WALDENSTROM’S MACROGLOBULINEMIA

1. WALDENSTROM’S MACROGLOBULINEMIA • DEFINATION:- IT IS MONOCLONAL PROLIFERATION OF B LYMPHOCYTES PROGENITES LEADING TO MALIGNANCY OF LYMPHOPLASMACYTOID CELLS THAT SECRETE IGM PARAPROTEIN • INCIDENCE:- • RELATIVELY RARE CONDITION • 1500 CASES DIAGNOSED PER YEAR IN USA • MEDIAN AGE IS 65 YEARS COMMONLY IN MALES • ETIOLOGY:- • UNKNOWN • ENVIRONMENTAL FACTOR • FAMILIAL FACTOR • GENETIC FACTOR • VIRAL FACTOR-{HEPATITIS C,G,HUMAN HERPES VIRUS 8}

2. PATHOPHYSIOLOGY • SECRETION OF IGM PARAPROTEIN LEADS TO HYPERVISCOSITY AND VASCULAR COMPLICATIONS BECAUSE OF PHYSICAL,CHEMICAL & IMMUNOLOGICAL PROPERTIES OF THE PARAPROTEIN • NEOPLASTIC LYMPHOPLASMACYTIC CELLS INFILTRATE THE BONE MARROW, SPLEEN & LYMPH NODES.LESS COMMONLY THESE CELLS INFILTRATE LIVER ,GI TRACT ,KIDNEYS , SKIN EYES, AND CNS • OCCASIONLY IGM PARAPROTEIN HAS:- • RHEUMATOID FACTOR ACTIVITY • ANTIMYELIN ACTIVITY CAUSING PERIPHERAL NEUROPATHY • IMMUNOLOGICALLY RELATED LUPUS ANTICOGULANT ACTIVITY

3. MORTALITY & MORBIDITY • CHRONIC INDOLENT LYMPHOPROLIFERATIVE DISORDER • MEDIAN SURVIVAL TIME IS APPROXIMATELY 78 MONTHS • MOST IMPORTANT CAUSES OF DEATH ARE :- • PROGRESSION OF PROLIFERATIVE PROCESS • INFECTION • CARDIAC FAILURE • RENAL FAILURE • STROKES • GI BLEED • TRANSFORMATION TO MORE AGGRESSIVE IMMUNOBLASTIC VARIANT

4. HISTORY • ONSET IS INCIDIOUS AND NON SPECIFIC • WEAKNESS- 66% • ANOREXIA- 25% • WEIGHT LOSS- 17% • FEVER- 15% • HYPERVISCOSITY SYMPTOMS • BLEEDING,DIZZINESS,HEADACHE,BLURRY VISION • PHYSICAL EXAMINATION • HEPATOMEGALY-20% • SPLENOMEGALY-19% • LYMPHADENOPATHY • PURPURA • HEMORRAGIC MANIFESTATIONS-7%

5. MANIFESTATIONS • CNS • PERPHERAL NEUROPATHY • IGM HAS SPECIFICITY FOR {MAG} WHICH CAUSES DEMYELINATION • MENTAL CHANGES • LETHARGY,…..,COMMA, • INFILTERATION OF CNS BY MALIGNANT CLONE CAUSE A SYNDROME OF CONFUSION ,MEMORY LOSS,DISORIENTATION& MOTOR ABNORMALITIES,CALLED BING-NEEL SYNDROME

6. OPTHALMIC • PAPILEDEMA SAUSAGE SHAPED {DISTENDED & TORTOUS} RETINAL VEINS & HEMORRAGE DUE TO HYPERVISCOSITY • SKIN • PURPURA,BULLOUS SKIN DISEASE,PAPULES , CHRONIC URTICARIA,RAYNOCID PHENOMENA ,LIVIDO RETICULARIS • CARDIO-RESPIRATORY • CONGESTIVE HEART FAILURE • PARENCHYMAL INFILTRATES,NODULES

7. DIFFERENTIALS • CHRONIC LYMPHOCYTIC LEUKEMIA • LYMPHOMA NON HODGKINS • MULTIPLE MYELOMA

8. LAB INVESTIGATIONS • NORMOCYTIC NORMOCHROMIC ANEAMIA • THROMBOCYTOPENIA • LEUKOPENIA/LEUKOCYTOSIS • NEUTROPENIA • PERIPHERAL SMEAR • PLASMACYTOID LYMPHOCYTES • NORMOCYTIC NORMOCHROMIC RBC • ROULEAUX FORMATION • ESR AND URIC ACID LEVELS ELEVATED • CREAT & ELECTROLYTES ARE OCCASSIONLY ELEVATED • HYPERCALCEMIA IS RARE{4%} • LDH LEVELS ARE ELEVATED INDICATING EXTENT OF TISSUE INVOLVEMENT

9. SERUM PROTEIN ELECTROPHORESIS REVEALS MONOCLONAL SPIKE THAT IS M COMPONENT BUT CANNOT ESTABLISH IT AS IGM .BETA TO GAMMA MOBILITY IS HIGH • IMMUNOELECTROPHORESIS & IMMUNO FIXATION STUDIES IDENTIFY THE TYPE OF IMMUNOGLOBULIN , CLONALITY OF LIGHT CHAIN • URINE ELECTROPHORESIS SUGGEST BENZ JONES PROTEIN OF LIGHT CHAIN KAPPA TYPE IN 80% • BONE MARROW ASPIRATION & BIOPSY SHOWS INFILTRATION BY LYMPHOPLASMACYTOID CELLS IN 3 PATTERN • NODULAR • INTERSTITIAL/NODULAR • PACKMARROW • NODULAR INFILTRATION HAS BEST PROGNOSIS & PACKED MARROW INDICATES WORST PROGNOSIS • FLOW CYTOMETRY SHOWS B- CELL MARKERS • CD5-/CD10-/CD19+/CD20+/CD23-/ARE DIAGNOSTIC OF WM

10. 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.

11. MANAGEMENT • 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.

12. 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. • 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).

13. INTERMITTENT PULSE REGIMEN • ALKYLATING AGENT + STEROID • 3 ALKYLATING AGENTS ARE USED • MELPHALAN{8MG/M2 }PER DAY • CHLORAMBUCIL{8MG/M2}PER DAY • CYCLOPHOSPHAMIDE{200MG/M2}PER DAY • CYCLOPHOSPHAMIDE IS SAFEST TO MARROW STEM CELL & PREVENTS MYELODYSPLASTIC SYNDROME SO IT IS PREFFERED • PREDNISONE 25-60 MG/M2/DAY IS USED IN COMBINATION OF CYCLOPHOSPHAMIDE FOR 4-7 DAYS EVERY 3-4 WEEKS • DURATION OF THERAPY IS USUALLY FOR 1-2 YEARS

14. PRIMARY THERAPY RESISTANT CASES • VAD COMBINATION THERAPY FOR 4 DAYS PER WEEK EVERY 3 WEEKS • VINCRISTINE .4MG/DAY IV • ADRIAMYCINE 9MG/M2/DAY IV • DEXAMETHASONE 40 MG /DAY • NOVAL AGENTS SUCH AS THALIDOMIDE & PROTEASOME INHIBITOR-VELCADE ARE USED IN RELAPSED & REFRACTORY CASES • THALIDOMIDE- 50MG/DAY TO MAX OF 200MG PER DAY • VELCADE- 1-2 MG/M2 ON 1-4-8-11 DAYS OF A 3 WEEK CYCLE • FLUDARABINE{25MG/M2/DAY} FOR 5 DAYS EVERY 4 WEEK • CLADRIBINE{0.1MG/KG/DAY} FOR 7 DAYS EVERY 4 WEEK • YHESE 2 ARE PURINE NUCLEOTIDE ANALOUGES • RITUXIMAB{ANTI CD20}60-75MG/M2 IV SINGLE DOSE EVERY 4 WEEK

15. RESPONSE CRITERIA • 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

16. 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

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