AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Waldenström macroglobulinemia (WM) is one of the malignant monoclonal gammopathies. Waldenström macroglobulinemia is a condition 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. Waldenström macroglobulinemia is a clonal disorder of B lymphocytes. This condition is considered to be lymphoplasmacytic lymphoma as defined by the Revised European American Lymphoma Classification (REAL) and World Health Organization (WHO) classification. The clinical manifestations of this condition result from the presence of the IgM paraprotein and malignant lymphoplasmacytic cell infiltration of the bone marrow and other tissue sites. The clinical presentation of Waldenström macroglobulinemia is similar to that of multiple myeloma (MM) except that (1) organomegaly is common in Waldenström macroglobulinemia and is uncommon in multiple myeloma and (2) lytic bonydisease and renal disease are uncommon in Waldenström macroglobulinemia but are common in multiple myeloma.

Pathophysiology

The clinical manifestations of this disorder result from two important factors.

First, secretion of the IgM paraprotein leads to hyperviscosity and vascular complications because of physical, chemical, and immunological properties of the paraprotein. Monoclonal IgM causes hyperviscosity syndrome, cryoglobulinemia types 1 and 2, coagulation abnormalities, sensorimotor peripheral neuropathy, cold agglutinin disease and anemia, primary amyloidosis, and 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 CNS. Infiltration of these organs causes numerous clinical symptoms and signs (see Clinical).

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

Frequency

United States

Waldenström macroglobulinemia is a relatively rare condition, with 1500 cases diagnosed per year, accounting for approximately 2% of hematologic malignancies. The incidence rate for Waldenström macroglobulinemia is higher among whites, with African descendants representing only 5% of all patients. The median age at diagnosis is 65 years, with a slight male predominance.

International

In the United Kingdom, the annual incidence is 10.3 per million.

Mortality/Morbidity

Waldenström macroglobulinemia is a chronic indolent lymphoproliferative disorder. Median survival time is approximately 78 months. Kaplan-Meier survival curves of patients with Waldenström macroglobulinemia do not show a plateau.

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

Race

See Frequency.

Sex

See Frequency.

Age

Waldenström macroglobulinemia is a disease of elderly individuals. Most patients present in the seventh or eighth decade of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 presenting features in 215 patients with Waldenström macroglobulinemia as follows:
• • 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 for several years.)
• Symptoms due to hyperviscosity syndrome include bleeding, dizziness, headache, blurry vision, and hearing or visual problems and can be life threatening.
• • Visual changes, such as blurred vision or double images, and spontaneous bleeding with minor trauma could be presenting features.
  • Patients often present with a history of abnormal bleeding.
• GI system findings may include malabsorption, GI bleeding, and diarrhea.

Physical

The physical findings result from tissue infiltration by the malignant clone, hyperviscosity state cause by antigen-antibody reactions triggered by the paraprotein, and derangement of the hemostatic system by the paraprotein.

• Merlini et al also reported physical findings in 215 patients evaluated for Waldenström macroglobulinemia, including the following:
• • Hepatomegaly - 20%
  • Splenomegaly - 19%
  • Lymphadenopathy - 15%
  • Purpura - 9%
  • Hemorrhagic manifestations - 7%
• Mental status changes include lethargy, stupor, or even coma. Infiltration of the CNS by the malignant clone can cause a syndrome of confusion, memory loss, disorientation, and motor abnormalities called the Bing-Neel syndrome.
• Papilledema, ie, sausage-shaped (distended and tortuous) retinal veins, and hemorrhages may be evident on funduscopic examination.
• Neuropathy is typically slowly progressive, distal, symmetric, 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.
• Hepatosplenomegaly and lymphadenopathy are common.
• Skin manifestations include purpura, bullous skin disease, papules on extremities, cutaneous plaques and nodules, chronic urticaria (Schnitzler syndrome), Raynaud phenomenon, livedo reticularis, and acrocyanosis.
• 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.

Causes

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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The laboratory diagnosis of Waldenström macroglobulinemia is contingent on demonstrating a significant monoclonal IgM spike and identifying malignant cells consistent with Waldenström macroglobulinemia (usually found in bone marrow biopsy samples and aspirates).
• General studies include a CBC count, red cell indices, platelet count, and a peripheral smear.
• • Normocytic normochromic anemia, leukopenia, and thrombocytopenia may be observed. Anemia is the most common finding, present in 80% of patients with symptomatic Waldenström macroglobulinemia.
  • The 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 lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), renal and hepatic function, total protein levels, and an albumin-to-globulin ratio.
• • The ESR and uric acid level may be elevated.
  • Creatinine is occasionally elevated and electrolytes are occasionally abnormal. Hypercalcemia is noted in approximately 4% of patients.
  • The LDH level is frequently elevated, indicating the extent of Waldenström macroglobulinemia–related tissue involvement.
  • Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can 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.
• Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional.
• 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 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 one M protein.
• Plasma viscosity must be measured.
• Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, are found in the urine.
• • Urine collections should be concentrated.
  • Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1 g/d in approximately 3% of patients.
• Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin associated glycoprotein serology.

Imaging Studies

• Chest radiographs should be obtained, to evaluated for pulmonary infiltrates, nodules or effusion, and congestive heart failure.
• Computed tomography images of the abdomen and pelvis may show evidence of abdominal adenopathy, hepatosplenomegaly, or both.
• Magnetic resonance imaging (MRI) is not essential; however, MRI of the spine shows findings of bone marrow involvement in 90% of patients.
• Cerebrospinal fluid analysis for patients with change in mental status may demonstrate elevated protein concentration and cerebrospinal fluid IgM paraprotein.

Procedures

• Bone marrow aspiration and biopsy are required to establish the diagnosis.
• • Bone marrow examination findings show infiltration by small lymphocytes showing plasma cell 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: (1) lymphoplasmacytoid cells (ie, predominantly lymphoplasmacytic and small lymphocytes) in a nodular pattern, (2) lymphoplasmacytic cells (ie, small lymphocytes, mature plasma cells, mast cells) in an interstitial/nodular pattern, and (3) 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).
• 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.
• Various chromosomal abnormalities are common in patients with Waldenström macroglobulinemia. Deletions of 6q encompassing 6q21-22 have been observed in 40-90% of patients. However, no evidence to date links Waldenström macroglobulinemia with consistent chromosomal or genetic changes, and prognostic implications are uncertain.
• Primary amyloidosis is a rare complication of IgM gammopathies. If suspected because of neuropathy, nephrotic syndrome, or cardiac failure, abdominal fat-pad needle aspiration, along with bone marrow biopsy, may help demonstrate amyloid deposits on Congo red staining (ie, apple-green birefringence under polarized light).

Histologic Findings

Bone marrow analysis reveals lymphoplasmacytoid cells. Plasma cells are fewer in number than in multiple myeloma. PAS staining results are often positive because of the high polysaccharide content in the cells. Lymphoid infiltration is either diffuse or nodular; however, some authors differentiate infiltration into 3 types: nodular, interstitial/nodular, and a "packed" marrow pattern. Nodular infiltration indicates the best prognosis among the other types of bone marrow infiltration. Packed marrow indicates the worst prognosis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Patients who meet criteria for Waldenström macroglobulinemia (serum IgM monoclonal protein, bone marrow lymphoplasmacytic infiltration, or both) without end-organ damage are considered to have indolent disease or smoldering Waldenström macroglobulinemia. No treatment is indicated for asymptomatic disease. Patients can be observed carefully with periodic measurement of the M component, immunoglobulin, and serum viscosity. Therapeutic intervention of Waldenström macroglobulinemia can be divided into treatment of IgM paraprotein complications and treatment of the disease per se. Current therapy available include plasmapheresis, alkylating agents, interferon alfa, purine nucleoside analogues, high-dose chemotherapy, splenectomy, rituximab (anti-CD20 antibody), thalidomide, bone marrow transplantation, and other new agents.

• 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. 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 2-4 U 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).
• Current therapy for Waldenström macroglobulinemia
• • Front line therapy consists of alkylator agents, nucleoside analogues, monoclonal antibody, and combination therapy. Currently, no randomized data determine the best option. Therapy is decided based on patient age, performance status, aggressiveness of disease, and paraprotein manifestations.
  • Single agent alkylating agent therapy has been traditionally used for over 40 years. Oral chlorambucil with or without prednisone is frequently used as initial therapy, especially in elderly patients. The response rate is approximately 60%, and the median survival 60 months. Kyle et al conducted a prospective study comparing daily with intermittent oral chlorambucil, and demonstrated no significant difference in response rate or survival. The optimal duration of treatment is unknown.
  • Cyclophosphamide alone or in combination is also effective, but no comparative data with chlorambucil exist.
  • Purine nucleoside analogues, fludarabine or cladribine, have demonstrated activity against Waldenström macroglobulinemia. They are effective therapy for patients who are primarily resistant or who relapse after alkylating agents. In 2001, Dhodapkar et al published results of the United States intergroup trial, evaluating fludarabine response in previously untreated and previously treated patients. The overall response rate was 36%, with 3% complete remissions, and the overall survival was 84 months. Fludarabine has also demonstrated activity for patients resistant to cladribine.
  • Cladribine is another nucleoside analogue used as initial therapy. Cladribine provides excellent response rates with minimal therapy. The M.D. 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. The median overall survival was 73 months.
  • The anti-CD20 monoclonal antibody, rituximab, 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. 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 indication for plasmapheresis.
  • Combination chemotherapy approaches have been explored, with response rates of more than 75%. Combinations include fludarabine plus rituximab, fludarabine plus cyclophosphamide, cladribine plus cyclophosphamide, cladribine plus cyclophosphamide and rituximab, and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). The German Low Grade Lymphoma Study Group reported results from 72 patients treated with either CHOP or R-CHOP. The response rates were 69% and 94%, respectively.
  • A phase III study of chlorambucil versus fludarabine as initial therapy is ongoing. Results from this trial will help to determine the best initial therapeutic approach and management of Waldenström macroglobulinemia.
  • Salvage therapy for patients with resistant disease or relapse includes reuse or alternative use of front line agent, combination therapy, thalidomide with or without steroids, autologous transplantation, monoclonal antibody (alemtuzumab).
  • There is only one randomized trial in patients with relapsed or refractory disease. Leblond et al compared fludarabine with the combination of cyclophosphamide, doxorubicin, and prednisone (CAP) in 92 patients with Waldenström macroglobulinemia who had previously received alkylating agent based therapy. Partial responses were observed in 30% of patients receiving fludarabine compared to 11% of those receiving CAP (P=.019). Responses were more durable in patients receiving fludarabine compared to CAP (19 mo vs 3 mo, respectively). There was no difference in overall survival between the 2 groups.
  • Thalidomide has demonstrated activity against Waldenström macroglobulinemia. Coleman et al reported the use of clarithromycin, thalidomide, and dexamethasone in 12 patients previously treated with a purine analogue or alkylating agent; 10 patients responded (3 near complete, 3 major, and 4 partial responses). This combination can be useful in heavily pretreated patients.
  • High-dose chemotherapy with autologous peripheral blood cell transplantation is reserved for selected younger patients with primary refractory or relapsed disease. Desikan et al reported 6 patients that received autologous transplant. All 6 achieved a partial response, 5 of the 6 are alive, and 4 are event-free from 2-52 months. Long-term disease control can be achieved, even in those with refractory disease.
  • Other agents are currently under way investigation to evaluate efficacy and tolerability. Interferon alpha, administered for 6 months in untreated and pretreated patients, showed a response rate of 50% with a median duration of response of 27 months. Sildenafil, a phosphodiesterase inhibitor used to treat erectile dysfunction, has demonstrated apoptosis activity against tumor cells in Waldenström macroglobulinemia. Clinical activity in 5 patients has been reported (1 complete response, 4 partial response). The Bcl-2 antisense oligonucleotide (oblimersen sodium) has apoptosis modulating activity in Waldenström macroglobulinemia. Of 16 patients evaluated (untreated and previously treated), all expressed Bcl-2. Phase I and II trials are ongoing to evaluate increased cell death and potential synergy with chemotherapeutic agents; bortezomib, a proteasome inhibitor, has demonstrated 6 partial responses of 16 patients evaluated.
• Asymptomatic Waldenström macroglobulinemia
  • Patients with Waldenström macroglobulinemia may not need any treatment apart from close observation.
  • Indications for initiating active treatment include clinical evidence of adverse effects of the paraprotein (hyperviscosity with neurological or ocular disturbance, peripheral neuropathy, amyloidosis, symptomatic cryoglobulinemia, cytopenias), disease progression, or development of constitutional symptoms.
• Remission and monitoring
  • The effectiveness of chemotherapy is monitored with serum monoclonal IgM concentration on protein electrophoresis and evaluation for signs or symptoms of active disease.
  • Response criteria from the Third International Workshop on Waldenström's Macroglobulinemia include the following:
    • Complete response - Disappearance of monoclonal protein by serum electrophoresis, no histologic evidence of bone marrow involvement, resolution of any adenopathy/organomegaly, or signs or 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 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

Surgical Care

Splenectomy has been shown to be effective in some patients in whom chemotherapy has failed. Surgical removal of the spleen removes a major source of cells that produce IgM. This surgery is rarely indicated with current treatment options.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Various drugs, including corticosteroids (eg, prednisone), alkylating agents (eg, chlorambucil, melphalan, cyclophosphamide), biological response modifiers (eg, interferon alfa, interferon gamma), and purine analogues (eg, fludarabine, 2-chlorodeoxyadenosine), are used in the treatment of Waldenström macroglobulinemia.

Drug Category: Corticosteroids

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

Drug Category: Antineoplastic agents

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

Drug Category: Biological response modifiers

These agents immunomodulate response against malignant cells.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Except for patients requiring emergency treatment of hyperviscosity syndrome, most patients can be treated as outpatients.

Further Outpatient Care

• 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.

Transfer

• Patients requiring emergency plasmapheresis should be transferred to a center that offers this therapy.

Complications

• Hyperviscosity syndrome
• Visual disturbances secondary to hyperviscosity syndrome
• Diarrhea and malabsorption secondary to 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
• 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

Prognosis

• Waldenström macroglobulinemia is an indolent disorder, and patients survive for a median of approximately 78 months. Different studies have been performed to assess prognosis, as follows:
• • A median survival of 7.7 years was noted in patients when their macroglobulin level was reduced by at least 75%.
  • Patients with a nodular type of bone marrow involvement tend to do better than those with diffuse involvement.
• Poor prognostic factors include (1) age older than 65 years, (2) hemoglobin value of less than 10 g/dL, (3) albumin level less than 4.0 g/dL, and (4) elevated beta-2-microglobulin level.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

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

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Betticher DC, Hsu Schmitz SF, Ratschiller D, et al. Cladribine (2-CDA) given as subcutaneous bolus injections is active in pretreated Waldenstrom''s macroglobulinaemia. Swiss Group for Clinical Cancer Research (SAKK). Br J Haematol. Nov 1997;99(2):358-63. [Medline].
• Delannoy A, Van Den Neste E, Michaux JL, et al. Cladribine for Waldenstrom''s macroglobulinaemia. Br J Haematol. Mar 1999;104(4):933-4. [Medline].
• Desikan R, Dhodapkar M, Siegel D, et al. High-dose therapy with autologous haemopoietic stem cell support for Waldenstrom''s macroglobulinaemia. Br J Haematol. Jun 1999;105(4):993-6. [Medline].
• Desikan R, Dhopapkar M, Siegel D. High-dose therapy with autologous haemopoietic stem cell support for Waldenstrom's macroblobulinaemia. Br J Haematol. 1999;105:993-996.
• Dhodapkar MV, Jacobson JL, Gertz MA. Prognostic factors and response to fludarabine therapy in patients with Waldenstrom macroglobulinemia: results of United States intergroup trial (Southwest Oncology Group S9003). Blood. 2001;98:41-48.
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• Foran JM, Rohatiner AZ, Coiffier B, et al. Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenstrom''s macroglobulinemia, and mantle-cell lymphoma. J Clin Oncol. Feb 1999;17(2):546-53. [Medline].
• Frankel SR. Oblimersen sodium (G3139 Bcl-2 antisense oligonucleotide) therapy in Waldenstrom's macroglobulinemia: a targeted approach to enhance apoptosis. Semin Oncol. 2003;30(2):300-4.
• Fridrik MA, Jager G, Baldinger C, et al. First-line treatment of Waldenstrom''s disease with cladribine. Arbeitsgemeinschaft Medikamentose Tumortherapie. Ann Hematol. Jan 1997;74(1):7-10. [Medline].
• Gertz M. Waldenstrom macroglobulinemia: a review of therapy. American Journal of Hematol. 2005;79:147-57.
• Gertz MA, Merlini G, Treon S. Amyloidosis and Waldenström’s Macroglobulinemia. Hematology. 2004;Abstract:257-282.
• Hellmann A, Lewandowski K, Zaucha JM, et al. Effect of a 2-hour infusion of 2-chlorodeoxyadenosine in the treatment of refractory or previously untreated Waldenstrom''s macroglobulinemia. Eur J Haematol. Jul 1999;63(1):35-41. [Medline].
• Johnson SA, Owen RG, Oscier DG. Phase III study of chlorambucil versus fludarabine as initial therapy for Waldenstrom's macroglobulinemia and related disorders. Clin Lymphoma. 2005;4:294-97.
• Jonhson SA, Birchall J, Luckie C. Guidelines on the management of waldenstrom macroglobulinaemia. British Society for Haematol. 2006;132:683-97.
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Article Last Updated: Nov 15, 2006