This article is more than 5 years old. Information may no longer be current.
Intensification of rituximab fails to benefit untreated patients with CLL
Additional doses of rituximab did not improve response rates among patients with chronic lymphocytic leukemia treated with the chemotherapy combination of fludarabine, cyclophosphamide and rituximab, according to results of a single-arm study.
Further, the intensification of rituximab (Rituxan; Genentech, Biogen Idec) increased the rate of secondary malignancies.
Susan M. O’Brien, MD, associate director for clinical science at Chao Family Comprehensive Cancer Center at University of California Irvine, and colleagues sought to evaluate whether intensification of rituximab in combination with fludarabine and cyclophosphamide would improve the rate of response among patients with untreated CLL.
Susan M. O'Brien
The analysis included 65 patients (median age, 59 years; 80% men) who received three intensified doses of rituximab in each chemotherapeutic cycle of fludarabine, cyclophosphamide and rituximab. Researchers then compared these results with data from a historical cohort of 300 patients with untreated CLL who received the standard chemoimmunotherapy combination without intensification of rituximab.
The primary objective of the study was to determine the complete response rate associated with the modified regimen. Secondary objectives included OS, time-to-progression, the overall response rate (ORR), minimal residual disease (MRD) negativity rate and toxicity.
The ORR was 97%, which included 75% of the patients who achieved a complete remission, 10% who achieved a nodular partial remission, and 6% who achieved a partial remission. These data did not statistically differ from the 72% complete-remission, 10% nodular partial-remission and 12% partial-remission rates observed in the historical control cohort.
Sixty-two percent of patients achieved MRD negativity, defined as less than 1% CD5- and CD19-coexpressing cells. The 71% MRD rate observed in the historical control cohort did not represent a statistically significant difference.
Median time to progression was 6.75 years (81 months) in the intensified cohort and 7 years (84 months) in the historical cohort.
After a median survivor follow-up of 9.7 years, 58% of patients from the intensified cohort were alive and median OS had not been reached. Median OS had also not been reached in the historical cohort, and 55% of patients were alive after 11.5 years of follow-up.
Forty-five percent of the patients in the intensified cohort experienced grade 3 to grade 4 neutropenia, 5% experienced thrombocytopenia and 1.9% of the patients experienced major infections.
Additionally, seven patients (11%) in the intensified cohort developed therapy-related myelodysplastic syndrome or therapy-related acute myelogenous leukemia compared with 2.7% of the historical cohort (P < .01).
“Despite prior reports of increased responses with dose-intensified rituximab, [this combination] did not result in significant improvements in response rates, MRD negativity, time-to-progression or OS in comparison with a historical cohort,” O’Brien and colleagues wrote. “It is possible that different mechanisms underlie the increased efficacy observed with dose-intensified single-agent rituximab and that observed when rituximab is combined with chemotherapy.
“The lack of improved response rates … suggests that when rituximab is used in combination with chemotherapy, there may be a ceiling beyond which higher cumulative doses of rituximab do not further potentiate the cytotoxic effects of the backbone chemotherapy regimen,” O’Brien and colleagues added. – by Anthony SanFilippo
Disclosure: The study was funded by Genentech. The researchers report consultant/advisory roles with and research funding from AbbVie, Ascerta, Celgene, Emergent, Genentech, Genzyme, Gilead, GlaxoSmithKline, Janssen, Juno Therapeutics, Karyopharm, KITE Pharma, Merck, Novartis, Pharmacyclics, Roche and Sanofi.