A randomized trial showed that patients with CLL and major comorbidities had significantly better outcomes when treated with obinutuzumab, an anti-CD20 monoclonal antibody, instead of rituximab.
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Valentin Goede, MD
A randomized trial showed that patients with chronic lymphocytic leukemia (CLL) and major comorbidities had significantly better outcomes when treated with obinutuzumab (Gazyva), an anti-CD20 monoclonal antibody, instead of rituximab (Rituxan).
The addition of obinutuzumab to chlorambucil led to a median progression-free survival (PFS) of 26.7 months as compared with 15.2 months for the rituximab/chlorambucil combination. PFS with the obinutuzumab/chlorambucil regimen was more than double that of patients who received chlorambucil alone.
Treatment with obinutuzumab led to a significantly higher objective response rate.
A preliminary overall survival analysis showed the median had yet to be reached with either regimen but suggested a trend favoring obinutuzumab, Valentin Goede, MD, reported at the 55th Annual Meeting of the American Society of Hematology.
“I think that we can conclude that [obinutuzumab] plus chlorambucil as first-line treatment of patients with CLL and comorbidities has an acceptable safety profile,” said Goede, an investigator in the Center for Integrated Oncology at the University of Cologne in Germany. “[Obinutuzumab] prolongs survival compared to chemotherapy alone and is superior to rituximab/chlorambucil with respect to PFS, complete response, and minimal residual disease.”
“I think this means a significant and perhaps practice-changing advance for this group of patients,” he added.
Chemoimmunotherapy is the clinical standard for CLL patients who are younger and in good general health. Development of chemoimmunotherapy for older, sicker patients has proceeded at a slower pace, and a paucity of phase III evidence exists.
Goede reported findings from a second-stage analysis of the phase III CLL11 trial, which evaluated three first-line regimens for CLL complicated by comorbidities (Cumulative Illness Rating Scale total score ≥6): chlorambucil alone or in combination with obinutuzumab or rituximab.
Data from the first phase of the trial showed that obinutuzumab/chlorambucil and rituximab/chlorambucil led to significantly better PFS (the primary endpoint) as compared with chlorambucil alone (ASCO 2013, Abstract 7004).
During the second phase of the trial, investigators accumulated and analyzed data from longer follow-up of the first stage and performed a head-to-head comparison of outcomes with the two combination regimens.
The CLL11 trial involved almost 800 patients, and Goede reported results from the comparison of 336 patients randomized to obinutuzumab/chlorambucil and 321 randomized to rituximab/chlorambucil.
Overall, more grade ≥3 adverse events occurred with obinutuzumab/chlorambucil than with rituximab/chlorambucil (70% vs 55%). In the obinutuzumab arm, infusion-related reactions (20% vs 4%) and thrombocytopenia (10% vs 3%) were more frequent. Neutropenia, anemia, and infection (including pneumonia) occurred in similar proportions of patients in the two groups.
The stage 2 analysis demonstrated an overall response rate of 78% with obinutuzumab and 65% with rituximab (P<.0001). The rates of complete response were 21% with obinutuzumab and 7% with rituximab. In each group, 58% of patients attained partial responses.
Minimal residual disease (MRD) has emerged as an indication of the completeness of response and has implications for relapse and survival. The results showed that 19.5% of patients in the obinutuzumab arm were MRD negative for bone marrow versus 2.6% of the rituximab group (P<.0001). Rates of MRD negativity in blood were 37.7% with obinutuzumab and 3.3% with rituximab.
The 11.5-month difference in PFS translated into a hazard ratio of 0.39, representing a 60% reduction in the hazard for progression in the obinutuzumab group (P<.0001). A separate comparison of chlorambucil alone versus in combination with obinutuzumab showed a median PFS of 26.7 months with the combination and 11.1 months with monotherapy. The difference represented an 82% reduction in the hazard for progression in favor of the obinutuzumab/chlorambucil combination (P<.0001).
Analysis of overall survival showed a significant benefit of obinutuzumab versus chlorambucil alone after a median follow-up of 23 months with the combination and 20 months in the chlorambucil monotherapy group (P= .0022).
Data remain immature for analysis of survival in the head-to-head comparison of the two combination regimens, said Goede. Even so, after a median follow-up of about 19 months, a hazard ratio of 0.66 has emerged in favor of obinutuzumab (P= .0849).
Goede V, Fischer K, Busch, et al. Head-to-head comparison of obinutuzumab (GA101) plus chlorambucil (Clb) versus rituximab plus Clb in patients with chronic lymphocytic leukemia (CLL) and co-existing medical conditions (comorbidities): final stage 2 results of the CLL11 trial. Presented at: 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 6.