Separate trials report strikingly positive results for idelalisib and ibrutinib in the treatment of patients with chronic lymphocytic leukemia, leading some researchers to suggest that patients could rely on targeted therapies and forego chemotherapy.

Two recently published trials promise to transform treatment of chronic lymphocytic leukemia (CLL), researchers say, potentially ending the need for chemotherapy in this disease.

In a study published in January in The New England Journal of Medicine, researchers found that idelalisib (Gilead), when added to the standard treatment rituximab (Rituxan; Genentech), is more effective than rituximab alone for patients with CLL who were not considered good candidates for chemotherapy (N Engl J Med 2014;370:997–1007).

Idelalisib targets the activity of the δ isoform of PI3 kinase (PI3K). CLL cells are dependent on this PI3K isoform, but it is not expressed in most other cells, so targeting it is an effective way to attack CLL without causing debilitating side effects, says lead researcher Richard Furman, MD, director of the CLL Research Center at Weill Cornell Medical College and a hematologist/oncologist at New York-Presbyterian/Weill Cornell Medical Center, both in New York, NY.

In the trial, the drug extended progression-free survival, and improved response rates and overall survival. Researchers stopped the trial early so that patients in the control arm could start idelalisib and share the benefits.

The results were particularly striking, Furman says, because the patients had comorbidities such as kidney dysfunction or bone marrow failure, and were no longer eligible for chemotherapy.

“I never assumed we'd find an overall survival advantage,” he says. “I was shocked when we saw that.”

Furman was also involved in a trial published in December in The Lancet Oncology that showed the effectiveness of the tyrosine kinase inhibitor ibrutinib in untreated patients over age 65 (Lancet Oncol 2014;15:48–58). Ibrutinib (Imbruvica), jointly marketed by Pharmacyclics of Sunnyvale, CA, and Janssen Biotech of Raritan, NJ, targets Bruton's tyrosine kinase, which is specific to B cells.

Ibrutinib was approved by the U.S. Food and Drug Administration (FDA) on February 12 for use in patients with CLL who have received at least one previous therapy; it was approved in November 2013 to treat mantle cell lymphoma. The FDA is expected to issue a decision on idelalisib for use in CLL this spring.

Furman, who's been involved in trials of 10 different kinase inhibitors, says the approval of these two “home run” drugs suggests that the majority of CLL patients may never need chemotherapy again.

“I would not give anyone chemotherapy, period,” he says.

Other researchers say that chemotherapy may still play a role in treatment, particularly in combination with a targeted therapy, in patients diagnosed in middle age or younger. Doctors don't yet know whether ibrutinib will keep CLL in check for decades, says Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston, MA. That's why they may want to combine it with chemotherapy.

“In younger, fit patients who can handle chemotherapy pretty well, it might be possible to combine novel agents with chemo immunotherapy and maybe that would move us toward cure,” says Brown, who is leading some combination trials for young patients now.

For his part, Furman says the publication of these two trials marks the culmination of his life's work.

“These drugs bring an end to clinical research in a lot of regards,” he says. “It's a very good reason to be out of work.”

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