RITUXIMAB INCREASES RISK OF SOLID TUMOR DEVELOPMENT

NEW YORK (Reuters Health) Jan 06 - The addition of rituximab to high-dose chemotherapy and autograft is effective in patients with high-risk lymphoma. But adding rituximab does have a downside: increased risk of secondary solid tumors. That's according to results from a study that appears in the Journal of Clinical Oncology online December 28.

Overall survival was 16.2 years, which the authors say was a surprise. The cumulative incidence of secondary myelodysplasia and acute leukemia (sMDS/AL) at 5 and 10 years was approximately 3.0% and 4.5%. The incidence of solid tumors was 2.5% to 6.8%.

Dr. Corrado Tarella and colleagues at the University of Torino, Italy, conducted a 20-year retrospective follow-up of 1,347 patients treated with high-dose sequential chemotherapy and autograft, with and without rituximab.

The researchers assessed long-term outcome, including the occurrence of sMDS/AL and solid tumors. Besides receiving chemotherapy and autograft, 39% of the patients got four to six doses of rituximab.

"Remarkably, factors associated with sMDS/AL were different from those found to be associated with solid tumor development," the authors note. Risk factors for sMDS/AL were male sex and the type of peripheral blood progenitor cells used for the graft.

Risks for development of solid tumors were advanced age, post-chemo radiotherapy, and the addition of rituximab to the chemotherapeutic regimen, the authors say.

Why the increased risk of solid tumors, but not sMDS/AL, with rituximab?

In an email to Reuters Health, Dr. Tarella responded, "The occurrence of sMDS/AL following high-dose therapy and autograft seems mainly due to direct DNA damage induced by cytotoxic drugs on hematopoietic cells."

He also said dysregulation of immune surveillance may be crucial in the development of solid tumors. "The later onset of solid tumors (median 5.5 years since autograft) compared to sMDS/AL (median 3.3 years since autograft) further supports this hypothesis."

Despite the increased risk of the development of solid tumors, adding rituximab was still associated with survival advantages. Overall survival for patients who received rituximab was 69% at 5 years and 61% at 10 and 15 years. That was compared with 62%, 55%, and 50%, respectively, in patients who did not receive rituximab.

Dr. Tarella had reported earlier on the superiority of rituximab-supplemented chemotherapy compared to standard chemotherapy alone. But the duration of the present study, along with the identification of rituximab as an independent risk factor for development of secondary solid tumors, adds significance to those findings, Dr. Tarella said.

He concluded by listing the primary clinical implications of the study:

-- The efficacy of the high-dose sequential chemotherapy program, particularly when delivered with rituximab, in patients with high-risk lymphoma.

-- The need to adequately inform patients undergoing high-dose therapy and autograft about the risks of secondary malignancy.

-- Careful selection of the cells to be employed for re-infusion in the autograft procedure.

-- Careful long-term surveillance in patients receiving high-dose therapy and autograft, particularly if supplemented with rituximab

-- Avoidance of prolonged use of rituximab outside controlled trials or outside clinical indications.

J Clin Oncol. Posted online December 28, 2010. Abstract