Waldenstrom Macroglobulinemia Guidelines

Updated: May 29, 2020
  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Guidelines

Guidelines Summary

Guidelines on the diagnosis, treatment, and follow-up of Waldenström macroglobulinemia (WM) have been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO). [54, 55]

Diagnosis

NCCN and ESMO guidelines concur that WM is diagnosed on the basis of histopathologic confirmation of bone marrow (BM) infiltration by monoclonal lymphoplasmacytic cells. [55, 54] 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. [54] The typical profile defined by ESMO is positive for CD19, CD20, CD22 and CD79a on the lymphocytic component and CD38 on the plasmacytic component. [55]

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. [54]

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. [55, 54]

Staging and Risk Assessment

Both guidelines concur that the initial workup for WM includes the following [55, 54] :

  • Complete blood cell (CBC) count
  • Serum chemistry
  • Beta-2 microglobulin (B2M)
  • Serum protein electrophoresis
  • IgM quantification
  • CT scans with contrast when possible

Although CXCR4 mutations are found in approximately 30% of patients with WM, testing for this genetic mutation is recommended only for patients considering treatment with ibrutinib. [55, 54]

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. [55, 54]

A retinal examination is recommended in patients with hyperviscosity symptoms. [55, 54]

NCCN finds the following additional tests useful in selected patients [54] :

  • Serum viscosity
  • 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
  • Hepatitis B testing, if treatment with rituximab is planned
  • 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:

  • Anemia should prompt consideration of Coombs testing, cold agglutinins, cryoglobulins, and iron status.
  • Risk assessment is currently based on the International Prognostic Scoring System for WM (IPSSWM).

Treatment

NCCN guidelines recommend treatment of WM only in patients with the following symptoms [54] :

  • Hyperviscosity
  • Neuropathy
  • Organomegaly
  • Amyloidosis
  • Cold agglutinin disease
  • Cryoglobulinemia
  • Anemia and other cytopenias associated with WM
  • Bulky adenopathy

High monoclonal IgM level alone generally does not justify treatment initiation in the absence of other symptoms. [55, 54]  

ESMO 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. [55]

Both guidelines recommend treating hyperviscosity syndrome with plasmapheresis for immediate relief, followed by appropriate systemic therapy. [55, 54]

The NCCN's preferred regimens for the primary treatment of WM include the following [54] :

  • Ibrutinib with or without rituximab (category 1 recommendation)
  • Bendamustine/rituximab
  • Bortezomib/dexamethasone/rituximab
  • Rituximab/cyclophosphamide/dexamethasone

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. [55]

ESMO guidelines do not recommend rituximab maintenance therapy; [55] The NCCN recommends considering rituximab for maintenance in patients who have achieved a complete, very good, partial, or minor response to induction therapy. [54]  

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. [54]

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. [55]

Autologous stem cell transplantation (ASCT) may be appropriate in select patients. [55, 54]

All patients with WM should be strongly encouraged to enroll in clinical trials.