Imbruvica Improves Outcomes in CLL, But Less Toxic Treatments Still Needed

Imbruvica (ibrutinib) has been approved as a frontline treatment for patients with chronic lymphocytic leukemia (CLL) since 2016. However, it has not been compared against many other agents, or in combination with other drugs — such as Rituxan (rituximab) – thus leaving physicians with no standard of care for older patients with the disease.

Recent research presented at the 2018 American Society of Hematology (ASH) Annual Meeting sought out to answer these questions.

“We undertook this study to determine the most effective therapies for older patients with CLL, which makes up the majority of CLL patients,” said Jennifer A. Woyach, M.D., author on the study and associate professor at The Ohio State University Cancer Center. “They have been traditionally under-represented in clinical trials, unless they are designed specifically for that age group.”

In a multicenter phase 3 trial, the researchers compared three different modalities of treatment:

• Arm 1: bendamustine plus Rituxan (BR);
• Arm 2: Imbruvica plus BR;
• Arm 3: Imbruvica plus Rituxan

The study’s goal was to see if combinations that included Ibrutinib had better progression-free outcomes than chemoimmunotherapy or targeted therapy regimens. They also wanted to determine if Imbruvica plus Rituximab was superior to Imbruvica alone.

Patients in the trial were previous untreated, aged 65 years or older and had symptomatic CLL. If patients progressed on BR, they were able to move on to the second arm (Imbruvica plus BR).

Average progression-free survival (PFS) in the BR arm was 41 months, and has not yet been reached for the Imbruvica plus BR and Imbruvica plus Rituxan arms. The two-year PFS estimates were 74 percent, 87 percent and 88 percent in arms 1, 2 and 3 respectively.

“In conclusion, ibrutinib and ibrutinib plus rituximab results in superior PFS compared with BR in the frontline setting of CLL,” Woyach said.

While the Imbruvica arms had clear PFS benefits, the overall survival (OS) benefits were not statistically significant between arms 1, 2 and 3 — 95 percent, 90 percent and 94 percent, respectively.

Moving forward, the researchers emphasized that their findings should set the stage for an Imbruvica-based regimen as the new standard of care for older patients with CLL.

However, despite promising survival findings, 428 of the 537 patients on the study experienced severe (grade 3 or higher) side effects. When it came to grade 3-plus hematologic events, 61 percent experienced them in arm 1; 41 percent in arm 2; and 38 percent in arm 3. Non-hematologic grade 3 or higher events were seen in 60, 72 and 71 percent of arms 1, 2 and 3 respectively. There were five adverse event-related deaths in arm 1, and 14 deaths each in arms 2 and 3.

Between the costs of the drugs and the potentially severe side effects that can accompany them, the researchers are hoping that future research efforts focus on reducing the need for long-term and continuous treatment for patients with CLL.

“Importantly, BTK inhibition is not without toxicity in this age group, including significant toxicities, so close monitoring will remain important, as will strategies to limit toxicity to either the use of more selective BTK inhibitors or potentially limiting the duration of therapy,” Woyach said. “That is of great interest.”