Waldenstrom Macroglobulinemia

Practice Essentials

Waldenström macroglobulinemia, one of the malignant monoclonal gammopathies, is a chronic, indolent, lymphoproliferative disorder.^{[1, 2]} It is characterized by the presence of a high level of a macroglobulin (immunoglobulin M [IgM]), elevated serum viscosity, and the presence of a lymphoplasmacytic infiltrate in the bone marrow.^[3] (See Pathophysiology, Etiology, and Workup.) 

A clonal disease of B lymphocytes, Waldenström macroglobulinemia is considered to be a lymphoplasmacytic lymphoma, as defined by the Revised European American Lymphoma Classification (REAL) and World Health Organization (WHO) classification.

The clinical manifestations of Waldenström macroglobulinemia result from the presence of the IgM paraprotein and malignant lymphoplasmacytic cell infiltration of the bone marrow and other tissue sites. The clinical presentation is similar to that of multiple myeloma except that (1) organomegaly is common in Waldenström macroglobulinemia and is uncommon in multiple myeloma and (2) lytic bony disease and renal disease are uncommon in Waldenström macroglobulinemia but are common in multiple myeloma. (See Pathophysiology, Presentation, and Workup.)

Waldenström macroglobulinemia is not curable, but a number of therapies have shown activity in the disease. Data from randomized trials remain sparse, however.^{[4, 5]}

For asymptomatic patients without end-organ damage, management consists of careful observation. In symptomatic patients, monotherapy with rituximab is the usual choice, especially for nonbulky disease. Bulky symptomatic disease may require combination regimens, such as chemotherapy.^[6] Ibrutinib has demonstrated efficacy as monotherapy for rituximab-resistant cases, especially those with mutations in the MYD88 gene.^[7]  Hyperviscosity syndrome may mandate emergency plasmapheresis. Autologous stem cell transplantation is a consideration in select cases. (See Treatment.)

Complications

Complications of Waldenström macroglobulinemia include the following:

• Hyperviscosity syndrome
• Visual disturbances secondary to hyperviscosity syndrome
• Diarrhea and malabsorption secondary to gastrointestinal (GI) involvement
• Renal disease (less common)
• Amyloidosis of the heart, kidney, liver, lungs, and joints
• Bleeding manifestations secondary to platelet dysfunction and coagulation factor and fibrinogen abnormalities due to interaction with plasma IgM
• Peripheral neuropathy
• Raynaud phenomenon secondary to cryoglobulinemia
• Increased predisposition to infection due to B-cell dysfunction (disease related) or T-cell dysfunction (therapy related, particularly after nucleoside analogues)
• Cardiac failure
• Increased incidence of lymphomas, myelodysplasia, and leukemias

• References

Pathophysiology

The clinical manifestations of this disorder result from 2 important factors. First, secretion of the IgM paraprotein leads to hyperviscosity and vascular complications because of physical, chemical, and immunologic properties of the paraprotein. These complications include the following:

• Hyperviscosity syndrome
• Cryoglobulinemia types 1 and 2
• Coagulation abnormalities
• Sensorimotor peripheral neuropathy
• Cold agglutinin disease and anemia
• Primary amyloidosis
• Tissue deposition of amorphous IgM in the skin, GI tract, kidneys, and other organs

Second, neoplastic lymphoplasmacytic cells infiltrate the bone marrow, spleen, and lymph nodes. Less commonly, these cells can infiltrate the liver, lungs, GI tract, kidneys, skin, eyes, and central nervous system (CNS). Infiltration of these organs causes numerous clinical symptoms and signs.

Occasionally, IgM paraprotein has (1) rheumatoid factor activity, (2) antimyelin activity that can contribute to peripheral neuropathy, and (3) immunologically related lupus anticoagulant activity.

A study by Pasricha et al found that bone marrow features, particularly the degree of plasma cell infiltration, correlates with IgM paraprotein concentration at diagnosis. Thus, evaluation of the plasma cell compartment in the bone marrow at baseline and after therapy may be helpful.^[8]

Jalali et al reported that levels of soluble programmed cell death protein 1 (PD-1) ligands are elevated in patients with Waldenström macroglobulinemia and, in addition to surface-bound ligands in bone marrow, could regulate T-cell function. These authors propose that soluble PD-1 ligands have the potential to promote disease progression in Waldenström macroglobulinemia.^[9]

• References

Etiology

No definite etiology exists for Waldenström macroglobulinemia. Environmental, familial, genetic, and viral factors have been reported. IgM monoclonal gammopathies of undetermined significance (MGUS) are considered a precursor of Waldenström macroglobulinemia.

A possible role for genetic factors has been suggested by reports of familial clustering of Waldenström macroglobulinemia. In one study, approximately 20% of 181 serial Waldenström macroglobulinemia patients presenting to a tertiary referral had a first-degree relative with either Waldenström macroglobulinemia or another B-cell lymphoproliferative disease. Reports of familial cases suggest a genetic predisposition.^{[10, 11]}

The MYD88 L265P somatic mutation, in which leucine is replaced by proline at position 265, is found in white blood cells in approximately 90% of Waldenström macroglobulinemia cases. The mutation results in overactivity of the altered MyD88 protein, stimulating the signaling molecules that activate nuclear factor-kappa-B; this may protect lymphoplasmacytic cells against apoptosis.^[12]

Less common somatic genetic changes that have been found in Waldenström macroglobulinemia include variants in ARID1A, which have been associated with increased disease burden, and variants in MLL2.^[10]  Other MYD88 mutations have also been found. Somatic activating mutations in the C-terminal domain of the C-X-C chemokine receptor type 4 (CXCR4) gene have been found in 20% to 40% of patients.^[13]

Hepatitis C, hepatitis G, and human herpesvirus 8 have been implicated, but as yet, no strong data support a causative link between these viruses and Waldenström macroglobulinemia.

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Epidemiology

Waldenström macroglobulinemia is a relatively rare condition, with the 1500 cases diagnosed per year in the United States accounting for approximately 2% of hematologic malignancies. The incidence rate for Waldenström macroglobulinemia in the United States is higher among whites, with people of African descent representing only 5% of all patients. In the United Kingdom, the annual incidence of the disease is 10.3 per million.^[14]

Waldenström macroglobulinemia is a disease of the elderly. Most patients present in the seventh or eighth decade of life. The median age at diagnosis in the United States is 65 years, with a slight male predominance.

• References

Prognosis

Waldenström macroglobulinemia is an indolent disorder, and patients survive for a median of approximately 78 months. Kaplan-Meier survival curves of patients with Waldenström macroglobulinemia do not show a plateau.^[15]

Different studies have been performed to assess prognosis. Patients with a nodular type of bone marrow involvement tend to do better than those with diffuse involvement.^[16]

Bustoros et al identified the following as independent predictors of progression from asymptomatic to overt Waldenström macroglobulinemia^[17] :

• Immunoglobulin M ≥4500 mg/dL
• Bone marrow lymphoplasmacytic infiltration ≥70%
• Beta2-microglobulin ≥4.0 mg/dL
• Serum albumin ≤3.5 g/dL 

Kastritis et al have developed and validated an updated international prognostic score system for Waldenström macroglobulinemia.^[18] The system uses the following criteria:

• Age: ≤65 years, 0 points; 66-75 years, 1 point; ≥76 years, 2 points
• Beta2-microglobulin > 4 mg/L: 1 point
• Lactate dehydrogenase ≥ 250 IU/L (upper limit of normal <  225 IU/L): 1 point
• Serum albumin < 3.5 g/dL: 1 point

Based on the point total, the system classifies patients into 5 risk groups (see the table below).

Table.  Prognostic score system for Waldenström macroglobulinemia

View Table

See Table

A study by Kastritis et al found that despite the evolution of treatment to include nucleoside analogues and other novel agents, no significant improvement in the outcome of patients with Waldenström macroglobulinemia has been noted since the late 20th century.^[19]

In contrast, a study by Castillo et al that was based on the Surveillance, Epidemiology and End Results database found that relative survival rates were higher in patients diagnosed with Waldenström macroglobulinemia during 2001-2010 than those diagnosed during 1980-2000: 5-year relative survival rates were 78% versus 67%, respectively, and 10-year relative survival rates were 66% versus 49%, respectively. Relative survival improved in whites and other races, but not in blacks.^[20]

Morbidity and mortality

The most important causes of death in Waldenström macroglobulinemia include progression of the proliferative process, infection, cardiac failure, renal failure, strokes, and GI bleeding. Transformation to a more aggressive immunoblastic variant is less common (6% of cases).

Treon et al reported that somatic mutations in MYD88 and CXCR4 in patients with Waldenström macroglobulinemia are determinants of clinical presentation and overall survival. Patients with MYD88 (L265P) and CXCR4 with warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome/nonsense (NS) mutations had significantly higher bone marrow disease involvement and symptomatic disease requiring therapy, including hyperviscosity syndrome.^[21]

Patients with MYD88 (L265P) and WHIM/frameshift (FS) CXCR4 mutations or wild type CXCR4 had intermediate bone marrow involvement, while those with wild type MYD88 and CXCR4 had the lowest bone marrow disease burden. Risk of death was not affected by CXCR4 mutation status, but was markedly increased by wild type MYD88 status (hazard ratio 10.54).^[21]

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History

Onset is insidious and nonspecific. Many patients are asymptomatic at presentation and are diagnosed incidentally from routine blood work. Weakness, anorexia and weight loss are the most common symptoms. Merlini et al reported the frequency of presenting features in 215 patients with Waldenström macroglobulinemia, as follows^[22] :

• Weakness - 66%
• Anorexia - 25%
• Peripheral neuropathy - 24%
• Weight loss - 17%
• Fever - 15%
• Raynaud phenomenon - 11%; Raynaud phenomenon is due to cryoglobulinemia and may precede other serious symptoms by several years

Mental status changes, including lethargy, stupor, or even coma, can occur. Infiltration of the central nervous system by the malignant clone can cause a syndrome of confusion, memory loss, disorientation, and motor abnormalities called the Bing-Neel syndrome.

Symptoms due to hyperviscosity syndrome, which can be life threatening, include the following^[23] :

• Bleeding
• Dizziness
• Headache
• Blurry vision
• Hearing or visual problems

Visual changes, such as blurred vision or double images, and spontaneous bleeding with minor trauma can be presenting features. Patients often present with a history of abnormal bleeding. Gastrointestinal (GI) findings may include malabsorption, GI bleeding, and diarrhea.

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Physical Examination

The physical findings result from tissue infiltration by the malignant clone, the hyperviscosity state caused by antigen-antibody reactions triggered by the paraprotein, and derangement of the hemostatic system by the paraprotein. Hepatosplenomegaly and lymphadenopathy are common. Merlini et al^[22] reported the following occurrences of symptoms in 215 patients evaluated for Waldenström macroglobulinemia:

• Hepatomegaly - 20%
• Splenomegaly - 19%
• Lymphadenopathy - 15%
• Purpura - 9%
• Hemorrhagic manifestations - 7%

Papilledema, ie, sausage-shaped (distended and tortuous) retinal veins, and hemorrhages may be evident on funduscopic examination.

Neuropathy is typically slowly progressive, distal, symmetrical, and sensorimotor. Other variants, including a chronic ataxic neuropathy known as Miller-Fisher syndrome (a variant of Guillain-Barré syndrome), have been described. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) also may be associated with Waldenström macroglobulinemia.

Skin manifestations include the following:

• Purpura (see the image below)
• Bullous skin disease
• Papules on extremities
• Cutaneous plaques and nodules
• Chronic urticaria (Schnitzler syndrome)
• Raynaud phenomenon
• Livedo reticularis
• Acrocyanosis

View Image

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....

Pulmonary involvement is rare (3-5%), with nodules, masses, parenchymal infiltrates, or pleural effusion.

Congestive heart failure is an unusual manifestation, presenting with jugular venous distention, displaced apical impulse, S3 gallop, rales at lung auscultation, and peripheral edema.

Periorbital masses resulting from infiltration into retro-orbital structures and the lacrimal gland have been described. This can cause proptosis and ocular nerve palsies. Osseous lesions and amyloidosis are rare.

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Approach Considerations

The manifestations of Waldenström macroglobulinemia are protean. Considering the diagnosis of Waldenström macroglobulinemia in patients who present with unexplained fatigue and weakness, neurologic symptoms, unexplained bleeding, visual blurring, and neuropathies is important, especially because hyperviscosity symptoms can be life threatening. Performing protein electrophoresis, immunoglobulin quantitation, and hyperviscosity measurements is critical.

The laboratory diagnosis of Waldenström macroglobulinemia is contingent on demonstrating a significant monoclonal IgM spike and identifying malignant cells consistent with Waldenström macroglobulinemia; thus, diagnosis requires monoclonal protein studies and bone marrow biopsy (with or without lymph node/involved tissue biopsy).

General studies include the following:

• Complete blood count (CBC)
• Red cell indices
• Platelet count
• Peripheral smear

Normocytic normochromic anemia, leukopenia, and thrombocytopenia may be observed. Anemia is the most common finding, being present in 80% of patients with symptomatic Waldenström macroglobulinemia.

Other workup includes the following:

• Imaging studies are used for assessment of lymphadenopathy, extramedullary disease, or organomegaly.
• Fundoscopic examination is recommended in all patients with visual disturbance, hyperviscosity symptoms, and/or an IgM level ≥3000 mg/dL.^[4]  
• Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin-associated glycoprotein serology.^[24]
•  

See also Waldenstrom Macroglobulinemia Staging.

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Laboratory Studies

A peripheral smear may reveal plasmacytoid lymphocytes, normocytic normochromic red cells, and rouleaux formation. Neutropenia can be found in some patients. Thrombocytopenia is found in approximately 50% of patients with bleeding diathesis.

Chemistry tests include the following^[25] :

• Lactate dehydrogenase (LDH) levels - May be elevated, indicating the extent of Waldenström macroglobulinemia–related tissue involvement
• Uric acid levels - May be elevated
• Erythrocyte sedimentation rate (ESR) - May be elevated
• Renal and hepatic function
• Total protein levels
• Albumin-to-globulin ratio
• Creatinine - Occasionally elevated
• Electrolytes - Occasionally abnormal; hypercalcemia is noted in approximately 4% of patients; hyponatremia may be present
• Rheumatoid factor, cryoglobulins, direct antiglobulin test, and cold agglutinin titer results - May be positive

Beta-2-microglobulin and C-reactive protein test results are not specific for Waldenström macroglobulinemia. Beta-2-microglobulin is elevated in proportion to tumor mass and is important in determining prognosis.

Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional.

Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, can be found in the urine. Urine collections should be concentrated. Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1g/day in approximately 3% of patients.

Electrophoresis and immunofixation

Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström macroglobulinemia.

Immunoelectrophoresis and immunofixation studies help to identify the type of immunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein. High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein. The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström macroglobulinemia may exhibit more than 1 M protein.

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Imaging Studies

Imaging studies used in the evaluation of Waldenström macroglobulinemia include the following^[26] :

• Chest radiographs - These should be obtained to evaluate for pulmonary infiltrates, nodules or effusion, and congestive heart failure
• Computed tomography (CT) scans - Images of the chest, abdomen, and pelvis may show evidence of adenopathy, hepatosplenomegaly, or both
• Magnetic resonance imaging (MRI) - This is usually not needed for clinical management; however, MRI of the spine shows findings of bone marrow involvement in 90% of patients

• References

Bone Marrow Aspiration and Biopsy

Histology

Bone marrow aspiration and biopsy are required to establish the diagnosis of Waldenström macroglobulinemia. Bone marrow examination findings show infiltration by small lymphocytes showing plasmacytic differentiation. The pattern of infiltration is diffuse or interstitial in most cases. A paratrabecular pattern should raise the possibility of follicular lymphoma.

Periodic acid-Schiff (PAS) staining results are often positive because of the high polysaccharide content in the cells.

Three patterns of marrow involvement are described, as follows:

• Lymphoplasmacytoid cells (ie, predominantly lymphoplasmacytic and small lymphocytes) in a nodular pattern
• Lymphoplasmacytic cells (ie, small lymphocytes, mature plasma cells, mast cells) in an interstitial/nodular pattern
• A polymorphous infiltrate (ie, small lymphocytes, plasma cells, plasmacytoid cells, immunoblasts with mitotic figures).

The abnormal cells may have PAS-positive intranuclear inclusions called Dutcher bodies (deposits of IgM around the nucleus).

Primary amyloidosis is a rare complication of IgM gammopathies. If this is suspected (because of neuropathy, nephrotic syndrome, or cardiac failure), then abdominal fat-pad needle aspiration, along with bone marrow biopsy, may help to demonstrate amyloid deposits on Congo red staining (ie, apple-green birefringence under polarized light).

Flow cytometry

Flow cytometry results show B-cell features with surface expression of IgM and B-cell differentiation markers. Waldenström macroglobulinemia is characterized in most cases by a surface IgM⁺ sIgD^+/- CD5^- CD10^- CD19⁺ CD20⁺ CD22⁺ CD23^- CD25⁺ CD27⁺ CD75^- CD79⁺ CD103^- CD138^- FMC7⁺ BCL^- 2⁺ BCL^- 6^- PAX^- 5⁺ immunophenotype. In practice, a sIgM⁺ CD5^- CD10^- CD19⁺ CD20⁺ CD23^- immunophenotype in association with a nonparatrabecular pattern of infiltration is diagnostic of Waldenström macroglobulinemia.

Genetic studies

Various chromosomal abnormalities are common in patients with Waldenström macroglobulinemia.The L265P mutation in MYD88 can be found in more than 90% of patients and has clinical and prognostic significance.^[5] Whole genome sequencing in 30 patients with Waldenström macroglobulinemia also found the WHIM (warts, hypogammaglobulinemia, infection, myelokathexis syndrome) mutation in CXCR4 (27%) and mutations in ARID1A (17%).^[27]

Although no evidence to date links Waldenström macroglobulinemia with consistent chromosomal or genetic changes, and prognostic implications are uncertain, a French study suggested that a polymorphism may be a prognostic factor following initiation of treatment for this disease. Poulain et al evaluated the distribution and clinical influence of the CXCL12 (-801GA) polymorphism in 114 patients with Waldenström macroglobulinemia and found that the CXCL12 (-801AA) genotype occurred more commonly in affected patients than in control subjects.^[28]

In addition, patients in the study with CXCL12 (-801GG) had a shorter median survival time following administration of first-line therapy than did the remaining patients. The investigators suggested the CXCL12 (-801GA) polymorphism may be associated with a higher incidence of Waldenström macroglobulinemia or may influence clinical outcome.

• References

Approach Considerations

Patients who meet the diagnostic criteria for Waldenström macroglobulinemia (WM) on the basis of serum IgM monoclonal protein, bone marrow lymphoplasmacytic infiltration, or both but who do not have evidence of end-organ damage are considered to have indolent disease or smoldering Waldenström macroglobulinemia. No treatment is indicated for asymptomatic disease.^[5] Patients can be observed carefully with periodic measurement of the M component, immunoglobulin, and serum viscosity.

Clinical indications for initiation of therapy include the following^[29] :

• Recurrent fever, night sweats, weight loss, fatigue 
• Hyperviscosity
• Lymphadenopathy, symptomatic or bulky (≥5 cm in maximum diameter) 
• Symptomatic hepatomegaly and/or splenomegaly 
• Symptomatic organomegaly and/or organ or tissue infiltration 
• Peripheral neuropathy from WM

Laboratory indications for initiation of therapy include the following^[29] :

• Symptomatic cryoglobulinemia 
• Symptomatic cold agglutinin anemia 
• Autoimmune hemolytic anemia and/or thrombocytopenia 
• WM-related nephropathy
• WM-related amyloidosis
• Hemoglobin ≤10 g/dL 
• Platelet count < 100 × 10⁹/L 

For patients with clinical or laboratory indications for treatment, the major classes of effective agents include the following^[4] :

• Monoclonal antibodies (eg, rituximab)
• Alkylating agents
• Purine nucleoside analogs
• Proteasome inhibitors
• Immunomodulatory drugs
• Mammalian target of rapamycin (mTOR) inhibitors

Because the paucity of high-quality data on WM treatment, Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) guidelines, issued in 2016, advocate participation in clinical trials. Outside of trials, mSMART guidelines recommend a single cycle of rituximab (with no maintenance therapy) for patients with any of the following^[4] :

• Hemoglobin < 11 g/dL or symptomatic
• Platelet count < 120 x 10⁹/L
• IgM-related neuropathy
• WM-associated hemolytic anemia
• Symptomatic cryoglobulinemia

For patients with bulky disease, profound cytopenia (hemoglobin ≤10 g/dL, platelets < 100 x 10⁹/L), constitutional symptoms, or hyperviscosity symptoms, mSMART guidelines recommend four to six cycles of bendamustine plus rituximab, preceded by plasmapheresis in patients with symptomatic hyperviscosity. An alternative, particularly for patients with nonbulky WM, is dexamethasone plus rituximab and cyclophosphamide. After entering remission, patients aged 70 years or younger who are potential candidates for autologous stem cell transplantation may be considered for stem cell harvest for future use.

Except for patients requiring emergency treatment of hyperviscosity syndrome, most patients can be treated as outpatients. Periodic physical examinations for organomegaly, routine chemistry evaluations, serum paraprotein level, serum viscosity, and coagulation tests should be performed to monitor for progression and to aid in treatment decisions. Patients requiring emergency plasmapheresis should be transferred to a center that offers this therapy.

For relapsed disease, patients who achieved a durable response (3 years or longer) with initial treatment and tolerated it well can be retreated with the original regimen. The US Food and Drug Administration (FDA) has approved an expanded indication for ibrutinib in WM beyond its use as a monotherapy to include combination use with rituximab.^[30] In patients with relapsed or refractory disease harboring the MYD88 L265P mutation, ibrutinib is highly effective. A bortezomib-rituximab–based option is reasonable for patients with relapsed or refractory disease who do not have neuropathy.

Autologous stem cell transplantation should be considered at the first or second relapse in select patients with chemosensitive disease. Everolimus and purine analogs are suitable options for refractory or multiply relapsed WM.^[4]

Treatment recommendations from the International Workshops on Waldenström Macroglobulinemia are as follows^[31] :

• Treatment should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, neuropathy)
• Combinations of rituximab with cyclophosphamide/dexamethasone, bendamustine, bortezomib/dexamethasone, or ibrutinib provide durable responses and are indicated for most patients
• New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), and mTOR inhibitors (eg, everolimus) are promising and may expand future treatment options
• Selection of a different regimen is typically recommended for relapsed or refractory disease, although reuse of a prior effective regimen may be appropriate in selected patients with relapsed disease after long-lasting remission
• Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features

Paulus et al reported that the anti-CD38 monoclonal antibody daratumumab has in vitro and in vivo (mouse model) activity against Waldenström macroglobulinemia. The therapeutic effect was augmented by cotreatment with ibrutinib, even in ibrutinib-resistant Waldenström macroglobulinemia cell lines.^[32]

See also Waldenstrom Macroglobulinemia Treatment Protocols.

• References

Emergent Treatment

Hyperviscosity syndrome manifestations should be treated promptly, and emergent care is paramount. The treatment of choice for symptoms related to hyperviscosity is urgent plasmapheresis.^[33] The principle behind management is that 80% of all IgM is confined to the intravascular space. Most often, half of the volume or more should be removed to significantly lower the serum viscosity.

Viscosity should be measured before and after plasmapheresis. Approximately 2-4U of plasma must be removed every 1-2 weeks because the effects produced are not permanent and plasma is replaced with albumin and saline.

Chemotherapy should be considered soon after stabilization to reduce the production of the paraprotein by the malignant lymphocytes.

Macroglobulinemia can cause complications similar to peripheral neuropathy; cryoglobulinemia or amyloidosis can occur in the absence of high IgM concentrations and manifestations of the lymphomatous process. These symptoms largely result from certain physicochemical properties of the monoclonal IgM protein and can be treated by repeated plasmapheresis followed by systemic therapy. However, evidence supporting plasma exchange for the treatment of peripheral neuropathy associated with IgM paraprotein is weak (grade of recommendation C).

• References

Pharmacologic Therapy

Front-line therapy consists of monoclonal antibody, alkylating agents, nucleoside analogues, and combination therapy. Currently, no randomized data determine the best option. Therapy is decided on the basis of patient age, performance status, aggressiveness of disease, and paraprotein manifestations.

Rituximab

Rituximab, an anti-CD20 monoclonal antibody, produces response rates of 20-50% irrespective of prior exposure to chemotherapy. Response to rituximab may be affected by polymorphisms in the Fc-gamma RIIIA (CD16) receptor gene.^[28] Time to response is slow and exceeds 3 months on average. The flare phenomenon (abrupt increase of IgM paraprotein level) has been described, which may result in hyperviscosity syndrome and require plasmapheresis.^[34]

Ibrutinib

In January 2015, ibrutinib (Imbruvica) became the first drug approved by the US Food and Drug Administration (FDA) for treatment of Waldenström macroglobulinemia.^[35] Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor; it forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. The approval is based on results of a multicenter phase II study in which 63 patients with previously treated Waldenström macroglobulinemia demonstrated a response rate of 62% (very good partial responses of 11% and partial responses of 51%). These responses were maintained and the median duration of response (DOR) has not been reached, with a range of 2.8+ to 18.8+ months.^[36]

Single-agent ibrutinib demonstrated high efficacy in an open-label substudy of the larger iNNOVATE trial. In 31 adults with WM that was refractory to rituximab and who had received a median of four previous therapy regimens, 90% of patients had an overall response, of which 71% were major responses, after a median follow-up of 18.1 months. The estimated 18-month progression-free survival rate was 86% (95% confidence interval [CI], 66-94%) and the estimated 18-month overall survival rate was 97% (95% CI, 79-100%).^[7]

Response to ibrutinib is highest in patients with the MYD88 L265 mutation and wild-type CXCR4, less in patients with MYD88 L265P and the CXCR4 WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) mutation, and lowest in those with wild-type MYD88. Treon et al have reported major responses to ibrutinib in two patients in two patients with wild-type MYD88, on the basis of allele-specific polymerase chain reaction (AS-PCR) assays, in whom Sanger sequencing in tumor samples identified harbored MYD88 mutations that were not amenable to AS-PCR analysis for MYD88 L265P.^[37]  

A  prospective study by Treon et al of ibrutinib as primary therapy in 30 symptomatic patients with untreated Waldenström macroglobulinemia found that ibrutinib monotherapy is highly active, produces durable responses, and is safe. In patients with wild-type CXCR4 versus those with mutated CXCR4, rates of major (94% vs 71%) and very good partial (31% vs 7%) responses were higher and time to major responses more rapid (1.8 vs 7.3 months; P = 0.01).^[38]

In August 2018, the FDA approved an expanded indication for ibrutinib in WM beyond its use as a monotherapy to include combination use with rituximab. Approval is based on results from the iNNOVATE study which compared ibrutinib plus rituximab with placebo plus rituximab in 150 patients with either relapsed/refractory disease or previously untreated Waldenström's macroglobulinemia. At 30 months, PFS rate was 82% with ibrutinib-rituximab compared with 28% for placebo-rituximab (hazard ratio for progression or death, 0.20; P< 0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P< 0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P< 0.001).^[30]

Fludarabine and cladribine

The purine nucleoside analogues fludarabine and cladribine have demonstrated activity against Waldenström macroglobulinemia. They are effective therapy for patients who are primarily resistant or who relapse after alkylating agents.

Dhodapkar et al, in a study evaluating fludarabine response in previously untreated and previously treated patients, reported an overall response rate of 36%, with 3% of patients experiencing complete remission; the overall survival period was 84 months. Fludarabine has also demonstrated activity for patients resistant to cladribine.^[39]

A phase III study that included 339 patients with Waldenström macroglobulinemia found that fludarabine was superior to chlorambucil.as initial therapy. Patients receiving fludarabine had significantly longer median progression-free survival than those receiving chlorambucil (37.8 versus 27.1 months, respectively; P = 0.015), and median overall survival was not reached with fludarabine but was 69.8 months with chlorambucil (P = 0.014).^[40]

Cladribine is also used as initial therapy, and it provides excellent response rates with minimal treatment. The MD Anderson Cancer Center published data from 90 patients treated with either cladribine alone or in combination with prednisone, cyclophosphamide, or rituximab. The overall response was 94% for cladribine alone, 60% for cladribine and prednisone, 84% for cladribine and cyclophosphamide, and 94% for cladribine, cyclophosphamide, and rituximab.^[41] The median overall^[42] survival was 73 months.

Combination chemotherapy

Combination chemotherapy approaches have been explored, with response rates of more than 75%. Combinations include the following^{[43, 44]} :

• Fludarabine plus rituximab
• Fludarabine plus cyclophosphamide
• Cladribine plus cyclophosphamide
• Cladribine plus cyclophosphamide and rituximab
• Bortezomib, dexamethasone, and rituximab (BDR)
• R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)

The German Low Grade Lymphoma Study Group reported response rates of 69% and 94%, respectively, in 72 patients treated with either CHOP or R-CHOP.^[45]

Salvage therapy

Salvage therapy for patients with resistant disease or relapse includes the reuse or alternative use of front-line agent, combination therapy, thalidomide (with or without steroids), bortezomib, everolimus, alemtuzumab, and stem cell transplantation.

Thalidomide

Thalidomide has demonstrated activity against Waldenström macroglobulinemia. Coleman et al, reporting on the use of clarithromycin, thalidomide, and dexamethasone in 12 patients previously treated with a purine analogue or alkylating agent, found that 10 patients responded (3 near-complete, 3 major, and 4 partial responses).^[46] This combination can be useful in heavily pretreated patients.

Bortezomib

Ghobrial et al treated 37 patients with relapsed/refractory Waldenstrom macroglobulinemia with weekly bortezomib and rituximab. A minimal response or better was observed in 81% of patients treated, with 2 patients (5%) obtaining a complete remission/near–complete remission, 17 patients (46%) obtaining a partial response, and 11 patients (30%) obtaining a minor response. The median time to progression was 16.4 months.^[47]

Everolimus

Ghobrial et al also studied the mTOR inhibitor everolimus in patients with relapsed/refractory Waldenström macroglobulinemia. Fifty patients were treated. The overall response rate (complete response plus partial remission plus minimal response) was 70%, with a partial response of 42% and minimal response of 28%. The median duration of response and median progression-free survival had not been reached at the time of the publication. The estimated progression-free survival at 6 and 12 months were 75% and 62%, respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematologic toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients.^[48]

Alemtuzumab

A study by Treon et al determined that alemtuzumab is an active therapy, but short-term and long-term toxicities need to be weighed against other options. Late-onset autoimmune thrombocytopenia is a complication of alemtuzumab.^[49]

There has been only 1 randomized trial in patients with relapsed or refractory disease. Leblond et al^[50] found better patient response to fludarabine than to the combination of cyclophosphamide, doxorubicin, and prednisone (CAP), in a study of 92 patients with Waldenström macroglobulinemia who had previously received alkylating agent ̶ based therapy. Partial responses were seen in 30% of patients receiving fludarabine, compared with 11% of those receiving CAP. Responses were more durable in patients receiving fludarabine when compared with CAP (19 mo vs 3 mo, respectively). However, there was no difference in overall survival between the 2 patient groups.

• References

Treatment Response Classification

The effectiveness of chemotherapy is monitored with serum monoclonal IgM concentration on protein electrophoresis, along with evaluation for signs or symptoms of active disease. Response criteria from the Third International Workshop on Waldenström's Macroglobulinemia include the following^[51] :

• Complete response - Disappearance of monoclonal protein by serum electrophoresis, no histologic evidence of bone marrow involvement, resolution of any adenopathy/organomegaly, or signs no symptoms attributable to Waldenström macroglobulinemia
• Partial response - At least 50% reduction of serum monoclonal IgM concentration on protein electrophoresis and at least 50% decrease in adenopathy/organomegaly; no new symptoms or signs of active disease
• Minor response - At least 25%, but less than 50%, reduction of serum monoclonal IgM by protein electrophoresis; no new symptoms or signs of active disease
• Stable disease - A less than 25% reduction and a less than 25% increase of serum monoclonal IgM by electrophoresis, without progression of adenopathy/organomegaly, cytopenias, or clinically significant symptoms due to disease and/or signs of Waldenström macroglobulinemia
• Progressive disease - At least 25% increase in serum monoclonal IgM by protein electrophoresis, confirmed by second measurement or progression of clinically significant findings due to disease or symptoms attributable to Waldenström macroglobulinemia

• References

Peripheral Neuropathy Treatment

A consensus panel from the eighth International Workshop on Waldenström macroglobulinaemia (IWWM8) has proposed treatment recommendations for patients with Waldenström macroglobulinemia.The panel advised that patients with slowly progressing Waldenström macroglobulinemia and/or peripheral neuropathy do not require immediate therapy, but steady progression of neuropathy with accumulating disability should prompt action. Possible options for patients who require treatment are as follows^[24] :

• Rituximab alone
• Dexamethasone, cyclophosphamide, and rituximab (DRC)
• Bendamustine-rituximab (BR)
• Carfilzomib, rituximab, dexamethasone (CARD) or purine analogue combinations
• Ibrutinib, where available, could be considered in the setting of intolerance of chemotherapy-based therapies or failure of previous therapies

Further IWWM8 recommendations include the following^[24]

• When treatment is indicated, patients require treatment of sufficient intensity to remit both the systemic disease and the neurological component
• Appropriate precautions should be taken in patients considered at high risk of a flare (IgM > 40 g/L), such as deferring rituximab until cycle 2 of combination chemotherapy or performing prior plasma exchange
• Neurotoxic agents should be avoided; in particular, the vinca alkaloids have no place in the management of Waldenström macroglobulinemia, particularly in patients with peripheral neuropathy
• Plasmapheresis, corticosteroids, and intravenous immunoglobulin (IVIg) are of little or no value in the treatment of Waldenström macroglobulinemia–associated neuropathy

• References

Stem Cell Transplantation

High-dose chemotherapy with autologous peripheral blood cell transplantation is reserved for selected younger patients with primary refractory or relapsed disease. In a study of 6 patients who received autologous transplant, Desikan et al reported that long-term control can be achieved even in patients with refractory disease.^[52] Reduced-intensity allogeneic stem cell transplantion may be an option in very select patients.

Cornell et al evaluated long-term outcomes of allogeneic hematopoietic cell transplantation in 144 patients with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma and reported durable survival in select patients.^[53] At 5 years, results were as follows:

• Progression-free survival: 46%
• Overall survival: 52%
• Relapse: 24%
• Nonrelapse mortality: 30%

Overall survival was significantly superior in patients with chemosensitive disease and better pretransplant disease status. Progression-free survival did not differ significantly in patients who received myeloablative conditioning and those who received reduced-intensity conditioning.^[53]

• References

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 MYD88^L265P 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.

• References

Medication Summary

The monoclonal antibody rituximab, as monotherapy or in combination with the alkylating agent bendamustine or a proteosome inhibitor, features prominently in treatment of Waldenström macroglobulinemia. Other drugs used include alkylating agents, purine nucleoside analogs,  immunomodulatory drugs, mammalian target of rapamycin (mTOR) inhibitors, and

Salvage therapy for patients with resistant disease or relapse includes reuse or alternative use of front-line agents, combination therapy, thalidomide (with or without steroids), autologous transplantation, and monoclonal antibody (alemtuzumab).

• References

Prednisone

• Dosing, Interactions, etc.

Clinical Context:  Prednisone is an immunosuppressant used for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity.

• References

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

• References

Ibrutinib (Imbruvica)

• Dosing, Interactions, etc.

Clinical Context:  Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor. It forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK's role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. It is indicated for Waldenström macroglobulinemia as either a single-agent or in combination with rituximab.

• References

Class Summary

Tyrosine kinase enzymes are responsible for activating many proteins by signal transduction cascades, phosphorylation, and other mechanisms. Tyrosine kinase inhibitors block these functions.

• References

Chlorambucil (Leukeran)

• Dosing, Interactions, etc.

Clinical Context:  This agent alkylates and cross-links strands of deoxyribonucleic acid (DNA), inhibiting DNA replication and ribonucleic acid (RNA) transcription. Chlorambucil is an important drug in the treatment of Waldenström macroglobulinemia. It is usually administered when extreme bone marrow infiltration, anemia, splenomegaly, lymphadenopathy, and bleeding are present.

• References

Melphalan (Alkeran)

• Dosing, Interactions, etc.

Clinical Context:  Melphalan inhibits mitosis by cross-linking DNA strands; it ultimately disrupts nucleic acid function.

• References

Cyclophosphamide

• Dosing, Interactions, etc.

Clinical Context:  Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

• References

Bendamustine (Bendeka)

• Dosing, Interactions, etc.

Clinical Context:  Alkylating agent that cross-links single or double DNA strands resulting in DNA breakdown; cell cycle-nonspecific

• References

Class Summary

These agents inhibit cell growth and proliferation. Many combinations of chemotherapeutic agents have been tried, with no evidence of clear superiority over single-agent chemotherapy with chlorambucil and considerably more toxicity.

• References

Cladribine (Leustatin)

• Dosing, Interactions, etc.

Clinical Context:  Cladribine is a synthetic antineoplastic agent for continuous intravenous (IV) infusion. The enzyme deoxycytidine kinase phosphorylates this compound into an active 5+-triphosphate derivative, which, in turn, breaks DNA strands and inhibits DNA synthesis. Cladribine disrupts cell metabolism, causing death to resting and dividing cells.

• References

Fludarabine (Fludara)

• Dosing, Interactions, etc.

Clinical Context:  Fludarabine is a nucleotide analogue of vidarabine converted to 2-fluoro-ara-A, which enters the cell and is phosphorylated to form active metabolite 2-fluoro-ara-adenosine triphosphate (ATP). It inhibits DNA synthesis.

• References

Class Summary

Antimetabolites inhibit cell growth and proliferation. Many combinations of chemotherapeutic agents have been tried, with no evidence of clear superiority over single-agent chemotherapy with chlorambucil and considerably more toxicity.

• References

Doxorubicin (Adriamycin)

• Dosing, Interactions, etc.

Clinical Context:  Doxorubicin inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA. The combination of these 2 events can, in turn, inhibit the growth of neoplastic cells. Doxorubicin may be effective in chlorambucil-refractory Waldenström macroglobulinemia.

• References

Class Summary

These agents immunomodulate the response to malignant cells.

• References

Rituximab (Rituxan)

• Dosing, Interactions, etc.

Clinical Context:  Rituximab is a genetically engineered human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes.

• References

Class Summary

These agents immunomodulate the response to malignant cells.

• References

Interferon gamma-1b (Actimmune)

• Dosing, Interactions, etc.

Clinical Context:  Interferon gamma-1b is a single-chain polypeptide containing 140 amino acids. It is produced by fermentation of genetically engineered Escherichia coli bacterium containing DNA that encodes for the human protein.

• References

Thalidomide (Thalomid)

• Dosing, Interactions, etc.

Clinical Context:  Thalidomide is a derivative of glutethimide. Its mode of action for immunosuppression is unclear. Inhibition of neutrophil chemotaxis and decreased monocyte phagocytosis may occur. Thalidomide may cause a 50-80% reduction of tumor necrosis factor–alpha.

• References

Class Summary

Immunomodulators modulate processes that promote immune reactions resulting from diverse stimuli.

• References

Bortezomib (Velcade)

• Dosing, Interactions, etc.

Clinical Context:  Bortezomib was the first of the anticancer agents known as proteasome inhibitors to be approved. The proteasome pathway is an enzyme complex existing in all cells. This complex degrades ubiquitinated proteins that control the cell cycle and cellular processes and maintains cellular homeostasis. Reversible proteasome inhibition disrupts pathways supporting cell growth, thus decreasing cancer cell survival.

• References

Class Summary

Proteosome inhibitors inhibit cell growth and proliferation.

• References

Everolimus (Afinitor, Zortress)

• Dosing, Interactions, etc.

Clinical Context:  Everolimus is a mammalian target of rapamycin (mTOR) inhibitor that is approved by the US Food and Drug Administration for the treatment of renal cell cancer, subependymal giant cell astrocytoma, and advanced neuroendocrine tumors of pancreatic origin. It is a kinase inhibitor that inhibits antigenic and interleukin (IL-2 and IL-5)–stimulated activation and proliferation of T and B lymphocytes. Phase II studies demonstrate activity in relapsed Waldenström macroglobulinemia.

• References

Class Summary

These antineoplastic agents have antiproliferative and antiangiogenic properties.

• References