eMedicine Specialties > Hematology > Plasma Cell Disorders

Waldenstrom Hypergammaglobulinemia

Doris Ponce, MD, Fellow, Department of Hematology/Oncology, New York Medical College
Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College; Vijay Ramu, MBBS, Staff Physician, Department of Internal Medicine, East Tennessee State University; Harsha Vyas, MD, Fellow, Section of Hematology and Oncology, Wake Forest University School of Medicine; Koyamangalath Krishnan, MD, FRCP, FACP, Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University

Updated: Aug 29, 2009

Introduction

Background

Waldenström macroglobulinemia (WM) is one of the malignant monoclonal gammopathies.^{[1 ]}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 bony disease 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

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.^{[2 ]}
  • 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^{[3 ]}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.^{[4,5 ]}
• 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.

Differential Diagnoses

Chronic Lymphocytic Leukemia
Lymphoma, Non-Hodgkin
Monoclonal Gammopathies of Uncertain Origin
Multiple Myeloma

Workup

Laboratory 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).^{[6 ]}
• 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.^{[7 ]}
  • 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, although no evidence to date links Waldenström macroglobulinemia with consistent chromosomal or genetic changes, and prognostic implications are uncertain, a recent French study suggests a polymorphism may be a prognostic factor following initiation of treatment for this disease.^{[8 ]}Poulain et al evaluated the distribution and clinical influence of the CXCL12 (-801GA) polymorphism in 114 patients with Waldenstrom macroglobulinemia and found the CXCL12 (-801AA) genotype occurred more commonly in affected patients than control subjects (P = 0.01).^{[8 ]}However, patients with CXCL12 (-801GG) had a shorter median survival following administration of first-line therapy than the remaining patients. The investigators suggested the CXCL12 (-801GA) polymorphism may be associated with a higher incidence of Waldenstrom macroglobulinemia or may influence clinical outcome.^{[8 ]}
• 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

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.^{[9 ]}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,^{[10 ]}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.^{[11 ]}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.^{[12 ]}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.^{[13 ]}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.^{[8 ]}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).^{[14 ]}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^{[15 ]}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^{[16 ]}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^{[17 ]}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.^{[18 ]}
• 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^{[19 ]}:
    • 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

Medication

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.

Corticosteroids

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

Prednisone (Deltasone, Orasone, Sterapred)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dosing

Adult

40 mg/m²/d PO for 4 d; repeat cycle q21d

Pediatric

Not established

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics; concomitant NSAID use can increase risk of GI bleed

Contraindications

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Caution in patients with leukopenia or thrombocytopenia (can cause lowering of blood counts, with a prolonged recovery phase); abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

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.

Chlorambucil (Leukeran)

Alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription.
Important drug in the treatment of WM. Usually administered when extreme bone marrow infiltration, anemia, splenomegaly, lymphadenopathy, and bleeding are present.

Dosing

Adult

0.3 mg/kg PO on days 1-5; repeat cycle q4-6wk; adjust dose based on blood counts

Pediatric

4.5 mg/m²/d PO; adjust dose based on blood counts

Interactions

None reported

Contraindications

Documented hypersensitivity; previous resistance to medication

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Caution in patients with a history of seizure disorders; nephrotic syndrome or bone marrow suppression; use in pregnancy only under life-threatening conditions; narrow therapeutic index, and adverse effects are common; monitor hematologic status regularly

Melphalan (Alkeran)

Inhibits mitosis by cross-linking DNA strands and ultimately disrupts nucleic acid function.

Dosing

Adult

8 mg/m²/d PO on days 1-4 with prednisone 40 mg/m²/d PO

Pediatric

Not established

Interactions

Concurrent administration with cyclosporine increases nephrotoxicity; cimetidine and H2 antagonists increase gastric pH, decreasing effects; cisplatin decreases clearance; concomitant use of nalidixic acid can cause severe hemorrhagic necrotizing enterocolitis

Contraindications

Documented hypersensitivity, severe bone marrow suppression, resistance to prior therapy

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Amenorrhea may occur; caution in patients previously diagnosed with myelosuppression; narrow therapeutic index (notify physician if fever, sore throat, rash, vasculitis, unusual lumps, or bleeding occurs); hematological monitoring is essential

Cyclophosphamide (Cytoxan)

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 growth of normal and neoplastic cells.

Dosing

Adult

125 mg/m² PO with prednisone 40 mg/m² PO for 7 d; repeat cycle q4-6wk depending on blood count results

Pediatric

Not established

Interactions

Allopurinol may increase risk of bleeding or infection and enhances myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity; mesna chemically interacts with the metabolites of drug in bladder and decreases incidence of bladder toxicity; can prolong activity of succinylcholine

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; narrow therapeutic index (use judiciously); notify physician if bleeding, sore throat, or fever occurs

Cladribine (Leustatin)

Synthetic antineoplastic agent for continuous IV infusion. The enzyme deoxycytidine kinase phosphorylates this compound into active 5+-triphosphate derivative, which, in turn, breaks DNA strands and inhibits DNA synthesis. Disrupts cell metabolism, causing death to resting and dividing cells.

Dosing

Adult

0.1 mg/kg/d IV continuous infusion on days 1-7 only or 0.12 mg/kg/d by 2-h continuous infusion for 5 consecutive d every mo

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Caution in patients with history of hematologic or immunologic dysfunction; neurotoxicity may occur; allopurinol can be used prophylactically to prevent hyperuricemia secondary to tumor lysis; discontinue if renal or neurotoxicities develop; narrow therapeutic index (use judiciously); notify physician if bleeding, sore throat, or fever occurs; tumor lysis syndrome can occur in patients with high tumor burden (monitor metabolic panel)

Fludarabine (Fludara)

Nucleotide analog of vidarabine converted to 2-fluoro-ara-A that enters the cell and is phosphorylated to form active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis.

Dosing

Adult

25 mg/m²/d IV for 5 d; repeat 5-d course q28d for as many as 6 cycles; adjust dose based on hematologic or nonhematologic toxicity

Pediatric

Not established

Interactions

Causes fatal pulmonary toxicity when used with pentostatin; cytarabine decreases antineoplastic effect when used prior to a dose of fludarabine

Contraindications

Documented hypersensitivity; breastfeeding; bone marrow suppression

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Perform frequent peripheral blood counts to detect development of anemia, thrombocytopenia, and neutropenia; monitor for tumor lysis syndrome; adjust dose for renal impairment, severe bone marrow suppression, severe neurological effects, or life-threatening and fatal autoimmune hemolytic anemia; narrow therapeutic index (use judiciously); notify physician if bleeding, sore throat, or fever occurs; monitor closely in pediatric and elderly populations; increased risk of opportunistic infections (eg, Pneumocystis carinii pneumonia and Listeria infections), prophylaxis with TMP-SMZ (160 mg TMP/800 mg SMZ PO q12h) for course of the fludarabine therapy and for at least 6 mo thereafter

Doxorubicin (Adriamycin)

Inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA. Combination of these 2 events can, in turn, inhibit growth of neoplastic cells. May be effective in chlorambucil-refractory WM.

Dosing

Adult

60-75 mg/m² IV as a single dose; repeat q21d
Alternatively, 20-30 mg/m²/d for 2-3 d; repeat in 4 wk

Pediatric

35-75 mg/m² IV as single dose; repeat q21d
Alternatively, 20-30 mg/m² once a week

Interactions

May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity

Contraindications

Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function, preexisting myelosuppression

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Irreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose in patients with impaired hepatic function

Biological response modifiers

These agents immunomodulate response against malignant cells.

Rituximab (Rituxan)

Genetically engineered human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes.

Dosing

Adult

375 mg/m² IV qwk for 4 doses

Pediatric

Not established

Interactions

Coadministration with cisplatin is known to cause severe renal toxicity including acute renal failure; may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 months of vaccine)

Contraindications

Documented hypersensitivity; IgE mediated reaction to murine proteins

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use with caution in patients with dormant infections such as hepatitis B, hepatitis C, or CMV due to risk of reactivation; hypotension, bronchospasm, and angioedema may occur, premedication with acetaminophen and diphenhydramine may decrease incidence; discontinue treatment if life-threatening cardiac arrhythmias occur; must administer by slow IV infusion, do not administer IV push or bolus

Interferon alfa (Intron, Roferon)

Protein product manufactured by recombinant DNA technology. Possesses complex antiviral, antineoplastic, and immunomodulating activities.

Dosing

Adult

3 million U SC qd for 30 d followed by 3 million U SC 3 times/wk for at least 5 mo; alternatively, 1 million U SC 3 times per wk

Pediatric

Not established

Interactions

Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity; can potentiate neurotoxicity of vidarabine; can enhance antiviral effect of acyclovir; can potentiate bone marrow suppression when used with other myelosuppressive drugs; antipyretics may decrease fever and attenuate myalgia when used before administering interferons

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in patients with brain metastases, debilitating cardiac and pulmonary conditions (perform baseline chest x-ray and ECG), severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, or compromised CNS; baseline ophthalmologic evaluation necessary in patients with diabetes and hypertension; elevation of triglycerides is potential adverse effect (monitor lipid panel)

Interferon gamma-1b (Actimmune)

Single-chain polypeptide containing 140 amino acids. Produced by fermentation of genetically engineered Escherichia coli bacterium containing DNA that encodes for the human protein.

Dosing

Adult

0.125-0.5 mg/m²/d IM

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in patients with myelosuppression, cardiac disease, and compromised CNS; regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression

Thalidomide (Thalomid)

A derivative of glutethimide; mode of action for immunosuppression is unclear; inhibition of neutrophil chemotaxis and decreased monocyte phagocytosis may occur; may cause 50-80% reduction of tumor necrosis factor–alpha

Dosing

Adult

50 mg PO; 200 mg/d maximum

Pediatric

Not established

Interactions

May be associated with increased risk of serious infection when used in combination with anakinra; may enhance sedative activity of other drugs such as ethanol, barbiturates, reserpine, and chlorpromazine;
may decrease serum concentrations and/or efficacy of hormonal contraceptives

Contraindications

Documented hypersensitivity to thalidomide or any component of the formulation; neuropathy (peripheral); pregnancy or women in childbearing years unless alternative therapies are inappropriate and adequate precautions are taken to avoid pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Effective contraception must be used for at least 4 weeks before initiating therapy, during therapy, and for 4 weeks following discontinuation of thalidomide
May cause sedation; patients must be warned to use caution when performing tasks which require alertness
Caution in patients with renal or hepatic impairment, neurological disorders, cardiovascular disease, or constipation; has been associated with the development of peripheral neuropathy, which may be irreversible; consider immediate discontinuation (if clinically appropriate) in patients who develop neuropathy; use caution in patients with a history of seizures, concurrent therapy with drugs which alter seizure threshold, or conditions which predispose to seizures; may cause neutropenia; discontinue therapy if absolute neutrophil count decreases to <750/mm³; caution in patients with HIV infection; has been associated with increased viral loads; may cause orthostasis and/or bradycardia; caution in patients with cardiovascular disease or in patients who would not tolerate transient hypotensive episodes ; thrombotic events reported (generally in patients with other risk factors for thrombosis [neoplastic disease, inflammatory disease, or concurrent therapy with other drugs which may cause thrombosis])

Bortezomib (Velcade)

First drug approved of anticancer agents known as proteasome inhibitors. 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 decreases cancer cell survival.

Dosing

Adult

Not established; 1.3 mg/m² IV on d 1, 4, 8, and 11 of a 3-wk cycle suggested

Pediatric

Not established

Interactions

Substrate of CYP450 isoenzymes1A2, 2C9, 2C19, 2D6, and 3A4; may inhibit CYP450 2C19, therefore caution with coadministration of isoenzyme 2C19 substrates (eg, barbiturates, phenytoin, valproic acid, imipramine, lansoprazole, warfarin)

Contraindications

Documented hypersensitivity to bortezomib, boron, mannitol, or any component of the formulation; pregnancy

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause peripheral neuropathy (usually sensory but may be mixed sensorimotor; risk may be increased with previous use of neurotoxic agents or pre-existing peripheral neuropathy; adjustment of dose and schedule may be required)
May cause orthostatic/postural hypotension; use caution with dehydration, history of syncope or medications associated with hypotension
Has been associated with the development or exacerbation of congestive heart failure; use caution in patients with risk factors or existing heart disease
May cause tumor lysis syndrome; risk is increased in patients with large tumor burden prior to treatment; hematologic toxicity with severe thrombocytopenia may occur (risk is increased in patients with pretreatment platelet counts <75,000 µL (frequent monitoring is required throughout treatment); use caution with hepatic or renal impairment

Follow-up

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

Medicolegal 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.

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Keywords

Waldenström hypergammaglobulinemia, macroglobulinemia, Waldenström's hypergammaglobulinemia, malignant lymphoproliferative disease, monoclonal gammopathy, malignant monoclonal gammopathies, Waldenström macroglobulinemia, Waldenström's macroglobulinemia, Waldenstrom macroglobulinemia, WM,

lymphoproliferative disorder, clonal disorder, B-lymphocyte disorder, blood malignancy, hematologic malignancy, blood cell cancer, plasmacytoid lymphocytic lymphoma, lymphoplasmacytoid lymphoma, primary macroglobulinemia, plasma cell neoplasms hemostatic disorders, paraproteinemias

Contributor Information and Disclosures

Author

Doris Ponce, MD, Fellow, Department of Hematology/Oncology, New York Medical College
Doris Ponce, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching

Vijay Ramu, MBBS, Staff Physician, Department of Internal Medicine, East Tennessee State University
Vijay Ramu, MBBS is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Harsha Vyas, MD, Fellow, Section of Hematology and Oncology, Wake Forest University School of Medicine
Harsha Vyas, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Koyamangalath Krishnan, MD, FRCP, FACP, Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University
Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians
Disclosure: Nothing to disclose.

Medical Editor

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Wendy Hu, MD, Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center
Wendy Hu, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Hematology, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Related eMedicine Topics

• Hemostatic Disorders, Nonplatelet
• Hyperviscosity Syndrome [in the Emergency Medicine section]
• Monoclonal Gammopathies of Uncertain Origin
• Multiple Myeloma

• Bortezomib and Rituximab for Patients With Waldenstrom's Macroglobulinemia
• Collecting Stem Cells in Patients With Waldenstrom's Macroglobulinemia
• LBH589 in Relapsed or Relapsed and Refractory Waldenstrom's Macroglobulinemia
• Simvastatin in Waldenstrom's Macroglobulinemia
• A Study for Patients That Have Been Previously Been Treated in Waldenstrom's Macroglobulinemia or Multiple Myeloma
• Trial Comparing Chlorambucil to Fludarabine in Patients With Advanced Waldenström Macroglobulinemia

• Guidelines on the management of Waldenstrom macroglobulinaemia. British Committee for Standards in Haematology - Professional Association. 2005. 31 pages. NGC:005101

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