Debating Obinutuzumab+Chlorambucil vs. Obinutuzumab Alone for Untreated CLL

FigureNEW YORK—Chlorambucil should be used with obinutuzumab in previously untreated patients with chronic lymphocytic leukemia (CLL). That was the consensus among those who listened to a debate on the benefits of combination therapy versus obinutuzumab monotherapy at the Lymphoma & Myeloma International Congress on Hematologic Malignancies here. Czuczman: Yes, Add Chlorambucil to Obinutuzumab One of the two debaters, Myron S. Czuczman, MD, Professor of Oncology, Chief of the Lymphoma/Myeloma Section, and Head of the Lymphoma Translational Research Lab at Roswell Park Cancer Institute, pointed to the landmark CLL 11 trial, published in the New England Journal of Medicine earlier this year (2014;370:1101-1110)—“the largest clinical trial combining obinutuzumab with chlorambucil in untreated CLL. “The FDA approved this combination for upfront CLL because of an overall survival advantage over chlorambucil alone in addition to better outcomes compared with rituximab-chlorambucil.” Obinutuzumab, he said, is the first type II, glycol-engineered, humanized anti-CD20 monoclonal antibody, and in preclinical studies, compared with rituximab, obinutuzumab provided increased induction of direct cell death and enhanced antibody-dependent cell-mediated cytotoxicity. The drug is now being evaluated in several B-cell malignancies. The authors of the CLL 11 trial, led by Valentin Goede, MD, concluded that the combination of an anti-CD20 antibody (obinutuzumab or rituximab) with chlorambucil improves outcomes for patients with previously untreated CLL and coexisting comorbidities. Obinutuzumab-chlorambucil provided an overall survival advantage over chlorambucil alone and induced deeper and longer remissions than rituximab-chlorambucil did. Czuczman commented: “We should use caution in extrapolating current data to previously treated CLL patients and/or other B-cell neoplasms. The use of more active chemotherapy agents, such as bendamustine or fludarabine-cyclophosphamide (FC), combined with rituximab versus obinutuzumab may not give similar results.” There is limited information available with respect to combining obinutuzumab with drugs other than chlorambucil in patients with untreated CLL, he continued. “Should we extrapolate and say we have other agents with different mechanisms of action and combine them with obinutuzumab? Should we use obinutuzumab in other B-cell neoplasms? They have different sensitivities and toxicities compared with CLL. We should use just obinutuzumab-chlorambucil in newly diagnosed CLL.” The GALTON trial, reported at the 2013 American Society of Hematology Annual Meeting (Abstract 523) examined the safety and efficacy of obinutuzumab with FC or bendamustine in the initial therapy of 41 patients with untreated CD 20+ CLL. The patients received standard regimens of FC or bendamustine along with obinutuzumab. After a median follow-up of one year, the overall response rate and complete response rate was higher in the bendamustine group of patients (90% and 20%, respectively) than in the FC arm (62% and 10%, respectively). Partial responses were also higher in the bendamustine arm (45%) than in the FC arm (38%). Czuczman noted that these responses are similar to those with the obinutuzumab-chlorambucil combination in the CLL 11 trial, which yielded a 72 percent overall response rate—21 percent complete response rate, and even higher partial response rate of 58 percent. Adverse Events “It is important to compare the adverse events, which appear to be higher with FC and bendamustine,” Czuczman said. Grade 3 or 4 adverse events occur in 70 percent of CLL patients who take low-dose chlorambucil plus obinutuzumab. The rates of grade 3 or 4 toxicities are about 85 percent with obinutuzumab plus FC or bendamustine, a 15 percent increase. Half of patients taking obinutuzumab plus bendamustine develop neutropenia, compared with one-third taking obinutuzumab-chlorambucil. Anemia occurs in 14 percent of those with the obinutuzumab-FC regimen, which is 10 percent more than with obintuzumab-chlorambucil.MYRON S. CZUCZMAN, MD. MYRON S. CZUCZMAN, MD: “We need more data and longer follow-up. For now, chlorambucil should be the only chemotherapy agent combined with obinutuzumab to treat upfront CLL outside of clinical trial participation.”“Febrile neutropenia is significantly increased by 10 to 20 percent with FC or bendamustine over standard regimens,” he said. “We can't simply say we can replace one antibody with another.” In addition, one-third of the obinutuzumab-FC patients discontinued therapy, primarily secondary to cytopenias. One patient showed elevated liver function tests, which is never seen with chlorambucil, he said. In the bendamustine group, 15 percent discontinued, again mostly due to cytopenias. In contrast, many chlorambucil patients are able to complete therapy, he said. “Treatment with FC or bendamustine is more toxic with no apparent improvement in activity. There is no data in respect to progression-free survival (PFS) or time to progression (TTP). Overall, median observation time is short. We can't determine durability yet.” In conclusion, Czuczman said, “the GALTON trial is a small Phase Ib study evaluating the safety and tolerability of combining obinutuzumab with FC or bendamustine in untreated CLL. My concern is that there is more toxicity in the GALTON trial compared with CLL 11. It is not clear that obinutuzumab-FC is better than rituximab-FC or that obinutuzumab-bendamustine is better than rituximab-bendamustine in upfront CLL. “We need more data and longer follow-up. For now, chlorambucil should be the only chemotherapy agent combined with obinutuzumab to treat upfront CLL outside of clinical trial participation.” Furman: No, Obinutuzumab Monotherapy May Be Enough The other speaker, Richard Furman, MD, Director of the CLL Research Center and Member of the Lymphoma and Myeloma Service of Weill Cornell Medical College, took the debate position that chlorambucil may not need to be added to obinutuzumab in the treatment of the “unfit” CLL patient. “The use of the two drugs together is an approach that is based on a clinical trial—CLL 11—that has a time frame that is not consistent with what is best for the patient,” he said. Furman also described the CLL 11 study, noting that it is the primary source of information: “The patient population was unfit, not the population that the FDA approved the drug for, which was any untreated CLL patient. One problem is the lack of single-agent data as a comparator in untreated CLL patients. We cannot rule out additive or synergistic effects. An increased antibody dose provides greater efficacy. Reduced tumor bulk provides greater efficacy.” Thinking towards the future, he said that long-term toxicity needs to be included in the treatment process. He noted that adding obinutuzumab to chlorambucil improved progression-free survival by 15.6 months. “Rituximab added little to obinutuzumab, with an improvement of 5.2 months. Obinutuzumab is a more effective antibody for CLL patients,” he said. “We know that an increased ratio of antibody to target predicts better response.” Time-to-next treatment (TNT) may be an even better endpoint than PFS, Furman added. TNT shows the ability of the antibody to clear from serum, which is an indicator of progression. “Giving obinutuzumab and chlorambucil at the same time does not allow sparing of the antibody,” he said. “We are still not sure there is an additive effect. It is obinutuzumab that is doing the heavy lifting—not chlorambucil.”RICHARD FURMAN, MD. RICHARD FURMAN, MD: “Does obinutuzumab need chlorambucil? Chlorambucil may aid obinutuzumab by reducing bulk, but it is unnecessary with higher doses of the antibody. Single-agent obinutuzumab approaches the PFS of combination therapies. There are greater toxicities with chlorambucil. We have not looked at the long-term toxicity of alkylator use.”The GAUGUIN trial, published in Blood in October (2014;124:2196-2202), found that obinutuzumab can be safely administered as monotherapy to patients with relapsed/refractory CLL, with mostly mild adverse events. The trial evaluated the safety and efficacy of obinutuzumab monotherapy in 33 patients with relapsed/refractory CLL. Infusion-related reactions occurred in nearly all patients, but few were grade 3 or 4. Grade 3 or 4 neutropenia occurred in seven patients in Phase I (but was not dose-related) and in four patients in Phase II. About two-thirds of patients showed partial responses in Phase I and 15 percent in Phase II. The best overall response rates were 62 and 30 percent, respectively. Phase II median PFS was 10.7 months, and the median duration of response was 8.9 months. The authors concluded that obinutuzumab monotherapy was active in patients with heavily pretreated relapsed/refractory CLL. Furman cited another study, the GAGE trial, presented at the most recent ASCO Annual Meeting (Abstract 7083), which showed single-agent efficacy of obinutuzumab at doses of 1,000 and 2,000 mg in 80 untreated CLL patients. The median progression-free survival time was 21 months for the obinutuzumab 1,000 mg group and 20 months for the obinutuzumab 2,000 mg group. Furman noted that this is similar to the 26.7 months PFS among the obinutuzumab-chlorambucil group in the CLL 11 trial. “There is little gain in PFS with the addition of chlorambucil,” he said. More Toxicity with the Combination He also pointed out that the CLL 11 trial also showed more adverse events with the obinutuzumab-chlorambucil combination than with chlorambucil alone in terms of neutropenia, thrombocytopenia, and leukopenia. “We see a few differences in adverse events with obinutuzumab, including worsening cytopenias,” he said. Secondary cancers have been noted with chlorambucil, which “is not a benign drug.” Czuczman, however, dismissed the increase in secondary malignancies with chlorambucil in the CLL 11 trial because “some patients were treated for years with alkylating agents first, and that may have had more of an effect.” Summing up, Furman asked: “Does obinutuzumab need chlorambucil? Chlorambucil may aid obinutuzumab by reducing bulk, but it is unnecessary with higher doses of the antibody. Single-agent obinutuzumab approaches the PFS of combination therapies. There are greater toxicities with chlorambucil. We have not looked at long-term toxicity of alkylator use.” Audience Reactions Before the debate, about two-thirds of the audience voted as agreeing that chlorambucil should be used with obinutuzumab in patients with untreated CLL. Afterwards, though, there was a slight increase in those who said there was no need to combine the two drugs, which appeared mostly to be movement from the undecided ranks pre-debate. In the question-and-answer period, someone asked whether there was enough evidence in elderly CLL patients to use obinutuzumab alone. Czuczman answered: “Deep remission appears when we give obinutuzumab with chlorambucil. There is single-agent activity, especially in CLL, which is heterogeneous. But chlorambucil may add to the combination. We can't kill all cells with one medication. There is some benefit even with lower-dose chlorambucil, and the toxicity is not that much worse.” Furman said that obinutuzumab is responsible for most cytopenias, but there is no difference in infections. “If we look at the long term, chlorambucil does generate problems because of its impact on marrow.” Another question was whether a type 2 antibody is better than rituximab in elderly CLL patients. Czuczman answered: “In smaller doses, I don't think so. Don't give rituximab in excess. My concern is to maintain the good effects on cell function.” Furman said, “The important clinical question is on which treatment regimen do patients do better—I think obinutuzumab is the better antibody than rituximab.” Czuczman countered that “high-dose rituximab elicits no dose response. You achieve an expensive partial response.” Czuczman had the final word: “If you give any antibody as a single agent, the patient will develop resistance. Combination-modality therapy leads to less pressure for a resistance phenotype.”