Rituximab Appears Active in Waldenström’s Macroglobulinemia

WASHINGTON—Walden-ström’s macroglobulinemia is a rare low-grade B-cell lymphoproliferative disorder. Patients with Waldenström’s also often have small lymphocytic lymphoma (SLL). Hyperviscosity in Waldenström’s responds temporarily to plasmapheresis. Alkylator therapy, fludarabine (Fludara), and cladribine (Leustatin) are effective in many cases, but there are no good options for patients refractory to purine analogs.

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that produces a 50% response rate in previously treated low-grade lymphoma but has low efficacy in small lymphocytic lymphoma (SLL). At the ASH meeting, John C. Byrd, MD, reported that rituximab has clinical activity in patients with SLL who have Wald-enström’s macroglobulinemia.

The work was done by Dr. Byrd and his colleagues at Walter Reed Army Medical Center (Washington DC), IDEC Pharmaceuticals Corp. (San Diego), University of Iowa (Iowa City), and University of Texas (Galveston).

Waldenström’s is characterized by IgM paraproteinemia, lymphoplasmacytic histology, and bright expression of CD20 antigen. Clinical signs and symptoms include anemia and secondary fatigue, hyperviscosity symptoms, and hepatosplenomegaly.

“We treated one SLL patient who responded nicely to rituximab and who had Wald-enström’s macroglobulinemia. This prompted us to go back and look at similar patients in the database of the pivotal clinical trial (patients classified as having SLL who also had an IgM component),” Dr. Byrd said. The researchers found six such patients in the trial records, and the patient treated at Walter Reed was added to this cohort. The study patients had a median age of 60 years. All were symptomatic, and all had measurable disease independent of paraproteinemia.

All seven patients had been heavily pretreated before receiving rituximab, with a median of three prior regimens, including alkylator therapy in all patients (five refractory) and fludarabine in four (all refractory). Five of seven were refractory to their last therapy before rituximab.

Four Partial Responses

All patients had IgM paraproteinemia with a mean value of 2.9 g/dL. Pretreatment laboratory features included mean leukocyte count of 5,100/mm³, hemoglobin of 10.5 g/dL, and platelet count of 219,000/mm³. All patients had good renal and hepatic function. Patients were treated with rituximab at 375 mg/m² weekly for 4 or 8 weeks.

There were four (57%) partial responses by the strict non-Hodgkin’s lymphoma criteria used in the rituximab pivotal study (at least 50% reduction in all measurable disease). There were also three (43%) partial responses by Waldenström’s criteria (50% or greater decrease in IgM). The median progression-free survival for all patients was 8 months (range, 3 to 27+ months).

Cellular immune function, as measured by mean CD4 count, CD8 count, and lymphocyte count, was not significantly altered by rituximab therapy. This sustained immune function provided protection against opportunistic infections; there was one case of post-therapy grade 3 bacterial sinusitis.

“These preliminary data suggest that rituximab has clinical activity in pretreated Waldenström’s macro-globulinemia without decrements in hematologic or cellular immune parameters that are commonly noted with other therapies employed in this disease,” Dr. Byrd said. “Based on these data, future studies utilizing rituximab in both previously treated and untreated Waldenström’s mac-roglobulinemia appear warranted.”

Dr. Byrd and his colleagues at Walter Reed and at Johns Hopkins will be studying rituximab further as part of the chronic lymphoproliferative disorders program at those institutions.

This study will involve giving rituximab three times a week for 4 weeks to optimize the pharmacokinetic profile observed in earlier rituximab studies. Drs. Ian Flinn and Michael Grever will be collaborating on this study.