Optimizing Current Treatments for CLL as New Agents Are Investigated

Jeffrey A. Jones, MD, MPH

With recent FDA approvals and ongoing clinical trials, the landscape for optimizing the treatment of chronic lymphocytic leukemia (CLL) is a dynamic one. Jeffrey Jones, MD, MPH, updated attendees at the 2016 NCCN Annual Conference on how these developments are impacting treatment choices in the clinic and highlighted some findings from early trials testing investigational agents which may be less toxic.

Jones, an assistant professor of Internal Medicine at The Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, highlighted four agents that have shown significant activity in patients with relapsed disease.

Ibrutinib (Imbruvica) was approved by the FDA for the treatment of relapsed CLL in 2014 based on findings from the phase III RESONATE trial. In this trial, ibrutinib reduced the risk of progression by 78% and 75% in the full population and in patients who harbored a 17p deletion, respectively, compared with ofatumumab (Arzerra).

The most important takeaway from this trial, according to Jones, was the toxicity data. Grade 1/2 diarrhea was observed in about 48% of patients, and grade 1/2 arthralgias were seen in 17% of patients. More seriously, Jones said, 10 cases of atrial fibrillation occurred in the ibrutinib arm of the trial compared with 1 case in the ofatumumab arm. Jones also noted that fatal bleeding events are possible and have occurred as a result of treatment with ibrutinib.

A second-generation Bruton’s tyrosine kinase (BTK) inhibitor, acalabrutinib, has also demonstrated activity in CLL, eliciting a 95% response rate and durable remissions with a favorable safety profile in a phase I/II study. Results were presented at the 2015 American Society of Hematology (ASH) Annual Meeting.¹ Acalabrutinib is more specific to BTK, according to Jones, which may make the drug more tolerable for patients.

“Some of the toxicities associated with ibrutinib, which many think are off-target kinase effects, could be mitigated,” Jones said.

Idelalisib (Zydelig), an inhibitor of PI3K delta, has also shown activity in the relapsed setting and is approved by the FDA. The agent reduced the risk of disease progression by 73% and extended progression-free survival (PFS) by more than 8 months compared with ofatumumab in the phase III Study 119 trial.²

Jones also took time to mention the toxicity profile of this agent. He said that diarrhea can present early on and be relatively easy to manage with antidiarrheal agents, or it can present severely later on and require stopping idelalisib to control it.

Finally, Jones discussed duvelisib, a PI3K inhibitor that is not approved. In a phase I study presented at the 2014 ASH meeting, the agent showed an objective response rate (ORR) of 57% with duvelisib.³

Like acalabrutinib and ibrutinib, duvelisib may be less toxic than its predecessor.

Alternative TKIs After Failure of First Choice

“[Duvelisib] has added properties of blocking the gamma isoform of PI3 kinase and in that case, it may have a different toxicity and efficacy profile [than idelalisib] that makes it worth watching.”

Jones also provided a brief overview of how patients should be treated if they fail on physician’s first choice. Though data are early, it has been seen that patients can switch from one of the approved small-molecule inhibitors to the other.

“We’re beginning to accrue some preliminary data suggesting that in the case of a kinase inhibitor failure, let’s say, that a patient treated with ibrutinib can be successfully salvaged with treatment with idelalisib, and vice versa,” Jones said.

Ibrutinib as First-Line Therapy

A third agent, the Bcl-2 inhibitor venetoclax (ABT-199/GDC-0199), also has shown activity in patients failing on ibrutinib and/or idelalisib. Preliminary results from a phase II study presented at the 2015 ASH meeting showed that 50% to 60% of patients responded and a favorable toxicity profile was observed, according to Jones.⁴In March 2016, ibrutinib gained FDA approval for the frontline treatment of CLL based on data from the RESONATE-2 trial, which were presented at the 2015 ASH meeting.^5,6 Today, there is an NCCN Category 1 recommendation for the use of ibrutinib in frail patients, patients aged 70 or older, and patients younger than 70 with significant comorbidities.

Though ibrutinib is appropriate for these groups of patients, Jones emphasized, chemotherapy remains the standard of care in the frontline for patients younger than 70. An important reason to treat patients younger than 70 upfront with chemotherapy, rather than ibrutinib, is toxicity.

“We don’t really know about the longer term. For [chemotherapy], we know what 10 years looks like,” Jones said. “For ibrutinib, we don’t know what 10 years looks like.”

Ongoing trials will further clarify the role of ibrutinib and chemotherapy in the frontline setting, Jones said.

Jones acknowledged that many challenges emerge any time there is a change to standard of care.

“Most community oncologists are relatively conservative by nature and in most situations, that’s exactly the way to be,” Jones said.

As new agents gain approval and make their way into NCCN guidelines, Jones said, community doctors will need to overcome the learning curve and adopt new agents into their practices.

References:

1. Byrd JC, Wierda W, Jones J, et al. The Bruton tyrosine kinase (Btk) inhibitor ACP-196: marked activity in relapsed/refractory CLL with a favorable safety profile. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 831.
2. Sharman JP, Coutre SE, Furman RR, et al. Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 330.
3. O'Brien S, Patel M, Kahl BS, et al. Duvelisib (IPI-145), a PI3K-δ,γ Inhibitor, Is Clinically Active in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. Presented at: the 56th Annual Meeting of the American Society of Hematology; December 6-9, 2014; San Francisco, California. Abstract 3334.
4. Jones J, Mato AR, Coutre S, et al. Preliminary results of a phase 2, open-label study of venetoclax (ABT-199 / GDC-0199) monotherapy in patients with chronic lymphocytic leukemia relapsed after or refractory to ibrutinib or idelalisib therapy. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 715.
5. Tedeschi A, Barr PM, Robak T, et al. Results from the international, randomized phase 3 study of ibrutinib versus chlorambucil in patients 65 years and older with treatment-naïve CLL/SLL (RESONATE-2). Presented at: the 57th Annual Meeting of the American Society of Hematology; Orlando, Florida; December 5-8, 2015. Abstract 495.
6. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia [published online December 6, 2015]. N Engl J Med. doi: 10.1056/NEJMoa1509388.

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