Therapeutic approaches

The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse small lymphocytic lymphoma/chronic lymphocytic leukemia.[46-48] If the serum viscosity relative to water is greater than four, the patient may have symptoms of hyperviscosity. Plasmapheresis is useful for temporary, acute symptoms such as retinopathy, congestive heart failure, and central nervous system (CNS) dysfunction. It can also be combined with chemotherapy for prolonged disease control. Symptomatic patients with a serum viscosity of four or lower are usually treated with chemoimmunotherapy or biologically directed therapies. Therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease; rituximab, bendamustine, and steroids are often used.[44] Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling. Sutimlimab, an immunoglobulin G4 monoclonal antibody that selectively inhibits the complement pathway at C15, can reduce hemolysis when therapies directed at the lymphoplasmacytic lymphoma are ineffective.[49]

First-line regimens include zanubrutinib (a Bruton tyrosine kinase [BTK] inhibitor), rituximab, and ibrutinib (another BTK inhibitor), rituximab alone, the nucleoside analogues, and alkylating agents, either as single agents or as part of combination chemotherapy.[50-53] In a randomized prospective trial, 150 symptomatic patients (including patients with previously untreated and relapsing disease) received either ibrutinib and rituximab or rituximab and a placebo. With a median follow-up of 50 months, the 4.5-year PFS rate was 68% in the ibrutinib-and-rituximab arm (95% CI, 55%–78%) and 25% in the rituximab-and-placebo arm (95% CI, 15%–37%) (hazard ratio [HR], 0.25; 95% CI, 0.15–0.42; P < .0001). The OS rate at 30 months was no different in the two arms (92%–94%).[52][Level of evidence B1] Zanubrutinib was compared with ibrutinib in a randomized prospective clinical trial of 164 patients with relapsed disease and 38 with previously untreated disease.[53] With a median follow-up of 44.4 months, the PFS rate was similar in both groups at 70% to 78% (HR, 0.63; 95% CI, 0.36–1.12), and the OS rate was similar in both groups at 85% to 87% (HR, 0.75; 95% CI, 0.36–1.59).[54] The zanubrutinib group had fewer cases of atrial fibrillation (11 vs. 1) and 50% fewer cases of hypertension (statistics not provided).[53][Level of evidence C3] BTK inhibition with ibrutinib allowed all 13 patients with cold-antibody–mediated autoimmune hemolytic anemia and acrocyanosis to attain clinical remission regardless of underlying pathology or MYD88 variant status.[55][Level of evidence C3]

Previously untreated patients who received rituximab had response rates of 60% to 80%, but close monitoring of the serum IgM is required because of a sudden rise in this paraprotein at the start of therapy.[56-58][Level of evidence C3] The rise of IgM after rituximab can be avoided with the concomitant use of an alkylating agent, such as cyclophosphamide, or the proteosome inhibitors bortezomib or ixazomib.[44,59-61] A combination of bortezomib, dexamethasone, and rituximab has been used without causing IgM rebound.[62-64] Previously untreated patients with lymphoplasmacytic lymphoma who received the nucleoside analogues cladribine and fludarabine showed similar response rates.[51,65,66][Level of evidence C3] Patients who received single-agent alkylators, bendamustine, bortezomib, venetoclax, and combination chemotherapy with or without rituximab also showed similar response rates.[51,59,61,67-71][Level of evidence C3] In the rare case of lymphoplasmacytic lymphoma involving the CNS (Bing-Neel syndrome), ibrutinib resulted in an 85% response rate in an anecdotal series of 28 patients.[72][Level of evidence C3]

Myeloablative therapy with autologous or allogeneic hematopoietic stem cell support is under clinical evaluation.[73-76] Candidates for this approach should avoid long-term use of alkylating agents or purine nucleoside analogues, which can deplete hematopoietic stem cells or predispose patients to myelodysplasia or acute leukemia.[56,77] After relapse from alkylating-agent therapy, 92 patients with lymphoplasmacytic lymphoma were randomly assigned to receive either fludarabine or cyclophosphamide, doxorubicin, and prednisone. Although relapse-free survival favored fludarabine (median duration of 19 months vs. 3 months; P < .01), no difference was observed in OS.[78][Level of evidence B1]