Oral Therapies Shift Treatment Paradigm in CLL

The treatment of patients with chronic lymphocytic leukemia (CLL) has undergone a dramatic transformation in the past year, with the approval of the novel oral agents ibrutinib (Imbruvica) and idelalisib (Zydelig).

"There has been a flurry of new targeted therapies in the B cell receptor pathway and some other agents that are not in the B cell receptor pathway that are also novel and exciting. It has really transformed how we treat patients," Nicole Lamanna, MD, clinical professor of medicine, Columbia University Medical Center, said in an interview with OncLive. "The world of CLL is changing, there's a lot of paradigm shifting going on with treatments. We're very excited to have these more targeted and focused therapies."

The FDA initially approved ibrutinib for patients with mantle cell lymphoma (MCL) who received at least one prior therapy in November 2013. The drug was approved as a treatment for patients with previously treated CLL in February 2014, which was followed by a full approval for patients with CLL in July 2014.

The approval for ibrutinib was based on data from the phase III RESONATE trial. In this study, at 6 months, 88% of patients treated with ibrutinib were progression-free compared with 65% with ofatumumab. At 12 months, the overall survival (OS) rate was 90% for patients treated with ibrutinib compared with 81% in the ofatumumab group. By traditional response criteria, the overall response rate (ORR) with ibrutinib was 43% compared with 4% for ofatumumab.

"There was a huge response from the ibrutinib arm," Lamanna said. "Clearly ibrutinib was much, much better than ofatumumab."

Idelalisib was approved in combination with rituximab as a treatment for patients with high-risk CLL, follicular lymphoma, and small lymphocytic lymphoma in July 2014. In supporting data from a phase III study, the addition of idelalisib to rituximab improved OS by 72% and PFS by 82% versus placebo and rituximab. At 24 weeks, 90% of patients treated with idelalisib remained progression-free compared with 50% with placebo.

"With the advent of new therapies, our patients are living longer, but after time, patients may stop responding or may develop resistance to the drug, hence the need to get new agents approved,” Jacqueline C. Barrientos, MD, an assistant professor at Hofstra North Shore-LIJ School of Medicine in New York, explained in an interview. "As a physician treating mainly hard-to-treat refractory cases, we need these new agents to salvage our patients after each relapse. CLL is a chronic condition and there is no cure for our patients."

Clinical trials continue to explore new agents and combinations as treatments for patients with CLL, with the most promising being the PI3K-delta and gamma inhibitor duvelisib (IPI-145) and the BCL-2 inhibitor ABT-199. In a phase I study exploring duvelisib in patients with relapsed or refractory CLL, the ORR was 47%. Additionally, 98% of patients with refractory disease had nodal responses, which did not differ between patients with or without the 17p deletion or p53 mutation.

In September 2014, the manufacturer of duvelisib, Infinity, announced a series of collaborations to explore the drug as a treatment for patients with hematologic malignancies. The agreements will lead to a phase Ib/II study of duvelisib in combination with obinutuzumab or rituximab for treatment-naïve patients with indolent non-Hodgkin lymphoma. Additionally, the company announced a phase Ib study of duvelisib in combination with obinutuzumab for patients with CLL who have progressed on a BTK inhibitor.

The other promising new agent, ABT-199, demonstrated efficacy when administered to patients with relapsed/refractory CLL in combination with rituximab, in a phase Ib study presented at the 19th Congress of the European Hematology Association.

In 18 evaluable patients, 39% achieved complete remission (CR) or CR with incomplete blood count recovery and 39% achieved partial remissions (ORR = 78%). Altogether, 22% were deemed minimal residual disease (MRD)-negative. In evaluable patients with 17p deletions, 81% achieved a response to ABT-199. In patients with fludarabine-refractory CLL, 78% achieved a response.

“ABT-199 has demonstrated significant clinical activity in CLL patients, including hard-to-treat conditions like fludarabine-refractory disease and in 17p deletion patients," Barrientos said. "Even though we now have the drug ibrutinib available to treat 17p deletion patients, at the end of the day, these are the patients that continue to do worse as evidenced by the curves showing an earlier relapse compared with other groups."

The most common adverse events with ABT-199 were neutropenia (43%), nausea (38%), and diarrhea (30%). The most common grade 3/4 side effects were neutropenia (43%), thrombocytopenia (16%) and anemia (11%).

ABT-199 is part of a class of drugs known as BH3 mimetics. This class of agent binds to the BCL-2 family of proteins in a manner analogous to endogenous BH3-only proteins, and thereby inhibits their antiapoptotic functions.

"ABT-199 is a BH3 mimetic that’s more selective, and you don’t see the thrombocytopenia, and the activity is much better," Brad S. Kahl, MD, an associate professor of Medicine at the University of Wisconsin, said in a Peer Exchange discussion. "This agent could be in the same ball park as ibrutinib in terms of effectiveness."

Ibrutinib is an irreversible BTK inhibitor that works by blocking B-cell activation and signaling, preventing the growth of malignant B cells that overexpress BTK. In an attempt to capitalize on the efficacy seen with ABT-199 and ibrutinib, preclinical studies have begun to study the two agents in combination.

According to data presented at a special AACR conference focused on hematologic malignancies, synergistic apoptosis was observed with the combination of ABT-199 and ibrutinib in circulating tumor cells from patients with CLL and MCL.

Molecular analysis in the study suggested that interactions between p53 and BIM were responsible for the synergy between the two agents. Overall, the combination of ibrutinib and ABT-199 induced cellular apoptosis in 23% of samples compared with 3.8% for single-agent ibrutinib and 3.0% with ABT-199.

"This is a great new drug and what’s really exciting is to think about the combinations that could be coming down the road," Kahl said. "Ibrutinib plus ABT-199, perhaps that will be a dynamite combination that will just change the whole paradigm of CLL therapy."