Newer Drug Combinations Offer Hope to Those With Mantle Cell Lymphoma

Patients with mantle cell lymphoma may have new hope in drug combinations, according to Dr. Timothy Fenske, an associate professor at the Medical College of Wisconsin.

Mantle cell lymphoma is an aggressive, rare form of non-Hodgkin lymphoma that is often associated with poorer survival outcomes. Patients tend to relapse or become resistant to treatment options. That’s where newer therapies combined with one another may prove beneficial.

“Beyond effective BTK inhibitors, novel combinations with Venclexta (venetoclax), PI3K inhibitors and proteasome inhibitors all have the potential to further improve survival in patients with relapsed/refractory mantle cell lymphoma,” Fenske said in an interview with OncologyLive®, CURE®’s sister publication.

Currently, first-line treatment of mantle cell lymphoma includes combination chemotherapy with the monoclonal antibody Ritxuan (rituximab), followed by autologous stem cell transplantation — using stem cells from the person being treated. However, if patients are frailer, less intensive chemotherapy followed by a prolonged course of Rituxan may be recommended.

In patients who have relapsed or stopped responding to treatment, second-line therapies consist of Calquence (acalabrutinib), Imbruvica (ibrutinib), Revlimid (lenalidomide) and Velcade (bortezomib) — the latter two therapies sometimes with Rituxan.

“Acalabrutinib and ibrutinib covalently bind to the BTK enzyme, and when you get a mutation where the drug resides, the drug can't bind anymore; this (results in the development of) resistance,” said Fenske. “There is a new category of BTK inhibitors that are noncovalent binders that, in vitro, still seem to block the enzyme even when that mutation is present.”

Ten or more next-generation BTK inhibitors are in development, explained Fenske. “I could envision a day, hopefully not too far down the road, when we could perform a BTK mutation analysis for a patient who shows resistance to ibrutinib or acalabrutinib and that would tell us which BTK inhibitor we should switch them to,” he said. “This is like what we are already doing in chronic myeloid leukemia with BCR-ABL mutation analysis.”

In several clinical trials, researchers are also looking at how the combination of Venclexta with BTK inhibitors could help improve survival. Fenske explained that the drug showed a 75% overall response rate in an early phase trial that included 20 or 30 patients with mantle cell lymphoma. Additionally, a small, single-group study published in the New England Journal of Medicine investigated Imbruvica with Venclexta and showed high rates of minimal residual disease negativity — meaning the amount of cancer cells remaining after treatment. “Even patients who had p53 mutations, which historically is a group that does very poorly, saw what looked like favorable outcomes,” said Fenske. “We definitely need more data with that particular combination, but it looked interesting. The bigger question will be whether combination therapy or sequential therapy is better in the long run.”

Proteasome inhibitors, such as Ninlaro (ixazomib), are also being studied in clinical trial. For instance, at the Medical College of Wisconsin, researchers are examining the drug with Imbruvica in patients with relapsed/refractory mantle cell lymphoma.

Also of interest is the use of chimeric antigen receptor (CAR)-T cell therapy, for which treatments have been approved by the Food and Drug Administration for the treatment of certain blood cancers, but how it could work for patients with mantle cell lymphoma is still being investigated. In an open trial that has included 12 patients thus far, five of which had mantle cell lymphoma, four patients achieved complete remission, according to Fenske.

Overall, Fenske explained that some of the aggressive treatment strategies are showing eight- to 10-year first remissions. However, this becomes a greater challenge once relapse occurs. “For most of the drugs, remissions are in the one- to two-year range,” said Fenske. “The long-term follow-up with acalabrutinib does look to be an excess of two years. We are starting to crack that (puzzle), but it’s been little by little.”