Rituximab® and High Dose Methylprednisolone (HDMP) as a First Line Treatment for Patients with Chronic Lymphocytic Leukemia.

High-dose methylprednisolone (HDMP) and the anti-CD20 mAb Rituximab® each can effect partial responses in patients with chronic lymphocytic leukemia (CLL). Previously, we noted that these two agents used in combination were highly effective in treating CLL patients with relapse/refractory disease. We examined whether patients with CLL could respond to these agents when used in combination as a first line therapy. To mitigate the toxicity associated with HDMP, the dose of methylprednisolone was reduced to 60% of that used in salvage regimens. Sixteen patients with CLL were treated with three four-week cycles of methylprednisolone at 1 gm/m2 daily for 3 days and weekly Rituximab® at 375 mg/m2 for four weeks. All patients satisfied NCI-working group criteria for requiring treatment. The median age of the patients was 60 years, the male to female ratio was 4:1, the ECOG performance status was ? 2. Eighty-six percent of the patients had high-risk disease prior to therapy, as per the modified Rai classification. Fifty-six percent of the patients had CLL cells that expressed ZAP-70 and/or unmutated immunoglobulin variable region genes. Response assessment was performed at the end of each cycle, two months after completion of treatment, and each 3–6 months thereafter until the patient experienced disease progression and/or required further treatment. Objective responses were observed in 14 out of 16 patients (Overall response rate 93%), with 1 patient achieving a complete response (CR) without disease detectable in the marrow, 1 patient achieving a nodular PR, 12 patients obtaining an excellent PR only with minimal residual disease in the bone marrow, and 1 patient having stable disease, as per the NCI-working group criteria. We observed significant reductions in the white blood cell (WBC) counts, increases in hemoglobin, elevations in platelet counts, and dramatic reduction and resolution in lymphadenopathy and splenomegaly. The median time to progression (TTP) after 12 months of follow up has not been reached. Overall, the treatment was well tolerated and all but one patient completed 3 cycles of therapy. Most adverse events were Grade I-II (fluid retention, cough, transient hyperglycemia, fatigue). We also observed 2 transient episodes of grade III–IV toxicity secondary to infection, resulting in pneumonia or sinusitis that resolved completely after antibiotic treatment. Pharmacodynamic studies showed that leukemia cells from patients responding to this combination regimen were induced to express pro-apoptotic molecules, such as Bid, Apaf-1, Smac-Diablo, and to downregulate expression of anti-apoptotic molecules, such as XIAP and Mcl-1. These data indicate that modified-dose HDMP/Rituximab® may be an effective and well-tolerated first line treatment for patients with CLL.