A New Era in CLL Treatment

Better understanding of disease biology propels development of novel targeted agents

Treatment for chronic lymphocytic leukemia (CLL) is undergoing a dramatic shift: Targeted drugs are replacing the often-debilitating chemotherapy regimens that have long been the standard of care in CLL but that keep the disease in check for only 5 to 7 years.

Two drugs leading the treatment revolution are ibrutinib (Imbruvica; Janssen Biotech and Pharmacyclics) and idelalisib (Zydelig; Gilead). The FDA approved ibrutinib in February and idelalisib plus rituximab (Rituxan; Genentech) in July, both for relapsed CLL.

The drugs are among a new class of oral kinase inhibitors that disable abnormally activated enzymes along the B-cell receptor (BCR) pathway. Ibrutinib inhibits Bruton's tyrosine kinase (BTK) and idelalisib inhibits the delta isoform of PI3K.

Richard R. Furman, MD, director of the CLL Research Center at Weill Cornell Medical College in New York, NY, has spent 15 years studying non-chemotherapy approaches to CLL. “We've tried many other agents and none have proven as effective as ibrutinib and idelalisib. It's been a remarkable turn of events,” he says. “These new agents have the potential to make CLL a truly chronic disease.”

The recent flurry of drug development stems from a decade's worth of research that has unraveled the biology of CLL, the most common form of leukemia in adults. “We now have a better understanding of the pathways that CLL cells are dependent on, and we have better drugs to target them,” says Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute in Boston, MA.

For example, she says, it became clear that BCR signaling plays a key role in the survival, proliferation, and trafficking of CLL cells. Other research pieced together the structural biology of BCL-2, a protein that allows malignant B cells to escape apoptosis. Such discoveries handed drug makers high-value targets to block.

It is an outcome John Byrd, MD, never expected. Back in the late 1990s when imatinib (Gleevec; Novartis) made a splash in chronic myeloid leukemia (CML), Byrd and other experts predicted a targeted therapy would never work across all types of CLL because, unlike CML, the disease lacks a common genetic target.

“What the new drugs have taught us is that if you have a real good target and a real good drug, you can impact an entire disease even if you don't have the same driving genetic aberration,” says Byrd, hematology division director at Ohio State University Comprehensive Cancer Center in Columbus.

Impressive trial results led Furman and other doctors to prescribe ibrutinib off-label months before its approval for previously treated CLL. (The FDA approved ibrutinib for mantle cell lymphoma in November 2013.) The study that prompted the CLL approval included 48 previously treated patients, of whom nearly 58% responded to the drug (N Engl J Med 2013;369:32–42). “We now have patients from that trial who have been on ibrutinib for 3 to 4-plus years,” says Byrd, the study's co–lead researcher.

Byrd also led the phase III RESONATE trial that showed ibrutinib significantly improved response rates and extended progression-free and overall survival compared to ofatumumab (Arzerra; GlaxoSmithKline; N Engl J Med 2014;371:213–23). The FDA approved ofatumumab, an intravenous anti-CD20 antibody, in April for first-line CLL treatment in combination with chlorambucil. (The FDA approved another first-line therapy—the intravenous anti-CD20 antibody obinutuzumab [Gazyva; Genentech] plus chlorambucil—last November.)

Furman and his co-investigators reported similar response rates and improved survival for idelalisib (N Engl J Med 2014;370:997–1007). When added to rituximab, idelalisib outperformed rituximab alone in patients not considered candidates for standard chemotherapy.

Ibrutinib and idelalisib are given indefinitely until disease progression, setting them up to be particularly lucrative. GlobalData analysts predict $2 billion in combined global sales for the two drugs in 2018.

“The upside of these very expensive drugs is they are very effective and well-tolerated when you compare them to chemotherapy,” says Bruce Cheson, MD, director of hematology research at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. Yet given the short follow-up periods, it is unclear how long these drugs work or what potential long-term side effects may develop after years of continuous use.

Ongoing trials are testing ibrutinib and idelalisib in the first-line setting, and Byrd anticipates a chemotherapy-free treatment approach to CLL within 5 years. Other researchers believe that because the novel agents result mostly in partial remissions, chemotherapy may still have a role in treating younger, fit patients who can withstand intensive therapy.

A growing number of experimental drugs are undergoing clinical testing in CLL. The BCL-2 inhibitor ABT-199 (AbbVie/Genentech) may be an option for CLL that does not respond to ibrutinib and idelalisib. IPI-145 (Infinity Pharmaceuticals) is a promising agent that inhibits both the delta and gamma isoforms of PI3K. Second-generation BTK inhibitors, such as ONO-4059 (Ono Pharmaceutical) and ACP-196 (Acerta Pharma), are also being tested. –Melissa Weber

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