Six Targeted Agents for CLL Command Spotlight at ASH

Beth Fand Incollingo
Published Online: Monday, February 10, 2014
Dr. Jennifer R. Brown

Jennifer R. Brown, MD, PhD

A crop of targeted agents have demonstrated promising results in fighting chronic lymphocytic leukemia (CLL), suggesting that a range of emerging therapies and drug combinations may be more effective and better tolerated than standard chemotherapy, according to research presented during the 55th Annual Meeting of the American Society of Hematology (ASH).

Jennifer R. Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston, expressed optimism about the impact that new therapeutic strategies might have on patients with CLL.

“These exciting developments in CLL therapy represent a shift toward treatments that hone in on specific regulators of cancer, ultimately providing a safer and more effective treatment regimen,” Brown said during the conference, held December 7-10, 2013, in New Orleans. “These data give us even more reason to believe that the future outlook for CLL patients is bright.”

Among the agents generating excitement during the conference was obinutuzumab (Gazyva), a novel, type 2 anti-CD20 monoclonal antibody that the FDA approved in November 2013 for the treatment of previously untreated CLL in combination with chlorambucil.

Updated data were presented during the ASH meeting showing that the drug, as compared with chlorambucil alone, demonstrated an overall survival (OS) benefit never before seen in an older CLL population with comorbidities, and that the combination generated significantly better progression- free survival (PFS) in comparison with a pairing of rituximab (Rituxan) and chlorambucil, noted Brown.

Also attracting attention were data supporting the efficacy and safety of ibrutinib (Imbruvica), an inhibitor of Bruton tyrosine kinase (BTK), in CLL. In mid-November, the FDA approved ibrutinib for the treatment of patients with mantle cell lymphoma after prior therapy. The FDA is evaluating ibrutinib under its Breakthrough Therapy program, designed to speed up the delivery of new medicines to patients, in CLL and in Waldenström macroglobulinemia.

Brown also expressed excitement about idelalisib, a first-in-class PI3K-delta inhibitor that—in combination with rituximab— sparked a >70% improvement in OS in patients with high-risk relapsed/refractory CLL; IPI-145, an inhibitor of PI3K-delta and -gamma associated with “response rates that are quite high and deep;” and ABT-199, a potent Bcl-2 inhibitor that “clears bone marrow more effectively than kinase inhibitors,” retaining its activity even in patients who have the difficult-to-treat 17p deletion.

Fresh data about ofatumumab (Arzerra), an anti-CD20 monoclonal antibody that the FDA approved for certain CLL populations in 2009, indicate that the agent might have broader applications in the future.

While it seems likely that some of these agents will be useful in combination, that arena, in most cases, has yet to be explored, Brown noted.

“These drugs have mostly been combined with antibodies or chemoimmunotherapy, but we’re interested in combining BTK inhibitors and PI3K inhibitors, and also combining the Bcl-2 inhibitor with BTK or PI3K inhibitors, and then selecting the best antibody, maybe obinutuzumab,” Brown said in an interview with OncologyLive. “For now, chemoimmunotherapy is still the standard of care, especially in young, fit patients, but these drugs will rapidly penetrate the relapsed setting and move upfront fairly soon thereafter.”

Obinutuzumab Bests Rituximab

A study1 presented during the meeting compared obinutuzumab with rituximab, an anti-CD20 agent that is less potent in CLL than it has been in non-Hodgkin lymphoma and other B-cell malignancies, and may not be tolerated well by older patients when paired with chemotherapy, ASH said in a written statement.

In a second-stage analysis of the phase III CLL11 trial, investigators found that patients with CLL and major comorbidities had significantly better outcomes when treated upfront with obinutuzumab and chlorambucil as opposed to rituximab and chlorambucil, or chloramucil alone.

The addition of obinutuzumab to chlorambucil led to a median PFS of 26.7 months as compared with 15.2 months for the rituximab/chlorambucil combination (HR = 0.39; P <.0001). The obinutuzumab/ chlorambucil regimen netted a PFS more than double that of patients who received chlorambucil alone, and a significantly higher objective response rate. A preliminary OS analysis suggested a trend favoring obinutuzumab, Valentin Goede, MD, reported during the ASH meeting.

The overall response rate was 78% with obinutuzumab and 65% with rituximab (P <.0001), and complete response rates (CRR) were 21% and 7%, respectively. In each group, 58% of patients attained partial responses.

The study found better minimal residual disease (MRD) levels in the obinutuzumab arm.

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