Waldenström macroglobulinemia (ORPHA:33226)
Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoproliferative disorder characterized by the accumulation of monoclonal cells in the bone marrow and peripheral lymphoid tissues, and associated with the production of serum immunoglobulin M (IgM) monoclonal protein.
Epidemiology
WM has an overall incidence of 1/260,000 persons/year in the USA and a prevalence estimate of about 1/102,220 in Europe. It accounts for approximately 2% of all hematological malignancies.
Clinical description
The median age at diagnosis is 72 years and it is twice as frequent in men. The main clinical features are hepatosplenomegaly, lymphadenopathy, constitutional symptoms, oronasal bleeding, hyperviscosity syndrome and cytopenia. Fatigue related to normochromic normocytic anemia is the most common presenting symptom. Visceral infiltration is rare but may target the stomach, small bowel, lungs, exocrine glands or skin, accounting for such symptoms as diarrhea, steatorrhea and purpura of the skin. Retinal hemorrhage or serious neurologic complications (mental confusion, stroke) may occur in cases with hyperviscosity syndrome. Peripheral neuropathy is present in up to 38% of WM patients. Nephrotic syndrome has been associated with WM in a few cases. Major complications include bone marrow failure, autoimmune cytopenia, large B-cell lymphoma, immune complex vasculitis and infections.
Etiology
Exact etiology is unknown. Immune-related factors are thought to be involved and WM clearly has a familial component as first degree relatives of WM patients have an increased risk of developing the disease. No susceptibility genes have yet been identified but susceptibility loci have been mapped to chromosome 6p21.3 and 4q and half of WM patients have 6q deletions on tumor cells. A highly recurrent MYD88 (3p22) somatic mutation (L265P) has recently been identified in 90% of WM patients.
Diagnostic methods
Diagnosis is confirmed by the presence of an IgM monoclonal protein in the serum and a bone marrow biopsy (showing ≥10% clonal lymphoplasmacytic cells). WM's pathologic designation is lymphoplasmacytic lymphoma according to the WHO Classification of Tumors. Cells test negative for CD3 and CD103 markers but express pan B cell markers CD19 and CD20. The median hemoglobin value seen at diagnosis is 10g/dL. Serum protein electrophoresis and immunofixation as well as computed tomography (CT) of abdomen and pelvis contribute to diagnosis. Splenomegaly and/ or lymphadenopathies are observed in 30% of the patients.
Differential diagnosis
Differential diagnoses include multiple myeloma, B-cell chronic lymphocytic leukemia, other forms of non-Hodgkin lymphoma (see these terms), and monoclonal gammapathies of undetermined significance. Infections like hepatitis, AIDS, and various rheumatological disorders also raise IgM levels. The presence of a MYD88 L265P mutation distinguishes WM from other closely-related B-cell chronic lymphoproliferative disorders such as marginal zone lymphoma without IgM spike.
Management and treatment
There is no cure for WM. Patients in an asymptomatic stage are simply monitored. Treatments given to symptomatic patients depend on many factors (e.g. age, disease progression) and can include alkylating agents, purine nucleoside analogs, rituximab (RT) and bortezomib. Initial treatment is usually an RT-based therapy like RT plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or dexamethasone, RT and cyclophosphamide (DRC). Bortezomib-based therapies are used when rapid disease control is needed or for patients who are candidates for autologous stem cell transplantation (ASCT). For those with profound cytopenias, DRC or RT is preferable. Salvage treatments can involve the use of the initial agents or agents of a different class, alone or combined. A PNA-based regimen or ASCT may be suitable for some as a salvage treatment option. Ibrutinib, a B-cell receptor pathway inhibitor, has recently been approved for symptomatic WM patients as a first-line treatment, particularly for those who are not candidates for chemo-immunotherapy, and in relapsing patients.
Prognosis
Median survival time is 5-6 years after starting treatment but WM can be stable or progress slowly for many years before needing treatment.

                            Last update: 
                            March 2016


                            - Expert reviewer(s): 
                            Pr Véronique LEBLOND