Venclexta Demonstrates ‘Very Impressive’ Responses for Patients With Waldenström Macroglobulinemia


The drug Venclexta may address an unmet need for patients with Waldenström macroglobulinemia via a non-chemotherapeutic, safe and effective treatment option.

Venclexta (venetoclax) is safe and effective for patients with previously treated Waldenström macroglobulinemia (WM), including treatment with burton tyrosine kinase (BTK) inhibitors, according to recent study results.

Dr. Jorge J. Castillo, lead author of the study and clinical director of the Waldenström Macroglobulinemia Program at the Dana-Farber Cancer Institute in Boston, explained to CURE® that BCL2 inhibitors like Venclexta are approved by the Food and Drug Administration for other cancers such as chronic lymphocytic leukemia and acute myeloid leukemia; however, this is the first clinical trial evaluating the drug in patients with WM. He further explained that WM has malignant BCL2 cells that “immortalize” themselves, so “they are not dying when they are supposed to.”

“So what (Venclexta) does in this setting is by blocking the BCL2 in these malignant cells, they essentially induce cell death,” he said. “So being the first clinical trial ever reported with this mechanism of action in patients with (WM), I think is one of the big aspects.”

Castillo and researchers evaluated Venclexta in 32 patients with WM who were previously treated for the disease. Of these patients, 16 were previously treated with BTK inhibitors. In addition, 17 patients had CXCR4 mutations, which can affect how the disease presents in patients, how it is diagnosed and how the disease responds to BTK inhibitors.

The dose of the drug increased over time from 200 milligrams to the maximum 800 milligrams for up to two years.

The median time to minor responses to the treatment (a reduction of tumor size between 25% and 50%) was 1.9 months, with a median time to a major response of 5.1 months. Patients previously treated with BTK inhibitors had a longer time to treatment response compared with those with no previous exposure to BTK inhibitors (4.5 months versus 1.4 months).

Results, which were published in the Journal of Clinical Oncology, demonstrated that 84% of patients had an overall response (percentage of patients with a partial or complete response) to the treatment, 81% had a major response (partial response or greater) and 19% had a very good partial response (at least 90% reduction in the monoclonal protein in the blood). Castillo said that this is “a very important outcome.”

He explained that a main marker of this disease is a protein in the blood called IgM, which everyone has but is typically higher in patients with WM. They use IgM to measure how a patient is responding to treatment. If it is effective, IgM levels start dropping. Specifically, a minor response will drop by 25%, by 50% is a partial response, and by 90% is a very good partial response.

“I think the importance is how effective it is. … These are patients that are heavily pretreated, so inducing an (81%) major response rate and (19%) very good response rates on these patients is actually an important outcome,” he said.

The major response rate was lower in those with refractory disease (50%) compared with relapsed disease (95%).

With a median follow-up time of 33 months, median progression-free survival (time during and after treatment when the patient lives without disease progression) was 30 months. Notably, CXCR4 mutations, which account for an estimated 30% to 40% of patients with WM, did not affect treatment response or progression-free survival.

“The depth of the response was very impressive. I think the duration of the response, compared to what other treatments might have been available at a time, is actually very impressive as well,” Castillo added.

Other treatments for WM include chemotherapy, proteasome inhibitors and BTK inhibitors. After those three lines of therapy, there is no other treatment that is as effective, meaning this study on Venclexta for this patient population is meeting an unmet need, he said. Additionally, this patient population has a long survival rate of 10 to 15 years, he said, so it is important to have another treatment option.

“There have been other trials with other medications that have shown some efficacy in that setting. But compared to what (Venclexta) is able to induce in terms of the response in that group of patients is really something that we have not seen before,” he explained.

The most common severe side effect, which occurred in 45% of patients, was neutropenia. Castillo explained that other mild and moderate side effects that were associated with the drug did not affect a patients’ daily life or activities.

“The opportunity to provide some patients with an option that is oral, that is not chemotherapeutic, that is very well tolerated with side effects (that) are very manageable and of a finite duration, that makes this study very innovative,” Castillo concluded.

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