Therapy‐related lymphomas in patients with autoimmune diseases after treatment with disease‐modifying anti‐rheumatic drugs

Ten patients developing lymphomas after disease modifying anti‐rheumatic drugs (DMARD) (methotrexate, n = 3, mean cumulative dose = 3.4 g; cyclophosphamide, n = 2, mean dose = 70 g; azathioprine, n = 6, mean dose = 243 g) were investigated. Methotrexate‐related lymphomas were Epstein‐Barr virus (EBV)‐positive, had infrequent aberrant methylation of p15 and p16, and responded well to methotrexate withdrawal or anti‐CD20 antibody (rituximab) alone without concomitant chemotherapy, implying that defective immunosurveillance was important in lymphomagenesis. However, 75% of cyclophosphamide/azathioprine‐related lymphomas were EBV‐negative, had frequent p15 and p16 methylation, and responded poorly to drug withdrawal and chemotherapy, implying that direct drug‐induced mutagenesis might be involved in lymphomagenesis. Am. J. Hematol. 81:5–11, 2006. © 2005 Wiley‐Liss, Inc.