Retrospective Analysis of the Experience with Rituximab and Methylprednisone In Elderly Patients with CLL

Single agent rituximab has limited activity in chronic lymphocytic at standard doses; however, the addition of rituximab to purine analogues, monoclonal antibodies or steroids has been shown to improve responses and response duration in patients with untreated and relapsed chronic lymphocytic leukemia (CLL). The combination of rituximab and high dose methylprednisone has shown activity in patients with untreated and fludarabine-refractory CLL (Castro 2008, Castro 2009); however, there is limited reported experience with this regimen in elderly patients. These data prompted us to review our center's experience with rituximab in combination with high dose methylprednisone in elderly patients with CLL.

We retrospectively identified 24 patients 65 years or older with CLL who received rituximab and methylprednisone between July 2002 and April 2010 at MD Anderson Cancer Center. Six patients received this treatment as initial therapy and 18 patients as salvage treatment. Rituximab 375–750 mg/m² and methylprednisone 500–2000 mg were administered i.v. weekly for 4 weeks. Three patients received further maintenance treatment with rituximab 375–750 mg/m² and methylprednisone 500 mg/m² every month or every 3 months until failure of response. Responses were assessed according to 2008 NCI-WG criteria. Estimated progression free survival and OS were analyzed from time of treatment to progression or death using Kaplan-Meier survival curves.

The median age was 71 (65 – 87) years and 17 of 24 (71%) had Rai stage III or IV disease. Two patients had concomitant autoimmune hemolytic anemia (AIHA), one patient had immune thrombocytopenic purpura and AIHA was the indication for therapy in one patient. Median β₂-microglobulin was 7.7 (2.3 – 21) mg/l and 5 patients had chromosome 17 abnormalities. Previously treated patients had received a median of 3 (1 – 7) prior treatments and 6 (32%) pts were refractory to fludarabine. Responses were observed in 4 of 6 untreated patients (ORR 67%) and included 3 clinical complete responses unconfirmed by bone marrow biopsy (CRu, 50%) and 1 partial response. The estimated median PFS and OS in this group were 13 and 55 months, respectively. Among patients who received rituximab and methylprednisone as salvage therapy, 7 patients achieved a partial response (ORR 39%), 10 (50%) patients failed treatment, 1 patient (6%) received another therapy after 1 cycle for lack of response and 1 patient (6%) was lost to follow-up. In the salvage group, estimated median PFS and OS were 4 and 18 months, respectively. Four deaths occurred 3, 5, 11 and 12 months after rituximab and methylprednisone without further therapy; 3 patients had progressive CLL and the cause of death was unknown in 1 patient. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in 6 (33%), 3 (14%) and 1 (5%) of evaluable patients. Four patients (17%) experienced grade 3 or 4 infections (3 pneumonia and 1 colonic abscess), 5 patients experienced minor infections and 3 patients experienced viral reactivations (1 CMV, 1 HSV, 2 VZV). There were four grade 3 or 4 non-hematological adverse events including grade 4 gastrointestinal and pulmonary hemorrhage (1), colitis (1), steroid myopathy (1) and peripheral edema (1). All grade 3 or 4 complication occurred in salvage patients.

Based on our experience, rituximab and methylprednisone therapy can be safely administered to older patients with CLL. As previously reported by Castro et al, higher response rates were seen in untreated patients, whereas responses were less frequent and shorter lasting in patients with relapsed disease, although this group had high risk disease based on β₂-microglobulin levels. Additional studies are required to explore the benefit of this regimen in elderly patients with CLL.

Off Label Use: Ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia. O'Brien:Celgene: Consultancy; Genentech BioOncology: Consultancy. Wierda:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Advisory Board, Consultancy, Speakers Bureau. Estrov:Celgene: Consultancy. Keating:Celgene: Consultancy; Genentech: Consultancy. Ferrajoli:Celgene: Research Funding; Genentech: Research Funding.