Waldenstrom’s macroglobulinemia


Low-grade lymphoma.

A lymphoplasmacytic lymphoma.

WM harbors two highly recurrent somatic mutations: MYD 88 and CXCR4 genes.

The MYD 88L L265P mutation has a prevalence of more than 90% of patients with WM and has helped overcome diagnostic challenges.

The MYD 88 L265P, and CXCR4  mutations are associated with specific clinical manifestations and correlate with prognosis.

The MYD 88 L265P  is a varianT in which leucine changes to proline at amino acid position 365 in the MYD 88 gene.

The prevalence of CXCR 4 gene mutations with WM is as high as 40% in some studies.

Patient with CXCR 4 and MYD 88 have more bone marrow involvement, lower platelet counts, higher serum levels of IgM, and a higher rate of hyperviscosity syndrome and acquired Von Willebrand disease in comparison with other groups.

Overall incidence is approximately 3- 5 cases per 1 million persons per year.

Incidence rate of 0.57 per 100,000 person-years.

Accounts for approximately 1-2% of hematologic cancers.

Approximately 1500 new cases a year reported in the US.

Incidence highest in white people.

Median age at diagnosis between 63 and 68 years.

Newly diagnosed patients are male 55-70% of the time.

Bone marrow infiltration and extra medullary sites of malignant B cells and elevated IgM levels account for symptoms.

The IgM paraprotein can result in significant comorbidities, including symptomatic hyperviscosity, neuropathy, and autoimmune related complications.

It occurs as a major progression event in the course of IgM MGUS.

Bone marrow has 10% or more bone marrow infiltration by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation, and the typical immunophenotype surface IgM+ positive, CD19+, CD20 +, CD5+/-, CD10-, and CD23-as well as as well as exclusion of other lymphoproliferative disorders including CLL and lymphoma.

The size of the monoclonal igM protein is often greater than 3 g/dL, but a specific level is not required for diagnosis.

An overlap exists between IGM gammopathy of undetermined significance and asymptomatic WM.

Approximately 25% of patients are asymptomatic at diagnosis.

Presentation usually involves nonspecific symptoms such as fatigue, fever, malaise, and weight loss.

Anemia is present in approximately one-third of patients due to multiple factors such as marrow infiltration of B cells, inadequate erythropoiesis, hyper viscosity related GI bleeding, decreased red cell survival due to IGM – associated hemolysis.

The most common disease manifestations are anemia and thrombocytopenia, related to bone marrow involvement.

Other frequent symptoms are caused by enlargement of lymph nodes and spleen.

Incurable at present, with a median survival of approximately 5 years.

Because it is a disease of the elderly approximately half of the patients die of causes unrelated to the disease.

Incidence higher in white people with only 5% of cases in blacks.

Accounts for 2% of monoclonal gammopathies.

55-70% of patients are men.

Half of patients die of causes unrelated to the disease.

Smoldering Waldenstrom’s macroglobulinemia is defined as the presence of serum monoclonal IgM protein of 3 g/dL or greater and 10% or more bone marrow lymphoplasmacytic infiltration but without evidence of an organ damage such as anemia, constitutional symptoms, hyperviscosity, symptomatic lymphadenopathy, or hepatosplenomegaly.

Prognostic factors include the patient’s age, beta2 microglobulin level, monoclonal protein level, hemoglobin concentration, and platelet count.

Median age 65 years.

20% present with hyperviscosity syndrome.

Characterized by elevated levels of IgM, symptoms of hyperviscosity and infiltration of tissues with lymphocytoid cells.

Bone marrow infiltration with lymphoplasmacytoid lymphoma.

Bone marrow is infiltrated in a predominantly intertrabecular pattern.

Associated with increased mast cells.

Bone marrow mast cells overexpress CD40 ligand a potent inducer of B cell expression.

Classified as lymphoplasmacytic lymphoma in the REAL classification and WHO schema, with bone marrow infiltration by lymphoplasmacytic lymphoma and IgM monoclonal gammopathy

Characterized by plasma cells proliferative disorder associated with production of abnormally large amounts of gammaglobulin of the 19S or IgM type.

Diagnosis supported by immunophenotypic profile of cell surface IgM, CD5-, CD10-, CD19+, CD20+, CD 22+ and CD23-, CD 27+, FMC-7+ and CD103-.

MYD88 L265P is a commonly recurring mutation in patients with WM.

MYD88 a single activating somatic mutation results in protein change from leucine to proline at amino acid position 265 .

The above mutation can be useful in differentiating Waldenstrom’s macroglobulinemia and non-IgM lymphoplasmacytic lymphoma (Treon SP et al).

Associated with multiple activating mutations at the C-terminal domain of CXCR4 .

MYD88 activates nuclear factor kB through divergent pathways involving Bruton’s tyrosine kinase.

10-20% of patients have positive CD5, positive CD10 and positive CD23., therefore the presence of these antigens do not exclude the diagnosis.

Absence of Ig heavy chain (IgH) rearrangements.

Mainly a sporadic disease.

Clinical manifestations of Waldenstrom’s macroglobulinemia include cytopenia from bone marrow infiltration by lymphoplasmacytic cells, paraprotein related cryoglobulinemia, the cold agglutinin syndrome, demyelinating neuropathy, and hyperviscosity syndrome.

IgM monoclonal gammopathy of unknown significance (MGUS) is characterized by the presence of monoclonal IgM protein in the absence of bone marrow disease involvement on histologic examination.

Anemia is the most common symptom.

Patients present with symptoms attributable to to bone marrow infiltration and or due to the monoclonal protein elevation.

IgG MGUS can progress to WM or other B-cell lymphoproliferative disorders, with an estimated progression of 1.5-3% per year.

Possible role of a single genetic defect with 18.7% of patients with at least one first degree relative with a familial history of Waldenstrom’s or another B cell disorder.

Patients with family history of Waldenstrom’s or a plasma cell disorder receive the diagnosis at a younger age and with increased bone marrow involvement.

Deletions in 6q21-22.1 confirmed in most patients.

Main risk factor is the presence of a preexisting IgM monoclonal gammopathy of undetermined significance, with a 46 times increases in relative risk.

In some patients predominant symptoms related the elevated serum viscosity related to IgM.

80% of IgM is intravascular and plasmapheresis may be effective management.

25% of patients have neurologic complications.

Most neurologic complications are related to serum hyperviscosity syndrome and immune related neuropathy.

Malignant lymphoid infiltration of the CNS is called above Bing-Neel syndrome, and is very rare.

Median survival 5-10 years.

Most patients die from disease progression.

Survival depends on tumor burden and aggressiveness of the disease at presentation.

Patients with low levels of B2M and hemoglobin levels of 12 gm/dL have excellent prognoses and have a low probability for requiring therapy.

The International Prognostic Staging System WM for symptomatic patients characterizes the patient’s into 3 distinct groups with a 5 year survival rate for the high risk group of 36%.

Initiation of therapy is necessary for patients with constitutional symptoms, symptomatic lymphadenopathy or splenomegaly, hemoglobin less than 10 g/dL, platelet count less than 100,000, with the presence of symptomatic hyperviscosity, severe sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, and symptomatic cryoglobulimemia.

Individuals considered for treatment include those with hemoglobin below 10.0 gm/dL, platelet count less than 100,000 mm/3, bulky lymph nodes, splenomegaly, hyperviscosity, neuropathy, cryoglobulinemia, cold agglutinin disease, amyloidosis, and disease transformation.

In rare cases diffuse infiltration of the lung with infiltrates, pleural effusion and nodules can occur.

Rare cases of involvement of the gastrointestinal tract, skull and orbit have been reported.

Rarely can involve the eye.

Hyperviscosity symptoms include mucocutaneous bleeding, visual disturbances from retinal flame shaped hemorrhages, headache, epistaxis, dizziness, deafness, and altered mental status.

Bing-Neel syndrome can occur when long standing hyperviscosity leads to vascular permeability and perivascular infiltration of malignant cells causing headache, vertigo, hearing deficits, ataxia, nystagmus, diplopia and coma.

Bing-Neel syndrome can present as a diffuse infiltrative process or an intraparenchymal tumoral lesion.

Bing-Neel syndrome reported at with almost equal frequency in men and women in the mean age of 61 years.

Bing-Neel syndrome usually a late presentation complication of Waldenstrom’s.

Most cases of Bing-Neel syndrome were discovered at autopsy, but today diagnosis can be made with clinical suspicion and the use of imaging modalities such as the MRI.

The prognosis of Bing-Neel syndrome has been quite poor with most patients dying within days to months of diagnosis, but today interventricular chemotherapy and cranial radiation may result in durable and sustainable remissions.

Ibrutinib has been found to have high efficacy in the Bing-Neel syndrome.

Chorambucil was the mainstay of therapy but the disease may respond to other alkylating agents, anti-CD20 monoclonal antibody, fludarabine and 2-CDA.

Oral chlorambucil results in partial response in approximately 50% of patients but with rare complete responses.

Chlorambucil causes a slow rate of decreased monoclonal protein level and associated with a median survival of 5.4 years.

Optimal duration of chlorambucil administration is unknown and maintenance does not prolong survival.

Rituximab at 375 mg/m2 per week times 4 results in a 27% partial response rate and if repeated at 12 weeks increases response rate to 44-48%.

Time to response following rituximab is slow and exceeds 3 months on average.

Rituximab mediated IgM flare occurs in about 40 – 50% of patients.

Dexamethasone-rituximab-cyclophosphamide can be an alternative treatment for patients with symptomatic Waldenstrom macroglobulinemia with a low disease burden.

Rituximab maintenance therapy is not recommended for routine use outside of clinical trials.

Rituximab monotherapy is contraindicated if patients have symptomatic hyperviscosity; without preemptive plasmapheresis, this treatment should be avoided in those with very high serum IgM.

Prompt start of therapeutic plasma exchange for hyperviscosity syndrome, is used before starting cytoreductive treatment.

Rituximab is indicated for symptomatic mild to moderate anemia, symptomatic cryoglobulinemia, or hemolytic anemia that does not respond to corticosteroids.

In cases of first or second relapse, autologous stem cell transplantation should be considered in patients with chemosensitive disease who are eligible for transplant.

IgM flare can cause significant morbidity with worsening serum viscosity and symptomatic hyperviscosity.

IgM flare can last up to several weeks or months.

Symptomatic patients should be treated while those without problems should be observed until disease progression.

Symptoms and signs include fever, sweats, fatigue, weight loss, hyperviscosity syndrome, amyloidosis, cryoglobulinemia, cold agglutinin disease, adenopathy, anemia and thrombocytopenia.

Since serum monoclonal protein levels do not correlate well with symptoms it should not be used associated an indication for treatment.

Monoclonal IgM levels greater than 5 g/dL put the patient at a high risk for hyperviscosity.

New Treatment Recommendations for Waldenstrom Macroglobulinemia

Therapeutic strategies are based on individual patient and disease characteristics.

Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients.

Four to six cycles of bendamustine/rituximab is the primary regimen of choice for symptomatic, treatment-naive patients with Waldenstrom macroglobulinemia, especially when rapid control is needed for bulky disease.

BTK inhibitor ibrutinib is an effective treatment option for both treatment-naive and relapsing patients.

As monotherapy Ibrutinib response rate for WM is 90% in overall group, Who are the two year progression for a survival of 69%.

Other B-cell receptor inhibitors, second-generation proteasome inhibitors, and mammalian target of rapamycin inhibitors are promising and may increase future treatment options.

Plasmapheresis can reduce serum IgM by 20-30% with a reduction in viscosity by 50-60% with as little as one exchange although several may be needed for prolonged relief of symptoms.

Allogeneic stem cell transplantation can induce remissions in selected young patients that have been heavily pretreated.

For Waldenstrom’s macroglobulinemia Ibrutinib responses are durable, reducing IgM levels and improving hemoglobin in patients with relapsed or refractory WM.

In patients with Waldenstrom’s with a CXCR4 mutation (appoximately 30% of such patients) are less likely to have a major response to Ibrutinib.

In the phase III INNOVATE trial the ibrutinib/Rituximab combination lowered the risk of disease progression or death by 80% versus rituximab alone.

Acallbrutinib has a high degree of efficacy in durable responses with an acceptable safety profile.

Venetoclax has a high degree of efficacy in the treatment of patients with relapse to refractory WM regardless of CXCR4 mutational status.

The combination of ixazomib with rituximab and dexamethasone has a high degree of efficacy, with deep responses and short of times to respond in the CXCR 4 patients.


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