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%) or T(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 reflectvariations in amount of lymphoid accumulation duringthe natural course of the disease
Interstitial(low risk)
Diffuse(high risk)
Nodular(low risk)
Courtesy of Randy Gascoyne, MD.1. Montserrat E, et al. Cancer. 1984;54:447-451.
Immunophenotype scoring system
Scoring system for B-CLL
Membrane marker
Points
1 0
Smlg Weak Moderate/strong
CD5 Positive Negative
CD23 Positive Negative
FMC7 Negative Positive
CD79b (SN8) Negative Positive
1. Matutes E, et al. Leukemia. 1994;8:1640-1645.2. Moreau EJ, et al. Am J Clin Pathol. 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
+/– ++ – –/+ + +/– –/+ ++ –/+ –
Prolymphocytic leukemia
++ +/– – –/+ + +/– + +/– – –
Hairy cell leukemia
+ – – ++ + + ++ –/+ + ++
Mantle cell lymphoma
+ ++ – – + + + – – –
Splenic marginal zone lymphoma
+ –/+ – +/– + + +/– – – –
Lymphoplasmacytoid lymphoma
–/+ –/+ – – + +/– +/– –/+ +/– –
Follicular center lymphoma
+ – + – + ++ + –/+ – –
Comparison of CLL and PLL
CLL PLLslg + ++CD19 ++ ++CD20 ++ ++CD5 ++ -/+
B-CLL CLL-PLL
Courtesy of Randy Gascoyne, MD.1. Bennett JM, et al. J Clin Pathol. 1989;42:567-584.
Genetic abnormalities in CLL
Genetic abnormality
Incidence (%)
Median survival (months)
Clinical correlation
13q14 55-62 133-292 Typical morphology Mutated VH genes Stable disease
+ 12 16-30 114-122 Atypical morphology
Progressive disease
del 11q23 18 79-117 Bulky lymphadenopathy Unmutated VH genes
Progressive disease Early relapse post autograft
p53loss/mutation/17p-
7 32-47 Atypical morphology
Unmutated VH genes
Advanced disease Drug resistance
1. DÖhner H, et al. N Engl J Med. 2000;343:1910-1916.2. Oscier DG, et al. 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
StageClinical Features at Diagnosis
Median Survival, Years*
A Blood and marrow lymphocytosis and less than 3 areas of 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
Prognostic Indicators
Prognosis: lymphocyte doubling time
Survival time according to LDT (all stages)
Months
Pro
babili
ty o
f su
rviv
al
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 ≤12 monthsDoubling time >12 months
1. Montserrat E, et al. Br J Haematol. 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 geneMedian = 117 monthsMutated VH geneMedian = 293 months
325
1. Hamblin TJ, et al. Blood. 1999;94:1848-1854.
Perc
en
t su
rviv
ing (
%)
Months
Prognosis: effect of VH gene mutations on survival
Prognosis: VH gene/p53 concordance
Months
VH gene/p53 multivariate analysis
1. Krober A, et al. Blood. 2002;100:1410-1416.2. Crespo M, et al. N Engl J Med. 2003;348:1764-1775.3. Oscier DG, et al. 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
03800 38 76 114 152 228190 304266 342
Unmutated VH geneMedian = 119 monthsMutated VH geneMedian = 310 months
p53 loss/mutationMedian = 47 months
Pro
babili
ty o
f su
rviv
al (%
)
Prognosis: effect of CD38 expression on survival
Months
1. Orchard JA, et al. Lancet. 2004;363:105-111.
Perc
en
t su
rviv
ing (
%)
CD38 ≥30%Mean = 163.2 months
CD38 <30%Mean = 288 months
N=162P=.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 DiseasesWilliams Hematology, 8e, 2010
From: Chapter 94. Chronic Lymphocytic Leukemia and Related DiseasesWilliams Hematology, 8e, 2010
Date of download: 8/5/2014 Copyright © 2014 McGraw-Hill Education. All rights reserved.
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:
From: Chapter 94. Chronic Lymphocytic Leukemia and Related DiseasesWilliams Hematology, 8e, 2010
From: Chapter 94. Chronic Lymphocytic Leukemia and Related DiseasesWilliams Hematology, 8e, 2010
Table 94–9. Prognostic Index Based on Presence of Risk Factors
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, × 109/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
Date of download: 8/5/2014 Copyright © 2014 McGraw-Hill Education. All rights reserved.
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:
From: Chapter 94. Chronic Lymphocytic Leukemia and Related DiseasesWilliams Hematology, 8e, 2010
From: Chapter 94. Chronic Lymphocytic Leukemia and Related DiseasesWilliams Hematology, 8e, 2010
Prognosis with serum markers: the effect of 2-microglobulin on survival in untreated CLL
Pts Died
2M
445 53 <2.1429 95 2.1-3.0183 53 3.1-4.0175 67 >4.0
Effect of 2-microglobulin on survival in untreated CLL
Years
Pro
port
ion s
urv
ivin
g
160 2 4 6 8 10 12 14
1.0
18
0.8
0.6
0.4
0.0
0.2
1. Keating M. Unpublished data.2. Hallek M, et al. Leuk Lymphoma. 1996;22:439-447.3. Sarfati M, et al. Blood. 1996;88:4259-4264.4. Fayad L, et al. 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
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Supportive Care
Supportive Care
Response Criteria
Ibrutinib-Btk inhibitor
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