WALDENSTROM

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WALDENSTROMS 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

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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

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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

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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

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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

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• 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

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DIFFERENTIALS

• CHRONIC LYMPHOCYTIC LEUKEMIA
• LYMPHOMA NON HODGKINS
• MULTIPLE MYELOMA

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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 RARE4
• LDH LEVELS ARE ELEVATED INDICATING EXTENT OF
  TISSUE INVOLVEMENT

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• 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

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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.

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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.

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• 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).

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INTERMITTENT PULSE REGIMEN

• ALKYLATING AGENT STEROID
• 3 ALKYLATING AGENTS ARE USED
• MELPHALAN8MG/M2 PER DAY
• CHLORAMBUCIL8MG/M2PER DAY
• CYCLOPHOSPHAMIDE200MG/M2PER 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

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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
• FLUDARABINE25MG/M2/DAY FOR 5 DAYS EVERY 4 WEEK
• CLADRIBINE0.1MG/KG/DAY FOR 7 DAYS EVERY 4 WEEK
• YHESE 2 ARE PURINE NUCLEOTIDE ANALOUGES
• RITUXIMABANTI CD2060-75MG/M2 IV SINGLE DOSE
  EVERY 4 WEEK

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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

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• 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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