New Drugs Poised to Expand Treatment Horizons in WM

Pam Harrison

May 25, 2018

ROSEMONT, Illinois — The discovery of a disease-distinguishing mutation giving rise to Waldenstrom's macroglobulinemia (WM) was a major breakthrough that led to treatment with a targeted drug, ibrutinib (Imbruvica, Pharmacyclics), that turns the mutation off and keeps a lid on the disease for prolonged periods.

Unfortunately, close to half of patients with WM also carry another mutation, the CXCR4 mutation, that eventually confers resistance to ibrutinib, allowing disease progression.

Thus, new pathways to overcome resistance and produce deeper, longer-lasting responses are being actively pursued, several of which were discussed here at the International Waldenstrom's Macroglobulinemia Foundation (IWMF) 2018 Forum.

"This is a really exciting time in WM in which we are seeing large studies in the disease that we never had before," Jorge Castillo, MD, clinical director, Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, told delegates here.

"And it's all about, 'How can we make ibrutinib better?'" he added.

Castillo outlined several new treatment approaches, as follows:  

  • Ixazomib, dexamethasone, and rituximab:  The proteasome inhibitor bortezomib (Velcade, Takedo Oncology) is highly active in WM, but treatment-related neuropathy is common and often leads to premature discontinuation of treatment, he commented. Ixazomib (Ninlaro, Takeda Oncology) is an oral proteasome inhibitor that causes much less neuropathy but has not until now been evaluated in WM. In a study involving 26 previously untreated patients, participants received six 4-week cycles of induction therapy consisting of ixazomib, 4 mg, plus dexamethasone, 20 mg, on days 1, 8, and 15 plus rituximab (Rituxan, Genentech), 375 mg/m2 on day 1, followed by six 8-week cycles of maintenance therapy for a total of 12 cycles. Rituximab was held for the first two cycles to minimize the risk for an IgM flare, for which it is well noted. After induction, median serum IgM dropped to 2279 mg/dL; median hemoglobin increased to 12.7 g/dL, and the median bone marrow involvement decreased to 15% (P < .001). At the end of the maintenance phase, median serum IgM had declined even further to 871 mg/dL, as did the median bone marrow involvement (5%), while median hemoglobin continued to increase (13.6 g/dL) as well. The overall response rate (ORR) was 96%, with 14% of patients showing very good partial responses; 62%, partial responses; 19%, major responses (MRs); and disease stabilizing, another 5%. At 18 months, 90% of patients were free of disease progression, and the regimen was well tolerated with little neuropathy. Importantly, CXCR4 mutations affected the time to response but not the depth of response to the regimen, Castillo commented.  

  • Single-agent venetoclax: Venetoclax (Venclexta, Roche) is a bcl-2 inhibitor currently approved for chronic lymphocytic leukemia. The bcl-2 protein is pivotal in WM because WM cells are packed with the protein and it is this protein that prevents WM cells from dying. "When we block bcl-2 with venetoclax, we are forcing the cells to die," Castillo noted. Dana-Farber Cancer Institute researchers have now completed enrollment of 30 previously treated patients with WM who will eventually receive venetoclax. Participants will initially receive 200 mg per day, then 400 mg per day, and finally 800 mg per day, the target dose being 800 mg per day. At approximately 8 months of follow-up, the ORR was 80% in patients who were evaluable at that time point, with 13% having very good partial responses; 43%, partial responses; and 23%, MRs. Those who had not previously been exposed to ibrutinib responded better to venetoclax than did those who had not, but responses were elicited in both groups. Venetoclax has a more dramatic effect on bone marrow involvement than ibrutinib does, decreasing levels to less than 10% after treatment initiation. Its main toxicity is neutropenia, which occurs in about one third of patients, but the drug is relatively benign, Castillo commented. "Stand by," he said, for a logical combination of ibrutinib and venetoclax, which should achieve both rapid IgM and hemoglobin improvement with ibrutinib and deep bone marrow clearance with venetoclax, with no overlapping toxicities.

  • Ibrutinib plus rituximab: In a phase 3 study involving 75 patients per group, the combination of ibrutinib plus rituximab was clearly superior to rituximab alone, Castillo noted. ORRs reached 92% for the combination group vs 47% for the rituximab group; 72% of patients in the combination group achieved an MR compared with 34% in the single agent group, while at 30 months, 82% of patients receiving the combination had no evidence of disease progression vs 28% of patients treated with rituximab alone. Interestingly, when the two drugs are given together, IgM flare rates were less than 10%, compared with 47% for treatment with rituximab alone. The combination also only slightly increased the toxicity profile. Importantly as well, patients with the ibrutinib-inhibiting CXCR4 mutation seemed to benefit as much from the combination as did those without the mutation, so Castillo predicted that this is an "up-and-coming" combination.

  • Second-generation Bruton's tyrosine kinase (BTK) inhibitors and targeted antibody therapies: Many second-generation BTK inhibitors, including acalabrutinib (Calquence, AstraZeneca) and zanubrutinib (BGB-3111, BeiGene), are in various phases of evaluation in WM. The hope here is that these new-generation inhibitors will overcome resistance caused by the CXCR4 mutation to first-generation ibrutinib.  Early research is also exploring the combination of ibrutinib plus an anti-CXCR4 antibody, ulocuplumab (BMS-936564, Bristol-Myers Squibb), which makes a lot of sense, Castillo commented. Another antibody, daratumumab (Darzalex, Genmab), blocks CD38. "In WM, we have three clones: the B-cell clone, the lymphoplasmacytic clone, and the plasma cell clone," Castillo explained. Because CD38 is largely expressed by the plasma cell clone, "we believe that if we attack the clone from the plasma cell side rather than attacking the clone from the B-cell side, we might decrease IgM levels at a faster rate because plasma cells are the clones that continue to produce IgM cells that are difficult to eradicate," Castillo observed.

Effective Therapies

Asked by Medscape Medical News to comment on the seeming flurry of research activity aimed at improving treatment of WM, Morie Gertz, MD, consultant hematologist, Mayo Clinic, Rochester, Minnesota, noted that the interest really isn't new at all. Rather, it's been going on for at least two decades and maybe longer.

"I think part of the interest is the increasing availability of effective therapies," he observed.

The other part is that patient advocacy groups have gotten behind those with WM and are lobbying both the National Institutes of Health and the Leukemia & Lymphoma Society to promote active research into the management of WM, he added.

Gertz seems certain that these research efforts will pay off in terms of prolonging what is already a fairly significant survival expectation following the diagnosis of WM for most patients.

"We've already gotten to the point where half of the patients with this disease are dying of completely unrelated causes, and of course, what we would like to do is make it so that 100% of these patients die of completely unrelated causes," he said. "But there are still patients who succumb to the disease so I think there is still room for improvement."

As for himself, Gertz remains motivated to provide the best possible care for patients with WM because the disease itself is challenging to manage, and it takes training and nuance to make sure every patient is appropriately managed.

A community oncologist might see one patient with WM every 5 to 10 years.  

"I think there is a need for centers of excellence [such as the Mayo Clinic] where physicians have the experience to make critical decisions about when to treat — because not everyone needs treatment immediately," he reaffirmed.

"And when you have so many options for therapy, it can be a bit confusing for an inexperienced provider as to how to most effectively sequence therapies," Gertz emphasized.

Castillo reports he has served as a consultant to Janssen, Merck, and Pharmacyclics and has received research funding from AbbVie, Gilead Sciences, Janssen, Millennium Pharmaceuticals, and BeiGene. Gertz reports personal fees from Ionis, Alnylym, Prothena, Celgene, Janssen, Annexon, Appellis, Amgen, Medscape, Physicians Education Resource, AbbVie, Research to Practice, Teva, Dava Oncology, and Johnson & Johnson and grants and personal fees from Spectrum.

International Waldenstrom's Macroglobulinemia Foundation (IWMF) 2018 Forum. Presented May 19, 2018.

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