Novel Treatments for Chronic Lymphocytic Leukemia Result in Improved Outcomes, Lower Adverse Effects

The treatment of chronic lymphocytic leukemia (CLL) has been developing at a rapid pace, with new data and approvals shifting the way CLL is approached. In a presentation at the Community Oncology Alliance 2021 Virtual Conference, Jeff Sharman, MD, summarized the most important developments in care.

According to Sharman, BTK inhibitors are more effective in the treatment of both frontline and relapsed/refractory (r/r) CLL than chemotherapy and PI3K inhibitors. Further, recent studies have shown that next generation BTK inhibitors are leading to fewer adverse effects (AEs) without sacrificing efficacy. For example, a study found that among 33 patients who were intolerant of the BTK inhibitor ibrutinib, 23 were able to remain on the second generation BTK inhibitor acalabrutinib, with no reductions in dose occurring. Additionally, 72% of AEs from ibrutinib did not recur after the switch in medications, and a further 13% recurred at a lower grade.

Research has also shown promising results for the BCL-2 inhibitor venetoclax, which is intended to be a fixed duration treatment, unlike a BTK inhibitor. According to Sharman, venetoclax often leads to very deep remissions and notable rates of minimal residual disease negativity.

Additionally, venetoclax had a 4-year progression-free survival (PFS) rate of 57% and an overall survival rate of 85% for patients with r/r CLL, both of which were considerable improvements over the percentages found when using a combination of bendamustine and rituximab. Venetoclax was also found to avoid accelerating clonal regrowth, which cannot be said for chemotherapy.

“There’s really no role for chemoimmunotherapy in relapsed/refractory CLL if novel options are available,” Sharman said.

It is currently uncertain whether immunomodulators that bind to CD20 can function in a significant supporting role alongside BTK inhibitors in the treatment of CLL. Considerable data suggest that adding an anti-CD20 alongside ibrutinib has no significant effect, but a trial combining the anti-CD20 obinutuzumab with acalabrutinib found a minor—though potentially not statistically significant—improvement in PFS, according to Sharman.

“I don’t think at the initial presentation this really changed many people’s minds,” Sharman said. “However, we should be updating this [sic] data soon, and I think some of those results will be provocative. I look forward to sharing those when they’re actually available.”

Additionally, data published by Sharman’s group in Lancet Hematology suggest that adding the second generation anti-CD20 ublituximab to ibrutinib in patients with r/r high-risk CLL had a statistically significant improvement in PFS.

“CD20 doesn’t add to BTK, or maybe it does,” Sharman said. “It’s a story obviously still in evolution. The way I see it is, it can, but with some additional toxicity and you may be on either side of that depending upon the patient you’re looking at.”

Sharman also points to chimeric antigen receptor T-cell therapies as a potential point of hope for future improvements in outcomes, with these therapies seeing approval for use in a number of lymphatic cancers.

“This has been a whirlwind of approvals in lymphoid malignancies,” Sharman said. “Diffuse large B-cell lymphoma, mantle cell, follicular, and multiple myeloma are all already approved. So, 5 indications already covered, and I think the question is, ‘is CLL going to be next, and which agent would it be?’ I think at least 1 of the manufacturers out there is optimistic that we could see regulatory approval in the coming year or 2.”


Jeff Sharman. The Latest in Chronic Lymphocytic Leukemia (CLL) Treatment. Presented at: Virtual Community Oncology Conference 2021; April 9, 2021; Virtual.