Combination of Obinutuzumab Plus Chlorambucil Improves Survival in Patients with Chronic Lymphocytic Leukemia and Other Health Conditions
In an international randomized phase III trial, previously untreated patients with chronic lymphocytic leukemia (CLL) and other health conditions who received a combination of obinutuzumab (Gazyva™) and chlorambucil (Leukeran®) lived longer without their disease getting worse (progression-free survival) than patients who received chlorambucil alone. Patients who received obinutuzumab plus chlorambucil also had better overall survival than those who received chlorambucil alone, and they were more likely to have all signs of their disease disappear (complete response).
Patients who received obinutuzumab plus chlorambucil also had longer progression-free survival and higher complete response rates than patients who received rituximab (Rituxan®) plus chlorambucil. Overall survival did not differ between the two groups.
New England Journal of Medicine, January 8, 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 and bone marrow.
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. The most common treatments for CLL that has progressed to the point of causing symptoms include chemotherapy, with or without steroids, and drugs called monoclonal antibodies that target CD20, a protein that is found on B lymphocytes.
Obinutuzumab is a CD20-targeted monoclonal antibody that appears to work in a somewhat different way than rituximab. Although rituximab, another CD20-targeted antibody, has been found in clinical trials to improve survival in relatively young, healthy patients, the majority of patients with CLL are older and have clinically significant health conditions in addition to cancer. Such patients have been underrepresented in clinical trials, and rituximab has not been shown to improve their survival.
This study was conducted to determine whether combining a CD20-targeted drug with the chemotherapy chlorambucil would improve survival in older patients with CLL and other health conditions. The study also investigated whether the combination of obinutuzumab plus chlorambucil would be more effective than the combination of rituximab plus chlorambucil.
The trial enrolled 781 patients with CLL who had not received treatment for their cancer and who also had other health conditions, including cardiovascular, pulmonary, gastrointestinal, renal, endocrine, metabolic, and/or neurologic illnesses. The participants were randomly assigned to receive one of three treatments: chlorambucil alone, chlorambucil plus rituximab, or chlorambucil plus obinutuzumab.
Progression-free survival was the primary endpoint of this open-label study. The secondary endpoints included overall survival and disease response rate. The median age of patients enrolled in the trial was 73 years. Most (82 percent) of the patients in the trial had more than three health conditions in addition to CLL, and 27 percent of the patients had at least one health condition that was not well controlled.
The trial was led by Valentin Goede, MD, and his colleagues in the German CLL Study Group at the University Hospital Cologne in Germany. The trial was funded by F. Hoffmann–La Roche, which manufactures obinutuzumab.
In one analysis, the investigators compared progression-free and overall survival in patients who received one of the combinations and patients who received chlorambucil alone. (See the table below.) Patients who received chlorambucil alone had a lower median progression-free survival than patients who received either combination therapy—a difference that was statistically significant in both cases.
Patients who received obinutuzumab plus chlorambucil had a statistically significantly lower death rate than patients who received chlorambucil alone. The difference in death rates between the rituximab plus chlorambucil and chlorambucil-alone arms was not statistically significant.
|Study Group||Median Progression-Free Survival (months)||Death Rate (percent)|
|obinutuzumab plus chlorambucil||26.7||9|
|rituximab plus chlorambucil||16.3||15|
In a separate analysis that included additional patients, the researchers compared just the two combination therapies. (See the table below.) Patients who received obinutuzumab plus chlorambucil had longer median progression-free survival than patients who received rituximab plus chlorambucil. The differences in death rates in the obinutuzumab and rituximab groups were not statistically significant, and patients have not been followed long enough to determine the median overall survival in either group.
The investigators also compared the rates of complete response at 3 months after the end of treatment in the two combination groups. They found that patients who received obinutuzumab plus chlorambucil had a higher complete response rate than patients who received chlorambucil plus rituximab. Fewer patients in the obinutuzumab group had minimal residual disease—the appearance of leukemia cells in the blood or bone marrow following treatment—than patients in the rituximab group.
Two-Way Comparison of Combinations
|Study Group||Median Progression-Free Survival (months)||Death Rate (percent)||Complete Response Rate (percent)|
|obinutuzumab plus chlorambucil||26.7||8||20.7|
|rituximab plus chlorambucil||15.2||12||7.0|
Several serious side effects were more common among patients who received obinutuzumab. The most common were reactions during infusion of the drug and a substantial drop in certain types of white blood cells (neutropenia), although the latter problem did not result in more infections. Severe infusion-related reactions (grade 3 or 4) in patients who received obinutuzumab were limited to the initial infusion of obinutuzumab; none occurred during subsequent infusions.
According to Dr. Goede, these reactions included dizziness, fever, shivering or flushing, and drops in blood pressure.
Delivering the initial dose of obinutuzumab over 2 days or administering steroids prior to the initial dose of obinutuzumab had a "moderate effect on the frequency of infusion-related reactions," the study authors reported.
In November 2013, based on the results of this trial, the U.S. Food and Drug Administration approved obinutuzumab in combination with chlorambucil for the treatment of patients with previously untreated CLL.
The dose of obinutuzumab used in the trial was higher than the dose of rituximab, and the authors wrote that "it is unclear to what extent this higher dose contributed to the greater activity of obinutuzumab [plus] chlorambucil as compared with that of rituxumab [plus] chlorambucil." They noted, however, that results from previous clinical trials suggested that high-dose rituximab plus chemotherapy provided no additional benefit compared with standard-dose rituximab plus chemotherapy.
Although several CD20-targeted drugs have been shown to improve survival in patients with CLL, this trial was the first to test these two CD20-targeted drugs head to head in patients with CLL, the study authors explained.
"This study showed more complete responses and longer progression-free survival with obinutuzumab than with rituximab, when both were given in combination with chlorambucil," they continued. "With longer follow-up, the higher rate of eradication of minimal residual disease that was observed with obinutuzumab as compared with rituximab may lead to an overall survival benefit in addition to the improvement in progression-free survival."
But while adding obinutuzumab to chlorambucil improved efficacy, they cautioned, the combination also added toxicity to the treatment.
Infusion-related reactions, particularly those that cause patients to discontinue therapy, "are always a concern," said Richard Little, MD, of NCI’s Cancer Therapy Evaluation Program. In the trial, 7 percent of patients receiving obinutuzumab plus chlorambucil discontinued treatment because of an infusion reaction, compared with less than 1 percent of patients receiving rituximab plus chlorambucil.
"The question is whether these side effects can be prevented with adequate premedication, or by delaying the antibody therapy until later in treatment," Dr. Little continued. "However, this does not lessen the importance of the study findings."
The infusion-related reactions "resolved either spontaneously or after symptomatic treatment," Dr. Goede explained in an e-mail. Treatments included administration of fluids, steroids or antihistamines, and acetaminophen, he noted.