Chronic Lymphocytic Leukemia CLL

Definition (Nejm 2005:352 804)

• Monoclonal accumulation of immunologically incompetent mature B-lymphocytes

• CLL & small lymphocytic lymphoma (SLL) now classified as same disease (WHO) Epidemiology and risk factors

10.000 new cases y, median age at dx is 65 y; most common adult leukemia

• T incidence in 1st-degree relatives; no known association with radiation, chemicals, drugs Clinical manifestations

• Symptoms: often asx & identified when CBC reveals lymphocytosis; 10-20% p w fatigue.

malaise, night sweats, weight loss (ie. lymphoma "B" sx)

• Signs: lymphadenopathy (80%) and hepatosplenomegaly (50%)

• Autoimmune hemolytic anemia (AIHA) or thrombocytopenia (ITP)

• Hypogammaglobulinemia - neutropenia — t susceptibility to infections

• Bone marrow failure

• Monoclonal gammopathy in 5%

• Aggressive transformation: 5% develop Richter's syndrome - transformation into high-grade lymphoma (usually DLBCL) and sudden clinical deterioration Diagnostic evaluation (see "Lymphoma" for general approach)

• Peripheral smear: lymphocytosis ( -5000 jxl. mature-appearing small cells)

"smudge" cells from damage to abnl lymphs from shear stress of making blood smear

• Bone marrow: normo- or hypercellular; infiltrated w small B-cell lymph (:-30%)

• Lymph nodes: infiltrated w small lymphocytic or diffuse small cleaved cells = SLL

• Flow cytometry:dim surface Ig (slg);CD5-.CD19*.CD20».CD23'.CD38' or

ZAP70+ a/w unmutated Ig variable heavy chain region & worse prognosis

• Cytogenetics: 11q22-23 & 17p13 are unfavorable, trisomy 12 is neutral, while 13q14

is favorable (N£/M 2000.343:1910)

CLL Staging

Rai System

Median

Binet System

Stage

Description

survival

Description

Stage

0

Lymphocytosis only

>10 y

<3 node areas

A

1

' lymphadenopathy

Ty

>3 node areas

B

II

• hepatosplenomegaly

III

ffi anemia (not AIHA)

1-2 y

Anemia or

C

IV

© thrombocytopenia (not ITP)

thrombocytopenia

• Treatment is palliative . early stage disease can be followed w o Rx

• Indications for treatment Rai stages lll/IV, Binet stage C. disease-related sx.

progressive disease. AIHA or ITP refractory to steroids, recurrent infections

• Options for treatment purine analogs: fludarabine ("F"), pentostatin ("P")

alkylating agents: cyclophosphamide ("C"). CVP. CHOP; chlorambucil for elderly monoclonal Ab against CD20 (rituximab."R") or CD52 (alemtuzumab)

survival w/ single agents, although higher response rate w F (NifM 2000.343:1750) combination regimens most popular (ie. FR. FC. FCR. PCR)

• Role of autologous and allogeneic HSCT being studied

• Supportive care: PCP, HZV. VZV prophylaxis; CMV monitoring for Pts receiving CD52;

AIHA ITP — steroids; recurrent infections — IVIg; bulky disease with compressive symptoms -» XRT; splenomegaly with refractory cytopenias — splenectomy

Prognostic Factors & Median Survival in CLL

Factor

Years

Factor

Years

Cytogenetics

CD38 expression

17p-

2.5

Low ( 20-30%)

8

11q-

6.6

High ( 20-30%)

Unclear

Trisomy 12 or Normal

9

Zop-70 expression

13q*

11

Low (-:20-30%)

24.3

IgVH gene status

High (>20-30%)

9.3

Mutated (>2%)'

>24

*% difference c w germline

Unmutated (^2%)* <8

(nejm 2004:351:893 & 2005:353:1793)

(nejm 2004:351:893 & 2005:353:1793)

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