Phase II Study Suggests Benefit of Adding Rituximab to Chlorambucil in First-Line Treatment for Chronic Lymphocytic Leukemia


Key Points

  • Toxicities were manageable, with hematologic adverse events accounting for most grade 3 or 4 events and febrile neutropenia or neutropenic sepsis for most serious adverse reactions.
  • Response was achieved in 84% of patients, with complete response in 10%.

In a UK phase II study reported in the Journal of Clinical Oncology, Hillmen et al assessed the safety and activity of adding rituximab (Rituxan) to chlorambucil (Leukeran) in first-line treatment of chronic lymphocytic leukemia (CLL). Such a regimen may be an alternative to fludarabine-based treatment or chlorambucil monotherapy in elderly patients and those with comorbidities.

Study Details

In the study, 100 patients in 12 UK centers received first-line rituximab (375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 thereafter) plus chlorambucil (10 mg/m2 on days 1–7) for six 28-day cycles. Patients responding but not achieving complete response could receive an additional six cycles of chlorambucil alone.

Patients had a median age of 70 years (range, 43–86 years) and a median of seven comorbidities, 66% were male, 56% had Binet stage C disease, 36% had IgVH  mutation, and 13q deletion, 12q trisomy, 11q deletion, and 17p deletion were present in 43%, 16%, 13%, and 3%, respectively.

Safety Profile

A total of 69 patients competed six cycles of combination treatment and 17 patients received an additional six cycles of chlorambucil. Median follow-up was 30 months. Grade 3 or 4 hematologic toxicities consisted of lymphopenia in 41% of patients, neutropenia in 41%, leukopenia in 23%, anemia in 19%, and thrombocytopenia in 18%.

The most common nonhematologic toxicities of any grade were nausea (52%), fatigue (31%), pyrexia (29%), vomiting (22%), diarrhea (20%), and cough (20%), with the most common grade 3 or 4 events being fatigue (4%), dizziness (4%), and headache (2%). The most common serious adverse events were febrile neutropenia (5%), neutropenic sepsis (4%), infusion-related reactions (3%), and back pain, cytokine release syndrome, joint swelling, pneumonia, pyrexia, and vomiting (2% each). Neutropenic episodes led to rituximab dose interruption in 26 patients, chlorambucil dose reduction or interruption in 29, and discontinuation of rituximab and chlorambucil in 11.

Of 15 deaths, 7 were due to progressive disease, 2 to secondary malignancies (squamous cell carcinoma and malignant mesothelioma), 2 to infection, 3 to central nervous system events (subdural hematoma, stroke, and cerebral infarction), and 1 to cardiac arrest.


The overall response rate was 84%, with complete response in 10% of patients. There was a trend for higher response rate in patients with 12q trisomy (94%). Median duration of response was 21.2 months. Median progression-free survival was 23.5 months. Median progression-free survival was lower in patients with vs without 11q deletions (359 vs 730 days) and greater in patients with vs without 12q trisomy (1,038 vs 660 days). Progression-free survival was longer in patients with vs without response to treatment (730 vs 255 days). Median overall survival was not reached.

The investigators concluded, “These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. [Rituximab]-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments.”

Peter Hillmen, MB, ChB, PhD, of St James’s University Hospital, Leeds, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by F. Hoffmann-La Roche. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.