INTRODUCTION — The term "macroglobulinemia" refers to the production of excess immunoglobulin M (IgM) monoclonal protein that occurs in certain clonal lymphoproliferative disorders and plasma cell dyscrasias. Waldenström macroglobulinemia (WM) is a distinct clinicopathologic entity demonstrating lymphoplasmacytic lymphoma (LPL) in the bone marrow with an IgM monoclonal gammopathy (macroglobulinemia) in the blood. Patients may present with symptoms related to the infiltration of the lymph nodes and spleen or the effects of monoclonal IgM in the blood.
There is no standard therapy for the treatment of symptomatic WM. Whenever possible, patients should be encouraged to participate in clinical trials. This topic review presents suggestions for the treatment of patients who are not eligible for clinical trials or who choose not to participate in clinical trials.
The treatment and prognosis of WM will be reviewed here. The clinical manifestations and diagnosis of this disorder are discussed separately. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia" and "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma".)
PRETREATMENT EVALUATION — The initial evaluation of patients with WM must establish the diagnosis, the extent of disease, the presence of associated conditions, and the performance status of the patient. Particular attention should be paid in the history and physical examination to the following:
●Symptoms of hyperviscosity (eg, epistaxis, bleeding gums, visual changes, headache, dizziness). Funduscopic examination should be performed in all patients with symptoms of hyperviscosity and/or immunoglobulin M (IgM) ≥3000 mg/dL. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome'.)
●History of infections, fevers, weight loss, drenching night sweats, and fatigue.
●Clinical manifestations of cryoglobulinemia (eg, purpura, digital ischemia, arthralgia, fever, Raynaud phenomenon) or cold agglutinin disease (eg, livido reticularis, acrocyanosis, Raynaud phenomenon). (See "Overview of cryoglobulins and cryoglobulinemia" and "Cold agglutinin disease".)
●Peripheral neuropathy, which may be related to myelin-associated glycoprotein antibody-positive demyelinating peripheral neuropathy. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis".)
●Clinical manifestations of AL amyloidosis (eg, unexplained cardiac failure, intestinal dysmotility, purpura, macroglossia). (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)
●Clinical manifestations of extramedullary disease (eg, lymphadenopathy, hepatosplenomegaly, pleural effusions, central nervous system involvement).
It is our practice to perform the following pretreatment studies in patients with WM:
●Standard laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, lactate dehydrogenase, serum protein electrophoresis, quantitative immunoglobulins and immunofixation, beta-2 microglobulin, and serum free light chains.
Serum viscosity should be obtained if the hyperviscosity syndrome is suspected. Coombs test is obtained in those with suspected cold agglutinin disease. Hepatitis C serology should be obtained for patients with cryoglobulinemia. Hepatitis B serology should be obtained for patients whose planned treatment includes rituximab. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Extrahepatic manifestations of hepatitis C virus infection", section on 'Essential mixed cryoglobulinemia'.)
●Unilateral bone marrow aspiration and biopsy for pathologic review including immunophenotyping and MYD88 mutation analysis. Consider assessment of CXCR4 mutations in patients being considered for ibrutinib. (See 'BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib)' below.)
●Computed tomography (CT) of the chest, abdomen, and pelvis with intravenous contrast to measure lymphadenopathy and extramedullary involvement. Integrated whole body positron emission tomography with computed tomography (PET/CT) in cases suspected to have a more aggressive histology. Areas with intense fluorodeoxyglucose (FDG) avidity may require biopsy. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Imaging'.)
●Patients with peripheral neuropathy should be tested for the presence of anti-myelin-associated glycoprotein and anti-ganglioside M1 and anti-sulfatide IgM antibodies. They should also undergo electromyography (EMG) and evaluation for amyloid deposition. Other causes of neuropathy, such as diabetes, cobalamin (vitamin B12) deficiency, thyroid dysfunction, and Lyme disease, among others, should be appropriately ruled out. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Neuropathy'.)
●The evaluation of patients with symptoms suggestive of infiltration of the central nervous system (ie, Bing Neel syndrome) should include an assessment of the cerebral spinal fluid as well as magnetic resonance imaging (MRI) of the central nervous system [1].
●Patients with childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
INDICATIONS FOR TREATMENT
Asymptomatic patients — Approximately one-quarter of patients with WM have no constitutional symptoms or anemia, and no symptoms attributable to their immunoglobulin M (IgM) monoclonal protein or tumor infiltration at the time of presentation [2]. These patients are considered to have smoldering (asymptomatic, indolent) WM and should not be treated until symptoms develop [3]. The decision to postpone treatment in this population is largely based on their good prognosis without therapy and concerns over the short- and long-term complications of treatment.
While the severity of anemia and/or thrombocytopenia that merits treatment is unknown, we generally consider a hemoglobin ≥10 g/dL and platelet count ≥100,000/microL to be adequate [4]. We follow asymptomatic patients every four to six months with complete blood counts and monoclonal protein levels for the first five years and then annually, if stable. Those who develop symptomatic disease, anemia, or thrombocytopenia are offered therapy. If disease progression is unclear, repeat studies obtained three to six months later can help to clarify the disease tempo and whether treatment is indicated.
Studies that have used varying hemoglobin values (<10 g/dL to <12 g/dL) to implement treatment have all noted that smoldering WM may remain stable without treatment for long periods of time [3,5-9]. Overall survival approximates that of the normal population with a 10-year survival rate of 70 to 75 percent [4,10].
The risk of progression to symptomatic disease is greater in the first five years after diagnosis with an estimated annual rate of progression in case series ranging from 4 to 15 percent [3,5,7,11]. As an example, a study of 48 patients with smoldering WM followed for a median of 15 years reported a cumulative rate of evolution to symptomatic WM, amyloidosis, or lymphoma of 6 percent at one year, 39 percent at three years, 59 percent at five years, and 68 percent at 10 years [3]. On multivariate analysis, higher rates of disease evolution were seen in patients with higher serum levels of IgM, lower levels of hemoglobin, and a higher percentage of lymphoplasmacytic cells in the bone marrow.
In another retrospective cohort study, progression to symptomatic WM was identified in 317 of 439 patients (72 percent) with smoldering WM followed for a median of 7.8 years [11]. Symptoms at progression included anemia (67 percent), neuropathy (20 percent), hyperviscosity (15 percent), and organomegaly (10 percent). The following variables were identified as independent predictors for progression:
●IgM ≥4500 mg/dL
●Bone marrow lymphoplasmacytic infiltration ≥70 percent
●Beta-2 microglobulin ≥4 mg/dL
●Albumin ≤3.5 g/dL
A prognostic model that used these predictors as continuous variables effectively separated the cohort into three risk groups with different median time to progression: high risk (1.8 years), intermediate risk (4.8 years), and low risk (9.3 years). This model was validated in two independent cohorts. Analysis of a combined cohort also identified wild type MYD88 as an independent risk factor for progression. The high-risk group identified using this model may reasonably choose to participate in clinical trials of early intervention.
WM is incurable with current therapy and there is no evidence that the treatment of asymptomatic patients provides a survival benefit when compared with treatment at the time symptoms develop. Treatment is also associated with both short- and long-term complications that can decrease quality of life and potentially affect survival. As an example, rituximab administration can result in a clinically important temporary increase in serum IgM levels (IgM flare), prolonged immunosuppression, and the reactivation of a latent hepatitis B virus infection. As another example, a small percentage of patients treated with nucleoside analogs or alkylating agents develop a more aggressive lymphoma or leukemia [12].
Symptomatic patients — Treatment is indicated for patients with symptomatic WM (table 1 and algorithm 1). Symptoms can be divided into four major clinical groups [13]:
●Symptoms related to the underlying lymphoproliferative process (eg, constitutional symptoms, cytopenias, or tissue infiltration)
●Hyperviscosity related to the overproduction of IgM
●Symptoms due to associated conditions (eg, amyloid, cryoglobulinemia, hemolytic anemia, cold agglutinin)
●Paraneoplastic neuropathy
The presence of any of the following symptoms may be used as an indication for the initiation of therapy (table 1):
●This topic will discuss treatment directed against the proliferating malignant cells, which is indicated in patients with any of the following:
•Systemic symptoms – Fever, drenching night sweats, fatigue, weight loss, and/or severe neuropathy
•Physical findings – Symptomatic or bulky (≥5 cm) lymphadenopathy, symptomatic hepatomegaly, and/or symptomatic splenomegaly
•Laboratory abnormalities – Hemoglobin ≤10 g/dL or platelet count <100,000/microL
•Coexisting disease – Immunoglobulin light chain (AL) amyloidosis with organ dysfunction, symptomatic cryoglobulinemia, cold agglutinin anemia, immune hemolytic anemia and/or thrombocytopenia, or nephropathy due to WM
●The presence of hyperviscosity is suggested by symptoms and signs such as oronasal bleeding, blurred vision, headaches, dizziness, paresthesias, retinal vein engorgement and flame-shaped hemorrhages, papilledema, and, finally, stupor and coma. It is confirmed by the demonstration of increased serum viscosity, which is usually greater than four centipoise (CP). (See 'Emergency management of hyperviscosity' below and "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome' and "Laboratory methods for analyzing monoclonal proteins", section on 'Blood viscosity'.)
●Management of the paraneoplastic neuropathy is considered separately. The management of patients with WM-associated peripheral neuropathy requires coordination between clinicians with expertise in hematology and neurology [14]. Treatment of the underlying WM can ameliorate the peripheral neuropathy, but complete resolution is uncommon. Plasmapheresis alone, corticosteroids, and intravenous immune globulin (IVIG) have little or no value in this setting. Care should be taken to limit exposure to potentially neurotoxic agents and minimize the risk of IgM flare. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Neuropathy'.)
INITIAL TREATMENT — WM cannot be cured with current therapies. Instead, the goals of treatment are to control symptoms and prevent end-organ damage, while maximizing quality of life. There is no standard therapy for the treatment of WM. While various drugs and combinations have demonstrated clinical benefit in prospective trials, few have been compared directly in randomized trials. In addition, individual trials have used different response criteria thereby making it difficult to compare these agents or regimens based on response rates alone.
Our approach is generally consistent with the consensus treatment recommendations proposed by the International Workshops on WM (IWWM-10), Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART), British Society for Haematology, and National Comprehensive Cancer Network (NCCN) (algorithm 1) [15-18]. There are limited data comparing different treatment approaches and other experts advocate for the earlier incorporation of novel agents (eg, Bruton tyrosine kinase inhibitors) [19].
Approach to initial therapy — The initial management of patients with symptomatic WM is dependent on age, the severity of symptoms, presence of comorbidities, and patient preferences (algorithm 1).
Experts differ in their preferred initial therapy. For most patients, we prefer rituximab plus chemotherapy (eg, bendamustine plus rituximab [BR]) as it is an effective option that can be given over a short, defined course (four to six months) with an acceptable toxicity profile. Continuous therapy with a Bruton tyrosine kinase (BTK) inhibitor is an appropriate alternative for elderly patients and for others who are not eligible for or do not want systemic chemotherapy. While we prefer to reserve BTK inhibitors for the treatment of relapsed or refractory WM, other experts advocate for their more widespread use as initial therapy based on their good toxicity profiles and studies suggesting similar efficacy.
When choosing a therapy, the following principles apply:
●Therapy should be reserved for patients with symptomatic disease since asymptomatic patients may do well without therapy and treatment has potential short- and long-term complications. (See 'Asymptomatic patients' above.)
●Patients with symptoms of hyperviscosity require emergency plasmapheresis in addition to therapy directed at the malignant clone. (See 'Emergency management of hyperviscosity' below.)
●The intensity of the regimen is dictated by the severity of symptoms; more intense regimens (eg, bendamustine plus rituximab; or bortezomib, dexamethasone, and rituximab) that may have a quicker response time but increased side effects are offered to patients with highly symptomatic disease, while patients with minimal symptoms are offered regimens (eg, dexamethasone, rituximab, and cyclophosphamide) that are better tolerated, but slower. (See 'Selection of chemotherapy regimen' below.)
●The treatment regimens vary by delivery route and length of therapy. Rituximab-based and bortezomib-based regimens are administered parenterally over a defined period of time. BTK inhibitors are oral medications administered daily until progression.
●Rituximab is frequently associated with a transient increase in serum immunoglobulin M (IgM) level (IgM flare) after administration, which can result in symptoms of hyperviscosity. To reduce the risk of IgM flare, we usually withhold rituximab from the first cycle of therapy in patients with high IgM levels (>4000 mg/dL). Alternatively, plasmapheresis may be used before rituximab administration to prevent flare in such patients. (See 'Minimizing risk of IgM flare' below.)
●Experts differ in their use of maintenance rituximab. The goal of therapy is the alleviation of the signs or symptoms that prompted treatment initiation. Once there is improvement in these parameters, further therapy has not been shown to improve survival. As such, we do not offer routine maintenance therapy. (See 'Role of maintenance therapy' below.)
Emergency management of hyperviscosity — Symptomatic hyperviscosity is a medical emergency that requires prompt plasmapheresis. Red blood cell transfusions should be avoided, if possible, prior to plasmapheresis since they might further increase serum viscosity. Although the diagnosis is established by measuring serum viscosity, the clinician should make the decision to initiate plasmapheresis on the basis of the patient's symptoms and physical findings (eg, oronasal bleeding, blurred vision, headaches, dizziness, paresthesias, retinal vein engorgement and flame-shaped hemorrhages, papilledema, stupor and coma), rather than on the magnitude of the viscosity measurement. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome'.)
The only effective treatment for the hyperviscosity syndrome is the removal of IgM from the circulation via plasmapheresis. The large size of the IgM molecule restricts it mainly to the intravascular space such that it can be rapidly removed with plasmapheresis resulting in prompt alleviation of symptoms. Once plasmapheresis is complete, patients will need to initiate therapy to control the malignant clone. Details of the plasmapheresis procedure are discussed separately. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)
The following general principles regarding plasmapheresis for hyperviscosity syndrome are important:
●Patients presenting with severe neurologic impairment, such as stupor or coma in the absence of subdural or intracranial bleeding, should be treated with plasmapheresis on an emergency basis.
●Symptoms should subside with the lowering of serum viscosity. However, irreversible changes can occur, such as those due to venous thrombosis in the central nervous system and other sites.
●Plasmapheresis does not affect the disease process. In most cases, serum IgM levels will rise and symptoms of hyperviscosity will recur within a few weeks of stopping plasmapheresis unless therapy directed at the malignant cells is initiated.
●A reasonable initial prescription is a total plasma volume exchange (ie, 3 to 4 liters in an adult) replaced with albumin (rather than plasma), repeated daily until symptoms subside or until serum viscosity is normal.
●Hyperviscosity syndromes are usually associated with an increased plasma volume. Thus, the volume of plasma needed for a "one volume exchange" may be greater than that calculated by commonly used formulae.
●Transfusion with packed red blood cells during this period may further increase whole blood viscosity and precipitate or aggravate heart failure.
Our approach is consistent with the 2019 guidelines published by the American Society for Apheresis [20] and the 2020 consensus treatment recommendations proposed by the International Workshops on WM (IWWM-10) [15], which conclude that plasmapheresis is first-line therapy for hyperviscosity syndrome and may be used before rituximab administration to prevent flare in patients with high IgM levels (typically >4000 mg/dL).
This recommendation is supported by moderate quality evidence from small observational studies demonstrating efficacy of plasmapheresis in this setting and large observational studies demonstrating the safety of plasmapheresis in general. There have been no randomized trials of plasmapheresis in the management of hyperviscosity syndrome.
The published literature consists of prospective trials with historical controls, case series, and case reports accumulating data on approximately 300 patients [21]. These studies have demonstrated that a single plasmapheresis treatment reduces IgM levels by 30 to 50 percent and is associated with a decrease in serum viscosity, an increase in capillary blood flow, and improvement in the clinical manifestations of hyperviscosity [20,22-28]. Complications due to plasmapheresis are seen in less than 2 percent of patients replaced with albumin and most commonly consist of citrate-induced paresthesias, muscle cramps, and urticaria. The complications of plasmapheresis are discussed in detail separately. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)
Rituximab-based therapy — For most patients with symptomatic WM, we suggest initial treatment with a regimen that incorporates rituximab plus chemotherapy rather than a BTK inhibitor (algorithm 1). This is largely based on its short, defined course of therapy, a low toxicity profile, and acceptable response rates in phase II studies. Additionally, a single randomized trial of combination chemotherapy with or without rituximab reported higher response rates and longer event-free survival in patients receiving rituximab-based therapy [29].
A transient, yet clinically important, increase in serum IgM levels (IgM flare) and viscosity may occur after the administration of rituximab. Clinical and laboratory monitoring is therefore warranted in patients receiving rituximab for WM during the first one to two cycles. (See 'Minimizing risk of IgM flare' below.)
General side effects of rituximab include infusion reactions, increased risk of infection, and impaired vaccination responses. Rituximab therapy is associated with risk of hepatitis B reactivation among patients positive for HBsAg or anti-HBc. Side effects of rituximab therapy are discussed in more detail separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)
Patients with symptoms of hyperviscosity should be treated with plasmapheresis prior to initiating rituximab-based therapy directed at the malignant clone. (See 'Emergency management of hyperviscosity' above.)
Selection of chemotherapy regimen — Rituximab plus chemotherapy is our preferred treatment option for most patients with symptomatic WM (algorithm 1). Patients who are candidates for autologous HCT should be treated initially with regimens that will not impair the ability to collect stem cells in the future. Several regimens have demonstrated activity in WM and do not appear to be toxic to stem cells. Most of these regimens have not been directly compared with each other in prospective trials. In addition, it is difficult to compare these agents based on response rates alone since individual trials have used different response criteria. The most commonly used regimens are:
●Bendamustine plus rituximab (BR) [30] – This regimen consists of intravenous bendamustine (90 mg/m2 given over 30 to 60 minutes on days 1 and 2 of each cycle) in combination with rituximab (375 mg/m2 on day 1 of each cycle). This regimen is repeated every four weeks for four to six cycles. Lower doses of bendamustine are used for elderly patients and those with renal impairment. (See 'Bendamustine plus rituximab' below.)
●Dexamethasone, rituximab, cyclophosphamide (DRC) [31] – This regimen consists of intravenous dexamethasone (20 mg on day 1) followed by intravenous rituximab (375 mg/m2 on day 1) in addition to oral cyclophosphamide (100 mg/m2 twice daily on days 1 to 5) [31]. This regimen is repeated every 21 days for a total of six courses. (See 'Dexamethasone, rituximab, and cyclophosphamide' below.)
●Bortezomib plus rituximab with or without dexamethasone (BDR) [32-36] – This regimen usually consists of weekly bortezomib combined with rituximab at various schedules with or without dexamethasone. Subcutaneous administration of bortezomib helps to reduce neuropathy. (See 'Bortezomib-based regimens' below.)
A choice among the available regimens is primarily made based on the toxicity profiles and the clinician's comfort with the regimen. We prefer BR as the initial therapy for most patients [30,37-39]; the vast majority will have a partial response (PR) or complete response (CR) with this approach. If the disease burden is low, DRC is an acceptable alternative. Given the increased risk of neurotoxicity with bortezomib, we generally reserve the combination of bortezomib, rituximab, and dexamethasone for relapsed disease.
Treatment with a Bruton tyrosine kinase inhibitor is an appropriate alternative for elderly patients and for others who are not eligible for or do not want systemic chemotherapy. While we prefer BR for the initial treatment of WM, other experts advocate for the earlier incorporation of BTK inhibitors [19]. (See 'BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib)' below.)
Minimizing risk of IgM flare — We agree with the 2019 guidelines published by the American Society for Apheresis [20] and the 2020 consensus treatment recommendations proposed by the International Workshops on WM (IWWM-10) [15], which conclude that plasmapheresis is first-line therapy for hyperviscosity syndrome and may be used before rituximab administration to prevent flare in patients with high IgM levels (typically >4000 mg/dL). Alternatively, rituximab may be withheld for the first cycle in patients with high IgM levels receiving combination therapy.
Bendamustine plus rituximab — Bendamustine plus rituximab (BR) is our preferred regimen for patients with high tumor burden or moderate/severe symptoms (algorithm 1). BR consists of intravenous bendamustine (90 mg/m2 given over 30 to 60 minutes on days 1 and 2 of each cycle) in combination with rituximab (375 mg/m2 on day 1 of each cycle) [30]. This regimen is repeated every four weeks for four cycles. Lower doses of bendamustine are used for elderly patients and those with renal impairment.
Support for the use of BR in WM comes from the following prospective trials, which have demonstrated high response rates and relatively good tolerability:
●A phase II trial of BR in 63 patients with low grade lymphoma included 17 patients with lymphoplasmacytic lymphoma [30]. Overall and CR rates were 90 and 60 percent, respectively. The most common toxicity was myelosuppression with severe (grade 3/4) leukopenia and thrombocytopenia in 16 and 3 percent, respectively.
●The phase III Study Group Indolent Lymphomas (StiL) trial compared BR versus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in patients with indolent lymphomas [37]. A subset analysis of the 41 patients with WM found that, when compared with R-CHOP, BR was better tolerated (eg, lower rates of infections, cytopenias, neuropathy, stomatitis, and alopecia), resulted in a similar overall response rate (approximately 95 percent), and improved median progression-free survival (PFS; 70 versus 28 months).
Similar response rates and PFS were reported in a larger multicenter retrospective study of BR in WM [40]. It is important to note that there may be a small risk of secondary leukemia associated with the use of bendamustine [41].
Dexamethasone, rituximab, and cyclophosphamide — If the disease burden is low, dexamethasone, rituximab, cyclophosphamide (DRC) is an acceptable alternative to BR and is associated with fewer toxicities. DRC consists of intravenous dexamethasone (20 mg on day 1) followed by intravenous rituximab (375 mg/m2 on day 1) in addition to oral cyclophosphamide (100 mg/m2 twice daily on days 1 to 5) [31]. This regimen is repeated every 21 days for a total of six courses.
●A phase II trial investigated the use of DRC in 72 patients with previously untreated symptomatic WM [31]. Overall and CR rates were 83 and 7 percent, respectively, with two-year overall survival (OS) and PFS rates of 81 and 67 percent, respectively. Median time to response was 4.1 months. Toxicities were generally mild (grade 1/2) and included nausea, alopecia, and neutropenia. Chills, fever, and headache that occurred during rituximab infusion were readily reversible after reduction of the infusion rate.
●Additional data come from a retrospective analysis of outcomes following DRC [42]. Among the 50 patients with previously untreated WM, the overall response rate was 96 percent and the median PFS was 34 months. Among the 50 patients with relapsed or refractory WM, the overall response rate was 87 percent and the median PFS was 32 months. The response rate and duration of response were independent of MYD88 mutation status.
Bortezomib-based regimens — The following prospective trials have evaluated bortezomib and rituximab, with or without dexamethasone in WM; while high response rates are seen, there are also clinically significant rates of peripheral neuropathy. In addition, changes in serum IgM levels may not be reflective of a response in the bone marrow in a small portion of patients treated with bortezomib [43,44]. Given the increased risk of neurotoxicity with bortezomib, we generally reserve the combination of bortezomib, rituximab, and dexamethasone for relapsed disease.
●A phase II trial of BDR in 23 patients with symptomatic, previously untreated WM found overall and major response rates of 96 and 83 percent, respectively [32]. Peripheral neuropathy was the most common toxicity with 69 percent of patients developing neuropathy that impaired function. Mandatory prophylactic antiviral therapy was added to the treatment protocol after four of the first seven patients developed herpes zoster. None of the patients who took antiviral prophylaxis developed herpes zoster.
●A multicenter phase II trial of BDR in 59 patients with symptomatic, previously untreated WM reported an overall response rate of 85 percent (3 percent complete) with most patients demonstrating an initial response at three months [36,45]. Median PFS was 43 months. OS at seven years was 66 percent. Toxicity resulted in treatment discontinuation in 27 percent. The rate of peripheral neuropathy of any grade was 46 percent (7 percent severe). The lower rate of severe neuropathy may reflect the use of subcutaneous rather than intravenous bortezomib in this trial.
●In another phase II study, once weekly bortezomib was combined with rituximab, which was given weekly during cycles 1 and 4 [46]. Among 37 patients treated for relapsed or refractory WM, a minor response or better (ie, 25 percent or greater reduction in monoclonal protein levels) was seen in 81 percent of patients, including two CRs. The median time to progression was 16 months. Using this weekly schedule of bortezomib, grade 3 neurotoxicity was observed in only two cases (5 percent).
Limited role for single-agent rituximab — Single-agent rituximab is no longer used routinely for WM, particularly if the IgM level is >4000 mg/dL. It is less effective than other treatment options and frequently results in a transient increase in serum IgM level (IgM flare) that may lead to complications of hyperviscosity. Instead, rituximab is combined with chemotherapy such as bendamustine (which increases efficacy and decreases the risk of IgM flare) or a BTK inhibitor is used instead. A potential exception is that single-agent rituximab may be offered to highly selected patients with manifestations of WM limited to neuropathy alone or hemolysis alone.
Single-agent rituximab can achieve a PR in approximately half of patients; CRs have not been reported [47-52]. Median times to partial and best response are approximately 4 and 17 months, respectively. Studies have reported abrupt and clinically important increases in serum IgM levels and viscosity in approximately half of patients at a mean of four weeks (range: one to eight) following initiation of treatment with rituximab [51,53]. Clinical and laboratory monitoring for IgM flare is warranted. Symptoms of hyperviscosity must be treated with emergency plasmapheresis. (See 'Emergency management of hyperviscosity' above.)
A small proportion of WM patients can become intolerant to rituximab [54]. Rituximab intolerance was seen in 7 percent of WM patients exposed to rituximab. Rituximab intolerance can develop while getting rituximab alone or in combination. In these patients, ofatumumab has been used with good tolerability.
BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) — Prospective studies have demonstrated high response rates and sustained remissions with the Bruton tyrosine kinase (BTK) inhibitors ibrutinib, acalabrutinib, and zanubrutinib. However, there have been no randomized trials comparing the efficacy and tolerability of these agents versus other treatment regimens in WM. We prefer BR as the initial therapy for most patients (algorithm 1).
We consider BTK inhibitors to be an appropriate alternative initial therapy for elderly patients and for others who are not eligible for or do not want systemic chemotherapy. While we prefer to reserve these agents for the treatment or relapsed or refractory WM, other experts advocate for their earlier incorporation in most patients [19]. Some but not all data suggest that ibrutinib is less effective in WM with CXCR4 mutations [55-58]. Ibrutinib and zanubrutinib are approved by the US Food and Drug Administration (FDA) for the treatment of WM. As these BTK inhibitors appear to be equally effective, drug choice is based on side effect profile, convenience, and availability.
Ibrutinib is administered at a dose of 420 mg by mouth daily until disease progression or unacceptable toxicity [59]. If included, rituximab (375 mg/m2) is administered once per week on weeks 1 through 4 and 17 through 20 [52]. While generally well tolerated, uncommon toxicities, including bleeding, infection, atrial fibrillation, ventricular arrhythmias, and hypertension are seen [59-62]. Ibrutinib is generally avoided in patients with a history of arrhythmia, significant hepatic impairment, or severe bleeding, and in those on anticoagulation, although some of these (eg, atrial fibrillation, anticoagulation) may become less of a concern as experience with ibrutinib increases. Consider holding ibrutinib for three to seven days before and after surgery to mitigate the risk of perioperative bleeding. Case reports have described withdrawal symptoms and IgM flare in some patients following temporary or permanent discontinuation [62-64]. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)
While prospective trials have evaluated the use of ibrutinib as a single agent and in combination with rituximab, none has compared these two approaches. In general, we use single-agent ibrutinib.
Zanubrutinib is administered by mouth at a dose of 160 mg twice daily or 320 mg once daily until disease progression or unacceptable toxicity [65]. Prescribing information highlights the need to monitor for bleeding, infections, cytopenias, and cardiac arrhythmias. Consider holding zanubrutinib for three to seven days before and after surgery to mitigate the risk of perioperative bleeding. Patients have developed second primary malignancies, including skin cancers, and patients are advised to use sun protection.
Data regarding the efficacy and toxicity of BTK inhibitors in WM come from the following studies:
●Ibrutinib – The combination of ibrutinib plus rituximab was compared to placebo plus rituximab in a randomized trial that enrolled 150 patients with symptomatic WM, 68 of whom had not received prior therapy [52,58]. The addition of ibrutinib to rituximab resulted in higher rates of major response (72 versus 32 percent) and sustained improvement in hemoglobin (73 versus 41 percent), and improved PFS (54-month PFS 68 versus 25 percent; hazard ratio 0.25, 95% CI 0.15-0.42) regardless of CXCR4 mutation status. Ibrutinib plus rituximab resulted in higher rates of atrial fibrillation (12 versus 1 percent) and hypertension (13 versus 4 percent) and lower rates of anemia (11 versus 17 percent), infusion reactions (1 versus 16 percent), and IgM flare (8 versus 47 percent). OS data are immature with >50 percent of patients in both arms alive at 54 months (HR 0.81; 95% CI 0.33 to 1.99). These results demonstrate that the addition of ibrutinib to rituximab improves PFS and decreases the risk of IgM flare and associated complications. It is unknown how this combination compares with ibrutinib as a single agent or with other rituximab-based combination therapies.
Three smaller, single-arm trials evaluated ibrutinib monotherapy in a total of 124 patients with symptomatic WM [55,66-71]. Overall response rate was >90 percent. There were no complete responses. Responses appeared to be deeper among those with mutated MYD88 and wild-type CXCR4. In one trial with a median follow-up of 59 months, estimated PFS at 5 years was 54 percent for the population as a whole, and differed by mutation status (MYD88MutCXCRWT 70 percent; MYD88MutCXRCMut 38 percent; MYD88WTCXCRWT 0 percent) [55].
Similar response rates were reported in a multicenter retrospective study of ibrutinib in 28 patients with infiltration of the central nervous system (Bing-Neel syndrome) [72].
●Acalabrutinib – In a multicenter phase II trial of 106 patients treated with acalabrutinib, the overall response rate was 93 percent (none complete) [73]. After a median follow-up of 27 months, estimated 24-month PFS and OS rates were 90 and 92 percent, respectively. Thirty patients (28 percent) discontinued acalabrutinib during the study period. Adverse events were consistent with those seen in patients taking acalabrutinib for other conditions. The most common were headache, diarrhea, contusion, dizziness, fatigue, nausea, upper respiratory tract infection, and constipation. Serious adverse events occurred in approximately half of patients and there was one treatment-related death secondary to intracranial hematoma.
●Zanubrutinib – In a multicenter phase III trial (ASPEN), 201 patients with MYD88 mutated WM were randomly assigned to zanubrutinib or ibrutinib, each given until disease progression or unacceptable toxicity [74]. The two arms demonstrated similar efficacy with regards to rates of CR plus VGPR (28 versus 19 percent), PFS (18 month PFS 85 versus 84 percent), and OS (18 month OS 97 versus 93 percent). Zanubrutinib was less toxic with lower rates of muscle spasms, peripheral edema, hypertension, and atrial fibrillation/atrial flutter; while there was a higher rate of neutropenia (25 versus 12 percent), infection rates were similar.
The ASPEN trial also reported outcomes with zanubrutinib in 26 patients with MYD88 wild type WM and two with unknown MYD88 status [75]. Rates of VGPR and PR were 27 and 23 percent, respectively. There were no complete responses. Estimated PFS and OS at 18 months were 68 and 88 percent, respectively.
A single-arm trial evaluated two dosing schedules of zanubrutinib in patients with treatment naïve (24 patients) or relapsed/refractory (53 patients) WM [76]. Rates of CR plus VGPR increased with time and were 44 percent at 24 months. At a median follow-up of 36 months, the estimated rates of PFS and OS at three years were 81 and 85 percent, respectively.
FOLLOW-UP — Patients should be evaluated periodically to determine the disease response to treatment and should be followed longitudinally for relapse.
Assessing response to therapy — The International Working Group on Waldenström Macroglobulinemia has developed uniform response criteria that are used to measure the effect of treatment for WM (table 2) [77-79]. These criteria should be used to determine the patient's best response to treatment and to define when a relapse has occurred.
Patients are evaluated before each treatment cycle to determine how their disease is responding to therapy. This evaluation consists of a history and physical examination in addition to the measurement of monoclonal (M)-protein in serum or urine. Some clinicians also follow serum free light chain (sFLC) assays [80,81]. A bone marrow aspiration and biopsy is not routinely needed; it may be helpful if there is doubt about the extent of response. A CT scan of the chest/abdomen may be needed to assess response if there was significant lymphadenopathy or hepatosplenomegaly at baseline.
While studies suggest that it may have prognostic value, we do not routinely obtain PET/CT [82].
Data from this evaluation is then used to determine disease response, as follows:
●Complete response (CR) – Disappearance of monoclonal protein by immunofixation; normal serum immunoglobulin M (IgM) level; no histological evidence of bone marrow involvement, resolution of any adenopathy, hepatomegaly, or splenomegaly (confirmed by CT scan), and resolution of any signs or symptoms attributable to WM. CR status must be reconfirmed at least six weeks later with a second immunofixation.
●Very good partial response (VGPR) – At least 90 percent reduction in serum monoclonal IgM concentration on protein electrophoresis; resolution of any adenopathy, hepatomegaly, or splenomegaly (confirmed by CT scan); and resolution of any signs or symptoms attributable to WM. No new symptoms or signs of active disease.
●Partial response (PR) – At least 50 percent but less than 90 percent reduction in serum monoclonal IgM concentration on protein electrophoresis and at least 50 percent decrease in adenopathy, hepatomegaly, and splenomegaly on physical examination or CT scan. No new symptoms or signs of active disease.
●Minor response (MR) – At least 25 percent but less than 50 percent reduction of serum monoclonal IgM by protein electrophoresis. No new symptoms or signs of active disease.
●Stable disease (SD) – Does not fulfill criteria for MR or progressive disease.
●Progressive disease (PD) – Two measurements showing an at least 25 percent increase in serum monoclonal IgM by protein electrophoresis or progression of clinically significant anemia, thrombocytopenia, leukopenia, adenopathy, hepatomegaly, or splenomegaly or increase in symptoms attributable to WM, which may include unexplained recurrent fever, drenching night sweats, at least 10 percent body weight loss, hyperviscosity, neuropathy, symptomatic cryoglobulinemia, or amyloidosis. (See "Overview of amyloidosis".)
The term "major response" is used to identify patients who qualify for a partial, very good partial, or complete response. Serum monoclonal IgM levels provide an easily accessible measure of disease status, but can sometimes fluctuate independent of disease activity. As an example, IgM levels can increase transiently after treatment with rituximab or bortezomib. As such, bone marrow biopsy should be considered in patients with a clinical picture that does not appear concordant with the serum monoclonal IgM level.
Importantly, IgM values are dependent on the method of measurement used (eg, nephelometry, densitometry). As such, sequential response assessments for individual patients should be performed in the same laboratory using the same methodology.
Patients who have stable or progressive disease are treated as refractory disease. Responses to some chemotherapy regimens may not be seen until after several cycles of therapy. As such, we do not usually switch therapies for stable disease unless there is no response after three or more cycles. (See 'Treatment of relapsed or refractory disease' below.)
Role of maintenance therapy — Maintenance therapy refers to the prolonged administration of agents with low toxicity profiles in an attempt to prevent progression of disease. Maintenance therapy has been incorporated into the management of other indolent forms of non-Hodgkin lymphoma principally based on its ability to prolong time to progression in these subtypes. There are limited data regarding the use of maintenance therapy in WM and no randomized trials.
Experts differ in their use of maintenance rituximab. We do not offer maintenance therapy to patients with WM. This differs from the recommendations of the National Comprehensive Cancer Network (NCCN) which offer maintenance rituximab as an option for patients who have a partial or minor response to initial treatment. We believe that the goal of therapy is the alleviation of the signs or symptoms that prompted treatment initiation. Once there is improvement in these parameters, maintenance rituximab has not been shown to improve survival.
A randomized, multicenter, phase 3 trial (StiL NHL7-2008 MAINTAIN) evaluated the addition of two years of maintenance rituximab following initial response to bendamustine plus rituximab induction [83]. An abstract presentation of this trial reported that, after a median follow-up of 5.9 years, median progression-free survival (PFS) was numerically longer with maintenance rituximab, but this difference did not reach statistical significance (median PFS 101 versus 83 months; HR 0.80, 95% CI 0.51-1.25). Unless further data in support of maintenance therapy are reported, we offer observation with treatment at the time of progression rather than the use of maintenance therapy. Maintenance therapy has associated side effects, inconvenience, and cost and has not demonstrated a clinical benefit.
Monitoring for progressive disease — Following the completion of therapy, restaging, and documentation of a response, patients are seen at periodic intervals to monitor for disease progression. The frequency and extent of these visits depends on the comfort of both the patient and physician. Our approach to patient surveillance is to schedule patient visits every three months for the first year then every six months. At these visits we perform a history and physical examination, complete blood count, and measurement of M-protein in serum or urine. There is no role for routine imaging studies in the longitudinal follow-up of asymptomatic patients after response assessment.
Histologic transformation — Relapsed or refractory disease must be distinguished from histologic transformation, which requires a different treatment approach. Histologic transformation of WM into a rapidly progressive, high-grade malignant lymphoma may occur after a typical low-grade course [84,85]. The transformation is usually associated with a decrease in performance status, rapid development of lymphadenopathy, increase in serum lactate dehydrogenase levels, presence of abnormal metaphase cytogenetics of involved bone marrow or lymph nodes, and often a decrease in the serum IgM level. Histologic transformation can be suggested by changes on imaging studies, but can only be confirmed by biopsy. As such, a biopsy should always be obtained to document histologic transformation before proceeding with therapy. Survival from the time of transformation is usually very short, and response to treatment has been short-lived. Approach is similar to that of histologic transformation of follicular lymphoma, which is discussed separately. (See "Histologic transformation of follicular lymphoma".)
TREATMENT OF RELAPSED OR REFRACTORY DISEASE
Choice of therapy — All patients with WM will ultimately relapse after an initial response to therapy. Treatment options for patients with relapsed disease include reinstitution of the initial therapy and use of an alternative first-line agent. High dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) is rarely used in WM. (See 'Selection of chemotherapy regimen' above and 'Other combination regimens' below.)
In general, it is not necessary to restart therapy based on M-protein elevations alone in patients who have previously achieved a major response to therapy; rather, the criteria for re-initiation of therapy are similar to those used in newly diagnosed patients and include recurrence of symptoms and cytopenias. Rarely, palliative splenectomy may be offered to patients with symptomatic, painful splenomegaly or hypersplenism. (See 'Symptomatic patients' above.)
There is no standard treatment and there have been no randomized trials to guide therapy. The following approach is based on a review of the existing data, clinical experience, and observations [86]:
●For symptomatic patients relapsing more than three years following initial treatment, we repeat the original treatment. With such an approach, patients may respond almost equally well as they did the first time.
●For symptomatic patients relapsing less than three years after initial therapy, we suggest treatment with alternative first-line agents (alone or in combination). As an example, we offer a Bruton tyrosine kinase (BTK) inhibitor to patients relapsing less than three years after bendamustine plus rituximab.
The use of alternative first-line agents in relapsed disease is presented in the sections above, when appropriate. (See 'Initial treatment' above.)
Nucleoside analog-based regimens — Purine nucleoside analogs, and alkylating agents such as chlorambucil, were used alone as initial therapy prior to the incorporation of rituximab in the treatment of newly diagnosed WM. These agents are both associated with a risk of stem cell damage, and hence are not used as initial therapy in patients who are candidates for stem cell transplantation. Purine nucleoside analogs have also been associated with a higher degree of transformation. The use of these agents is primarily reserved for patients with multiply relapsed or refractory WM and a good performance status.
A single-institution retrospective analysis of 439 patients with WM who received nucleoside analog-containing regimens (193 patients), regimens that did not contain nucleoside analogs (136 patients), or observation alone (110 patients) reported a higher combined rate of transformation to an aggressive lymphoma (Richter syndrome), myelodysplasia, or acute leukemia in patients who received nucleoside analog-based therapy (6.2 versus 0.4 percent, respectively) after a median follow-up of five years [12].
Nucleoside analogs (such as fludarabine or cladribine) are active in WM, but are associated with stem cell toxicity and/or a risk of transformation to a higher grade lymphoma [12,87]. Therefore, these regimens should be avoided as initial therapy in patients who are candidates for autologous HCT until stem cells have been collected. The main toxicities with nucleoside-analog-containing regimens are myelosuppression and immunosuppression resulting in infections and a treatment-related mortality rate, which may be as high as 5 percent. In addition, a single-institution retrospective analysis of 439 patients with WM who received nucleoside-analog-containing regimens (193 patients), regimens that did not contain nucleoside analogs (136 patients), or observation alone (110 patients) reported a higher combined rate of transformation to an aggressive lymphoma (Richter syndrome), myelodysplasia, or acute leukemia in patients who received nucleoside-analog-based therapy (6.2 versus 0.4 percent, respectively) after a median follow-up of five years [12]. (See "Risk of infections in patients with chronic lymphocytic leukemia".)
Data on regimens using nucleoside analogs are described below:
●Cladribine plus rituximab – A phase II trial of four monthly cycles of combination therapy with rituximab (375 mg/m2 day 1) plus subcutaneous cladribine (0.1 mg/kg day 1 through 5) in 29 patients with newly diagnosed or previously treated WM reported overall and complete response rates of 90 and 24 percent, respectively [88]. The median time to best response was four months. The most common toxicities were neutropenia and anemia. These were generally mild with 10 episodes and one episode of severe (grade 3/4) neutropenia and anemia, respectively.
●Fludarabine plus rituximab – A prospective, multicenter trial evaluated treatment with six cycles of fludarabine (25 mg/m2 per day for five days) plus eight weekly infusions of rituximab (375 mg/m2 per week) in 43 patients with WM who had received less than two prior therapies [89]. The overall response rate was 95 percent (2 percent complete). Median time to best response and time to progression were 19 and 51 months, respectively. Severe toxicities included neutropenia (27 patients), thrombocytopenia (seven patients), and pneumonia (six patients). After a median follow-up of 40.3 months, there were three patients with transformation to aggressive lymphoma and three cases of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). After three cases of herpes zoster were noted in the first 21 patients, prophylaxis with acyclovir or famciclovir was given to subsequent patients until one year after treatment cessation.
●Fludarabine plus cyclophosphamide and rituximab – In a prospective, multicenter Italian trial, 43 patients with symptomatic WM were treated with rituximab (375 mg/m2 on day 1) plus fludarabine (25 mg/m2 on days 2 through 4) and cyclophosphamide (250 mg/m2 on days 2 through 4), administered every 28 days for up to six cycles [90]. Prophylaxis with trimethoprim-sulfamethoxazole and acyclovir were mandatory. The overall response rate was 79 percent (12 percent complete) with a median time to 25 and 50 percent reductions in serum monoclonal protein of two and three months, respectively. The median event-free survival was 50 months. Severe (grade 3/4) toxicities included neutropenia, which was seen in 88 percent of patients and was prolonged in 44 percent.
Other combination regimens — Several other rituximab-containing regimens have been investigated and shown activity. The data on these regimens are provided below; these regimens are typically used only in patients with relapsed refractory disease. Data on initial therapy are limited or not yet available.
●Carfilzomib, rituximab, dexamethasone (CaRD) – A phase II trial of CaRD in 31 patients with symptomatic WM who had not received prior rituximab or bortezomib reported an overall response rate of 87 percent (1 complete) [91]. The median times to first and best response were 2 and 13 months, respectively. At a median follow-up of 15 months, 20 remained free of progression. The most common severe (grade 3/4) toxicities were hyperglycemia (77 percent), elevated serum lipase (42 percent), and rituximab-related infusion reactions (19 percent). Mild to moderate peripheral neuropathy (all grade 1/2) was seen in 19 percent.
●Thalidomide plus rituximab – A prospective phase II trial of thalidomide plus rituximab in 35 patients with symptomatic WM, naïve to either agent, reported overall and major response rates of 72 and 64 percent, respectively [92]. Neuropathy was the dose-limiting toxicity and 11 patients developed neuropathy that impaired function (≥grade 2). This neuropathy resolved with cessation of therapy in 10 of these patients at a median of 6.7 months. Dose reductions were required in all patients.
Of note, a prospective phase II trial of the thalidomide-analog lenalidomide plus rituximab was halted due to a high rate of rapid-onset severe anemia [93]. As such, the combination of lenalidomide plus rituximab is not recommended for the treatment of WM outside of a clinical trial.
Investigational agents — Agents under study, both as single agents and in combinations, include ixazomib, ofatumumab, obinutuzumab, CXCR4 antagonists (plerixafor, ulocuplumab), daratumumab, pembrolizumab, and venetoclax. As examples:
●Ixazomib – A phase II study evaluated the oral proteasome inhibitor ixazomib in combination with dexamethasone and rituximab (IRD) in 26 patients with symptomatic, previously untreated WM [94,95]. The overall response rate (ORR) was 96 percent, and the major response rate was 77 percent, with a median time to response of eight weeks. At a median follow-up of 52 months, all patients were alive and the median progression-free survival (PFS) was 40 months. There were no grade 4 adverse events. Grade 3 adverse events included infection (2 patients), hyperglycemia (2 patients), infusion reactions (2 patients), and neuropathy (1 patient). In another phase I/II study of IRD in 59 patients with WM, the ORR was 71 percent and estimated two-year PFS and OS were 56 and 88 percent, respectively [96].
●Idelalisib plus obinutuzumab – In a phase II study of idelalisib plus obinutuzumab in 48 patients with relapsed or refractory WM, the ORR was 71 percent with no complete responses [97]. Median PFS was 25 months. Toxicity was substantial with 26 patients discontinuing therapy due to toxicity after a median of three cycles.
●Venetoclax – A phase II study evaluated up to 24 months of venetoclax in 32 patients with relapsed or refractory WM after a median of two prior therapies [98]. The ORR was 84 percent with no complete responses. Median PFS was 30 months. There was a rapid decline of PFS following treatment discontinuation at month 24 suggesting that continued therapy is likely required to maintain disease control. Six patients developed grade 4 neutropenia, one had febrile neutropenia, and one had tumor lysis syndrome.
●Daratumumab – A small multicenter phase II trial of single-agent daratumumab in patients with previously treated WM reported an overall response rate of 23 percent and a median PFS of two months [99].
Acalabrutinib is discussed in more detail separately. (See 'BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib)' above.)
Hematopoietic cell transplantation — High dose chemotherapy followed by autologous HCT is rarely used for the treatment of WM. Treatment-related mortality appears to be less than 10 percent, and autologous HCT may be able to produce long-term responses even in heavily pretreated patients [100-105]. Different conditioning regimens have been proposed but none has demonstrated superior efficacy over another. With available treatment options, the role of autologous HCT in WM is limited, and it is reserved for selected patients with good performance status in whom other treatment options have been exhausted. Allogeneic HCT carries a much higher risk of nonrelapse mortality and should not be considered outside the context of a clinical trial [86,102,104,106-108].
Data regarding the efficacy of HCT in WM come from a meta-analysis of 15 retrospective studies that included 278 patients who underwent autologous HCT and 311 patients who underwent allogeneic HCT across several decades [109]. All patients undergoing allogeneic HCT and most patients undergoing autologous HCT had relapsed or refractory disease. Most studies reported overall survival (OS), PFS, and relapse rates (RR) at three to five years and nonrelapse mortality (NRM) at one year. Pooled estimates were as follows:
●Autologous HCT – OS 76 percent (95% CI 65-86 percent), PFS 55 percent (95% CI 42-68 percent), RR 42 percent (95% CI 30-55 percent), and NRM 4 percent (95% CI 1-7 percent).
●Allogeneic HCT – OS 57 percent (95% CI 50-65 percent), PFS 49 percent (95% CI 42-56 percent), NRM 29 percent (95% CI 23-34 percent), RR 23 percent (95% CI 18-28 percent). Acute graft-versus-host disease (GVHD) was reported in 71 percent and usually grade I to II. Chronic GVHD was reported in 51 percent. Results following allogeneic HCT were heterogeneous, likely reflecting diversity in conditioning regimens, donor type, stem cell source, and GVHD prophylaxis used at different institutions and across time.
PROGNOSIS — For most patients treated with modern therapy, WM is an indolent disease with a median survival over 10 years [110-112]. Many patients will die of causes other than WM, especially those diagnosed in older age [113]. However, this is a heterogeneous group and outcomes are variable.
A number of multivariate models have been proposed to assess survival in this disorder [114-120]. Many use similar clinical and laboratory variables in different combinations and it is not clear if any of these models is superior to another. Poor prognostic factors that are common to most of these systems include older age, cytopenias, and an elevated beta-2 microglobulin level (B2M). In addition, initial studies suggest that patients with a high von Willebrand factor antigen level have shorter survival [121].
We calculate the International Prognostic Staging System for WM (IPSSWM) to assess prognosis. The current survival rates are likely better than what was observed when this prognostic index was developed since less than 5 percent of patients in this study were exposed to rituximab. The IPSSWM was formulated with data from a large number of previously untreated, symptomatic patients and incorporates the following five adverse features to stratify patients into low, intermediate, and high risk groups [119,120]:
●Age >65
●Hemoglobin ≤11.5 g/dL
●Platelet count ≤100,000/microL
●B2M >3 mg/L
●Serum IgM >70 g/L
Low-risk patients are those under 65 years of age who have zero or one risk factor. High-risk patients are those who have more than two risk factors. Intermediate-risk patients are those with two risk factors or those over age 65 who have less than three risk factors. Five-year survival rates for patients in the low, intermediate, and high risk groups were 87, 68, and 36 percent, respectively.
Other studies have noted the following:
●A prospective multicenter observational study created a staging system for WM utilizing serum B2M level, hemoglobin concentration (Hb), and serum IgM concentration [8]:
•Stage A (low risk) – B2M <3 mg/L and Hb ≥12.0 g/dL
•Stage B (medium risk) – B2M <3 mg/L and Hb <12.0 g/dL
•Stage C (medium risk) – B2M ≥3 mg/L and serum IgM ≥4.0 g/dL
•Stage D (high risk) – B2M ≥3 mg/L and IgM <4.0 g/dL
Five-year rates of overall survival for patients with stage A, B, C, or D disease were 87, 63, 53, and 21 percent, respectively. Rates of five-year progression-free survival were 83, 55, 33, and 12 percent, respectively. Stage D patients had a significantly higher incidence of anemia, hypoalbuminemia, lymphadenopathy, and hepatosplenomegaly than those in other stages.
Ten-year follow-up of this cohort identified elevated serum lactate dehydrogenase (LDH) levels as a poor prognostic factor with value added to both the original model and the IPSSWM described above [6]. In addition, there appeared to be a subset of patients with "smoldering macroglobulinemia" who had an excellent prognosis without treatment. (See 'Asymptomatic patients' above.)
●In a Swedish population-based study of 1555 patients with WM or lymphoplasmacytic lymphoma diagnosed from 1980 to 2005, relative survival rates (RSR) at five years compared with the general population improved sequentially from 1980-1985 (RSR 0.57; 95% CI 0.46-0.68) to 2001-2005 (RSR 0.78; 95% CI 0.71-0.85) [122]. Similarly, an analysis of the United States SEER database that included 2696 patients with WM diagnosed from 1988 to 2005 reported a decline in death rates with each five-year calendar period (hazard ratio [HR] 0.90; 95% CI 0.84-0.96) [123]. This improvement in survival appeared to be driven by large improvements in younger patients. The decrease in death rates was greatest in patients <50 years (HR 0.70; 95% CI 0.58-0.84). While the estimated five-year survival for the entire cohort was 52 percent, this varied dramatically by age: 71 percent in patients <70 years and 39 percent in older patients.
●Analyses of the SEER database evaluated over 6000 patients with WM diagnosed between 1980 and 2010 [124,125]. In these studies, the relative as well as the overall survival of patients with WM improved in the period 2001 to 2010 when compared with previous years. In a multivariate analysis, older age, male sex, and Black ethnicity were independent adverse prognostic factors for survival. The rate of WM-related death at 10 years ranged from 10 to 20 percent, and the median overall survival was estimated at nine years.
Patients with WM have a different microRNA expression pattern when compared with healthy subjects [126]. MicroRNAs are short, noncoding RNAs that downregulate gene expression in many tumor types and also play a role in regulating normal physiologic processes. MicroRNA expression may be involved in the pathogenesis of WM and expression levels may differ among patients of different IPSS risk groups. More studies are required to further evaluate the prognostic potential of microRNAs in WM.
CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).
WEBSITES FOR ADDITIONAL INFORMATION — Clinicians and/or their patients may search for additional information concerning the treatment of WM on various websites. The following are listed:
●The National Cancer Institute provides information for clinicians and patients. Information concerning WM can be found at its website [127].
●The International Waldenström's Macroglobulinemia Foundation has a website and provides information to patients with WM, friends, caregivers, and members of the medical profession [128].
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Waldenström macroglobulinemia".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Waldenström macroglobulinemia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Indications for treatment – Many patients with Waldenström macroglobulinemia (WM) are asymptomatic (ie, "smoldering" WM) and can be observed for months or years after the diagnosis is established before requiring treatment (algorithm 1). There is no clear advantage to early therapy. (See 'Asymptomatic patients' above.)
Indications for treatment include (table 1) (see 'Indications for treatment' above):
•The presence of systemic symptoms (eg, weakness, fever, night sweats, fatigue, weight loss), along with physical findings (eg, symptomatic lymphadenopathy, hepatomegaly, and/or splenomegaly) and cytopenias (eg, anemia, thrombocytopenia, neutropenia).
•Signs and symptoms due to the presence of hyperviscosity (eg, oronasal bleeding, blurred vision, headaches, dizziness, paresthesias, retinal vein engorgement and flame-shaped hemorrhages, papilledema, stupor and coma). Patients presenting with severe neurologic impairment, such as stupor or coma, should be treated with plasmapheresis on an emergency basis. (See 'Symptomatic patients' above.)
•Presence of severe neuropathy.
While the severity of anemia and/or thrombocytopenia that merits treatment is unknown, we generally consider a hemoglobin ≥10 g/dL and platelet count ≥100,000/microL to be adequate. Asymptomatic patients are followed periodically with complete blood counts and monoclonal protein levels. (See 'Asymptomatic patients' above.)
●Emergency management of hyperviscosity – For patients who present with symptoms due to hyperviscosity or who develop hyperviscosity during treatment, we recommend the immediate institution of therapeutic plasmapheresis (Grade 1B). Red blood cell transfusions should be avoided, if possible, prior to plasmapheresis since they might further increase serum viscosity. Once plasmapheresis is completed, patients will need to initiate treatment to control the malignant clone. (See 'Emergency management of hyperviscosity' above.)
●Initial therapy – There is no standard therapy for the treatment of WM. While various drugs and combinations have demonstrated clinical benefit in prospective trials, these have not been compared directly in randomized trials. In addition, individual trials have used different response criteria thereby making it difficult to compare these agents or regimens based on response rates alone.
For most patients with WM requiring treatment, we suggest bendamustine plus rituximab (BR) rather than a Bruton tyrosine kinase (BTK) inhibitor (algorithm 1) (Grade 2C). BR is administered intravenously over a short, defined course (4 to 6 months) with an acceptable toxicity profile. (See 'Bendamustine plus rituximab' above.)
A BTK inhibitor is an appropriate alternative for elderly patients and for others who are not eligible for or do not want systemic chemotherapy. BTK inhibitors are well tolerated oral drugs that are administered daily until progression. While we prefer to reserve these agents for the treatment or relapsed or refractory WM, other experts advocate for their more widespread use as initial therapy. (See 'BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib)' above.)
Single-agent rituximab is no longer used routinely for WM, particularly if the IgM level is >4000 mg/dL. It is less effective than other treatment options and frequently results in a transient increase in serum IgM level (IgM flare) that may lead to complications of hyperviscosity. (See 'Limited role for single-agent rituximab' above.)
●Relapsed disease – The choice of therapy for patients with relapsed disease is dependent upon the duration of remission from their most recent therapy:
•For symptomatic patients relapsing more than three years following the completion of initial treatment, we suggest that the original treatment be repeated first (Grade 2C). (See 'Treatment of relapsed or refractory disease' above.)
•For symptomatic patients relapsing less than three years after initial therapy, we suggest using alternative first-line agents, alone or in combination (Grade 2C). As an example, we offer a BTK inhibitor to patients relapsing less than three years after BR. (See 'Treatment of relapsed or refractory disease' above.)
•The role of high dose chemotherapy followed by autologous hematopoietic cell transplantation in WM is limited, and it is reserved for selected patients with good performance status in whom other treatment options have been exhausted. (See 'Hematopoietic cell transplantation' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert A Kyle, MD, who contributed to an earlier version of this topic review.
