Approach

Waldenström macroglobulinemia (WM) is an indolent lymphoma with long progression-free survival (PFS) and overall survival (OS), particularly with the use of Bruton tyrosine kinase (BTK) inhibitors and other novel agents.[57][58]

WM is incurable; therefore, the goals of treatment are to reduce symptoms, improve quality of life, and prolong survival.

Patients should be screened for hepatitis B and C and HIV before initiating treatment.

All patients should be encouraged to participate in a clinical trial where possible.

Asymptomatic patients

Treatment should not be initiated in asymptomatic patients, or initiated based on immunoglobulin M (IgM) levels alone.[37]​ Asymptomatic patients usually have an indolent disease course and do not require therapy for a long period of time, even if IgM is >30 g/L.[3][59]​

Close observation (e.g., follow-up every 3-6 months) is recommended for asymptomatic patients.​​[36][37][56]​ See Monitoring.​

Criteria for initiating treatment

Treatment should be initiated in patients with symptomatic disease.[36][37][56][59]​ 

Indications for treatment include:[36][37][56][59][60]​​​​

  • Symptoms related to bone marrow involvement by tumor cells (e.g., anemia and other cytopenias; B-symptoms [fevers, night sweats, weight loss])

  • Symptomatic IgM-related complications (e.g., hyperviscosity, amyloidosis, cryoglobulinemia, cold agglutinin disease, and peripheral neuropathy)

  • Rarely, symptoms related to bulky nodal/splenic involvement by tumor cells (e.g., lymphadenopathy, splenomegaly, and bulky extramedullary disease)

Patients with symptomatic hyperviscosity, moderate to severe hemolytic anemia, or symptomatic cryoglobulinemia require immediate treatment to control disease and alleviate symptoms.

Primary treatment options

Commonly used first-line treatment regimens for symptomatic patients include:[37][56]​​​[59][61][62]

  • Bendamustine plus rituximab (BR)

  • Bortezomib plus dexamethasone plus rituximab (BDR)

  • Dexamethasone plus rituximab plus cyclophosphamide (DRC)

  • Bortezomib plus rituximab (VR)

  • Ibrutinib (with or without rituximab)

  • Zanubrutinib

Other regimens recommended for first-line treatment include:[37][56]

  • Rituximab plus cyclophosphamide plus prednisone

  • Carfilzomib plus rituximab plus dexamethasone

  • Ixazomib plus rituximab plus dexamethasone

  • Bendamustine

  • Rituximab

  • Chlorambucil

Regimens containing carfilzomib or ixazomib are not yet used in routine clinical practice.

Primary treatment options: chemoimmunotherapy regimens

Rituximab-containing chemoimmunotherapy regimens (e.g., BR, BDR, DRC, and VR) are fixed-duration (i.e., administered for a limited amount of time).[37]

Rituximab (an anti-CD20 monoclonal antibody) causes a transient increase in the IgM monoclonal protein (flare) in approximately 50% of cases, which can lead to worsening hyperviscosity.[59][63]​​​ Rituximab is therefore omitted from treatment if IgM monoclonal protein is >40 g/L (or serum viscosity [SV] is >4 centipoise), but can be introduced at a later cycle when IgM levels fall below 40 g/L (or SV is <4 centipoise).[62]

BR has demonstrated improved median PFS versus intensive immunochemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; 69.5 vs. 28.1 months, respectively).[64] A study comparing BR versus DRC reported an overall response rate of 93% versus 96%, respectively, and a 2-year PFS rate of 88% versus 61%, respectively.[65] Although effective in treating WM, bendamustine is associated with an increased risk of hematologic toxicity (e.g., cytopenia, neutropenia, anemia, and thrombocytopenia) and infections.[66][67]​​​ Dose reduction with BR is required in older patients and those with renal impairment; BR is not appropriate in those who are frail.[56]

BDR is reported to have a response rate of 85% (3% complete; 58% partial).[68] Median PFS and 7-year OS rates are reported to be 43 months and 66%, respectively.[68] Peripheral neuropathy is an adverse effect associated with bortezomib-containing regimens (e.g., BDR and VR).[69][70]

DRC is reported to have a response rate of 83% (7% complete; 67% partial).[71][72]​​​ Median PFS and median OS are reported to be approximately 3 and 8 years, respectively.[72]​​​

VR is reported to have a response rate of 100% (8% complete or near complete; 58% partial).[73] Median PFS is reported to be approximately 3 years; 5-year PFS and OS rates are reported to be 41% and 94%, respectively (data from abstract).[74]

Primary treatment options: Bruton tyrosine kinase (BTK) inhibitor regimens

Ibrutinib, an oral BTK inhibitor, is approved for the management of WM as a single agent, or combined with rituximab. Single-agent ibrutinib is reported to have an overall response rate of 100% (0% complete; 63% partial) in previously untreated patients; however, lower and slower response rates occur in patients with CXCR4 mutations.[75] The estimated 18-month PFS rate is reported to be 92%.[75] Ibrutinib plus rituximab has been shown to improve 24-month PFS rate versus placebo plus rituximab in previously untreated patients (82% vs. 28%, respectively).[76] MYD88 and CXCR4 mutations have been found to have little impact on PFS outcomes with ibrutinib plus rituximab.[76][77]​​​​​

Zanubrutinib, a next-generation oral BTK inhibitor, is approved for the treatment of WM. Zanubrutinib improved response rate (complete response or very good partial response) versus ibrutinib (36.3% vs. 25.3%, respectively, at 44.4-month follow-up) in patients with MYD88 L265P-mutated WM (18.4% treatment naive; 81.6% relapsed/refractory WM).[78][79]​​ Median PFS and OS were not reached at 44.4 months. A lower response rate is reported in those with CXCR4 mutation (21.2% with zanubrutinib vs. 10.0% with ibrutinib).

BTK inhibitors (ibrutinib, zanubrutinib) are given continuously (orally) until disease progression or intolerability.[37]

BTK inhibitors: safety and tolerability

There is an increased risk of fatal and serious cardiac arrhythmias, cardiac failure, hypertension, and bleeding/bruising with ibrutinib.[18][75][76][80][81][82][83]​​​​​​​​ Risk is increased in patients with cardiac comorbidities (e.g., hypertension, diabetes mellitus, history of cardiac arrhythmia) and those with acute infection or who are receiving warfarin.

Clinical evaluation of cardiac history and function should be performed prior to initiating ibrutinib. Patients should be carefully monitored during treatment for cardiac arrhythmias and signs of deterioration of cardiac function and clinically managed as appropriate. Blood pressure should be monitored and antihypertensive medication should be started or adjusted as needed.[84]

The risks and benefits of initiating or continued treatment with ibrutinib should be carefully assessed; alternative treatment may need to be considered.

Cardiac arrhythmias may occur with zanubrutinib; patients with cardiac comorbidities or acute infection may be at a higher risk.[85][86]​​​ Zanubrutinib may, however, cause less cardiovascular toxicity than ibrutinib.[78][79]​​ Consider implementing ibrutinib safety precautions (described above) in patients receiving any BTK inhibitor. UK practice guidelines for managing cardiovascular complications associated with BTK inhibitors have been published.[81]

​IgM rebound may occur following discontinuation of BTK inhibitor therapy. Continue BTK inhibitor therapy until the next line of therapy is started, or monitor for IgM rebound after discontinuation of BTK inhibitor therapy.[37]

Plasmapheresis for symptomatic hyperviscosity

Plasmapheresis (plasma exchange) can be used to urgently treat patients with WM who have symptomatic hyperviscosity (hyperviscosity syndrome).[35][36][56][87] It can also be carried out prophylactically (before initiating rituximab-based treatment) in patients with IgM >40 g/L (or SV >4 centipoise) to minimize the risk of tumor flare. Although plasmapheresis rapidly reduces serum IgM in WM, its effects are usually transient.[87]

Red blood cell transfusions may be given after plasmapheresis if the patient has severe anemia, but care is required to prevent exacerbating hyperviscosity.[29] Blood warmers should be used during plasmapheresis in patients with cryoglobulinemia or cold agglutinin disease to prevent cryoprecipitation and/or erythrocyte agglutination.[29][35]​​​​[87]

Factors that inform treatment selection

The optimal treatment approach for WM is unclear because randomized controlled trials comparing different regimens are lacking.[88]​ Most drug trials in WM are small (<100 patients) and observational.

Treatment decisions in symptomatic patients are primarily based on:[36][37][55][56][60][62]​​

  • Need for immediate disease control or symptom relief from complication (i.e., tumor burden)

  • Patient fitness/frailty

  • Patient preference

Low tumor burden

  • Patients with low tumor burden (i.e., mild anemia without other cytopenias, hyperviscosity, or organomegaly) and mild symptoms do not require treatment for immediate disease control.[56]

  • DRC or BR is the preferred initial treatment for younger fit patients with low tumor burden.[56]

High tumor burden

  • Symptomatic patients with high tumor burden (e.g., with severe cytopenias, hyperviscosity, organomegaly, symptomatic cryoglobulinemia, severe hemolysis due to cold agglutinin disease) require treatment for immediate disease control and symptom relief.[36][37][60]

  • Rapid-acting regimens, such as BR, BDR, VR, and ibrutinib (with or without rituximab), can be used as initial treatment in younger fit patients with high tumor burden.[56]

  • Plasmapheresis can be used to urgently treat symptomatic hyperviscosity. It can also be used prophylactically (i.e., before initiating rituximab-based treatment) in patients with IgM >40 g/L (or SV >4 centipoise) to minimize the risk of IgM flare.[35][56][87]

Patient fitness/frailty

  • Older, frail patients and those with significant comorbidities can be considered for initial treatment with less toxic regimens, such as DRC or ibrutinib (with or without rituximab).[29][56][59][60]​​ Ibrutinib may also be an option for patients unable to tolerate chemotherapy. Alternative regimens include single-agent chemotherapy (e.g., chlorambucil) with or without rituximab, or rituximab alone.[29][56][59][60]

  • Patients with cardiac comorbidities (e.g., hypertension, diabetes mellitus, history of cardiac arrhythmia) and those with acute infection or who are receiving warfarin may be at increased risk of toxicity with ibrutinib; therefore, careful consideration of the risks and benefits is required.[18][75][80]

  • Zanubrutinib is highly effective and overall causes less cardiovascular toxicity than ibrutinib.[78][79]

Maintenance therapy

Patients who respond to initial treatment with rituximab-containing chemoimmunotherapy are observed until relapse. Patients may be considered for maintenance therapy with rituximab monotherapy, but this is not routinely recommended and is controversial given the limited data and uncertainty regarding its impact on survival, and risk of toxicity (e.g., increased secondary immunosuppression and infections).[89][90][91]​​

National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of maintenance rituximab in select patients who may benefit from maintenance (e.g., those ages >65 years, and those with a high International Prognostic Scoring System for Waldenström macroglobulinemia [IPSSWM] risk score).[37][91]

Relapsed or refractory disease

Relapse following initial treatment is common in patients with WM. Salvage therapy can be used following relapse or if there is no response to initial treatment (i.e., refractory disease). Patients should be encouraged to participate in a clinical trial where possible.

There is no standard of care for relapsed or refractory disease. However, duration of response with initial treatment can help guide salvage therapy.[35][55][56][60][92]​​​ Other considerations include:​

  • Type of response achieved with initial treatment (e.g., complete, very good partial, partial, or minimal). See Criteria.

  • Regimen used for initial treatment

  • Tolerance of initial treatment

  • Patient characteristics (e.g., age, comorbidities)

  • Disease characteristics and complications at relapse (e.g., hyperviscosity)

  • Suitability for stem cell transplantation (SCT; and avoidance of stem cell-toxic agents)

Relapse occurring <1 year after initial treatment, or refractory disease

  • Ibrutinib (with or without rituximab) as salvage therapy can be considered if relapse occurs <1 year after initial chemoimmunotherapy, or if there is refractory disease (i.e., no response to initial chemoimmunotherapy).[56]

  • Single-agent ibrutinib is reported to have an overall response rate of 90.5% in previously treated patients, but response was affected by MYD88 and CXCR4 mutation status.[18] Patients with wild-type MYD88 and wild-type CXCR4 were least responsive to single-agent ibrutinib. Patients with MYD88 mutation and wild-type CXCR4 had the highest response.[18] The 5-year OS was 87% (93% for patients with MYD88 mutation/CXCR4 wild type; 80% for MYD88 mutation/CXCR4 mutation).[93]

  • Ibrutinib plus rituximab is reported to have a 30-month PFS rate of 80% compared with 22% with placebo plus rituximab in previously treated patients (subgroup data).[76] MYD88 and CXCR4 mutations have been found to have little impact on PFS outcomes with ibrutinib plus rituximab.[76][77]​​

  • Next-generation BTK inhibitors, zanubrutinib and acalabrutinib, are highly effective and overall have less cardiovascular toxicity than ibrutinib.[78][79]​​[94]​ Acalabrutinib is not approved for the treatment of WM in the US or Europe, but NCCN guidelines recommend off-label use in previously treated WM (based on the results of a large single-arm phase 2 trial).[37]​​[94]

  • Salvage chemotherapy followed by SCT (autologous or allogeneic) is an option for highly selected patients (e.g., younger fit patients with advanced or aggressive chemosensitive disease who have relapsed, or who have refractory disease).[29][56][59]

Relapse occurring between 1 and 3 years after initial treatment

  • Ibrutinib (with or without rituximab) as salvage therapy can be considered if relapse occurs between 1 and 3 years after initial chemoimmunotherapy.[56]​

  • A different chemoimmunotherapy regimen from that used for initial treatment can also be considered for salvage therapy if ibrutinib is unsuitable or if relapse occurs later in this time period (e.g., 3 years).​​​​​[56]​​ For example, if DRC was used initially, then BR, BDR, or VR may be considered, depending on age, comorbidities, and patient preference.[65][95][96][97][98][99]

  • Ibrutinib may be considered for older, frail patients and those unable to tolerate chemotherapy. Patients with cardiac comorbidities (e.g., hypertension, diabetes mellitus, history of cardiac arrhythmia) and those with acute infection or who are receiving warfarin may be at increased risk of toxicity with ibrutinib; therefore, careful consideration of the risks and benefits is required.[18][75][80]

  • Next-generation BTK inhibitors, zanubrutinib and acalabrutinib, are highly effective and overall have less cardiovascular toxicity than ibrutinib.[78][94]​ Acalabrutinib is not approved for the treatment of WM in the US or Europe, but NCCN guidelines recommend off-label use in previously treated WM (based on the results of a large single-arm phase 2 trial).[37]​​[94]

  • Salvage chemotherapy followed by SCT (autologous or allogeneic) is an option for highly selected patients (e.g., younger fit patients with advanced or aggressive chemosensitive disease who have relapsed, or who have refractory disease).[29][56][59]

Relapse occurring >3 years after initial treatment

  • Given the efficacy and tolerability of BTK inhibitors, they are increasingly used in the setting of relapse, including late relapses, as they are much better tolerated than chemotherapy. However, patients relapsing >3 years after receiving initial chemoimmunotherapy can be treated with the same regimen used for initial treatment, if tolerated and acceptable to the patient.[56]​ Alternatively, a different regimen can be used. For example, if DRC was used initially, then BR, BDR, VR, or ibrutinib (with or without rituximab) may be considered, depending on age, comorbidities, and patient preference.[65][95][96][97][98][99]

  • Ibrutinib may be considered for older, frail patients and those unable to tolerate chemotherapy. Patients with cardiac comorbidities (e.g., hypertension, diabetes mellitus, history of cardiac arrhythmia) and those with acute infection or who are receiving warfarin may be at increased risk of toxicity with ibrutinib; therefore, careful consideration of the risks and benefits is required.[18][75][80]

  • Next-generation BTK inhibitors, zanubrutinib and acalabrutinib, are highly effective and overall have less cardiovascular toxicity than ibrutinib.[78][94]​​ Acalabrutinib is not approved for the treatment of WM in the US or Europe, but NCCN guidelines recommend off-label use in previously treated WM (based on the results of a large single-arm phase 2 trial).[37][94]

  • Other chemoimmunotherapy regimens may be considered for salvage therapy, but should be used cautiously due to toxicity.[100][101]​​ Alkylating agents and nucleoside analogs are toxic to stem cells, and should be avoided in those who might be considered for autologous SCT.

  • Salvage chemotherapy followed by SCT (autologous or allogeneic) is an option for highly selected patients (e.g., younger fit patients with advanced or aggressive chemosensitive disease who have relapsed, or who have refractory disease).[29][56][59]

Plasmapheresis can be carried out in patients with relapsed or refractory disease to urgently treat symptomatic hyperviscosity. It can also be carried out prophylactically (i.e., before initiating rituximab-based salvage therapy) in patients with IgM >40 g/L (or SV >4 centipoise) to minimize the risk of IgM flare.[35][56][87]

Stem cell transplantation

Pretransplant recipient evaluation may inform the preparative regimen and is used to estimate risk for posttransplant complications.[102]

Autologous stem cell transplantation (ASCT)

  • Salvage chemotherapy followed by ASCT is an option for highly selected patients (e.g., younger fit patients with advanced or aggressive chemosensitive disease who have relapsed, or who have refractory disease).[29][56][59]

  • ASCT is not recommended for patients with chemoresistant disease or those who have received more than three lines of chemotherapy.[59][103]

  • Use of ASCT in WM is controversial due to the lack of randomized trials and the availability of effective targeted therapies.[36] Although ASCT is safe and effective, it is unclear whether it leads to better outcomes than other treatments.[103][104]

  • Nonrelapse mortality rate with ASCT at 5 years is reported to be 5.6%, and 5-year OS rate is reported to be 68.5%.[103]

  • For younger fit patients who are candidates for ASCT, exposure to alkylating agents and nucleoside analogs should be carefully considered as these agents are toxic to stem cells.[29][37]​​[56][59]​​​​​ However, plerixafor can be used to mobilize stem cells for harvesting, even after treatment with stem cell-toxic agents.[102]

Allogeneic stem cell transplantation (alloSCT)

  • AlloSCT (with myeloablative, nonmyeloablative, or reduced-intensity conditioning) may be considered for salvage therapy in highly selected patients with chemosensitive disease (e.g., younger fit patients who have failed all other treatments, including ibrutinib and ASCT). However, there is a high risk of early mortality and morbidity with this procedure. Preferably it should be carried out in a clinical trial setting.[37][56][59]​​​​

  • Nonrelapse mortality rate with alloSCT at 5 years is reported to be approximately 30%, and 5-year OS rate is reported to be 50% and 60%.[105][106][107]

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