and abnormal blood counts due to damage to the bone marrow. After front-line therapies, a majority of patients see this cancer relapse after initially responding to treatment. Ibrutinib is currently approved for relapsed mantle cell lymphoma in many countries, but its approval was withdrawn for mantle cell lymphoma in the United States after a confirmatory trial met its primary progression-free survival endpoint but failed to meet its secondary overall survival endpoint.  

Ibrutinib and venetoclax are oral cancer drugs that are designed to affect different biochemical pathways. Ibrutinib targets Bruton tyrosine kinase (BTK), an enzyme involved in cell signaling, whereas venetoclax inhibits BCL2 proteins, which are involved in cell survival and growth. 

The combination was synergistic, with a complete response rate that is higher than the additive complete response rate of the two drugs... This is a clinical benefit for the patient and a landmark achievement for the treatment of mantle cell lymphoma.
— Michael Wang, MD

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Sympatico Study

For the phase III trial, researchers enrolled 267 patients with mantle cell lymphoma whose cancer had not responded to previous treatments or had returned after an initial response. After a median follow-up of 51 months, the results showed significantly better outcomes with the ibrutinib/venetoclax combination. The median progression-free survival, the trial’s primary endpoint, was significantly longer—31.9 months in the combination group compared with 22.1 months in the placebo group. 

Treatment with ibrutinib and venetoclax was also associated with a significantly better rate of complete response, which was achieved in 54% of those assigned to the combination therapy and 32% of those in the placebo group. 

“The combination was synergistic, with a complete response rate that is higher than the additive complete response rate of the two drugs,” said Dr. Wang. “This is a clinical benefit for the patient and a landmark achievement for the treatment of mantle cell lymphoma.”

The benefits of the combination therapy were consistent across subgroups of patients with high-risk features. The overall survival rate was numerically higher in the group that received the combination therapy, but the difference was not statistically significant. 

Adverse events were more common among patients who received the combination therapy, with the most frequent events including low white blood cell count, low platelet count, pneumonia, and anemia. About 60% of participants in both study arms experienced adverse events that were considered serious. Grade ≥ 3 adverse events were more common among those receiving the combination therapy, 84% of whom experienced such events compared to 76% in the control arm. 

Disclosure: The study was funded by AbbVie, manufacturer of ibrutinib. For full disclosures of the study authors, visit

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