Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

In general, treatment with standard agents rarely produces a cure in patients whose disease has relapsed. Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, but relapse will usually ensue. Favorable survival after relapse has been associated with an age younger than 60 years, complete remission rather than partial remission, and duration of response longer than 1 year. Even the most favorable subset, however, has a 10-fold greater mortality compared with age-adjusted U.S. population rates.[1] Patients who experience a relapse with indolent lymphoma can often have their disease controlled with palliative radiation therapy, chemotherapy, or rituximab, an anti-CD20 monoclonal antibody.[2,3] Long-term freedom from second relapse, however, is uncommon and multiple relapses will usually occur. Significant activity for fludarabine and 2-chlorodeoxyadenosine has been demonstrated in relapsed low-grade lymphomas, both as single agents and in combination with other drugs.[4,5,6,7,8,9] Rituximab results in a 40% to 50% response rate in patients who relapse with indolent B-cell lymphomas.[10,11,12,13] Rituximab can also be combined with combination chemotherapy.[14] Durable responses to radiolabeled monoclonal antibodies, such as yttrium-90 ibritumomab (commercially available) and iodine-131 tositumomab, have also been reported; subsequent chemotherapy regimens can be delivered at the time of relapse following radioimmunotherapy.[15,16,17,18,19,20] In two randomized prospective studies involving previously treated patients with relapsed indolent lymphoma, patients were randomly assigned to rituximab maintenance after retreatment with combination chemotherapy (with or without rituximab during induction); both trials showed prolongation of response duration,[21,22] and one trial demonstrated improvment in median progression-free survival (52 vs. 15 months, P < .001) and overall survival (OS) (85% vs. 77%, P = .01) at 3 years with a median folllow-up of 39 months favoring maintenance rituximab.[22][Level of evidence: 1iiA]

In many institutions, bone marrow transplantation (BMT) is being used for patients whose disease has relapsed. Such an approach is still under evaluation but should be considered in the context of a clinical trial.[23,24,25,26,27,28] The German Low-Grade Lymphoma Study Group treated 307 patients with follicular lymphoma with two cycles of CHOP-like induction chemotherapy and then randomized to autologous stem cell transplantation versus interferon maintenance.[29] With a median follow-up of 4.2 years, the 5-year progression-free survival was 65% for transplantation versus 33% for interferon (P < .001), but with no difference in OS.[29][Level of evidence: 1iiDiii]