Combating Low-Grade Lymphomas with Less Toxic Approaches

New treatments paradigms are on the horizon that may provide improved outcomes but with less toxicity for patients with low-grade lymphomas. Currently, there are several new drug candidates entering clinical trials and about to usher in a new era of targeted therapies and immunotherapies. It is hoped these new approaches will bring a new level of improved efficacy and lack to toxicity for this patient population.

“Almost all new options of treatment on clinical trials show an advantage over conventional standard therapy options. Ten years ago the advantages of clinical trials was too much of a hit and miss and we did not have a good selection of candidate drugs. Now, the candidate drugs have more promising outcomes,” says Felipe Samaniego, MD, associate professor in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at MD Anderson Cancer Center, Houston, TX.

Samaniego and his colleagues recently completed a multicenter, open-label, Phase II study of umbralisib monotherapy in patients with relapsed/refractory marginal zone lymphoma (MZL). Umbralisib is a novel, next-generation PI3K-delta inhibitor. It has unique inhibition of casein kinase-1ε (CK1ε) and it has an improved tolerability profile with reduced rates of immune-mediated toxicity compared to earlier generation PI3K-delta inhibitors.

The researchers found that 55% of patients who had at least six months of follow-up had a partial or complete response after receiving umbralisib. The trial included 69 patients (median age 67 years) and the median number of prior systemic therapies was 2 (range, 1-5). Each patient received umbralisib 800 mg orally once a day until disease progression or unacceptable toxicity. The investigators reported on the first 38 patients who were eligible for assessment with at least 6 months of follow-up. Among these 38 patients, 23 had extranodal disease, 8 had nodal disease and 7 had splenic disease. The researchers found that progression-free survival (PFS) was 71% after one year.

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The typical MZL patient is diagnosed at about age 60 and is usually treated with rituximab either alone or in combination with chemotherapy. While producing high response rates, approximately about 70 % of patients relapse and have few treatment options. “The FDA has granted breakthrough designation for the use of umbralisib for relapsed MZL. With this recognition, we have started two new trials: umbralisib plus ublituximab (a third generation anti-CD20 antibody) for relapsed follicular lymphoma, and umbralisib plus ublituximab for relapsed marginal zone lymphoma,” says Samaniego.

In the just completed phase II study, the most common (≥20%) adverse events (AEs) of any grade were diarrhea (45%), nausea (29%), fatigue (26%), headache (26%), cough (24%), and decreased appetite (21%). Neutropenia (8%), febrile neutropenia (5%), and diarrhea (5%) were the most common Grade 3/4 events. “Umbralisib is a Pi3K (phosphoinositidel 3 kinase) inhibitor. It blocks the driver pathway that stimulates growth of many B cell lymphomas. There are other Pi3K inhibitors in use of lymphoma treatment, but umbralisib is head and shoulders above the others because it has minimal toxicity and lymphoma reduction properties in excess of 60%,” says Samaniego.

Xylina Gregg, MD, hematologist/oncologist at Intermountain Healthcare in Salt Lake City, UT, says these study findings are encouraging and they are particular good news for patients with MZL. She says this is a patient population that historically has had few treatment choices when it comes to salvage therapy. “Although a preliminary small phase II study, it is interesting that they specifically target marginal zone lymphoma being different from other low grade lymphomas,” Gregg says. “Thus, this novel therapy for this often neglected lymphoma is promising.”