These patients are usually treated with combination chemotherapy, with radiation therapy sometimes added for patients who have large masses of lymphoma. Drugs used for stages I and II intermediate grade NHL are also used for stages III and IV. For people with a high prognostic index, the standard chemotherapy regimens have not been satisfactory. For these people, high-dose chemotherapy with bone marrow or peripheral blood stem cell transplantation is being studied as an option for initial therapy. Among this high-risk group of patients with intermediate NHL, one study found use of high-dose chemotherapy and transplantation to increase the 5-year survival rate to 53%, a considerable improvement over the 32% rate obtained with standard dose chemotherapy. Larger studies including more patients must be done to confirm these results. Transplantation is also used for people who relapse after treatment. One major requirement is that their disease shows some response to chemotherapy even if they have relapsed.

For patients who relapse after transplantation, investigational chemotherapy drugs and/or other new treatment approaches being studied in clinical trials are treatment options.

Until recently, patients with high grade lymphomas were all thought to have a very poor prognosis. However, use of very intensive chemotherapy protocols (treatment plans) similar to those used for acute lymphoblastic leukemia has greatly improved the outlook for patients with Burkitt's lymphoma, Burkitt's-like lymphoma, and lymphoblastic lymphoma. Because these lymphomas tend to spread to the brain and spinal cord, prophylactic (preventive) treatment of the central nervous system is often done. In the past, radiation therapy of the brain and spinal cord was often used, but now, chemotherapy given into the spinal fluid is the most common approach for preventing spread of lymphoma to the nervous system.

These treatments are effective for most cases of Burkitt's Burkitt's-like and lymphoblastic lymphoma, but many patients ultimately relapse and 5-year survival rates are below 30% for lymphoblastic lymphoma and 30% to 50 % for the Burkitt and Burkitt-like lymphomas. This rate is higher in those with good prognostic indices and lower in those with poor indices. High-dose chemotherapy with bone marrow or peripheral blood stem cell transplantation is an option for these high-risk patients as well as for other patients with highly aggressive NHL recurring after treatment. Investigational biological therapies and new chemotherapy drugs are also options for these patients.

The outlook for patients with acute T-cell leukemia/lymphoma and mantle cell lymphoma is poor. Unlike other poor prognosis lymphomas, little progress has been made in finding effective treatment options. T-cell lymphoma is associated with HTLV-1 (human T-cell leukemia/lymphoma virus) infection. Because this virus is related to human immunodeficiency virus (HIV, the AIDS virus), some of the antiviral drugs used for HIV infection have been tried, and show promise in treating this cancer. Other options include investigational chemotherapy and biological therapies.