NEW YORK—With both the pro and con positions drawing on data from the phase 3 CLL11 trial, two speakers at the Lymphoma & Myeloma2014 congress faced off on whether it’s necessary to use chlorambucil with obinutuzumab in untreated chronic lymphocytic leukemia (CLL).
Myron S. Czuczman, MD, of Roswell Park Cancer Institute in Buffalo, New York, argued in favor of using chlorambucil. And Richard R. Furman, MD, of Weill Cornell Medical College in New York, argued against it.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
It was approved by the US Food and Drug Administration based on initial results from the phase 3 CLL11 study, in which 781 patients were randomized to receive chlorambucil alone or chlorambucil with either obinutuzumab or rituximab.
Pro
Dr Czuczman pointed out that while the obinutuzumab-chlorambucil combination had more toxicity than the rituximab-chlorambucil combination, the overall response rate and complete response rate with obinutuzumab were significantly higher than with rituximab (P<0.0001).
Progression-free survival (PFS), which was the primary endpoint, was significantly higher with either obinutuzumab at 26.7 months, or rituximab, at 16.3 months, than with chlorambucil alone, at 11.1 months.
And in the head-to-head portion of CLL11, PFS with obinutuzumab-chlorambucil was significantly better at 26.7 months than with rituximab-chlorambucil, at 15.2 months (P<0.001).
Dr Czuczman also reviewed data on obinutuzumab combined with drugs other than chlorambucil.
The GALTON trial, a small, phase 1b trial in untreated CLL, compared obinutuzumab plus fludarabine and cyclophosphamide to obinutuzumab plus bendamustine.
Dr Czuczman showed that while there is more toxicity when obinutuzumab is combined with cyclophosphamide or bendamustine than with chlorambucil, “there is not much more activity.”
He said it’s not clear whether obinutuzumab with cyclophosphamide is better than rituximab with cyclophosphamide or if obinutuzumab with bendamustine is better than rituximab with bendamustine in upfront CLL.
“For now,” he said, “chloramubucil should be the only chemo agent combined with obinutuzumab to treat upfront CLL—outside of clinical trial participation.”
Con
Dr Furman also reviewed the CLL11 trial, noting that rituximab did not add very much to chlorambucil, but obinutuzumab did, in terms of overall survival and PFS. He cautioned, however, that additive or synergistic effects cannot be ruled out in the combination studies.
He then reviewed the GAGE trial, which compared 2 doses of single-agent obinutuzumab in untreated CLL. The 2000 mg dose produced a greater overall response rate than the 1000 mg dose, but the difference between the 2 arms was not significant (P=0.08).
PFS was 21 months in the 1000 mg arm and 20 months in the 2000 mg arm (P=0.07). PFS for obinutuzumab plus chlorambucil in the CLL11 trial was 26.7 months.
However, second cancers may be more of an issue with chlorambucil. In CALGB 9011, investigators reported 27 epithelial cancers, 9 with fludarabine, 11 with chlorambucil, and 7 with fludarabine plus chlorambucil.
Dr Furman concluded that while chlorambucil may aid obinutuzumab by reducing bulk, it may be unnecessary if higher doses of the antibody are used. Single-agent obinutuzumab produces a similar PFS as the combination with chlorambucil, and there are greater toxicities with chlorambucil.
