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Obinutuzumab, rituximab improved chlorambucil efficacy in CLL
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CHICAGO — Response rates and survival outcomes with chlorambucil plus obinutuzumab or rituximab were superior to those with chlorambucil alone in a cohort of individuals with chronic lymphocytic leukemia, according to phase 3 study results presented at the ASCO Annual Meeting.
The researchers investigated chemoimmunotherapy as a treatment of less fit individuals with CLL. The regimens under analysis included
- chlorambucil (Leukeran, Aspen Global) alone (0.5 mg/kg orally on days 1 and 15 every 28 days for 6 cycles);
- obinutuzumab (GA101, Roche) plus chlorambucil (100 mg IV on day 1, 900 mg on day 2, and 1,000 mg on day 8 and day 15 of cycle 1; 1,000 mg on day 1 of cycles 2-6); and
- rituximab (Rituxan, Genentech/Idec Pharmaceuticals) plus chlorambucil (375 mg/m2 IV on day 1 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6).
The researchers assigned 118 patients to the chlorambucil alone group, 238 to the obinutuzumab group and 233 to the rituximab group.
Investigator-assessed PFS served as the primary endpoint. Stage 1a compared chlorambucil with the obinutuzumab regimen, and stage 1b compared chlorambucil with the rituximab-containing regimen.
Eligible participants were treatment naïve with a Cumulative Illness Rating Scale total score >6 and/or an estimated creatinine clearance <70 mL/min.
The overall response for chlorambucil in stage 1a was 30.2%, compared with 75.5% for the obinutuzumab-containing regimen. Chlorambucil alone yielded an overall response rate of 30% in stage 1b, compared with 65.9% for the rituximab regimen.
Complete response rates were 0% for chlorambucil alone in both comparisons. Complete response rates were 22.2% in the obinutuzumab arm and 8.3% in the rituximab arm.
Median PFS rates for chlorambucil alone were 10.9 months in stage 1a and 10.8 months in stage 1b, compared with 23 months for obinutuzumab and 15.7 months for the rituximab-containing regimen.
The grade 3-5 adverse event rates were 41% for chlorambucil alone in both stages, 67% for obinutuzumab and 46% for rituximab.
No infusion-related reactions were reported with chlorambucil alone, compared with 21 reactions with obinutuzumab and four with rituximab.
Both obinutuzumab and rituximab with chlorambucil are active in CLL, the researchers concluded.
For more information:
Goede V. #7004. Presented at: ASCO Annual Meeting; May 31-June 4, 2013; Chicago.
Disclosure: The researchers report research funding and honoraria from, consultant/advisory roles and employment/leadership positions with, and stock ownership in Mundipharma and Roche.
Perspective
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John C. Byrd, MD
What’s very exciting about this abstract is it shows that CD20 antibodies work in a prospective manner in elderly patients when added to chemotherapy. It also validates that second-generation antibodies warrant further study in exploration in other diseases, and with other agents — such as Bruton’s tyrosine kinase inhibitors and PI3 kinase inhibitors — that are also in development.
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Kanti R. Rai, MD
This extremely interesting trial — which was properly planned and executed — explored frontline therapy in patients with comorbidities, a group we should address more often because they form the largest majority of the CLL population. The results confirm chlorambucil, which we in the United States have virtually thrown out the window as ineffective, may not be so if it is used in combination with an anti-CD20 monoclonal antibody. This is an excellent result. How often have you seen complete remissions with chlorambucil alone? Never. But this combination of chlorambucil and GA101 produced a significant minority of complete remissions. Not only that, but many of those complete remissions had minimum residual disease negativity. These are very encouraging observations.
So chlorambucil still has hope, not as a single agent but in combination. The trial shows that combining chlorambucil with GA101 is extraordinarily more effective and probably more toxic than when combined with rituximab. The toxicity should not frighten us. It gives us a challenge to go further and find ways of using GA101 more safely. One of the themes of this annual meeting of ASCO has been underserved populations. It is the underserved population where chlorambucil still has some life and can make a difference for CLL patients when it is combined with a more effective monoclonal antibody.
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