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Combination of Idelalisib and Rituximab Improves Survival in Patients with Relapsed Chronic Lymphocytic Leukemia


In an international randomized double-blind phase III clinical trial, patients with relapsed chronic lymphocytic leukemia (CLL) who received the investigational drug idelalisib in combination with rituximab (Rituxan®) lived substantially longer without their disease getting worse than patients who received a placebo plus rituximab.

Overall survival was also improved in patients who received idelalisib plus rituximab. Patients who received idelalisib and rituximab were also more likely to live 12 months after beginning treatment and to have their cancer regress compared with patients who received a placebo plus rituximab.


New England Journal of Medicine, January 22, 2014. (See the journal abstract.)


CLL is the most common type of leukemia in adults and is most often diagnosed in older adults. In people with CLL, the body produces abnormal white blood cells (lymphocytes) that are present at higher-than-normal levels. As the disease gets worse (progresses), these cells grow out of control, crowding out healthy cells in the blood, bone marrow, lymph nodes, and spleen.

CLL usually progresses slowly. Patients diagnosed with early-stage disease have few, if any, symptoms and are monitored regularly for disease progression that requires treatment. People with CLL that has progressed to the point of causing symptoms are commonly treated with chemotherapy plus drugs called monoclonal antibodies that target CD20, a protein that is found only on B lymphocytes.

Most patients who are treated with chemotherapy for CLL experience a return of their cancer after treatment is discontinued. Treatment options are limited for patients with relapsed or refractory CLL—particularly elderly patients and those with health conditions other than cancer. That is because many are unable to safely receive chemotherapy because of serious side effects, including bone marrow damage, infections, and damage to other organs induced by the original treatments. The CD20-targeting drug rituximab is often used to treat such patients when their cancer returns. However, its benefits typically do not last.

Idelalisib blocks a form of a protein called PI3K that plays a critical role in the signaling pathway that drives the proliferation and survival of CLL B cells. Early-phase clinical trials have suggested that idelalisib may be effective against relapsed CLL when used either alone or in combination with other drugs, including rituximab.

The Study

In the trial, 220 patients with relapsed CLL who were not healthy enough to receive cytotoxic therapy because of co-existing health conditions, poor kidney function, or bone marrow damage from previous chemotherapy treatment were randomly assigned to receive either idelalisib plus rituximab or a placebo plus rituximab. The primary endpoint of this double-blinded trial was progression-free survival, and the secondary endpoints included overall survival and overall response rate.

Most of the patients (78 percent) were aged 65 years old or older, approximately two-thirds had advanced-stage CLL, and 85 percent had at least one other health condition in addition to CLL.

Richard R. Furman, MD, of Weill Cornell Medical College in New York led the trial. Gilead Sciences, which manufactures idelalisib, funded the trial.


At 24 weeks of follow up, 93 percent of patients in the idelalisib-plus-rituximab group were alive with no progression of their cancer, compared with 46 percent of patients in the placebo-plus-rituximab group. Twelve patients in the idelalisib group had their cancer progress compared with 53 patients in the placebo group.  

Median progression-free survival was 5.5 months in the placebo group. The investigators were not able to determine the median progression-free survival for the idelalisib group because too few of those patients had experienced a worsening of their disease at the time of the study analysis. 

The independent Data and Safety Monitoring Board overseeing the trial stopped the trial early based on the substantial improvement in progression-free survival among patients who received idelalisib. All of the patients in the trial’s rituximab-plus-placebo group then began receiving idelalisib.

Progression-free survival was similar across different patient subgroups, including those grouped by CLL characteristics associated with prognosis, age, and sex.

At 12 months of follow-up, 92 percent of patients in the idelalisib group were still alive, compared with 80 percent of patients in the placebo group. Median overall survival had not yet been reached in either group.

Most patients (81 percent) who received idelalisib plus rituximab had a partial response—that is, their cancer regressed—compared with 13 percent of patients who received a placebo plus rituximab. Both of these differences were statistically significant.

The frequency and severity of adverse events—which included fever, fatigue, nausea, and diarrhea—were similar among the treatment groups. Forty-four patients (40 percent) who received idelalisib and 37 patients (35 percent) who received a placebo reported at least one serious adverse event.

"Since the study was stopped early for efficacy," the study authors wrote, "severe diarrhea, which is typically a late-onset event, may yet occur in some patients."


According to Richard Little, MD, of NCI’s Cancer Therapy Evaluation Program, one potential missing element from the results reported thus far is whether there is a difference in progression-free survival between patients truly refractory to rituximab and those who still respond to it.  He noted that given the primary question being asked in the trial—whether idelalisib improves progression-free and overall survival—such information would be helpful in applying the results and would provide important information for planning therapy. If certain patient characteristics are associated with cancer progression after starting this therapy, that information could inform treatment decisions as well as future studies, explained Dr. Little.

Idelalisib is not yet approved by the U.S. Food and Drug Administration (FDA) for the treatment of CLL. In 2013, however, the FDA designated idelalisib a Breakthrough Therapy for CLL. The FDA assigns this designation to a drug when early clinical evidence suggests that it may demonstrate substantial improvement over existing therapies. The Breakthrough Therapy designation also means the FDA will expedite its review of the drug.


Patients with relapsed CLL who have coexisting health conditions are often unable to undergo standard chemotherapy and are frequently excluded from clinical trials. Thus, the patients in this trial are representative of the CLL population typically seen in clinical practice, Dr. Furman explained. And rituximab, he continued, "is the most commonly used agent in the community, based upon available usage data."

Considering the large difference in progression-free survival in the trial, "it is encouraging to also see an effect on overall survival," Dr. Little noted. "It will be interesting to see what happens to overall survival with longer follow-up."

The addition of idelalisib to rituximab did not increase the rate of adverse events compared with placebo and rituximab. "Overall, the toxicities were very manageable," Dr. Furman wrote in an e-mail. Rash and diarrhea are the only toxicities "likely to be truly related to idelalisib," he added.

Although chemotherapy can be beneficial over the short term, it can also cause serious adverse events—including bone marrow failure and myelodysplastic syndrome—that "limit patients’ long-term survival," Dr. Furman explained. So having options like idelalisib, if it is approved by the FDA, is important. "My belief is that avoiding chemotherapy is the most important thing for patients," he said.

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