Chronic Lymphocytic Leukemia

Epidemiology
 CLL has an average incidence of 2.7 persons per 100,000
in the United States.
 The risk of developing CLL increases progressively with
age and is 2.8 times higher for older men than for older
women. M:F=2:1
 This disease accounts for approximately 0.8 percent of
all cancers and nearly 30 percent of all leukemias at any
point in time.
 It is the most prevalent adult leukemia in Western
societies.
 Generally, the neoplastic lymphocytes are of the B-cell
lineage.
 In less than 2 percent of cases, however, the neoplastic
cells are of T-cell origin and are included in the category
T-cell prolymphocytic leukemia.

Etiology and Pathogenesis
 Farming may play a role
 ?Hepatitis C
 Familial cases described
 Mostly idiopathic
 Cytogenetics
 clonal chromosomal abnormalities are detected in
approximately 50% of CLL patients
 the most common clonal abnormalities are:
 trisomy 12
 structural abnormalities of chromosomes 13, 17 and 11
 patients with abnormal karyotypes have a worse
prognosis

Clinical Features
 More than 25 percent of patients are
asymptomatic at diagnosis (detected due
to non tender lymphadenopathy or an
unexplained absolute lymphocytosis).
 Mild symptoms of reduced exercise tolerance,
fatigue, or malaise.
 Patients sometimes present with an
exacerbation of another underlying medical
condition, such as pulmonary, cerebrovascular,
or coronary artery disease.

Clinical Features
 Night sweats and fevers (the so-called B
symptoms) are uncommon and should
prompt evaluation for complicating infectious
disease
 Patients with CLL are more prone to viral or
bacterial infections secondary to impaired T-
cell immunity or hypogammaglobulinemia,
respectively.

Clinical Features
 80 percent of all CLL patients have nontender
lymphadenopathy at diagnosis, most
commonly involving the cervical,
supraclavicular, or axillary lymph nodes.
 Upper airway obstruction because of oral-
pharyngeal lymphadenopathy.
 Lymphedema of the extremities is rare, even
in the setting of massive axillary and cervical
adenopathy, and superior vena cava
obstruction is uncommon.

Clinical Features
 Large retroperitoneal adenopathy can result
in ureteral obstruction and hydronephrosis.
 Rarely, patients may develop periportal
lymph node enlargement that results in
biliary tract obstruction.
 Splenomegaly may cause early satiety and/or
abdominal fullness.

Clinical Features
 Renal involvement uncommon
 Retroorbital involvement may lead to
proptosis.
 Constrictive pericarditis
 Leukemic infiltration of pleura causing
hemorrhagic or chylous effusions.
 GI ulceration/bleeding
 CNS involvement

Clinical Features
 Chronic rhinitis secondary to nasal
involvement of CLL cells
 Sensorimotor polyneuropathy associated
with IgM antibody to various
gangliosidespatients Patients may note
exaggerated responses to insect bites,
particularly to those of mosquitoes
 Weight loss, recurrent infections, bleeding
secondary to thrombocytopenia, and/or
symptomatic anemia.

Lab Evaluation
 The diagnosis of CLL requires a sustained
monoclonal lymphocytosis greater than 5000/μL (5
× 109/L).
 Clonal expansion of B (99%) orT(1%) lymphocyte
 In B-cell CLL clonality is confirmed by
 the expression of either  or  light chains on the cell surface
membrane
 the presence of unique idiotypic specificities on the immunoglobulins
produced by CLL cells
 by immunoglobulin gene rearrangements
 typical B-cell CLL are unique in being CD19+ and CD5+
 10 - 25% of patients with CLL develop
autoimmune hemolytic anemia, with a positive
direct Coombs’ test
 The marrow aspirates shows greater than 30%
of the nucleated cells as being lymphoid

Protein Electrophoresis
 The most common finding on serum protein
electrophoreses is hypogammaglobulinemia.
 Reduction in the serum levels of IgM precedes
that of IgG and IgA.
 The degree of hypogammaglobulinemia
correlates loosely with clinical stage.
 5 percent of patients have a serum
monoclonal immunoglobulin paraprotein.

Prognosis: histologic bone marrow
patterns
 The different bone marrow patterns probably reflect
variations in amount of lymphoid accumulation during
the natural course of the disease
Interstitial
(low risk)
Diffuse
(high risk)
Nodular
(low risk)
CourtesyofRandyGascoyne,MD.
1.MontserratE, et al. Cancer.1984;54:447-451.

Immunophenotype scoring system
Scoringsystem forB-CLL
Membrane marker
Points
1 0
Smlg Weak Moderate/strong
CD5 Positive Negative
CD23 Positive Negative
FMC7 Negative Positive
CD79b(SN8) Negative Positive
1.MatutesE, etal.Leukemia.1994;8:1640-1645.
2.MoreauEJ, etal.AmJClinPathol.1997;108:378-382.

Table 94–1. Immunophenotype of Chronic B-
Cell Leukemias/Lymphomas
Disease
Entity
sIg CD5 CD10 CD11c CD19 CD20 CD22 CD23 CD25 CD103
Chronic
lymphocytic
leukemia
+/– ++ – –/+ + +/– –/+ ++ –/+ –
Prolymphocy
tic leukemia
++ +/– – –/+ + +/– + +/– – –
Hairy cell
leukemia
+ – – ++ + + ++ –/+ + ++
Mantle cell
lymphoma
+ ++ – – + + + – – –
Splenic
marginal
zone
lymphoma
+ –/+ – +/– + + +/– – – –
Lymphoplas
macytoid
lymphoma
–/+ –/+ – – + +/– +/– –/+ +/– –
Follicular
center
lymphoma
+ – + – + ++ + –/+ – –

Comparison of CLL and PLL
CLL PLL
slg + ++
CD19 ++ ++
CD20 ++ ++
CD5 ++ -/+
B-CLL CLL-PLL
CourtesyofRandyGascoyne,MD.
1.BennettJM, etal.JClinPathol.1989;42:567-584.

Genetic abnormalities in CLL
Genetic abnormality
Incidence
(%)
Median
survival
(months) Clinicalcorrelation
13q14 55-62 133-292 Typicalmorphology
Mutated VH genes
Stable disease
+12 16-30 114-122 Atypical morphology
Progressive disease
del11q23 18 79-117 Bulky lymphadenopathy
Unmutated VH genes
Progressive disease
Earlyrelapse
post autograft
p53
loss/mutation/17p-
7 32-47 Atypical morphology
Unmutated VH genes
Advanceddisease
Drug resistance
1.DÖhnerH, etal.NEnglJMed.2000;343:1910-1916.
2.OscierDG, etal. Blood.2002;100:1177-1184.

Differential diagnosis
 Infectious causes
 bacterial (tuberculosis)
 viral (mononucleosis)
 Malignant causes
 B-cell
 T-cell
 leukemic phase of non-Hodgkin lymphomas
 Hairy-cell leukemia
 Waldenstrom macroglobulinemia
 large granular lymphocytic leukemia

Table 94–2. RAI Clinical Staging System
*Survival data updated as per Wierda et al.
Revised Staging System Original Staging System
Clinical Features at
Diagnosis
Median Survival,Years*
Low risk 0 Blood and marrow
lymphocytosis
12
I Lymphocytosis and
enlarged lymph nodes
11
Intermediate risk II Lymphocytosis and
enlarged spleen and/or
liver
8
High risk III Lymphocytosis and
anemia (hemoglobin
below 11 g/dL)
5
IV Lymphocytosis and
thrombocytopenia
(platelets below
100,000/μL)
7

Table 94–3. Binet Clinical Staging System
Stage Clinical Features at Diagnosis Median Survival,Years*
A Blood and marrow lymphocytosis
and less than 3 areasof palpable
lymphoid-tissue enlargement
12
B Blood and marrow lymphocytosis
and 3 or more areas of palpable
lymphoid-tissue enlargement
9
C Same as B with anemia (hemoglobin
below 11 g/dL in men or 10 g/dL in
women) or thrombocytopenia
(platelets less than
100,000/μL)
7

Prognosis: lymphocyte doubling time
Survival time accordingtoLDT(all stages)
Months
Probabilityofsurvival
1600 20 40 60 80 100 120 140
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Doubling time ≤12months
Doubling time>12months
1.MontserratE, et al. BrJHaematol.1986;62:567-575.

90
225 3000 50 100 150 200 25025 75 125 175 275
100
80
60
40
0
20
70
50
30
10
Unmutated VH gene
Median =117 months
Mutated VH gene
Median =293 months
325
1.HamblinTJ,etal.Blood.1999;94:1848-1854.
Percentsurviving(%)
Months
Prognosis: effect of VH gene mutations
on survival

Prognosis: VH gene/p53 concordance
Months
VH gene/p53 multivariateanalysis
1.KroberA,et al. Blood.2002;100:1410-1416.
2.CrespoM, etal. NEnglJMed.2003;348:1764-1775.
3.OscierDG, etal. Blood.2002;100:1177-1184.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
3800 38 76 114 152 228190 304266 342
Unmutated VH gene
Median =119 months
Mutated VH gene
Median = 310 months
p53 loss/mutation
Median =47 months
Probabilityofsurvival(%)

Prognosis: effect of CD38 expression
on survival
Months
1.OrchardJA,etal.Lancet.2004;363:105-111.
Percentsurviving(%)
CD38≥30%
Mean =163.2 months
CD38<30%
Mean =288 months
N=162
P=.008
100
80
60
40
0
20
90
70
50
30
10
0 100 200 300 400 500

Date of download: 8/5/2014 Copyright © 2014 McGraw-Hill Education. All rights reserved.
Relationship between ZAP-70 and IgHV mutational status and time from diagnosis to initial therapy. Kaplan-Meier curves depicting
the proportion of untreated patients over time from diagnosis of different groups of cases segregated with respect to IgHV mutational
status and whether they did (ZAP+) or did not (ZAPNeg) express ZAP-70.
Legend:
From: Chapter 94. Chronic Lymphocytic Leukemia and Related Diseases
Williams Hematology, 8e, 2010

Prognostic relevance of genomic aberrations in chronic lymphocytic leukemia (CLL). Estimated survival probabilities from the date of
diagnosis in 325 CLL patients divided into five categories defines in a hierarchical model of genomic aberrations in CLL. The median
survival times for the 17p deletion (n = 23), 11q deletion (n = 56), 12p trisomy (n = 47), normal karyotype (n = 57), and 13q deletions
(as single abnormality, n = 117) groups were 32, 79, 114, 111, 133 months, respectively. (Reproduced with permission from Zenz T,
Dohner H, Stilgenbaer S.918)
Legend:

Table 94–9. Prognostic Index Based on Presence of Ris
Characteristic
Age, y
Point Contribution
0 1 2 3
— <50 50–65 >65
β2M, mg/L < ULN 1–2 × ULN >2 × ULN N/A
ALC, × 10
9
/L <20 20–50 >50 N/A
Sex Female Male N/A N/A
Rai Stage 0–II III–IV N/A N/A
No. of involved nodal
groups
⩽2 3 N/A N/A

Nomogram for survival of untreated patients with CLL. The points identified on the top scale for each independent covariate in the
top part of the figure are added together to determine the total prognosis score, which then is used on the total points scale (shown
in the bottom part of the figure) to identify the estimated median survival time (years) and the probability of 5- and 10-year survival.
(Reproduced with permission from Wierda WG et al.443 Copyright © the American Society of Hematology.)
Legend:

Prognosis with serum markers: the effect of
2-microglobulin on survival in untreated CLL
Pts Died 2M
445 53 <2.1
429 95 2.1-3.0
183 53 3.1-4.0
175 67 >4.0
Effectof 2-microglobulinon survival in untreatedCLL
Years
Proportionsurviving
160 2 4 6 8 10 12 14
1.0
18
0.8
0.6
0.4
0.0
0.2
1.KeatingM. Unpublisheddata.
2.HallekM, etal. LeukLymphoma.1996;22:439-447.
3.SarfatiM, etal.Blood.1996;88:4259-4264.
4.FayadL,etal.Blood.2001;97:256-263.

Table 94–4. Indications for Therapy in CLL
Anemia
Thrombocytopenia
Disease-related symptoms
Markedly enlarged or painful spleen
Symptomatic lymphadenopathy
Blood lymphocyte count doubling time <6
months
Prolymphocytic transformation
Richter transformation
(a) evidence of progressive
marrow failure causing
worsening anemia and/or
thrombocytopenia;
(b) massive or progressive
lymphadenopathy; or
(c) massive (i.e., >6 cm below
the left costal margin) or
progressive splenomegaly
(d) progressive lymphocytosis
with an increase of greater than
50 percent over a 2-month
period, or LDT of less than 6
months;
(e) intractable autoimmune
anemia and/or
thrombocytopenia

Indications for Therapy in CLL
 (f) Symptomatic disease
 (1) unintentional weight loss greater than or
equal to 10 percent within the previous 6
months,
 (2) significant fatigue (i.e., Eastern Cooperative
Oncology Group performance status of ⩾2;
inability to work or perform usual activities),
 (3) fevers greater than or equal to 38.0° C for 2 or
more weeks without other evidence of infection,
or
 (4) night sweats for 1 or more months without
evidence of infection.

Treatment
 Alkylating agents (chlorambucil, cyclophosphamide,
bendamustine)
 Nucleoside analogs (cladribine, fludarabine,
pentostatin)
 Biological response modifiers (lenalidomide)
 Monoclonal antibodies (rituximab, alemtuzumab,
ofatumumab, Obinituzumab)
 Bone marrow transplantation

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Chronic Lymphocytic Leukemia

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