Download Heme-Onc Step3 Review

HEME-ONC STEP 3 REVIEW
By James K. Rustad, M.D.
Copyright © 2009 All Rights Reserved
OUTLINE
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Anemia
Iron Deficiency Anemia
Beta and Alpha
Thalassemia
Vitamin B12 deficiency
and Schilling test
Hemolytic Anemia
(Autoimmune,
Hereditary
Spherocytosis, DrugInduced, and
Microangiopathic)
G6PD Deficiency
Sickle cell Anemia
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Blood Transfusion
Reactions
Neutropenia
ITP
Heparin Induced
Thrombocytopenia
Coagulation tree,
abnormalities, and
testing
Oncology: Leukemias
and Lymphomas
Multiple Myeloma
ANEMIA
ANEMIA
What to do?
 Check CBC and Retic Count
 If Retic index > 2.5 OR Absolute retic count >
75000 ----- likely Hemolysis or Hemorrhage
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MEAN CORPUSCULAR VOLUME (MCV)
Measure of average RBC volume (size)
 Microcytic anemia < 80 (Iron Deficiency)
 Normocytic/Normochromic 80-95: chronic
disease, renal failure, hypothyroidism
 Macrocytic > 95 (B12, Folate deficiency).
Remember “hypersegmented (lobed) neutophils”
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IRON DEFICIENCY ANEMIA VS. ACD
Lab Value
IRON Deficiency
Anemia of Chronic
Disease
Iron
Decreased
Decreased
TIBC
Increased
Decreased
Ferritin
Decreased
Normal or Elevated
CLINICAL CASE SCENARIO
CBC suggests Microcytic Anemia (low MCV),
Next step?
 Iron Studies. If normal, what is next step?
 Hb electrophoresis. If normal, what is diagnosis?
 Alpha-Thalassemia Trait, which is a Diagnosis
of Exclusion
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CLINICAL NUGGETS OF KNOWLEDGE
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Retic Count will
increase one week after
starting oral iron.
Take iron 2 hours before
and 4 hours after
calcium/antacids
(decreases absorption).
If not tolerating Ferrous
sulfate (abdominal
cramps), switch to
Ferrous gluconate.
BETA THALASSEMIA
Normal
Minor
Major
HbA
97-99%
90%
0-10%
HbA2
1-3%
4-8%
4-10%
HbF
0%
1-5%
90-96%
BETA THALASSEMIA MAJOR (COOLEY’S
ANEMIA)
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Homozygous
Severe anemia: patient
cannot survive without
transfusion! To
Diagnose?
Hb electrophoresis
On Peripheral Smear:
Target cells (also
present in sickle cell,
S.C. disease)
Basophilic stippling
(also present in alcohol
abuse, lead poisoning)
BETA THALASSEMIA
Extramedullary
and Intramedullary
erythropoiesis
 Chipmunk facies
 Hair on end
appearance in skull
x-ray due to
marrow expansion.
 Treatment: Blood
transfusion,
allogenic bone
marrow transplant.
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ALPHA THALASSEMIA
There are four alpha
globin genes.
 One deleted: silent
carrier, normal.
 Two deleted:
Thalassemia minor or
Alpha Thalassemia
Trait. Low Hct with
very low MCV.
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Three deleted: HbH
disease. Severe
hemolytic anemia,
increased Retic count,
Hb Electrophoresis
shows HbH. Tx:
repeated transfusion.
Poor prognosis.
 Four deleted:
Hydrops Fetalis (Hb
Electrophoresis shows
Hb Bart): Death in
utero.
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SCHILLING TEST
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To differentiate the
cause of Vitamin B12
deficiency:
Decreased intake
Decreased
production of
intrinsic factor
Decreased absorption
Vitamin B12 IM to
saturate plasma level
then radio-labeled B12
administered orally.
ALGORITHM STEP ONE: 24 HOUR URINE TEST
If normal (7% of oral dose in urine), cause is
decreased intake.
 If abnormal, give Radio-labeled B12 and
Intrinsic Factor.
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ALGORITHM STEP TWO: RADIO-LABELED
B12 AND IF
Normal: Intrinsic Factor
Deficiency caused by
Pernicious anemia or
Gastrectomy
Abnormal: Cause is
decreased absorption of B12
caused by Blind Loop
syndrome, Crohn’s or Ileal
Resection.
SUSPECTED BLIND LOOP SYNDROME
Treat with
antibiotics and
repeat testing. If
normal: blind loop
syndrome.
 If still abnormal:
caused by Crohn’s or
ileal resection.
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SCHILLING TEST ALGORITHM
NML:
7% of
oral
dose
in
urine
24
hour
urine
ABNL:
Give
B12
and IF
NML: I.F.
Deficient
Pernicious
Anemia or
Gastrectomy
AABNL:
Decreased
absorption
If improved after ABX:
Blind loop syndrome.
Otherwise: Crohn’s or
ileal resection
HEMOLYTIC ANEMIA
Anemia and jaundice
 Increased: retic index,
LDH, indirect
bilirubin
 Decreased:
haptoglobin
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AUTOIMMUNE HEMOLYTIC ANEMIA
Warm antibody
induced
Cold antibody
induced
Antibody
IgG against Rh
antigen
IgM against I antigen
Causes
Idiopathic, drug
induced, lymphoma,
leukemia
Idiopathic,
mycoplasma, mono,
Waldenstrom’s
macroglobulinemia
Coomb’s Test
+ IgG or IgG and C3
- IgG Only C3 +
Cold agglutinin
Negative
Positive
Treatment
Steroid,
Splenectomy. If
treatment refractory:
immunosuppressive!
Cyclophosphamide or
Cyclosporin.
No Steroid or
Splenectomy.
Immunosuppressive
treatment!!
Cyclophosphamide or
Chlorambucil.
INCREASED MHC AND SPHEROCYTES
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MHC: Mean
corpuscular
hemoglobin
Two causes:
Autoimmune hemolytic
anemia (Coombs test
positive)
Hereditary
Spherocytosis (Coombs
test negative)
Spherocytes are
hyperchromic; they have
no area of central pallor
(normal red blood cells
do!)
CLINICAL SCENARIO
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Child with anemia,
icterus, jaundice and
splenomegaly on
exam.
Spherocytes in
peripheral smear.
Retic count and
MCHC increased.
Coombs test negative.
Most likely
diagnosis?
Hereditary
spherocytosis!
HERIDITARY SPHEROCYTOSIS
Confirmatory test:
Osmotic Fragility Test
 Treatment:
Splenectomy
 You may also give
Folic Acid.
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DRUG INDUCED HEMOLYTIC ANEMIA
AlphaMethyldopa
Type
Penicillin
Type
Quinidine
Type
Direct Coomb’s
IgG+ C3+
IgG+ C3+
IgG negative
C3+
Indirect
Coomb’s
Positive
without
adding Drug
Positive ONLY
when adding
drug
Positive ONLY
when adding
drug
CLINICAL CASE
30 year old pregnant patient with anemia.
 On Methyldopa for Hypertension and started on
Penicillin for recent UTI.
 On exam: pallor.
 Labs: increased retic count, increased LDH,
spherocytes present on smear. Direct Coombs +
for IgG and C3.
 Indirect Coombs positive ONLY when drug
added.
 Most likely cause of anemia?
 PENICILLIN
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MICROANGIOPATHIC HEMOLYTIC ANEMIA
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Fragmented RBC’s
Schistocytes (black
arrows)
Helmet cells (red
arrows)
Causes:
TTP
HUS
DIC
Prosthetic Heart Valve
HELLP syndrome in
pregnancy
THROMBOTIC THROMBOCYTOPENIC
PURPURA (TTP)
Microangiopathic
hemolytic anemia
 Neuro: change in
mental status
(confusion waxes and
wanes in minutes)
 May have renal
insufficiency
 PT, PTT normal
 Cause: unknown
 Treatment:
plasmapheresis
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HEMOLYTIC UREMIC SYNDROME
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Causes: unknown OR
diarrhea with E. Coli
O157: H7, Shigella,
Salmonella.
G6PD DEFICIENCY
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X-linked recessive
(usually male)
Usually in Black
Americans
G6PD Deficiency can
cause hemolytic anemia.
Common precipitants
include:
Infection
Drugs such as Dapsone,
Quinine, Sulfonamide,
Primaquin, Quinidine,
Nitrofurantoin
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Bite cells
SICKLE CELL ANEMIA
Valine replaces glutamic acid at position 6 of beta
chain
 Sickle Hb forms polymer when dehydrated
 Hb electrophoresis HbS positive
 RBC containing HbF does not sickle (fewer
crises)
 Chronic hemolysis: RUQ pain secondary to
calcium bilirubinate gallstone
 Spleen not palpable
 Poorly healing ulcers of the lower extremity
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SICKLE CELL ANEMIA (SS) VS. SICKLE
CELL TRAIT (SA)
Sickle cell anemia (SS):
Sickle cell trait (SA)
HbS: 75%-95%
HbF: 2%-20%
HbA2: 2-4%
HbS: 40%
HbA: 60%
Factors precipitating sickling:
Hypoxia, dehydration, acidosis,
hypothermia
Crisis only w/ severe hypoxia:
Examples include
mountaineering and skiing.
Hematuria more frequent than
in SS.
CLINICAL CASE
Patient with sickle cell anemia complains of SOB,
weakness. CBC shows hemoglobin of 5 (baseline
9-10)
 Next study?
 Retic count to differentiate between Hemolytic
Crisis (Retic count high) secondary to splenic
sequestration or co-existent G6PD deficiency vs.
Aplastic crisis (Retic count low).
 Treatment of sequestration is splenectomy.
 On exam of patient with splenic sequestration:
spleen palpable whereas it was not palpable on
prior exams.
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CLINICAL CASE
Patient with sickle cell complains of weakness.
 Hematocrit 20 and low Retic index at 0.8.
 History of febrile illness and skin rash one week
ago.
 Most likely diagnosis?
 Aplastic crisis secondary to PARVOVIRUS.
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CLINICAL CASE
Patient with sickle cell comes to ER with cough
and chest pain worse on inspiration and lying
down.
 CXR shows infiltration and patient started on IV
fluids and antibiotics.
 In 48 hours NO clinical improvement, severe
chest pain continues. Diagnosis and next step in
management?
 Acute Chest Pain Syndrome; arrange for
Exchange Transfusion
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BLOOD TRANSFUSION
REACTIONS
Clinical Case Scenarios
CLINICAL CASE SCENARIO
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Patient with anemia
receives blood
transfusion and
develops
chills/fever/chest and
flank pain. Most likely
diagnosis?
ABO incompatibility
Treatment: Stop
transfusion and start IV
hydration to prevent
Acute Tubular Necrosis!
CASE SCENARIO
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Patient underwent
complete compatibility
testing, receives blood
transfusion and four
hours later develops
fever, chills. What
happened?
Leukoagglutinin
reaction (not secondary
to hemolysis).
Treatment?
Acetaminophen and
Diphenhydramine
CASE SCENARIO
Patient with
lymphoma (immunocompromised) needs
blood transfusion.
What to do?
 Transfuse GAMMA
Radiated Blood to
prevent Graft vs. Host
Disease.
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CASE SCENARIO
History of Febrile
Reaction with Blood
Transfusion. Needs to
be transfused again --what to do?
 Leukocyte
depletion filter.
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CASE SCENARIO
A blood transfusion
leads to hives and
bronchospasm caused
by plasma proteins. If
another transfusion is
necessary, what is the
next step?
 Transfuse WASHED
(“like the laundry”)
packed RBC’s!
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NEUTROPENIA
18 y.o. black
male, WBC
2000,
Polymorphs
38%,
asymptomatic
Repeat CBC
in 3-4 weeks,
if WBC same
= Benign
neutropenia
with no risk
infection
If after 3-4 weeks,
WBC increased, repeat
again in 3-4 weeks. If
WBC goes down,
Cyclic Neutropenia.
Increased risk of
infection and treat with
Granulocyte
Macrophage Colony
Stimulating Factor!
IDIOPATHIC THROMBOCYTOPENIA (ITP)
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Case: Young Female
Patient with Platelets
8000. Started on
Prednisone 40 mg.
After 4 weeks, platelet
count 150,000. When
Prednisone tapered to
20 mg, platelet count
drops below 20,000.
Next step?

Plan for Splenectomy
as patient needs high
dose Prednisone to
maintain platelet
counts.
HEPARIN INDUCED
THROMBOCYTOPENIA
Type I usually mild
and self limited; Type
II (immune) is of
clinical concern.
 Type II occurs 5-15
days after starting
therapy.
 Increased risk of
Thrombosis due to
heparin induced
platelet aggregation.
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(HIT)
HIT II DIAGNOSIS
Diagnosis: 14C
serotonin release
assay;
antiheparin/platelet
factor 4 antibody.
 Treatment: Stop all
forms of heparin even
the flush for the IV
line.
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HIT II TREATMENT
If anticoagulation
needed use
Danaproid, Lepirudin,
Hirudin, or
Argatroban. These
have no Antidote!
 Remember, “if you’ve
got the poison
(Heparin), then I’ve
got the remedy
(Protamine sulfate).”
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CLINICAL CASE
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Patient in hospital
received heparin for
DVT prophylaxis.
Returned home and
then after one week
came back to ER in
severe abdominal pain;
on exam abdomen
mildly tender in periumbilical area
(subjective greater than
objective pain).
Labs: WBC count and
Lactic Acid high,
Platelets law.
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Most likely diagnosis?
Acute Mesenteric
Ischemia secondary to
HIT II.
COAGULATION TREE
Coagulation Abnormalities and Testing
COAGULATION CASCADE
Extrinsic (PT)
Intrinsic
(PTT)
TF
12
11
9
8
Factor 10 (changes
Prothrombin to
Thrombin)
7
COAGULATION CASCADE (CONTINUED)
Fibrinogen
to Fibrin
Monomer
via
Thrombin
Monomer to
Polymer
Polymer to
Cross linked
fibrin via
Factor 13
VON WILLENBRAND’S DISEASE
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Deficiency of vWF
Most common
inherited bleeding
disorder. Autosomal
dominant.
Functions: Bridge for
platelet adhesion and
aggregation. Carrier for
factor 8 (increases half
life by five-fold).
Prolonged bleeding time
despite normal platelet
count.
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Treatment?
Desmopressin in mild
bleeding.
Factor 8 concentrate for
severe bleeding or prior
to surgery or if patient
is still bleeding after
desmopressin.
COAGULATION TESTS
Prolonged PTT
and Normal PT
No
bleeding:
Factor 12
deficiency
Mild or rare
bleeding:
Factor 11
deficiency
Frequent and
severe
bleeding:
Factor 9 or 8
deficiency!!
HEMOPHILIA A VS. HEMOPHILIA B
Hemophilia A
Hemophilia B
Affects only male
Affects only male
Low factor 8 coagulation activity
Low factor 9 coagulant activity
Prolonged PTT (normal PTT on
mixing study), normal PT
Prolonged PTT (normal PTT on
mixing study), normal PT
Family history
Family history
Spontaneous bleeding in the
joints
Spontaneous bleeding in the
joints
Treatment: Factor 8 concentrate
Treatment: Factor 9 concentrate
Normal Factor 8 antigen
COAGULATION TESTS
Prolonged PT,
normal PTT
Coumadin
Primary
Factor 7
deficiency
Early Vitamin K
deficiency (Vit K
dependent
2,7,9,10) due to
diet, broad
spectrum ABX
which kill gut
bacteria
COAGULATION TESTING
Both PTT and PT prolonged?
 Defect in common pathway
 DIC, Liver Disease, Vitamin K deficiency
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MIXING STUDIES
Patient bleeding
with platelets, PT,
bleeding time normal
but PTT elevated
Mixing Study
with normal
plasma: PTT
normal.
Factor 8 or
9 level
(deficiency?)
Tx: FFP
Mixing
Study: PTT
not corrected
due to
circulating
anticoagulant
Factor 8
antibody
(bleeding)
Patient with history
of recurrent abortion
and stroke, increased
PTT
Mixing Study: PTT
not corrected due to
Lupus anticoagulant
(not bleeding in
Lupus:
hypercoagulable
state)
CLINICAL CASE SCENARIO
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After a dental extraction,
patient develops severe
bleeding. Normal
platelets, bleeding time,
PT, PTT. Most likely
diagnosis?
Factor 13 deficiency
(problem with forming
cross-linked fibrin)
Diagnosis: Clot solubility
in 5M urea
Treatment: FFP
ONCOLOGY
Leukemia and Lymphoma
ACUTE LEUKEMIA
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In children: 80% acute leukemia: ALL
In adults 80% acute leukemia: AML
S/Sx: fatigue, gum bleeding, epistaxis, ecchymosis,
purpura, petechiae, bone pain, recurrent infection.
On exam: hepatosplenomegaly, lymphadenopathy non
tender, firm, rubbery (especially ALL).
Labs: decreased platelet, decreased RBC and Hb/Hct,
increased WBC with 90% blast cell in peripheral smear
(patients have leukopenia but due to blast cells total count
increases).
Bone marrow: hypercellular with > 30% blast cells
ACUTE LEUKEMIA
AML
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AML cells have
granules, Auer Rods,
histochemical stain
suggests myeloid
enzyme such as
peroxidase.
Worst prognosis:
Monosomy 5 and 7
Treatment: Cytarabine
and Daunorubicin.
After remission
consider Bone Marrow
Transplant.
ALL
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ALL cells have surface
marker TdT (terminal dexy
nucleotidal transferase).
Worst prognosis: t (9:22) and
t (4:11)
Treatment: Vincristine,
Prednisone, Daunorubicin,
L-Asperginase – after
remission CNS prophylaxis
with intrathecal
Methotrexate and cranial
irradiation; also consider
Bone Marrow Transplant.
CHRONIC MYELOGENOUS LEUKEMIA
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Hallmark: WBC >
100,000
Most cells mature (less
than 5% blast cells)
Low leukocyte Alk.
phos.
: fatigue, night sweats,
low grade fever
On exam: splenomegaly,
sternal tenderness
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Drug of choice: Imatinib
mesylate (inhibit
tyrosine kinase activty
of bcl/abl oncogene).
Bone marrow transplant
(only curative treatment
< 60 year old with HLA
matched sibling).
CML (PHILADELPHIA CHROMOSOME)

Philadelphia
chromosome negative
CML has poorer
prognosis than
Philadelphia
chromosome positive.
CHRONIC LYMPHOCYTIC LEUKEMIA
Hallmark:
lymphocytosis
 WBC usually greater
than 20,000 (75-95%
of cells are mature
lymphocytes)
 Usually CD19 is a
marker of B and CD5
of T lymphocyte.
 Usually patient will
be >65 yr of age.


If Anemia +
Thrombocytopenia: IV
Fludrabine (IV),
Chlorambucil.
Refractory CLL:
Alemtuzumab
HODGKIN’S LYMPHOMA
Commonly presents as
painless cervical
lymphadenopathy in
young children.
 To diagnose?
 Lymph node biopsy


“Reed-Sternberg” cells
HODGKIN’S LYMPHOMA
Most common:
nodular sclerosing
type.
 Staging:
 I: one lymph node
 II: two or more lymph
nodes on one side of
diaphragm
 III: both sides of
diaphragm
 IV: disseminated
disease

A: No constitutional
symptoms
 B: fever, night sweats
 Treatment: IA and
IIA: radiation.
 Others: chemotherapy
 ABVD: Adriamycin,
Bleomycin,
Vincristine,
Dacarbazine
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BURKITT’S LYMPHOMA
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B-cell lymphoma
Translocation of
protooncogene C-myc from
Chromosome 8 to 14
Presentation: abdominal
pain/fullness
Retroperitoneal or pelvic
lymphadenopathy
Treatment: low risk –
chemotherapy and high
risk – autologous stem cell
transplant

Dx: lymph node biopsy
(uniform small cells
with scant cytoplasm),
“starry sky”
MULTIPLE MYELOMA
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Age > 65
Anemia, bone pain, renal
failure, increased calcium,
proteinuria
Plasma cell malignancy
(paraproteins produced)
Dx: SPEP, UPEP
Bence Jones protein in urine
Dipstick (detects albumin,
intact globulin) will be
negative, urine protein
quantitation will have
proteinuria
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Monoclonal spike in beta or
gamma globulin region. IgG
– 60%, IgA – 25%, light
chain – 15%
Bone x-ray with lytic lesion
Bone marrow infiltrated
with plasma cells
Treatment: Combination
chemo with VAD
(Vincristine, Adriamycin,
Dexamethasone). If not
tolerated: Thalidomide +
Dexamethasone
< 70 yo: consider autologous
stem cell transplant.
THANK YOU FOR YOUR ATTENTION

Questions?