Chronic Lymphocytic Leukemia

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



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 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


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 <2.1429 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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Chronic Lymphocytic Leukemia