Patients diagnosed with relapsed or refractory (r/r) mantle cell lymphoma (MCL) who received ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech) in combination with venetoclax (Venclexta® / Venclyxto®; Abbvie/Genentech) experienced significantly better rates of progression-free survival compared with patients who received ibrutinib and placebo.[1]

This conclusion is based on the outcome of an international, multinational, randomized, double-blind study phase 3 study trial reported during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition.

These findings suggest that ibrutinib in combination with venetoclax, which have different modes of action, work synergistically, resulting in a better response than either drug alone.

“Ibrutinib plus venetoclax is very effective, safe, and well tolerated, and could benefit many patients with relapsed MCL,” noted 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 MCL patients in countries ibrutinib is approved for MCL,” Wang added.

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A rare disease
MCL is an aggressive, but rare form of non-Hodgkin lymphoma, a cancer of white blood cells, that is most common in older adults. Patients affected with this cancer often have swollen lymph nodes, enlarged spleen, and abnormal blood counts due to damage to the bone marrow by this form of cancer.

In most cases, MCL involves the gastrointestinal tract and bone marrow. Overproduction of a protein called cyclin D1, a 36-kDa protein and important regulator of the cell cycle, in lymphoma cells is found in more than 90% of patients with MCL. The identification of excess cyclin D1 from a biopsy is generally considered a very sensitive tool for a diagnosis of MCL.[2]

In addition, 25% to 50% of patients diagnosed with MCL also have higher-than-normal levels of certain proteins that circulate in the blood, such as lactate dehydrogenase (LDH), an enzyme found in nearly all living cells, and beta2 microglobulin (B2M), an important prognostic marker in a large number of hematologic and nonhematologic diseases. Measuring levels of these and other proteins can help determine how aggressive the disease is and guide therapy decisions.

Relapse
Despite high response rates to frontline therapies, most patients diagnosed with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease after initially responding to treatment. Ibrutinib is currently approved for relapsed MCL in many countries but was withdrawn for MCL in the U.S. after a confirmatory trial met its primary progression-free survival (PFS) endpoint but failed to meet its secondary overall survival (OS) 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.

Trial design
For the phase 3 trial, researchers enrolled 267 patients with MCL 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 with 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 (CR, or the eradication of cancer as measured with standard imaging methods), 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 CR rate that is higher than the additive CR rate of the two drugs,” Wang said.

“This is a clinical benefit for the patient and a landmark achievement for the treatment of MCL.”

Treatment benefit
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. Adverse events of grade three or higher were more common among those receiving the combination therapy, 84% of whom experienced such events compared to 76% in the control arm.

Clinical trials
Study of Ibrutinib Combined With Venetoclax in Subjects With Mantle Cell Lymphoma (SYMPATICO) – ClinicalTrials.gov – ID NCT03112174

Highlights of Prescribing Information
Ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech)[Prescribing Information]
Venetoclax (Venclexta® / Venclyxto®; Abbvie/Genentech)[Prescribing Information]

ASH presentation
[1] LBA-2: Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study

References
[2] Montalto FI, De Amicis F. Cyclin D1 in Cancer: A Molecular Connection for Cell Cycle Control, Adhesion and Invasion in Tumor and Stroma. Cells. 2020 Dec 9;9(12):2648. doi: 10.3390/cells9122648. PMID: 33317149; PMCID: PMC7763888.

Featured image courtesy © 2019 – 2024 American Society of Hematology ASH/Matt Herp. Used with permission.

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