Ibrutinib Improves Survival Compared with Ofatumumab in Patients with Previously Treated Chronic Lymphocytic Leukemia
In an international randomized phase III clinical trial, patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who were treated with ibrutinib (Imbruvica®) lived longer without their disease getting worse (progression-free survival) than patients who received ofatumumab (Arzerra®). Patients who received ibrutinib also lived longer (overall survival) and were more likely to show a clinical response to treatment than those who received ofatumumab.
New England Journal of Medicine, May 31, 2014. (See the journal article.)
CLL is the most common type of leukemia in adults and is most often diagnosed in older individuals. In people with CLL, the body produces abnormal white blood cells (lymphocytes)—specifically, B cells—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, liver, spleen, and lymph nodes. When most of the cancer cells are located in the blood and bone marrow, the disease is called CLL (also called chronic lymphoid leukemia), whereas when the disease is in the lymph nodes and bone marrow it is called SLL (also called small lymphocytic leukemia).
CLL usually progresses slowly. Patients diagnosed with early-stage disease have few, if any, symptoms and are monitored regularly for disease progression requiring treatment. However, in almost all patients who receive treatment, CLL eventually returns. Treatment options are limited for patients with relapsed or refractory CLL or SLL.
Both ibrutinib and ofatumumab have been approved by the Food and Drug Administration (FDA) to treat patients with relapsed or refractory CLL. The two drugs work in different ways. Ofatumumab is a monoclonal antibody that binds to the CD20 antigen on the CLL/SLL cells. This binding directly induces cancer cell death; it also triggers the immune system to destroy the cells. Ibrutinib inhibits the action of a protein called Bruton tyrosine kinase. This protein is involved in a key signaling pathway controlled by the B-cell receptor that is important for the growth and survival of B cells.
The randomized open-label RESONATE trial enrolled 391 patients with CLL (including 18 patients with SLL) that had returned after, or did not respond to, prior treatment. Trial participants had received at least one prior treatment and were not candidates for treatment with chemotherapy drugs called purine analogues. The trial included patients from the United States, Europe, and Australia.
Participants were randomly assigned to receive ibrutinib, which was taken orally once daily, or ofatumumab, which was given by intravenous infusion once weekly for up to 24 weeks. Patients assigned to the ofatumumab group whose disease progressed during the trial could cross over and receive ibrutinib. The majority of patients had advanced-stage disease and approximately half of the patients had received three or more prior therapies.
The primary endpoint of the trial was progression-free survival, and the secondary endpoints included overall survival and response rate. John Byrd, M.D., of the Ohio State University Comprehensive Cancer Center, led the study, which was funded by Pharmacyclics and Janssen.
The median follow-up in the trial was 9.4 months. Fewer than half the patients who received ibrutinib experienced a worsening of the disease or died, whereas half of patients who received ofatumumab had disease progression or died after 8.1 months. Thus, patients who received ibrutinib had a 78 percent reduction in the risk of disease progression or death compared with those in the ofatumumab group.
At 12 months of follow-up, 90 percent of patients in the ibrutinib group were still alive, compared with 81 percent of patients in the ofatumumab group. The reduction in the risk of death was 57 percent for those who received ibrutinib.
The improvement in survival outcomes with ibrutinib was seen regardless of whether patients had certain clinical or molecular features associated with more aggressive disease, such as tumors that had not responded to purine analogue therapy or that had a specific deletion in chromosome 17.
The response rate, as assessed by independent reviewers, was much higher for patients in the ibrutinib group than the ofatumumab group: 43 percent versus 4 percent.
At the time of the last analysis, 57 patients in the ofatumumab group whose disease had progressed had crossed over and begun receiving treatment with ibrutinib.
The most common side effects in patients taking ibrutinib were diarrhea, fatigue, fever, and nausea. More patients in the ibrutinib group than in the ofatumumab group had at least one adverse event of grade 3 or higher (57 percent versus 47 percent). Adverse events (grade 3 or higher) that occurred more frequently in patients taking ibrutinib than in those taking ofatumumab included diarrhea (4 percent versus 2 percent) and irregular or rapid heart rate (3 percent versus 0 percent). Bleeding-related adverse events of any grade were also more common in the ibrutinib group than in the ofatumumab group (44 percent versus 12 percent). Ocular symptoms, including blurred vision and cataracts, were also more common in patients who received ibrutinib, the authors reported.
Measuring the response rate in the RESONATE trial was complicated by several factors, explained Wyndham Wilson, M.D., who conducts clinical trials in leukemia and lymphoma in NCI's Center for Cancer Research.
In the case of ibrutinib, he explained, the drug’s mechanism of action often causes lymphocytosis (an increased level of lymphocytes in the blood), which typically resolves within several months. Although lymphocytosis is normally evidence of disease progression, its presence in ibrutinib-treated patients does not necessarily mean that the disease has worsened. Indeed, 20 percent of the ibrutinib-treated patients had both lymphocytosis and indications of a response to the drug (such as a reduction in spleen or lymph node enlargement). The trial investigators noted that when these patients were taken into account, the response rate in the ibrutinib group was actually 63 percent.
Also complicating the analysis of response rate was the finding that the patients treated with ofatumumab had a substantially lower response rate than was seen in the clinical trial that led to FDA's approval of this therapy. The RESONATE investigators noted that this difference likely reflects their use of serial computed tomography (CT) scans to assess patient response, which the previous trial did not. In patients with CLL, CT scans are now commonly used to confirm suspected treatment responses by assessing whether there is a reduction in the size of patients' lymph nodes and spleen.
On average, patients in the ibrutinib group took the drug for more than 3 months longer than patients received ofatumumab, the study authors pointed out. A higher incidence of cataracts, observed in 3 percent of patients taking ibrutinib compared with 1 percent of patients receiving ofatumumab "bears noting, since longer exposure [to ibrutinib] may be associated with an increased risk," the authors noted. The higher rate of atrial fibrillation associated with ibrutinib, they continued, is also being explored.
The RESONATE trial "not only shows a very striking progression-free survival advantage with ibrutinib," Dr. Wilson said, "but a relatively meaningful overall survival advantage as well.
"In my view, ibrutinib, and other drugs that affect B-cell receptor signaling, are probably the most important agents to come along for B-cell lymphomas since rituximab," he continued. "Their development represents a real milestone in the treatment of B-cell lymphomas, and in this case, for CLL."