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Expert Discusses Optimal Care for Relapsed/Refractory CLL

Jason M. Broderick @jasoncology
Published: Monday, Aug 29, 2016

Jennifer Woyach, MD

Jennifer Woyach, MD

Following the emergence of several new treatment options for relapsed/refractory chronic lymphocytic leukemia (CLL) in recent years, researchers and clinicians are now focusing on the optimal use of these novel agents.

Jennifer Woyach, MD, offered her expert insight into the practical clinical use of these treatments at the PER meeting, Medical Crossfire: Redefining Treatment Paradigms in the Management of Chronic Lymphocytic Leukemia.

Woyach, an associate professor, division of hematology, department of internal medicine, The Ohio State University, discussed using the FDA-approved agents ibrutinib (Imbruvica), idelalisib (Zydelig), and venetoclax (Venclexta) in a hypothetical patient scenario, and highlighted emerging targets and treatments in relapsed/refractory CLL.

Second-Line Therapy

Woyach detailed a hypothetical patient with CLL whose first-line treatment was the chemotherapy regimen of fludarabine, cyclophosphamide, and rituximab (FCR). After 7 years, the patient now has progressive disease with progressive symptomatic adenopathy and splenomegaly. The individual is otherwise healthy and highly active. FISH testing shows trisomy 12 but no other abnormalities.

The available treatment options are to repeat chemoimmunotherapy, use an anti-CD20 antibody, or use kinase inhibitor therapy.

“Far and away, I believe that the kinase inhibitors are the best option at this point,” Woyach said. She then detailed the available data for the use of the tyrosine kinase inhibitors (TKIs) ibrutinib and idelalisib.

In the initial single-agent phase I study of idelalisib, 54 patients with relapsed/refractory CLL were treated with varying doses of the the PI3K inhibitor.1 The overall response rate (ORR) was 72%, comprised of all partial responses. It is “very unlikely to reach a complete response with idelalisib,” Woyach said.

The median progression free survival (PFS) was 31.9 months among the 28 patients who received idelalisib at ≥150 mg twice daily. In the group of 26 patients treated with idelalisib at <150 mg twice daily, the median PFS was 6.6 months. The median overall survival (OS) was not reached.

The phase III Study 116 trial led to the FDA approval of idelalisib in July 2014 for use in combination with rituximab (Rituxan) in patients with high-risk relapsed or refractory CLL.2 Study 116 randomized 220 previously treated patients with relapsed or refractory CLL in a 1:1 ratio to receive idelalisib plus rituximab (n = 110) or rituximab and placebo (n = 110).

The ORR for the idelalisib combination was 81% versus 13% in the control arm. The 1-year OS rate was 92% versus 80%, respectively. The median PFS was not yet reached in the idelalisib combination arm compared with 5.5 months in patients who received rituximab alone (HR, 0.15; P <.001).

Switching to ibrutinib, Woyach discussed the phase III RESONATE study, which both confirmed the accelerated FDA approval of the BTK inhibitor as a treatment for patients with CLL who have received at least 1 previous therapy, and expanded the approval to include the treatment of patients with a 17p deletion (del[17p]).3

The RESONATE trial randomized 391 patients to single-agent therapy with ibrutinib (n = 195) or ofatumumab (Arzerra; n = 196). Ibrutinib reduced the risk of progression or death by 78% versus ofatumumab (HR, 0.22; P <.0001). The median PFS was 8.08 months with ofatumumab and was not reached with ibrutinib. Ibrutinib also reduced the risk of death by 57% (HR, 0.43; log-rank P = .0049).

Based on the currently available evidence for the 2 agents, Woyach said the best choice for second-line therapy for the hypothetical patient would be ibrutinib. However, she noted that there are cases in which idelalisib may be preferred.

“There are patients who don’t tolerate ibrutinib or who have contraindications to the drug—people who have had bleeding in the past or who are on warfarin. For those patients, idelalisib plus rituximab is a good option.”

Woyach also stressed that the optimal choice is far from settled, and clinicians must consider options beyond TKIs.

“We have not cured CLL in the relapsed setting. There are still a number of open questions. So a clinical trial of either a completely novel agent or a kinase inhibitor therapy–based combination is really an alternative that should be explored with patients who are interested.”

She also stressed that clinicians should not forget about the potential for transplant.

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