Dr. Castillo on Emerging Treatment Approaches in Waldenstrom Macroglobulinemia

Jorge J. Castillo, MD, clinical director, Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, highlights ongoing research with emerging treatment approaches in Waldenström macroglobulinemia.

There are several novel approaches under investigation in the realm of Waldenström macroglobulinemia, says Castillo. For example, there are newer proteasome inhibitors, such as ixazomib (Ninlaro), that are emerging in the paradigm. This agent is being explored in combination with rituximab (Rituxan) and dexamethasone and will be added to the National Comprehensive Cancer Network guidelines in the future. Oprozomib (ONX 0912) is another agent that has been investigated in multiple myeloma and Waldenström, says Castillo.

BTK inhibitors, such as acalabrutinib (Calquence) and zanubrutinib (BGB-3111), have also shown promise in this space. Acalabrutinib has already received FDA approval for use in mantle cell lymphoma, and zanubrutinib is currently being compared head-to-head against ibrutinib (Imbruvica) in clinical trials. Both of these agents are more selective to BTK, explains Castillo, and unlike ibrutinib, they do not tend to have other off-target effects. However, these agents must be taken twice daily, while the dosing for ibrutinib is only once daily. How this dosing might affect patient compliance remains to be seen.

Venetoclax (Venclexta), a BCL-2 inhibitor previously FDA approved for use in chronic lymphocytic leukemia and acute myeloid leukemia, is another agent that is currently being evaluated in 30 patients with Waldenström macroglobulinemia. Preliminary data have shown that the agent is efficacious, says Castillo. Specifically, half of the patients who had progressed on ibrutinib and were given venetoclax responded to the agent.

Resistance to ibrutinib is mediated by a mutation in the BTK, explains Castillo, and the hope is that new BTK inhibitors will be able to overcome that resistance and rescue patients in whom ibrutinib is failing. Beyond this effort, ibrutinib is also being investigated in combination with ulocuplumab (BMS-936564), an antibody against CXCR4, in what is potentially the first genomically-driven clinical trial in patients with Waldenström, says Castillo. This trial is currently undergoing accrual. Another trial opening in the future will examine a small molecule targeting CXCR4 in these patients as well, he adds.

Lastly, investigators will be examining ibrutinib in combination with venetoclax in a trial that is slated to be launched later this year, concludes Castillo. In the trial, the combination will be given to 50 treatment-naïve patients for a limited duration of time, about 2 years.