Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

asymptomatic

1st line – close observation

Back
ACUTE
|
asymptomatic
1st line – 

close observation

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][56]

Close observation (e.g., follow-up every 3-6 months) is recommended for asymptomatic patients.[36][37][57]​​ See Monitoring.

Patients should be screened for hepatitis B and C and HIV before initiating treatment.[36][37]

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

symptomatic with low tumour burden

1st line – dexamethasone + rituximab + cyclophosphamide (DRC); or bendamustine + rituximab (BR); or ibrutinib ± rituximab; or zanubrutinib

Back
ACUTE
|
symptomatic with low tumour burden
|
younger or fit
1st line – 

dexamethasone + rituximab + cyclophosphamide (DRC); or bendamustine + rituximab (BR); or ibrutinib ± rituximab; or zanubrutinib

Treatment decisions in symptomatic patients are primarily based on need for immediate disease control or symptom relief from complications (i.e., tumour burden), patient fitness/frailty, and patient preference.[36][37]​​[57][58][60][87]

Goals of treatment are to reduce symptoms, improve quality of life, and prolong survival.

Patients with low tumour burden (i.e., mild anaemia without other cytopenias, hyperviscosity, or organomegaly) and mild symptoms do not require treatment for immediate disease control.[57]

DRC or BR is the preferred initial treatment for younger fit patients with low tumour burden.[57]

DRC is reported to have a response rate of 83% (7% complete; 67% partial).[69][70]​​ Median progression-free survival (PFS) and median overall survival (OS) are reported to be approximately 3 years and 8 years, respectively.[70]

BR has demonstrated improved median PFS versus intensive immunochemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone; 69.5 vs. 28.1 months, respectively).[62] 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.[63] Although effective in treating WM, bendamustine is associated with an increased risk of haematological toxicity (e.g., cytopenia, neutropenia, anaemia, and thrombocytopenia) and infections.[64][65]

Rituximab-containing chemoimmunotherapy regimens (e.g., DRC, BR) are fixed-duration (i.e., administered for a limited amount of time).[37]​ Rituximab causes a transient increase in the immunoglobulin M (IgM) monoclonal protein (flare) in approximately 50% of cases, which can lead to worsening hyperviscosity.[56][61]​​ Rituximab is therefore omitted from treatment if IgM monoclonal protein is >40 g/L (or serum viscosity [SV] is >4 centipoise), but it can be introduced at a later cycle when IgM levels fall below 40 g/L (or SV is <4 centipoise).[60]

Ibrutinib, an oral Bruton's tyrosine kinase (BTK) inhibitor, is approved in the US for the management of WM as a single agent, or combined with rituximab. In Europe, it is approved as a single agent for second-line use, or first-line use if chemoimmunotherapy is unsuitable. 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.[73]​ The estimated 18-month PFS rate is reported to be 92%.[73] Ibrutinib plus rituximab has been shown to improve 24-month PFS rate versus placebo plus rituximab in previously untreated patients (82% vs. 28%, respectively).[74]​ MYD88 and CXCR4 mutations have been found to have little impact on PFS outcomes with ibrutinib plus rituximab.[74][75]

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).[76][77]​ 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 are given continuously (orally) until disease progression or intolerability.[37]

There is an increased risk of fatal and serious cardiac arrhythmias, cardiac failure, hypertension, and bleeding/bruising with ibrutinib.[18][73][74][78][79][80]​​[81]​​​​ 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 anti-hypertensive medication should be started or adjusted as needed.[82]​

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 also occur with zanubrutinib; patients with cardiac comorbidities or acute infection may be at a higher risk.[83][84]​ Zanubrutinib may, however, cause less cardiovascular toxicity than ibrutinib.[76][77]​ 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.[79]

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]

Patients suitable for autologous stem cell transplantation should avoid or reduce exposure to oral alkylating agents and nucleoside analogues as these agents are toxic to stem cells.[29][37]​​[56][57]​​​ However, plerixafor can be used to mobilise stem cells for harvesting, even after treatment with stem cell-toxic agents.[101]

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

See local specialist protocol for dosing guidelines.

Primary options

DRC

dexamethasone

and

rituximab

and

cyclophosphamide

OR

BR

bendamustine

and

rituximab

OR

ibrutinib

OR

ibrutinib

and

rituximab

OR

zanubrutinib

1st line – dexamethasone + rituximab + cyclophosphamide (DRC); or ibrutinib ± rituximab; or single-agent chemotherapy ± rituximab; or rituximab alone; or zanubrutinib

Back
ACUTE
|
symptomatic with low tumour burden
|
older or unfit
1st line – 

dexamethasone + rituximab + cyclophosphamide (DRC); or ibrutinib ± rituximab; or single-agent chemotherapy ± rituximab; or rituximab alone; or zanubrutinib

Treatment decisions in symptomatic patients are primarily based on need for immediate disease control or symptom relief from complications (i.e., tumour burden), patient fitness/frailty, and patient preference.[36][37]​​[57][58][60][87]

Goals of treatment are to reduce symptoms, improve quality of life, and prolong survival.

Patients with low tumour burden (i.e., mild anaemia without other cytopenias, hyperviscosity, or organomegaly) and mild symptoms do not require treatment for immediate disease control.[57]

Older, frail patients and those with significant comorbidities can be considered for less toxic regimens, such as DRC or ibrutinib (with or without rituximab).[29][56][57][58]​​​ Ibrutinib (an oral Bruton's tyrosine kinase [BTK] inhibitor) 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][57][58]​​

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][73][78]

Zanubrutinib, a next-generation oral BTK inhibitor, is highly effective and overall causes less cardiovascular toxicity than ibrutinib.[76][77]

DRC is reported to have a response rate of 83% (7% complete; 67% partial).[69][70]​​​ Median progression-free survival (PFS) and median overall survival (OS) are reported to be approximately 3 years and 8 years, respectively.[70]

Rituximab-containing chemoimmunotherapy regimens (e.g., DRC) are fixed-duration (i.e., administered for a limited amount of time).[37]​ Rituximab causes a transient increase in the immunoglobulin M (IgM) monoclonal protein (flare) in approximately 50% of cases, which can lead to worsening hyperviscosity.[56][61]​​ Rituximab is therefore omitted from treatment if IgM monoclonal protein is >40 g/L (or serum viscosity [SV] is >4 centipoise), but it can be introduced at a later cycle when IgM levels fall below 40 g/L (or SV is <4 centipoise).[60]

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.[73] The estimated 18-month PFS rate is reported to be 92%.[73] Ibrutinib plus rituximab has been shown to improve 24-month PFS rate versus placebo plus rituximab in previously untreated patients (82% vs. 28%, respectively).[74] MYD88 and CXCR4 mutations have been found to have little impact on PFS outcomes with ibrutinib plus rituximab.[74][75]​​​

Zanubrutinib 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).[76][77]​​ 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 are given continuously (orally) until disease progression or intolerability.[37]

There is an increased risk of fatal and serious cardiac arrhythmias, cardiac failure, hypertension, and bleeding/bruising with ibrutinib.[18][73][74][78][79][80][81]​​ 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 anti-hypertensive medication should be started or adjusted as needed.[82]

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.[83][84]​ Zanubrutinib may, however, cause less cardiovascular toxicity than ibrutinib.[76][77]​ 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.[79]

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]

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

See local specialist protocol for dosing guidelines.

Primary options

DRC

dexamethasone

and

rituximab

and

cyclophosphamide

OR

ibrutinib

OR

ibrutinib

and

rituximab

OR

zanubrutinib

Secondary options

chlorambucil

OR

chlorambucil

and

rituximab

OR

rituximab

symptomatic with high tumour burden

1st line – bendamustine + rituximab (BR); or bortezomib + dexamethasone + rituximab (BDR); or bortezomib + rituximab (VR); or ibrutinib ± rituximab; or zanubrutinib

Back
ACUTE
|
symptomatic with high tumour burden
|
younger or fit
1st line – 

bendamustine + rituximab (BR); or bortezomib + dexamethasone + rituximab (BDR); or bortezomib + rituximab (VR); or ibrutinib ± rituximab; or zanubrutinib

Treatment decisions in symptomatic patients are primarily based on need for immediate disease control or symptom relief from complications (i.e., tumour burden), patient fitness/frailty, and patient preference.[36][37]​​[57][58][60][87]

Goals of treatment are to reduce symptoms, improve quality of life, and prolong survival.

Symptomatic patients with high tumour burden (e.g., with severe cytopenias, hyperviscosity, organomegaly, symptomatic cryoglobulinaemia, severe haemolysis due to cold agglutinin disease) require treatment for urgent disease control and symptom relief.[36][37][58]

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 tumour burden.[57]​ 

BR has demonstrated improved median progression-free survival (PFS) versus intensive immunochemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone; 69.5 vs. 28.1 months, respectively).[62] 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.[63] Although effective in treating WM, bendamustine is associated with an increased risk of haematological toxicity (e.g., cytopenia, neutropenia, anaemia, and thrombocytopenia) and infections.[64][65]​​​ Dose reduction with BR is required in older patients and those with renal impairment; BR is not appropriate in those who are frail.[70]

BDR is reported to have a response rate of 85% (3% complete; 58% partial).[66] Median PFS and 7-year overall survival (OS) rates are reported to be 43 months and 66%, respectively.[66] Peripheral neuropathy is an adverse effect associated with bortezomib-containing regimens (e.g., BDR and VR).[67][68]

VR is reported to have a response rate of 100% (8% complete or near complete; 58% partial).[71][72]​​ 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).[72]

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

Rituximab causes a transient increase in the immunoglobulin M (IgM) monoclonal protein (flare) in approximately 50% of cases, which can lead to worsening hyperviscosity.[56][61]​​ Rituximab is therefore omitted from treatment if IgM monoclonal protein is >40 g/L (or serum viscosity [SV] is >4 centipoise), but it can be introduced at a later cycle when IgM levels fall below 40 g/L (or SV is <4 centipoise).[60]

Ibrutinib, an oral Bruton's tyrosine kinase (BTK) inhibitor, is approved in the US for the management of WM as a single agent, or combined with rituximab. In Europe, it is approved as a single agent for second-line use, or first-line use if chemoimmunotherapy is unsuitable. 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.[73] The estimated 18-month PFS rate is reported to be 92%.[73] Ibrutinib plus rituximab has been shown to improve 24-month PFS rate versus placebo plus rituximab in previously untreated patients (82% vs. 28%, respectively).[74] MYD88 and CXCR4 mutations have been found to have little impact on PFS outcomes with ibrutinib plus rituximab.[74][75]

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).[76][77]​ 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 are given continuously (orally) until disease progression or intolerability.[37]

There is an increased risk of fatal and serious cardiac arrhythmias, cardiac failure, hypertension, and bleeding/bruising with ibrutinib.[18][73][74][78][79][80][81]​​ 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 anti-hypertensive medication should be started or adjusted as needed.[82]​

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.[83][84]​​ Zanubrutinib may, however, cause less cardiovascular toxicity than ibrutinib.[76][77]​​ 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.[79]

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]

Patients suitable for autologous stem cell transplantation should avoid or reduce exposure to oral alkylating agents and nucleoside analogues as these agents are toxic to stem cells.[29][37]​​[56][57]​​ However, plerixafor can be used to mobilise stem cells for harvesting, even after treatment with stem cell-toxic agents.

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

See local specialist protocol for dosing guidelines.

Primary options

BR

bendamustine

and

rituximab

OR

BDR

bortezomib

and

dexamethasone

and

rituximab

OR

VR

bortezomib

and

rituximab

OR

ibrutinib

OR

ibrutinib

and

rituximab

OR

zanubrutinib

Consider – plasmapheresis (for symptomatic hyperviscosity)

Back
ACUTE
|
symptomatic with high tumour burden
|
younger or fit
Consider – 

plasmapheresis (for symptomatic hyperviscosity)

Additional treatment recommended for SOME patients in selected patient group

Plasmapheresis (plasma exchange) can be used to urgently treat symptomatic hyperviscosity (hyperviscosity syndrome).[35][36][57][85]

It can also be used prophylactically (i.e., before initiating rituximab-based treatment) in patients with immunoglobulin M (IgM) >40 g/L (or serum viscosity >4 centipoise) to minimise the risk of IgM flare.

Although plasmapheresis rapidly reduces serum IgM in WM, its effects are usually transient.[85]

Red blood cell transfusions may be given after plasmapheresis if the patient has severe anaemia, but care is required to prevent exacerbating hyperviscosity.[29]

Blood warmers should be used during plasmapheresis in patients with cryoglobulinaemia or cold agglutinin disease to prevent cryoprecipitation and/or erythrocyte agglutination.[29][35]​​​​[85]

1st line – dexamethasone + rituximab + cyclophosphamide (DRC); or ibrutinib ± rituximab; or single-agent chemotherapy ± rituximab; or rituximab alone; or zanubrutinib

Back
ACUTE
|
symptomatic with high tumour burden
|
older or unfit
1st line – 

dexamethasone + rituximab + cyclophosphamide (DRC); or ibrutinib ± rituximab; or single-agent chemotherapy ± rituximab; or rituximab alone; or zanubrutinib

Treatment decisions in symptomatic patients are primarily based on need for immediate disease control or symptom relief from complications (i.e., tumour burden), patient fitness/frailty, and patient preference.[36][37]​​[57][58]​​[60][87]

Goals of treatment are to reduce symptoms, improve quality of life, and prolong survival.

Symptomatic patients with high tumour burden (e.g., with severe cytopenias, hyperviscosity, organomegaly, symptomatic cryoglobulinaemia, severe haemolysis due to cold agglutinin disease) require treatment for urgent disease control and symptom relief.[36][37][58]​ 

Older, frail patients and those with significant comorbidities can be considered for less toxic regimens, such as DRC or ibrutinib (with or without rituximab).[29][56][57][58]​​ 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]​​[57]​​[58]

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][73][78]

Zanubrutinib, a next-generation oral Bruton's tyrosine kinase (BTK) inhibitor, is highly effective and overall causes less cardiovascular toxicity than ibrutinib.[76][77]

DRC is reported to have a response rate of 83% (7% complete; 67% partial).[69][70]​​​ Median progression-free survival (PFS) and median overall survival (OS) are reported to be approximately 3 years and 8 years, respectively.[70]

Rituximab-containing chemoimmunotherapy regimens (e.g., DRC) are fixed-duration (i.e., administered for a limited amount of time). Rituximab causes a transient increase in the immunoglobulin M (IgM) monoclonal protein (flare) in approximately 50% of cases, which can lead to worsening hyperviscosity.[56][61]​​ Rituximab is therefore omitted from treatment if IgM monoclonal protein is >40 g/L (or 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).[60]

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.[73] The estimated 18-month PFS rate is reported to be 92%.[73] Ibrutinib plus rituximab has been shown to improve 24-month PFS rate versus placebo plus rituximab in previously untreated patients (82% vs. 28%, respectively).[74] MYD88 and CXCR4 mutations have been found to have little impact on PFS outcomes with ibrutinib plus rituximab.[74][75]​​​

Zanubrutinib 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).[76][77]​​​ 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 are given continuously (orally) until disease progression or intolerability.[37]

There is an increased risk of fatal and serious cardiac arrhythmias, cardiac failure, hypertension, and bleeding/bruising with ibrutinib.[18][73][74][78][79][80][81]​​ 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 anti-hypertensive medication should be started or adjusted as needed.[82]​

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 also occur with zanubrutinib, and patients with cardiac comorbidities or acute infection may be at a higher risk.[83][84]​​ Zanubrutinib may, however, cause less cardiovascular toxicity than ibrutinib.[76][77]​​ 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.[79]

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]

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

See local specialist protocol for dosing guidelines.

Primary options

DRC

dexamethasone

and

rituximab

and

cyclophosphamide

OR

ibrutinib

OR

ibrutinib

and

rituximab

OR

zanubrutinib

Secondary options

chlorambucil

OR

chlorambucil

and

rituximab

OR

rituximab

Consider – plasmapheresis (for symptomatic hyperviscosity)

Back
ACUTE
|
symptomatic with high tumour burden
|
older or unfit
Consider – 

plasmapheresis (for symptomatic hyperviscosity)

Additional treatment recommended for SOME patients in selected patient group

Plasmapheresis (plasma exchange) can be used to urgently treat symptomatic hyperviscosity (hyperviscosity syndrome).[35][36][57][85]

It can also be used prophylactically (i.e., before initiating rituximab-based treatment) in patients with immunoglobulin M (IgM) >40 g/L (or serum viscosity >4 centipoise) to minimise the risk of IgM flare.

Although plasmapheresis rapidly reduces serum IgM in WM, its effects are usually transient.[85]

Red blood cell transfusions may be given after plasmapheresis if the patient has severe anaemia, but care is required to prevent exacerbating hyperviscosity.[29]

Blood warmers should be used during plasmapheresis in patients with cryoglobulinaemia or cold agglutinin disease to prevent cryoprecipitation and/or erythrocyte agglutination.[29][35]​​​​[85]

ONGOING

responders to initial rituximab-containing chemoimmunotherapy regimens

1st line – observation or maintenance rituximab (in select patients)

Back
ONGOING
|
responders to initial rituximab-containing chemoimmunotherapy regimens
1st line – 

observation or maintenance rituximab (in select patients)

Rituximab-containing chemoimmunotherapy regimens are fixed-duration (i.e., administered for a limited amount of time).

Patients who respond to initial treatment with a rituximab-containing chemoimmunotherapy regimen are observed until relapse.

Patients may be considered for maintenance therapy with rituximab, 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).[88][89][90]​​ 

The US National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of maintenance rituximab in select patients who may benefit from maintenance (e.g., those aged >65 years, and those with a high International Prognostic Scoring System for Waldenström's macroglobulinaemia [IPSSWM] risk score).[37][90]​​ European guidelines do not recommend maintenance rituximab due to lack of prospective data.[36][57]

See local specialist protocol for dosing guidelines.

Primary options

rituximab

relapse or refractory disease

1st line – ibrutinib ± rituximab; or zanubrutinib; or acalabrutinib

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring <1 year after initial treatment
1st line – 

ibrutinib ± rituximab; or zanubrutinib; or acalabrutinib

Relapse following initial treatment is common in patients with WM.

Salvage therapy can be used following relapse.

There is no standard of care for relapsed or refractory disease. However, duration of response with initial treatment can help guide salvage therapy.[35]​​​​[57][58][91][87]​​​​​​ 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), and suitability for stem cell transplantation.​

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).[57]

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 overall survival (OS) was 87% (93% for patients with MYD88 mutation/CXCR4 wild type; 80% for MYD88 mutation/CXCR4 mutation).[92]

Ibrutinib plus rituximab is reported to have a 30-month progression-free survival (PFS) rate of 80% compared with 22% with placebo plus rituximab in previously treated patients (subgroup data).[74] MYD88 and CXCR4 mutations have been found to have little impact on PFS outcomes with ibrutinib plus rituximab.[74][75]

Next-generation Bruton's tyrosine kinase (BTK) inhibitors, zanubrutinib and acalabrutinib, are highly effective and overall have less cardiovascular toxicity than ibrutinib.[76][77][93]

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).[76][77]​ 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).

Acalabrutinib is not approved for the treatment of WM in the US or Europe, but US NCCN guidelines recommend off-label use in previously treated WM (based on the results of a large single-arm phase 2 trial).[37][93]

There is an increased risk of fatal and serious cardiac arrhythmias, cardiac failure, hypertension, and bleeding/bruising with ibrutinib.[18][73][74][78][79][80][81]​​ 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 anti-hypertensive medication should be started or adjusted as needed.[82]​

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.[83][84]​ Zanubrutinib may, however, cause less cardiovascular toxicity than ibrutinib.[76][77]​ 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.[79]

Immunoglobulin M (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]

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

See local specialist protocol for dosing guidelines.

Primary options

ibrutinib

OR

ibrutinib

and

rituximab

OR

zanubrutinib

OR

acalabrutinib

Consider – plasmapheresis (for symptomatic hyperviscosity)

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring <1 year after initial treatment
Consider – 

plasmapheresis (for symptomatic hyperviscosity)

Additional treatment recommended for SOME patients in selected patient group

Plasmapheresis (plasma exchange) can be used to urgently treat symptomatic hyperviscosity (hyperviscosity syndrome).[35][36][57][85]

It can also be used prophylactically (i.e., before initiating rituximab-based treatment) in patients with immunoglobulin M (IgM) >40 g/L (or serum viscosity >4 centipoise) to minimise the risk of IgM flare.

Although plasmapheresis rapidly reduces serum IgM in WM, its effects are usually transient.[85]

Red blood cell transfusions may be given after plasmapheresis if the patient has severe anaemia, but care is required to prevent exacerbating hyperviscosity.[29]

Blood warmers should be used during plasmapheresis in patients with cryoglobulinaemia or cold agglutinin disease to prevent cryoprecipitation and/or erythrocyte agglutination.[29][35]​​​​[85]

2nd line – salvage chemotherapy + stem cell transplantation (in select patients)

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring <1 year after initial treatment
2nd line – 

salvage chemotherapy + stem cell transplantation (in select patients)

Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is an option for highly selected patients (e.g., younger fit patients with advanced or chemosensitive aggressive disease who have relapsed, or who have refractory disease).[29][56][57]

ASCT is not recommended for patients with chemoresistant disease or those who have received more than three lines of chemotherapy.[56][102]

Use of ASCT in WM is controversial due to the lack of randomised 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.[102][103]

Non-relapse mortality rate with ASCT at 5 years is reported to be 5.6%, and 5-year overall survival (OS) rate is reported to be 68.5%.[102]

Allogeneic stem cell transplantation (alloSCT) with myeloablative, non-myeloablative, 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][57]

Non-relapse mortality rate with alloSCT at 5 years is reported to be approximately 30%, and 5-year OS rate is reported to be 50% to 60%.[104][105][106]

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

1st line – ibrutinib ± rituximab; or zanubrutinib; or acalabrutinib

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring between 1 and 3 years after initial treatment
1st line – 

ibrutinib ± rituximab; or zanubrutinib; or acalabrutinib

Relapse following initial treatment is common in patients with WM.

Salvage therapy can be used following relapse.

There is no standard of care for relapsed or refractory disease. However, duration of response with initial treatment can help guide salvage therapy.[35]​​​​[57][58][91][87]​​​​​​ 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), and suitability for stem cell transplantation.​

Ibrutinib (with or without rituximab) as salvage therapy can be considered if relapse occurs between 1 and 3 years after initial chemoimmunotherapy.[57]

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 overall survival (OS) was 87% (93% for patients with MYD88 mutation/CXCR4 wild type; 80% for MYD88 mutation/CXCR4 mutation).[92]​ 

Ibrutinib plus rituximab is reported to have a 30-month progression-free survival (PFS) rate of 80% compared with 22% with placebo plus rituximab in previously treated patients (subgroup data).[74] MYD88 and CXCR4 mutations have been found to have little impact on PFS outcomes with ibrutinib plus rituximab.[74][75]​​​

Next-generation Bruton's tyrosine kinase (BTK) inhibitors, zanubrutinib and acalabrutinib, are highly effective and overall have less cardiovascular toxicity than ibrutinib.[76][77][93]

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).[76][77]​​ 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).

Acalabrutinib is not approved for the treatment of WM in the US or Europe, but US NCCN guidelines recommend off-label use in previously treated WM (based on the results of a large single-arm phase 2 trial).[37][93]

There is an increased risk of fatal and serious cardiac arrhythmias, cardiac failure, hypertension, and bleeding/bruising with ibrutinib.[18][73][74][78][79][80][81]​​​​ 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 anti-hypertensive medication should be started or adjusted as needed.[82]​

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.[83][84]​ Zanubrutinib may, however, cause less cardiovascular toxicity than ibrutinib.[76][77]​ 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.[79]

Immunoglobulin M (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]

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

See local specialist protocol for dosing guidelines.

Primary options

ibrutinib

OR

ibrutinib

and

rituximab

OR

zanubrutinib

OR

acalabrutinib

Consider – plasmapheresis (for symptomatic hyperviscosity)

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring between 1 and 3 years after initial treatment
Consider – 

plasmapheresis (for symptomatic hyperviscosity)

Additional treatment recommended for SOME patients in selected patient group

Plasmapheresis (plasma exchange) can be used to urgently treat symptomatic hyperviscosity (hyperviscosity syndrome).[35][36][57][85]

It can also be used prophylactically (i.e., before initiating rituximab-based treatment) in patients with immunoglobulin M (IgM) >40 g/L (or serum viscosity >4 centipoise) to minimise the risk of IgM flare.

Although plasmapheresis rapidly reduces serum IgM in WM, its effects are usually transient.[85]

Red blood cell transfusions may be given after plasmapheresis if the patient has severe anaemia, but care is required to prevent exacerbating hyperviscosity.[29]

Blood warmers should be used during plasmapheresis in patients with cryoglobulinaemia or cold agglutinin disease to prevent cryoprecipitation and/or erythrocyte agglutination.[29][35]​​​​[85]

1st line – alternative chemoimmunotherapy

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring between 1 and 3 years after initial treatment
1st line – 

alternative chemoimmunotherapy

A different chemoimmunotherapy regimen from that used for initial treatment can be considered for salvage therapy if ibrutinib is unsuitable or if relapse occurs later in this time period (e.g., 3 years).[57]​​ For example, if DRC was used initially, then BR, BDR, or VR may be considered, depending on age, comorbidities, and patient preference.[63][94][95][96][97][98]

For younger fit patients who are candidates for autologous stem cell transplantation, exposure to alkylating agents (e.g., bendamustine, cyclophosphamide) and nucleoside analogues should be carefully considered as these are toxic to stem cells.[29][56][57]​​ However, plerixafor can be used to mobilise stem cells for harvesting, even after treatment with stem cell-toxic agents.[101]

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

Consider – plasmapheresis (for symptomatic hyperviscosity)

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring between 1 and 3 years after initial treatment
Consider – 

plasmapheresis (for symptomatic hyperviscosity)

Additional treatment recommended for SOME patients in selected patient group

Plasmapheresis (plasma exchange) can be used to urgently treat symptomatic hyperviscosity (hyperviscosity syndrome).[35][36][57][85]

It can also be used prophylactically (i.e., before initiating rituximab-based treatment) in patients with immunoglobulin M (IgM) >40 g/L (or serum viscosity >4 centipoise) to minimise the risk of IgM flare.

Although plasmapheresis rapidly reduces serum IgM in WM, its effects are usually transient.[85]

Red blood cell transfusions may be given after plasmapheresis if the patient has severe anaemia, but care is required to prevent exacerbating hyperviscosity.[29]

Blood warmers should be used during plasmapheresis in patients with cryoglobulinaemia or cold agglutinin disease to prevent cryoprecipitation and/or erythrocyte agglutination.[29][35]​​​​[85]

2nd line – salvage chemotherapy + stem cell transplantation (in select patients)

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring between 1 and 3 years after initial treatment
2nd line – 

salvage chemotherapy + stem cell transplantation (in select patients)

Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is an option for highly selected patients (e.g., younger fit patients with advanced or chemosensitive aggressive disease who have relapsed, or who have refractory disease).[29][56][57]

ASCT is not recommended for patients with chemoresistant disease or those who have received more than three lines of chemotherapy.[56][102]

Use of ASCT in WM is controversial due to the lack of randomised 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.[102][103]

Non-relapse mortality rate with ASCT at 5 years is reported to be 5.6%, and 5-year overall survival (OS) rate is reported to be 68.5%.[102]

Allogeneic stem cell transplantation (alloSCT) with myeloablative, non-myeloablative, 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]​​​[57]​​​​​

Non-relapse mortality rate with alloSCT at 5 years is reported to be approximately 30%, and 5-year OS rate is reported to be 50% to 60%.[104][105][106]

All patients should be encouraged to participate in a clinical trial where possible.[101]​

1st line – repeat initial chemoimmunotherapy, or use a different chemoimmunotherapy regimen

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring >3 years after initial treatment
1st line – 

repeat initial chemoimmunotherapy, or use a different chemoimmunotherapy regimen

Relapse following initial treatment is common in patients with WM.

Salvage therapy can be used following relapse.

There is no standard of care for relapsed or refractory disease. However, duration of response with initial treatment can help guide salvage therapy.[35]​​​​[57][58][91][87]​​​​​ 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), and suitability for stem cell transplantation.​

Given the efficacy and tolerability of Bruton's tyrosine kinase (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.[57]

Alternatively, a different regimen can be used. For example, if DRC was used initially, then BR, BDR, or VR may be considered, depending on age, comorbidities, and patient preference.[63][94][95][96][97][98]

Other chemoimmunotherapy regimens (e.g., R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone] or FCR [fludarabine plus cyclophosphamide plus rituximab]) may be considered for salvage therapy, but should be used cautiously due to toxicity.[99][100]

For younger fit patients who are candidates for autologous stem cell transplantation, exposure to alkylating agents (e.g., bendamustine, cyclophosphamide, and chlorambucil) and nucleoside analogues (e.g., fludarabine) should be carefully considered as these are toxic to stem cells.[29][56][57]​ However, plerixafor can be used to mobilise stem cells for harvesting, even after treatment with stem cell-toxic agents.[101]

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

Consider – plasmapheresis (for symptomatic hyperviscosity)

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring >3 years after initial treatment
Consider – 

plasmapheresis (for symptomatic hyperviscosity)

Additional treatment recommended for SOME patients in selected patient group

Plasmapheresis (plasma exchange) can be used to urgently treat symptomatic hyperviscosity (hyperviscosity syndrome).[35][36][57][85]

It can also be used prophylactically (i.e., before initiating rituximab-based treatment) in patients with immunoglobulin M (IgM) >40 g/L (or serum viscosity >4 centipoise) to minimise the risk of IgM flare.

Although plasmapheresis rapidly reduces serum IgM in WM, its effects are usually transient.[85]

Red blood cell transfusions may be given after plasmapheresis if the patient has severe anaemia, but care is required to prevent exacerbating hyperviscosity.[29]

Blood warmers should be used during plasmapheresis in patients with cryoglobulinaemia or cold agglutinin disease to prevent cryoprecipitation and/or erythrocyte agglutination.[29][35]​​​​[85]

1st line – ibrutinib ± rituximab; or zanubrutinib; or acalabrutinib

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring >3 years after initial treatment
1st line – 

ibrutinib ± rituximab; or zanubrutinib; or acalabrutinib

Ibrutinib (with or without rituximab) as salvage therapy can be considered if relapse occurs >3 years after initial chemoimmunotherapy.[57]

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][73][78]

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 overall survival (OS) was 87% (93% for patients with MYD88 mutation/CXCR4 wild type; 80% for MYD88 mutation/CXCR4 mutation).[92]

Ibrutinib plus rituximab is reported to have a 30-month progression-free survival (PFS) rate of 80% compared with 22% with placebo plus rituximab in previously treated patients (subgroup data).[74] MYD88 and CXCR4 mutations have been found to have little impact on PFS outcomes with ibrutinib plus rituximab.[74][75]

Next-generation Bruton's tyrosine kinase (BTK) inhibitors, zanubrutinib and acalabrutinib, are highly effective and overall have less cardiovascular toxicity than ibrutinib.[76][77][93]

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).[76][77]​​ 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).

Acalabrutinib is not approved for the treatment of WM in the US or Europe, but US NCCN guidelines recommend off-label use in previously treated WM (based on the results of a large single-arm phase 2 trial).[37][93]

There is an increased risk of fatal and serious cardiac arrhythmias, cardiac failure, hypertension, and bleeding/bruising with ibrutinib.[18][73][74][78][79][80][81]​​ 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 anti-hypertensive medication should be started or adjusted as needed.[82]​

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.[83][84]​ Zanubrutinib may, however, cause less cardiovascular toxicity than ibrutinib.[76][77]​ 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.[79]

Immunoglobulin M (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]

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

See local specialist protocol for dosing guidelines.

Primary options

ibrutinib

OR

ibrutinib

and

rituximab

OR

zanubrutinib

OR

acalabrutinib

Consider – plasmapheresis (for symptomatic hyperviscosity)

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring >3 years after initial treatment
Consider – 

plasmapheresis (for symptomatic hyperviscosity)

Additional treatment recommended for SOME patients in selected patient group

Plasmapheresis (plasma exchange) can be used to urgently treat symptomatic hyperviscosity (hyperviscosity syndrome).[35][36][57][85]

It can also be used prophylactically (i.e., before initiating rituximab-based treatment) in patients with immunoglobulin M (IgM) >40 g/L (or serum viscosity >4 centipoise) to minimise the risk of IgM flare.

Although plasmapheresis rapidly reduces serum IgM in WM, its effects are usually transient.[85]

Red blood cell transfusions may be given after plasmapheresis if the patient has severe anaemia, but care is required to prevent exacerbating hyperviscosity.[29]

Blood warmers should be used during plasmapheresis in patients with cryoglobulinaemia or cold agglutinin disease to prevent cryoprecipitation and/or erythrocyte agglutination.[29][35]​​​​[85]

2nd line – salvage chemotherapy + stem cell transplantation (in select patients)

Back
ONGOING
|
relapse or refractory disease
|
relapse occurring >3 years after initial treatment
2nd line – 

salvage chemotherapy + stem cell transplantation (in select patients)

Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is an option for highly selected patients (e.g., younger fit patients with advanced or chemosensitive aggressive disease who have relapsed, or who have refractory disease).[29][56][57]

ASCT is not recommended for patients with chemoresistant disease or those who have received more than three lines of chemotherapy.[56][102]

Use of ASCT in WM is controversial due to the lack of randomised 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.[102][103]

Non-relapse mortality rate with ASCT at 5 years is reported to be 5.6%, and 5-year overall survival rate (OS) is reported to be 68.5%.[102]

Allogeneic stem cell transplantation (alloSCT) with myeloablative, non-myeloablative, 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][57]​​​​

Non-relapse mortality rate with alloSCT at 5 years is reported to be approximately 30%, and 5-year OS rate is reported to be 50% to 60%.[104][105][106]

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

1st line – ibrutinib ± rituximab; or zanubrutinib; or acalabrutinib

Back
ONGOING
|
relapse or refractory disease
|
refractory disease
1st line – 

ibrutinib ± rituximab; or zanubrutinib; or acalabrutinib

Salvage therapy can be used for refractory disease, but there is no standard of care.[35][57][58]​​[87][107]

Ibrutinib (with or without rituximab) as salvage therapy can be considered if there is no response to initial chemoimmunotherapy (i.e., primary refractory disease).[57]

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 overall survival (OS) was 87% (93% for patients with MYD88 mutation/CXCR4 wild type; 80% for MYD88 mutation/CXCR4 mutation).[92]

Ibrutinib plus rituximab is reported to have a 30-month progression-free survival (PFS) rate of 80% compared with 22% with placebo plus rituximab in previously treated patients (subgroup data).[74] MYD88 and CXCR4 mutations have been found to have little impact on PFS outcomes with ibrutinib plus rituximab.[74][75]​​​​

Next-generation Bruton's tyrosine kinase (BTK) inhibitors, zanubrutinib and acalabrutinib, are highly effective and overall have less cardiovascular toxicity than ibrutinib.[76][77][93]

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).[76][77]​ 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).

Acalabrutinib is not approved for the treatment of WM in the US or Europe, but US NCCN guidelines recommend off-label use in previously treated WM (based on the results of a large single-arm phase 2 trial).[37][93]

There is an increased risk of fatal and serious cardiac arrhythmias, cardiac failure, hypertension, and bleeding/bruising with ibrutinib.[18][73][74][78][79][80][81]​​​ 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 anti-hypertensive medication should be started or adjusted as needed.[82]​​

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.[83][84]​​ Zanubrutinib may, however, cause less cardiovascular toxicity than ibrutinib.[76][77]​​ 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.[79]

Immunoglobulin M (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]

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

See local specialist protocol for dosing guidelines.

Primary options

ibrutinib

OR

ibrutinib

and

rituximab

OR

zanubrutinib

OR

acalabrutinib

Consider – plasmapheresis (for symptomatic hyperviscosity)

Back
ONGOING
|
relapse or refractory disease
|
refractory disease
Consider – 

plasmapheresis (for symptomatic hyperviscosity)

Additional treatment recommended for SOME patients in selected patient group

Plasmapheresis (plasma exchange) can be used to urgently treat symptomatic hyperviscosity (hyperviscosity syndrome).[35][36][57][85]

It can also be used prophylactically (i.e., before initiating rituximab-based treatment) in patients with immunoglobulin M (IgM) >40 g/L (or serum viscosity >4 centipoise) to minimise the risk of IgM flare.

Although plasmapheresis rapidly reduces serum IgM in WM, its effects are usually transient.[85]

Red blood cell transfusions may be given after plasmapheresis if the patient has severe anaemia, but care is required to prevent exacerbating hyperviscosity.[29]

Blood warmers should be used during plasmapheresis in patients with cryoglobulinaemia or cold agglutinin disease to prevent cryoprecipitation and/or erythrocyte agglutination.[29][35]​​​​[85]

2nd line – salvage chemotherapy + stem cell transplantation (in select patients)

Back
ONGOING
|
relapse or refractory disease
|
refractory disease
2nd line – 

salvage chemotherapy + stem cell transplantation (in select patients)

Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is an option for highly selected patients (e.g., younger fit patients with advanced or chemosensitive aggressive disease who have relapsed, or who have refractory disease).[29][56][57]

ASCT is not recommended for patients with chemoresistant disease or those who have received more than three lines of chemotherapy.[56][102]

Use of ASCT in WM is controversial due to the lack of randomised 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.[102][103]

Non-relapse mortality rate with ASCT at 5 years is reported to be 5.6%, and 5-year overall survival (OS) rate is reported to be 68.5%.[102]

Allogeneic stem cell transplantation (alloSCT) with myeloablative, non-myeloablative, 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][57]​​​​

Non-relapse mortality rate with alloSCT at 5 years is reported to be approximately 30%, and 5-year OS rate is reported to be 50% to 60%.[104][105][106]

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

back arrow

Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

Use of this content is subject to our disclaimer