WM Macroglobulinemia Symptoms Causes Diagnosis

1
WALDENSTROMS MACROGLOBULINEMIA DR MAGDI AWAD SASI 2014
Waldenstroms macroglobulinemia
Waldenström macroglobulinemia, one of the malignant monoclonal gammopathies, is a chronic, indolent, lymphoproliferative disorder , which shares clinical characteristics with the indolent non-Hodgkin lymphomas 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. 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 2) Lytic bony disease and renal disease are uncommon in Waldenström macroglobulinemia but are common in multiple myeloma. ESSENTIAL FOR DIAGNOSIS:
Symptoms non specific , splenomegally
common
Monoclonal IgM paraprotein
Infiltration of bone marrow by plasmacytic
lymphocytic
Absence of lytic bone disease. DEFINITION:
Is a malignant disease of B cells that secret Ig M paraprotein and appear to be a hybrid of plasma cells and lymphocyte. The cancer cells in people with WM are similar to those of 2 other types of cancer: multiple myeloma and non-Hodgkin lymphoma. Multiple myeloma is considered a cancer of plasma cells and non-Hodgkin lymphoma is a cancer of lymphocytes. WM cells have features of both plasma cells and lymphocytes and are called lymphoplasmacytoid. 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. Waldenström's macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. Somatic mutations in MYD88 causing a change from leucine to proline at amino acid position 265 occur in over 90% of patients. Recently, somatic mutations in the C-terminal domain of CXCR4 which are similar to those that appear in the germline of patients with WHIM syndrome((A rare syndrome characterized by warts,

2
hypogammaglobulinemia (low blood gammaglobulin levels), recurring bacterial infections and myelokathexis (form of neutropenia)) were reported, along with small deletions effecting many genes involved in B-cell lymphoma genesis There has been an association demonstrated with the locus 6p21.3 on chromosome 6. There is a 2- to 3-fold risk increase of developing WM in people with a personal history of autoimmune diseases with autoantibodies and particularly elevated risks associated with hepatitis, human immunodeficiency virus, and rickettsiosis. There are genetic factors, with first-degree relatives shown to have a highly increased risk of also contracting Waldenström's. There is also evidence to suggest that environmental factors including exposure to farming, pesticides, wood dust, and organic solvents may influence the development of Waldenström's. EPIDEMIOLOGY: Of all cancers involving the same class of blood cell, 1% of cases are WM. WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually 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. The median age of onset of WM is between 60 and 65 years, with some cases occurring in late teens 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. 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 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.
C/F: Presents insidiously in patients in their 60 years or 70 years. Onset is insidious and nonspecific. Many patients are asymptomatic atpresentation and are diagnosed incidentally from routine blood work. Weakness, anorexia and weight loss are the most common symptoms.

3
In the early stages of the disease , the symptoms are few and far between. The majority of symptoms do not appear in patients until the disease is at a fairly advanced stage and even then the symptoms can vary hugely between patients. Many of the symptoms of waldenstrom's macroglobulinemia are identical to the symptoms of patients diagnosed with other types of non-Hodgkin lymphomas. These can include weakness and fatigue, fever, swollen lymph-nodes and weight loss. However, other waldenstrom's macroglobulinemia symptoms occur because of the overproduction of IG M which can cause hyper-viscosity in the blood which causes problems with circulation and the nervous system. If the circulation is reduced to the brain, problems are similar to a shake can occur. This problem with circulation can lead some patients with waldenstrom's macroglobulinemia to experience Raynaud's phenomenon which can cause blood vessels to tighten slowing the blood. This can cause circulation to be cut off to certain parts of the patient's body, primarily their hands and feet. Not all patients with waldenstrom's macroglobulinemia suffer with hyper-viscosity or Raynaud's phenomenon.
1. Fatigue related to anemia
Weakness((66%)) and fatigue; this is the most common symptom and can be caused by lymphoma cells crowding out red blood cells within bone marrow.
Why anemia?
1. Bone marrow failure
2. Decreased RBC survival
3. Blood loss
4. Haemodilution
2. Loss of appetite which appears in about a quarter of patients and can be caused by the spleen pressing on the stomach, which in turn can cause weight loss.
3. Hyperviscosity syndrome may be manifested in number of ways
IG M paraprotein----- increase viscosity , small ˃ 3g/dl
Retina ------engorged vessels exudates &hemorrhages, blurred discs. Symptoms due to hyperviscosity syndrome, which can be life threatening, include the following :  Bleeding  Dizziness  Headache  Blurry vision  Hearing or visual problems
4. Mucosal and gastrointestinal tract bleeding is related to:
I. Engorged blood vessels
II. Platelet dysfunction
III. Interference with coagulation factor GI system findings may include malabsorption, GI bleeding, and diarrhea.
5. Others ----- nausea , vertigo , visual disturbance

4
Visual changes, such as blurred vision or double images, and spontaneous bleeding with minor trauma can be presenting features
6. Alteration in consciousness vary from mild lethargy to stupor and coma. Mental status changes, including lethargy, stupor, or even coma, can occur. 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
7. IG M paraprotein may cause
symptoms of cold agglutin resulting in
Raynauds phenomena or peripheral
neuropathy. 11%; Raynaud phenomenon is due to cryoglobulinemia and may precede other serious symptoms by several years.
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 reported the following occurrences of symptoms in 215 patients evaluated for Waldenström macroglobulinemia: 1. Hepatomegaly - 20% 2. Splenomegaly - 19% 3. Lymphadenopathy - 15% 4. Purpura - 9% 5. 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) may be associated with W.M. Skin manifestations include the following: 1. Purpura 2. Bullous skin disease 3. Papules on extremities 4. Cutaneous plaques and nodules 5. Chronic urticaria (Schnitzler syndrome) 6. Raynaud phenomenon 7. Livedo reticularis 8. Acrocyanosis

5

6
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. NOTE: Lymphadenopathy, splenomegaly, and/or hepatomegaly are present in 30- 40%
Retinal veins engorged(( characteristic ))
There should be no bone tenderness. There is no evidence of renal failure.
Complications: Complications of Waldenström macroglobulinemia include the following: 1. Hyperviscosity syndrome 2. Visual disturbances secondary to hyperviscosity syndrome 3. Diarrhea and malabsorption secondary to gastrointestinal (GI) involvement 4. Renal disease (less common) 5. Amyloidosis of the heart, kidney, liver, lungs, and joints 6. Bleeding manifestations secondary to platelet dysfunction and coagulation factor and fibrinogen abnormalities due to interaction with plasma IgM 7. Raynaud phenomenon secondary to cryoglobulinemia 8. Increased predisposition to infection due to B-cell dysfunction (disease related) or T-cell dysfunction (therapy related, particularly after nucleoside analogues) 9. Cardiac failure 10. Increased incidence of lymphomas, myelodysplasia, and leukemias
Differential Diagnoses I. Chronic Lymphocytic Leukemia II. Lymphoma, Non-Hodgkin III. Monoclonal Gammopathies of Uncertain Origin IV. Multiple Myeloma

7
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 IG M spike and identifying malignant cells consistent with Waldenström macroglobulinemia (usually found in bone marrow biopsy samples and aspirates). General studies include the following: I. Complete blood count (CBC) II. Red cell indices III. Platelet count IV. 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.
RBC-----anemia is universal & normocytic normochromic , Rouleu formation is common.
------ It is related to expansion of plasma volume by 50—100% due to paraprotein
WBC & PLATELETS---- normal/ LOW
PERIPHERAL BLOOD FILM----- abnormal plasmacytic lymphocyte in small number
BONE MARROW ----is characteristically infiltrated by plasmacytic lymphocytes.
Neutropenia can be found in some patients. Thrombocytopenia is found in approximately 50% of patients with bleeding diathesis. Chemistry tests include the following : 1. Erythrocyte sedimentation rate (ESR) - May be elevated 2. Renal and hepatic function tests--- increased creatinine& total protein levels A. Albumin-to-globulin ratio B. Coagulation

8
abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed C. Electrolytes - Occasionally abnormal; hypercalcemia is noted in approximately 4% of patients; hyponatremia may be present 3. Lactate dehydrogenase (LDH) levels - May be elevated, indicate tissue involvement. 4. Uric acid levels - May be elevated 5. Rheumatoid factor, cryoglobulins, direct antiglobulin test, and cold agglutinin titre results - May be positive 6. 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. 7. Urine routine examoination--- 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. Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin-associated glycoprotein serology. Plasma viscosity must be measured. 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.

9
The hall mark of Waldenstroms macroglobulinemia is the presence of monoclonal IG M spike on SPEP in the beta or gamma region.
Serum viscosity is increased above normal 1.5 times of water.
Hyperviscosity develop----------- serum viscosity is ˃ 4 times of water viscosity.
------------ marked symptoms ˃6 times
There is no correlation between viscosity and concentration of paraprotein.
IG M paraprotein may cause positive coombs test , have cold agglutinin or cryoglobulin .
Bone radiographs are normal.
If one suspect macroglobulinemia but SPEP shows decreased level of ɤ Ig (( hypogammaglobulinemia)), one should repeat the test while taking a special measures to maintain the blood at 37c ,since paraprotein may precipitate at room temperature.
2 Variety:
1. Macroglobulinemia + Diffuse cellular infiltrates --- W.M. 2. Tumour masses ----malignant lymphoma with macroglobulinemia Bone Marrow Aspiration and Biopsy Histology Bone marrow aspiration and biopsy are required to establish the diagnosis. B.M. 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.

10
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). Imaging studies used include the following:  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 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. Deletions of 6q encompassing 6q21-22 have been observed in 40-90% of patients. 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. 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.

11
More recently, Hunter et al performed whole genome sequencing in 30 patients with Waldenström macroglobulinemia and found validated somatic mutations inMYD88 (in 90% of patients), CXCR4 (27%), and ARID1A (17% ). Mutations included the activating mutation L265P in MYD88 and the warts, hypogammaglobulinemia, infection, and myelokathexis syndrome – like mutations in CXCR4. Further research by these investigators showed that these mutations affect clinical presentation and overall survival. SUMMARY OF DIAGNOSTIC STUDIES: Recommended diagnostic studies to evaluate a suspected diagnosis of Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma are as follows: 1. History and physical examination 2. Complete neurologic and ophthalmologic examination 3. Complete blood cell (CBC) count and serum chemistries 4. Serum viscosity 5. Serum protein electrophoresis (SPEP) 6. Serum beta2-microglobulin 7. Serum free light-chain assay 8. Twenty-four–hour urine collection for protein electrophoresis 9. Quantitative serum immunoglobulin G, immunoglobulin A, and immunoglobulin M (IgM) (total levels of serum immunoglobulins should be assessed with nephelometry) 10. Serum immunofixation 11. Autoantibodies, Coombs test, cold agglutinins, cryoglobulins, anti–myelin-associated glycoprotein (MAG) antibodies (based on history and physical finding) 12. Bone marrow biopsy with cytogenetics, fluorescence in situ hybridization (FISH) (for lymphoma and myeloma), and flow cytometry (should include CD19, CD20, CD38, and CD138) 13. CT scanning of the chest, abdomen, and pelvis (to assess for lymphadenopathy and splenomegaly)
Staging/Prognostic Scoring System for W.M./Lymphoplasmacytic Lymphoma Each of the following positive prognostic factors is assigned a value of one, with the final sum used to assess prognostic score and predicted survival:  IgM level >7 g/dL  Age >65 years  Hemoglobin level ≤11.5 g/dL  Platelet count ≤100,000/μL  Beta2-microglobulin level >3 μg/mL
Score Stratum Median Survival (mo) 0-1a Low 142 2b Intermediate 96 >2 High 43 a Except age. b Age >65 years is also intermediate risk.

12
TREATMENT: 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. Patients who meet the 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. A. Initial management of asymptomatic/smoldering disease  Observation/no treatment is recommended.  Asymptomatic/smoldering disease is defined as hemoglobin level over 11 g/dL, a platelet count of more than 100 X 109/L, and an absence of neuropathy, hyperviscosity, or WM- associated hemolytic anemia or constitutional symptoms. B. Initial treatment of nonbulky symptomatic disease  Consider single-agent rituximab therapy.  Nonbulky symptomatic disease is characterized by WM-associated neuropathy, anemia or cytopenias, low-volume nodal disease, and asymptomatic splenomegaly. C. Emergent Treatment--  Hyperviscosity syndrome manifestations should be treated promptly, and emergent care is paramount  Hyperviscosity syndrome should be suspected only in patients with WM/LPL who have a serum viscosity greater than 4.  The treatment of choice 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 2-4U 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.

13
 Long-term plasma exchange is rarely required and is used only in patients who have relapsed refractory disease, in whom few systemic treatment approaches exist. Patients with WM/LPL and associated hyperviscosity may need emergent paraprotein reduction using plasmapheresis. Two to 3 exchanges are required to reduce the IgM levels by 30%- 60%. This is absolutely necessary, particularly before starting a rituximab-containing regimen, as rituximab is known to cause a flare reaction in patients with WM-associated hyperviscosity  However, evidence supporting plasma exchange for the peripheral neuropathy associated with IgM paraprotein is weak (grade of recommendation C) D. Treatment of bulky symptomatic disease: Bulky symptomatic disease is characterized by bulky adenopathy, symptomatic splenomegaly, cytopenias, hyperviscosity, neuropathy, or constitutional symptoms. Indications for initiating active treatment include : 1. Clinical evidence of adverse effects of the paraprotein (hyperviscosity with neurologic or ocular disturbance, peripheral neuropathy, amyloidosis, symptomatic cryoglobulinemia, cytopenias) 2. Disease progression (including progressive anemia). 3. Development of constitutional symptoms. Therapeutic intervention of Waldenström macroglobulinemia can be divided into treatment of IgM paraprotein complications and treatment of the disease per se. Current therapies include the use of the following:
Plasmapheresis (for patients with symptomatic hyperviscosity)
Rituximab (anti-CD20 antibody)
Purine nucleoside analogues
Alkylating agents
Thalidomide
Bortezomib
Everolimus
Alemtuzumab
Interferon alfa
Combination therapies
High-dose chemotherapy
Bone marrow transplantation Treatment recommendations from the International Workshops on Waldenström Macroglobulinemia are as follows : 1. 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, neyropathy). 2. Combinations of rituximab with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provide durable responses and are indicated for most patients 3. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options

14
4. 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 5. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features
MAIN LINES OF TREATMENT
 Plasmapharesis--
 Periodic plasmapharesis
 Intermittent cyclophosphamide or chlormbucil
 Cladribine E. Combination chemotherapy 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 response rates of 69% and 94%, respectively, in 72 patients treated with either CHOP or R-CHOP F. 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 G. Stem cell transplantation High-dose chemotherapy with autologous peripheral blood cell transplantation is reserved for selected younger patients with primary refractory or relapsed disease. Reduced- intensity allogeneic stem cell transplantion may be an option in very select patients
Medication: Various drugs, including corticosteroids (eg, prednisone), alkylating agents (eg, chlorambucil, melphalan, cyclophosphamide), biologic response modifiers (eg, interferon alfa, interferon gamma), and purine analogues (eg, fludarabine, 2-chlorodeoxyadenosine), are used in the treatment 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, and monoclonal antibody (alemtuzumab). 1. 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 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.

15
2. Antineoplastics, Alkylating 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. Chlorambucil (Leukeran) 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. Single-agent alkylating drug therapy has been traditionally used for over 40 years. Oral chlorambucil with or without prednisone is frequently used as initial therapy for Waldenström macroglobulinemia, especially in elderly patients. The response rate is approximately 60%, and the median survival is 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. Melphalan (Alkeran) Inhibits mitosis by cross-linking DNA strands; it ultimately disrupts nucleic acid function. Cyclophosphamide 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. Cyclophosphamide 750 mg/m2 3. Antineoplastics, Antimetabolite 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. 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. Cladribine (Leustatin) 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. 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. The median overall survival was 73 months. Cladribine 0.1 mg/kg SC

16
Fludarabine (Fludara) 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. Fludarabine 25 mg/m2 IV days 1-5 4. Antineoplastics, Anthracycline These agents immunomodulate the response to malignant cells. Doxorubicin (Adriamycin) 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. Doxorubicin 50 mg/m2 5. Antineoplastics, Monoclonal Antibody These agents immunomodulate the response to malignant cells. Rituximab (Rituxan) Rituximab is a genetically engineered human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. 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.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. Rituximab 375 mg/m2 IV once weekly x 4 weeks 6. Immunomodulators Immunomodulators modulate processes that promote immune reactions resulting from diverse stimuli. Interferon alfa-2b (Intron A) This is a protein product manufactured by recombinant DNA technology. It possesses complex antiviral, antineoplastic, and immunomodulating activities. 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. Interferon gamma-1b (Actimmune) 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.

17
Thalidomide (Thalomid) 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. 7. Antineoplastics, Proteasome Inhibitors Proteosome inhibitors inhibit cell growth and proliferation. Bortezomib (Velcade) 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. 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. 8. Antineoplastics, mTOr Kinase Inhibitor These antineoplastic agents have antiproliferative and antiangiogenic properties. Everolimus (Afinitor, Zortress) 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. It demonstrate activity in relapsed W.M. The combination therapy for untreated W.M.: CHOP-R Cyclophosphamide 750 mg/m2 IV day 1 RESPONSE 90% Doxorubicin 50 mg/m2 Vincristine 1.4 mg/m2 IV (max 2 mg) day 1 Prednisone 50 mg/m2 PO days 1-5 Rituximab 375 mg/m2 IV day 1 Primary: Repeat 21 day cycle for 6-8 cycles BR Bendamustine 90 mg/m2 IV days 1-2 RESPONSE 95% Rituximab 375 mg/m2 IV day 1 Primary: Repeat 21 day cycle for 6 cycles

18
BDR Bortezomib 1.3 mg/m2plus RESPONSE 96% Dexamethasone 40 mg IV days 1, 4, 8, and 11 Rituximab 375 mg/m2 IV day 11 Primary: Repeat 21 day cycle for 4 cycles DRC Dexamethasone 20 mg IV day 1 Rituximab 375 mg/m2 IV day 1 Cyclophosphamide 100 mg/m2 PO BID days 1-5 Primary: Repeat 21 day cycle for 6 cycles The combination therapy for untreated & previously treated W.M FCR Fludarabine 25 mg/m2 IV days 1-3 RESPONSE 79% Cyclophosphamide 250 mg/m2 IV days 1-3 Rituximab 375 mg/m2 IV day 1 Primary: Repeat 28 day cycle for 4-6 cycles May also be given with mitoxantrone 10 mg/m2 on day 1 Fludarabine/rituximab Fludarabine 25 mg/m2 IV days 1-5 RESPONSE 90% Rituximab 375 mg/m2 IV day 1 Repeat 28 day cycle for 4-6 cycles TR Thalidomide 50-200 mg/d PO days 1-28 RESPONSE 64% Rituximab 375 mg/m2 IV once weekly during weeks 2-5 and 13-16 Primary: Repeat 28 day cycle for 12 cycles CR Cladribine 0.1 mg/kg SC days 1-5 RESPONSE 86% Rituximab 375 mg/m2 IV day 1 Primary: Repeat 28 day cycle for 4 cycles BR/A Bendamustine 90 mg/m2 IV days 1-2 RESPONSE 83% Rituximab 375 mg/m2 IV or ofatumumab 300 mg IV day 1 of week 1, THEN 1000 mg IV day 1 of weeks 2, 3, and 4 Ofatumumab used for rituxumab intolerant individuals

19
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[34] :  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
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. Patients with a nodular type of bone marrow involvement tend to do better than those with diffuse involvement. Poor prognostic factors include the following: 1. Age older than 65 years 2. Hemoglobin value of less than 10 g/dL 3. Albumin level less than 4.0 g/dL 4. Elevated beta-2-microglobulin level
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. 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 1. Infection 2. Cardiac failure 3. Renal failure 4. Strokes 5. GI bleeding.
Transformation to a more aggressive immunoblastic variant is less common (6% of cases). Risk of death was not affected by CXCR4 mutation status, but was markedly increased by wild type MYD88 status (hazard ratio 10.54) DISEASES ASSOCIATION WITH W.M.:
HOPPING ALLAH ACCEPT MY WORK--- THE MOST KINDFUL, THE MOST MERCIFUL

WM Macroglobulinemia Symptoms Causes Diagnosis

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to WM Macroglobulinemia Symptoms Causes Diagnosis

Similar to WM Macroglobulinemia Symptoms Causes Diagnosis (20)

More from cardilogy

More from cardilogy (20)

Recently uploaded

Recently uploaded (20)

WM Macroglobulinemia Symptoms Causes Diagnosis