Guidelines Summary
Guidelines on the diagnosis, treatment, and follow-up of Waldenström macroglobulinemia (WM) have been published by the National Comprehensive Cancer Network (NCCN), the European Society for Medical Oncology (ESMO), and the British Society for Haematology. [58, 59] The 10th International Workshop for Waldenström Macroglobulinaemia (IWWM-10) has published consensus recommendations on treatment. [32]
Diagnosis (BSH)
NCCN and ESMO guidelines concur that WM is diagnosed on the basis of histopathologic confirmation of bone marrow (BM) infiltration by monoclonal lymphoplasmacytic cells. [59, 58] BM infiltration is supported by immunophenotypic studies such as flow cytometry and/or immunohistochemistry. NCCN guidelines define the typical profile of WM cells as positive for slgM, CD19, CD20, CD22. [58] The typical profile defined by ESMO is positive for CD19, CD20, CD22 and CD79a on the lymphocytic component and CD38 on the plasmacytic component. [59]
NCCN guidelines also note that although WM lymphocytes are typically negative for CD5, CD10, and CD23, this should not exclude diagnosis, as 10-20% of cases express these proteins. [58]
Approximately 90% of patients with WM have the MYD88L265P mutation. Although this mutation alone is not diagnostic of WM, it may be useful for differentiating WM from other types of lymphoma and IgM multiple myeloma. [59, 58] The BSH recommends assessment of MYD88L265P in all patients undergoing bone marrow assessment. [60]
Staging and Risk Assessment
All three guidelines concur that the initial workup for WM includes the following [59, 58, 60] :
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Complete blood cell (CBC) count
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Serum chemistry
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Beta-2 microglobulin (B2M)
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Serum protein electrophoresis
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IgM quantification
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CT scans with contrast when possible
Although CXCR4 mutations are found in approximately 30% of patients with WM, the NCCN and ESMO guidelines recommend testing for this genetic mutation only in patients considering treatment with ibrutinib. [59, 58]
A neurologist should be consulted for neuropathy, since it may not be associated with WM. Amyloidosis should be ruled out in patients presenting with nephrotic syndrome or unexplained cardiac issues. Amyloidosis is uncommon in patients with WM. If it is suspected, a fat aspirate stained with Congo red and cardiac and renal biomarkers should be evaluated. [59, 58, 60]
A retinal examination is recommended in patients with hyperviscosity symptoms. [59, 58]
The NCCN finds the following additional tests useful in selected patients [58] :
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Serum viscosity
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Hepatitis C testing and cryocrit for patients with suspected cryoglobulinemia; if cryocrit is positive, initial serum IgM test should be repeated and all subsequent IgM levels should be obtained in warm conditions
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Hepatitis B testing, if treatment with rituximab is planned
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Coagulation testing should be considered in patients with symptoms of excess bruising or bleeding; von Willebrand disease (VWD) testing is indicated only if clinical bleeding and bruising are present
The ESMO guidelines include the following additional recommendations:
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Anemia should prompt consideration of Coombs testing, cold agglutinins, cryoglobulins, and iron status.
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Risk assessment is currently based on the International Prognostic Scoring System for WM (IPSSWM).
The BSH guidelines consider that screening for hepatitis B and C and human immunodeficiency virus (HIV) infection is required prior to the introduction of treatment. [60]
Treatment
NCCN guidelines recommend treatment of WM only in patients with the following manifestations [58] :
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Hyperviscosity
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Neuropathy
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Organomegaly
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Amyloidosis
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Cold agglutinin disease
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Cryoglobulinemia
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Anemia and other cytopenias associated with WM
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Bulky adenopathy
ESMO and BSH guidelines similarly recommend treatment in patients with constitutional symptoms, cytopenias, hyperviscosity, moderate or severe neuropathy, amyloidosis, symptomatic cryoglobulinemias, and/or cold agglutinin disease. Asymptomatic WM should be managed with watchful waiting, with monitoring every 3-6 months. [59, 60]
The NCCN and ESMO advise that a high monoclonal IgM level alone generally does not justify treatment initiation in the absence of other symptoms. [59, 58] When treatment is indicated, however, BSH guidelines recommend deferring the introduction of rituximab or performing prophylactic plasmapheresis in patients considered at a higher risk of hyperviscosity, as defined by an IgM/M-protein > 40 g/L. [60] All three guidelines recommend treating hyperviscosity syndrome with plasmapheresis for immediate relief, followed by appropriate systemic therapy. [59, 58, 60]
For the primary treatment of WM, the NCCN and the IWWM-10 recommend the following as preferred regimens (listed aphabetically) [58, 32] :
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Bendamustine plus rituximab
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Bortezomib, dexamethasone, and rituximab
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Ibrutinib with or without rituximab (NCCN category 1 recommendation)
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Rituximab, cyclophosphamide, and dexamethasone
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Zanubrutinib (NCCN category 1 recommendation)
The IWWM-10 also lists the following as treatment options [32] :
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Acalabrutinib
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Carfilzomib, dexamethasone, and rituximab
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Fludarabine and rituximab
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Ixazomib, dexamethasone, and rituximab
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R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone)
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R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone)
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Rituximab
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Ofatumumab
Additional IWWM-10 treatment recommendations are as follows [32] :
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Avoid bortezomib and vincristine in patients with neuropathy
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Avoid carfilzomib in patients with cardiac disease and those older than 65 years
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Avoid nucleoside analogues (ie, fludarabine, cladribine) in patients who are candidates for stem-cell transplantation
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Consider delaying rituximab if serum IgM concentrations are greater than 4000 mg/dL, due to risk of IgM flare
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Consider ofatumumab in patients who are intolerant to rituximab
ESMO-recommended primary treatment options include rituximab plus alkylating agents (oral or IV cyclophosphamide or bendamustine) or proteasome inhibitors. Monotherapy with alkylating agents, nucleoside analogues, or rituximab should be considered only in patients who are not candidates for more effective chemoimmunotherapy combinations. [59]
ESMO and BSH guidelines do not recommend rituximab maintenance therapy; [59, 60] The NCCN recommends considering rituximab for maintenance in patients who have achieved a complete, very good, partial, or minor response to induction therapy. [58]
For relapsed disease, NCCN recommends repeating the regimen used for primary treatment, especially if it was well tolerated and the patient had a prolonged response. For relapse that occurs after less than 24 months, or progressive disease, the patient may be treated with a different class of drugs, either alone or in combination. Ofatumumab may be used for rituximab-intolerant patients. [58]
According to ESMO guidelines, the treatment of choice for WM relapse within 12 months of chemoimmunotherapy, including rituximab-refractory disease, is ibrutinib monotherapy. Ibrutinib monotherapy may be considered in patients who are ineligible for chemoimmunotherapy as first-line therapy. In patients with late WM relapses after chemoimmunotherapy, regimens to consider include an alternative chemoimmunotherapy combination, a prior effective regimen, or ibrutinib. [59]
Autologous stem cell transplantation (ASCT) may be appropriate in select patients. [59, 58] BSH guidelines recommend against offering ASCT to patients with less than a partial response but advise that ASCT can be considered as a second- or later line of therapy in selected chemotherapy-responsive patients (eg, those with amyloidosis who are in first remission), although its use remains contentious because of the new drugs becoming available. [60]
All patients with WM should be strongly encouraged to enroll in clinical trials.
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Purpura from Waldenström macroglobulinemia is evident in the forearm of a 65-year-old man who presented with a purpuric rash on all of his extremities. Although the patient had a history of hepatitis C, the possibility of hepatitis C cryoglobulinemia was excluded because the rash extended well beyond the hands and feet, and blood testing identified a type I cryoglobulinemia. Image courtesy of Jason Kolfenbach, MD, and Kevin Deane, MD, Division of Rheumatology, University of Colorado Denver School of Medicine.
Tables
Point total |
Risk group |
3-year WM-related death rate (%) |
10-year overall survival rate (%) |
| 0 | Very low |
0 |
84 |
| 1 | Low | 10 |
59 |
| 2 | Intermediate | 14 |
37 |
| 3 | High | 38 |
19 |
| 4-5 | Very high |
48 |
9 |
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