Overview of rational and individualized therapeutic strategies for non-Hodgkin's lymphomas

For nearly 20 years CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) has been the gold standard of therapy for aggressive non-Hodgkin's lymphomas (NHLs), curing = 30% of patients with diffuse large-cell NHL. A variety of strategies are being tested to identify regimens that might increase the disease-free survival rate for aggressive NHLs. One approach has been to intensify chemotherapy either by administering higher doses or by using shorter chemotherapy cycles. There are data suggesting that elderly patients benefit from CHOP given in 14-day cycles with granulocyte colony-stimulating factor. Based on in vitro observations that continuous exposure to cytotoxic agents can override multidrug-resistance pumps, several groups have studied combination chemotherapy regimens that include continuous 2- or 3-day intravenous infusions of cytotoxic agents. These studies have had short follow-up but encouraging early disease-free survival rates. There also has been interest in integrating monoclonal antibodies such as rituximab into therapies for aggressive NHLs. One randomized trial found CHOP/rituximab to be superior to CHOP alone in elderly patients with aggressive NHLs. With high-dose chemotherapy and stem cell support established as a salvage regimen for aggressive NHLs, many trials have evaluated the value of upfront high-dose therapy, especially in poor-prognosis patients. Other approaches to managing aggressive NHLs, which appear promising but are under investigation, are allogeneic transplants and lymphoma vaccines. An advance in the study of lymphoid malignancies is the development of a lymphoma classification system, the World Health Organization Classification of Lymphoid Malignancies, which recognizes the distinct molecular, morphologic, and genetic characteristics of differential lymphoma subtypes. It is anticipated that accurate and specific differential diagnosis, coupled with recognition of important clinical prognostic factors, will provide useful background for selecting and designing rational (and perhaps individualized) therapies for patients with aggressive NHLs.