DiseaseDisease

acute leukemia

h i l k ichronic leukemialymphomamyelomamyeloma

Usual phenotypeUsual phenotype

precursor

diff ti t ddifferentiated

Pre- Pre-B-cell B-cell

Ig Surface

Major malignant

B-ALL

CLL malignant counterpart

ALL

Major ↓GammaMajor immunolo-gical abnormality

↓Gamma globulins

y

TransformedTransformed B-cell Plasma cell

Surface Secreted

Macroglobu-linemia

Myeloma linemia

Monoclonal Monoclonal IgMonoclonal IgM

Monoclonal Ig or light chain

Chronic Lymph

• Most common leukemi

• Usual age > 50 yrs

• Increased proliferationaccumulation of neoplaaccumulation of neoplaincompetent, clonal lym– B cell origin > 99%B cell origin > 99%

hocytic Leukemia

a

and progressive astic immunologicallyastic, immunologically mphocytes

Clinical FeatClinical Feat• Highly variable preseng y p

– Asymptomatic, or vagucomplaints

– Recurrent infection 10%

• Signs– Lymphadenopathy (60– Splenomegaly (50%)– Hepatomegaly (< 40%)

tures of CLLtures of CLLntationue, non-specific

% (often pneumococcus)

%)

Clinical Feat• Laboratory

– blood and marrow lympy p– B cell monoclonality:

κ vs λ surface light chaini l Isingle Ig gene rearrangem

– hypoimmunoglobulinem

• Prognosis– Mean survival = 50-60 mMean survival 50 60 m– Range = few months to >

tures of CLL

hocytosisy

tmentmia

monthsmonths> 20 yrs

Immunological Abn• Disturbed Ab productio

Hypogammaglobulinemi– Hypogammaglobulinemi– Monoclonal Ig paraprote– Autoantibodies (10%)Autoantibodies (10%)

• Minor impairments in ceMinor impairments in ce

• Neoplastic lymphocytes• Neoplastic lymphocytes– Monoclonal surface Ig – Abnormal response to IgAbnormal response to Ig

normalities in CLLon

a (50%) → bacterial infectiona (50%) → bacterial infectionin in serum (10%)

ell-mediated immunityell mediated immunity

ss

g challengeg challenge

ComplicationsComplications

Recurrent infec

Immune hemol

Immune throm

P i diProgressive dis

s of CLLs of CLL

ctions

lysis

mbocytopenia

sease

Rai Staging SyRai Staging Sy

Stage

Featu

I Lymphocytosis

II Lymphocytosis + ly p y

III Lymphocytosis + s

IV Lymphocytosis + a

V Lymphocytosis + ty p y

ystem for CLLystem for CLLMedian

i lures

survival(years)

13

ymphadenopathy 8y p p y

splenomegaly 6

anemia 1-2

thrombocytopenia 1-2y p

Treatmen• Stage 0 or 1 diseas

therapy prolongs s• Asymptomatic: watAsymptomatic: wat• Symptomatic:

– Radiation for local com– Chemotherapy: fludar

bi ticombinations– Monoclonal antibodies– Stem cell transplantat

nt of CLLse: No evidence that urvivaltch and waittch and wait

mplicationsabine, alkylators,

s (eg, Campath)ion

Multiple Mp• Clonal malignancy

• Increasing incidenc

• Blacks:whites 2:1

• Age range 20-100 y

• Cause unknown(Environmental/Ge(Environmental/Ge

Myelomayof plasma cells

ce

yrs (peak age 70 yrs)

enetic factors)enetic factors)

Classical DiagnoClassical DiagnoMyel

• Plasmacytosis in

• Monoclonal protei• Monoclonal protei

• Lytic disease of bo

ostic Features ofostic Features of omamarrow

in in serum or urinein in serum or urine

one

Marrow PlasmacyMarrow Plasmacy

• Plasma cells > 10%

• Usually much higher

• Often present in ‘shee

• Alternatively, biopsy-p

• Other causes of plasm– inflammation, ci

ytosis in Myelomaytosis in Myeloma

ets’

proven plasmacytoma

macytosis: irrhosis, AIDS

Diagnosis of Myeloma

• 75-80% have serum mono(M-component, paraprot(M component, paraprotelectrophoresis)

• 10-20% make light chainsexcretion → no paelectrophoresis

• Non-secretory myeloma r

• Other causes of monoclo(eg, CLL, lymphoma, be

a: Monoclonal Proteins

oclonal Ig tein, or ‘spike’ ontein, or spike on

s only → rapid renal raprotein on serum protein

rare (< 1%)

onal proteinsnign monoclonal gammopathy)

Apply serum or urine

StainStain

Protein Electrophoresis (PEP):proteins separated according top ote s sepa ated acco d g to

charge and size

ScanScan

Serum Protein Electrophorese

#1

#2

es in 2 Patients with Myeloma

Immunofixationn Electropheresis

Bone DisM lMyel

• Unbalanced ostUnbalanced ost

Radiographic m• Radiographic mOsteoporosis almUsually multiple lAxial skeleton invOsteoblastic reac

• Hypercalciuria a

isease in llomateoclast activityteoclast activity

manifestationsmanifestationsmost invariablelytic lesionsvolved (active marrow)ction minimal

and hypercalcemia

Benign MoBenign MoGammo

• Monoclonal Ig as isol

• More common than m

• No bone disease, ane

M i bl• Most remain stable

Ab t 10% t ll• About 10% eventuallymyeloma

onoclonalonoclonal opathylated finding

myeloma

emia, renal dysfunction

d l l i ly develop classical

Myeloma at Py

• Early - asymptomaticy y pParaprotein on electrophorMild marrow plasmacytosisS lit l t (10Solitary plasmacytoma (10

L t t ti• Late - symptomaticBone pain (usually lower baPneumococcal infectionPneumococcal infectionSystemic symptoms (eg, w

Related to anemia, rena

Presentation

c, incidental diagnosis, gresiss% f )% of cases)

ack)

weakness, weight loss)al failure, hypercalcemiayp

HyperviscosiHyperviscosi

D t ti• Due to aggregating

• PathogenesisPathogenesis– Circulatory insuf

hemostasis

• ManifestationsBl di– Bleeding

– Dyspnea (congesEncephalopathy– Encephalopathy

ty Syndromety Syndrome

t ig paraprotein

fficiency, abnormal

stion on CXR)and visual disturbancesand visual disturbances

ImmunologicaMyelo

• Monoclonal Ig and/or monoMonoclonal Ig and/or mono

• ↓Levels of normal Ig’s (hyp↓Levels of normal Ig s (hyp

• Cellular immune responsesp

• Bacterial infections commoEarly: S pneumoniaeLate: S aureus, Gram nega

al Features of omaoclonal light chainoclonal light chain

pogammaglobulinemia)pogammaglobulinemia)

s usually preservedy p

on

ative rods

Amyloidosis• Due to light chain dep

• Incidence: λ amyloid >

• Organs commonly invSkinTongue and GITongue and GIHeartPeripheral nervespKidneys Soft tissues

• No effective therapy, e

s in Myelomaosition in tissues

> κ amyloid

volved:

except ?stem cell transplant

NEJM 2007; 356: 2406

Therapy fo

• Bisphosphonates (pa

• Radiotherapy

• Corticosteroids and c

• Thalidomide and lenaangiogenesis) g g )

• Bortezomib (proteaso

• Stem cell transplanta

r Myeloma

amidronate, zoledronate)

conventional chemotherapy

alidomide (anti-

ome inhibitor)

ation