Newer Agents, Combinations Being Studied for Targeted Therapies in CLL

Beth Fand Incollingo @fandincollingo
Published: Sunday, Mar 20, 2016

Dr Jennifer R. Brown

Jennifer R. Brown, MD, PhD

Targeted agents, particularly ibrutinib (Imbruvica) and idelalisib (Zydelig), are becoming increasingly important in the treatment of chronic lymphocytic leukemia (CLL), and have replaced chemotherapy in many settings. Both are the go-to drugs for heavily pretreated patients, and ibrutinib, strictly, is the first choice as initial therapy for patients with a 17p deletion, and for older patients.

Those were the messages shared by Jennifer Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, in a talk 2016 International Congress on Hematologic Malignancies.

“Not too many years ago, CLL therapy was based in chemotherapy with antibodies, and if patients had a long duration of remission, it was generally OK to retreat. If they had a short duration of remission or a 17p deletion, their options were limited, with a short PFS on the order of six months,” she said. “Then the world changed, starting with a couple of different targeted agents.”

An important goal now, Brown said, is to find drug combinations that can control disease without being administered indefinitely, and that are better tolerated. One contender is the combination of the novel agent venetoclax with rituximab (Rituxan).


The oral, once-daily BTK inhibitor Ibrutinib works by forming a specific and irreversible bond with cysteine-481 in BTK. It has demonstrated excellent results in relapsed/refractory CLL, with a PFS of about 68% at 30 months, a number that rises to 87% in patients who are free of the 11q and the 17p deletions, Brown said.

The limitations of the drug, she pointed out, are that it’s not a cure—it mostly induces partial remissions and must be taken continuously—and about 10% of patients discontinue the drug due to adverse events.

Another downside is that patients who progress on ibrutinib are typically very difficult to salvage, Brown said.

The patterns of response often seen with ibrutinib are unique, and Brown stressed that doctors should not be alarmed by an initial rapid and dramatic increase in lymphocyte count that can last a month or more, since that will drop and then plateau over time.

Results from the 1102 study1 of both pretreated and treatment-naïve patients, reported in 2014, showed that, as white counts came down, patients converted from “partial response with lymphocytosis” to partial remission and then in some cases to complete remission. Median time to best response was 7 months within 3 years of follow-up, and the response rate was 90%. Complete remissions were at about 23% in the upfront setting.

Three-year PFS was 96% in lower-risk patients, and 68% in the higher-risk group. Brown pointed out that patients without 11q or 17p deletions have a “quite remarkable 89% PFS at three years,” with patients affected by 11q mutations logging a 74% PFS rate and 17p deleted patients at 46%.2

Among treatment-naïve patients aged 65 and younger, 81% remained on ibrutinib at 2 years, with only one event of progressive disease that occurred in a patient with a 17p deletion, Brown noted. In the relapsed/refractory setting, 53% remained on ibrutinib after the same amount of time, with 21 patients experiencing progressive disease.

In pretreated patients, compared with the approved CLL drug ofatumumab (Arzerra), ibrutinib sparks better responses, according to the results of the RESONATE trial, Brown noted.3

“It’s still better than any other treatment we had to offer these patients, which is why ibrutinib got early approval for 17p deletion, but PFS still continues to decline in these patients, and there’s a reduction in overall survival,” she said. “We do have trouble salvaging these patients who were heavily pretreated when they relapsed, and there’s an incidence of Richter’s transformation in about a third of these patients.”

This transformation changes CLL into quickly growing diffuse, large B cell lymphoma, which is difficult to successfully treat. “Survival for patients with Richter’s is very poor, 3.5 months, whereas for patients with progressive CLL median overall survival (OS) is 17 months,” she said, citing a study from Ohio State University.4 “That may not be the same in patients who progress in frontline treatment, but we don’t know that yet.” The mutations that cause Richter’s are potentially targetable, Brown added.

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