The Changing Landscape of Relapsed/Refractory Chronic Lymphocytic Leukemia Treatment


Patients with relapsed or refractory chronic lymphocytic leukemia are generally divided by those exposed to Bruton's tyrosine kinase inhibitors (BTKi), patients relapsing after venetoclax, and patients relapsing after BTKi and B-cell lymphoma-2 inhibitors.

The landscape of relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) has changed significantly over the past several years, explained Jennifer Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, during a session at the Society of Hematologic Oncology 2021 conference.

For example, patients relapsing after minimal therapy are now considered to be essentially like frontline, which is a significant shift in practice, Brown explained. Most of the data demonstrating this shift in practice pertain to patients relapsing after chemoimmunotherapy with targeted agents. In this way, patients relapsing have been previously treated with targeted agents, and there is not yet enough data available on how to approach this when it occurs.

Brown noted that she generally divides patients with R/R CLL into the following categories: patients exposed to Bruton's tyrosine kinase (BTK) inhibitors (BTKi), patients relapsing after venetoclax, and patients relapsing after BTKi and B-cell lymphoma-2 (BCL-2) inhibitors.

“In terms of patients exposed to BTKi, in data from Ohio State, the most common reason for discontinuation was adverse events (AEs), and then over the long term, progression was the other main reason for discontinuation,” Brown said during the session.

In the study from Ohio State, investigators assessed toxicities and outcomes from ibrutinib-treated patients. The results showed that the most common AEs that led to discontinuation of therapy in patients with frontline CLL were arthralgia (42%), atrial fibrillation (25%), and rash (17%). For patients with R/R CLL, the most common AEs were atrial fibrillation (12%), infection (11%), pneumonitis (10%), bleeding (9%), and diarrhea (7%).

“Unfortunately, this does result in a reduced progression free survival compared to what we’ve seen in patients who stay on therapy in randomized trials,” Brown said during the session. “Those who come off for AEs have a better prognosis than those who progress and can still respond to other kinase inhibitors, such as phosphoinositide 3-kinases (PI3Ks) kinase inhibitors. However, in these real-world data, the best outcomes were with venetoclax.”

In addition to PI3Ks kinase inhibitors, data have demonstrated that patients who stop ibrutinib or another BTK inhibitor for an intolerance can respond with a relatively low rate of recurrence to acalabrutinib and zanubritinib, which demonstrates these are viable options for patients who stop BTKi due to the occurrence of AEs.

Additionally, patients who have stopped BTKi are at an increased risk of progression, Brown explained. Progression among these patients is most commonly due to mutations in BTK, with a subset of patients also having a mutation in phospholipase C gamma 2 (PLCG2).

“We now have data that similar mechanisms of resistance with mutations of C481 in BTK apply to acalabrutinib, in data from Ohio State, and also zanubritinib, in data from Australia. Our only prospective data specifically in this population are from a trial of venetoclax, in which the overall response rate (ORR) was 65%, which is really quite good,” Brown said during the session.

However, Brown noted that the complete response rate of 9% and the undetectable minimal residual disease (uMRD) of 42% are both lower than expected in patients who have not progressed after BTKi. Specifically, progressing after BTKi is associated with a lower response rate to venetoclax in combined analyses of outcomes.

To manage this lower response rate to venetoclax, some groups have responded by adding PI3Ks to venetoclax. In a study assessing umbralisib, ublituximab, and venetoclax, half the patients were R/R prior to BTKi, and the ORR to umbralisib and ublituximab in the first 3 cycles was 64% in patients with R/R CLL, Brown explained.

“This is rather encouraging,” Brown said during the session. “And then, of course, venetoclax was added, with very high rates of uMRD. Our study of duvelisib and venetoclax had similar results. So, there are opportunities for combinations in this space that can potentially enhance the efficacy of venetoclax.”


Brown J. Managing CLL Patients Relapsed or Refractory to Targeted Therapy. Presented at: Society of Hematologic Oncology 2021 Virtual Meeting. September 8, 2021. Accessed September 28, 2021.

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