Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy should be performed. Documentation of conversion to a more aggressive histology requires an appropriate change to a therapy applicable to that histologic type. Rapid growth or discordant growth between various disease sites may indicate a histologic conversion. The risk of histologic transformation was 30% by 10 years in a retrospective review of 325 patients from diagnosis between 1972 and 1999. In this series, high-risk factors for subsequent histologic transformation were advanced stage, high-risk FLIPI, and expectant management. The median survival after transformation was 1 to 2 years, with 25% of patients alive at 5 years and with approximately 10% to 20% of patients alive 10 years after retreatment. Histologic conversions should be treated with the regimens described in the Aggressive, Recurrent Adult Non-Hodgkin's Lymphoma section of this summary. The durability of the second remission may be short, and clinical trials should be considered.[27,28,29]
Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia)
Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia).[30,31,32] Most patients have bone marrow, lymph node, and splenic involvement, and some patients may develop hyperviscosity syndrome. Other lymphomas may also be associated with serum paraproteins.
The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse small lymphocytic lymphoma/chronic lymphocytic leukemia.[31,32,33,34,35,36] If the viscosity relative to water is greater than four, the patient may have manifestations of hyperviscosity. Plasmapheresis is useful for temporary, acute symptoms (such as retinopathy, congestive heart failure, and CNS dysfunction) but should be combined with chemotherapy for prolonged control of the disease. Symptomatic patients with a serum viscosity of not more than four are usually started directly on chemotherapy. Therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease; chlorambucil, with or without prednisone, is the mainstay. Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling.
Asymptomatic patients can be monitored for evidence of disease progression without immediate need for chemotherapy.[18,36] Prognostic factors associated with symptoms requiring therapy include age 70 or older, beta-2-microglobulin of 3 mg/dL or more, and increased serum LDH. First-line regimens include rituximab, the nucleoside analogs, and alkylating agents, either as single agents or as part of combination chemotherapy.[37,38,39] Rituximab shows 60% to 80% response rates in previously untreated patients, but close monitoring of the serum IgM is required because of a sudden rise in this paraprotein at the start of therapy.[37,40];[Level of evidence: 3iiiDiv] The nucleoside analogues 2-chlorodeoxyadenosine and fludarabine have shown similar response rates for previously untreated patients with lymphoplasmacytic lymphoma.[42,43];[Level of evidence: 3iiiDiv] Single-agent alkylators, bortezomib, and combination chemotherapy with or without rituximab also show similar response rates.[45,46,47][Level of evidence: 3iiiDiv] Currently, no randomized trials guide clinicians about the initial choice of rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, or combinations of these options.[31,32,37] A combination of bortezomib, dexamethasone, and rituximab has been proposed for its high response rate, rapidity of action, and avoidance of an IgM rebound.