This document provides an overview of chronic lymphocytic leukemia (CLL). It defines CLL as the accumulation of mature B lymphocytes in the blood, bone marrow, lymph nodes, and spleen. CLL most commonly affects older adults and has an unknown cause. The document outlines the clinical presentation, diagnostic criteria, staging systems, complications, treatment approaches, and poor prognostic factors of CLL. It also discusses new therapies that aim to induce complete remission and eliminate minimal residual disease to improve survival outcomes in CLL patients.

1. CHRONIC LYMPHOCYTIC
LEUKEMIA (CLL)
Olufemi-Aworinde K.J, FMCPath
Lecturer/Consultant Haematologist,
Bowen University, Iwo.

2. Introduction
• Is characterised by the accumulation of
nonproliferating mature-appearing
lymphocytes in the blood, marrow, lymph
nodes, and spleen
• In most cases, the cells are monoclonal B
lymphocytes that are CD5+
• T cell CLL can occur rarely

3. • Its the most common form of leukemia in
North America and Europe, but is extremely
rare in the Orient
• Typically occurs in older patients, with the
highest incidence being in those aged 50 to
55 years
• Median age at diagnosis is 65-70 years.
• Uncommon (10%) in patients under 50 years
• Affects men twice as often as women

4. Etiology
• The cause of CLL is unknown
• There is increased incidence in farmers,
rubber manufacturing workers, asbestos
workers, and tyre repair workers
• Genetic factors have been postulated to play
a role in high incidence of CLL in some
families

5. Aetiology
• 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, 14 and 11
– patients with abnormal karyotypes have a worse
prognosis
• Oncogenes

6. Clinical findings
• Approximately 40% of CLL patients are
asymptomatic at diagnosis
• In symptomatic cases the most common
complaint is fatigue
• Less often the initial complaint are enlarged
nodes or the development of an infection
(bacterial)

7. Clinical findings
• Most symptomatic patients have enlarged lymph
nodes (more commonly cervical and
supraclavicular) and splenomegaly
• The lymph nodes are usually discrete, freely
movable, and nontender
• Hepatomegaly may occur
• Less common manifestation are infiltration of
tonsils, mesenteric or retroperitoneal
lymphadenopathy, and skin infiltration
• Patients rarely present with features of anemia,
and bruising or bleeding

8. Clinical Course of CLL
• Disease has a variable course; however, it often
progresses from an indolent lymphocytosis without
other evident disease to one of generalized
lymphatic enlargement with concomitant
pancytopenia
• Progression: bone marrow impairment, 
susceptibility to infection
• Complications of pancytopenia, including
hemorrhage and infection, represent a major cause
of death in these patients

9. Laboratory findings
• The blood lymphocyte count above 5,0 G/L
• In most patients the leukemic cells have the
morphologic appearance of normal small
lymphocytes
• In the blood smears are commonly seen
ruptured lymphocytes (“basket” or “smudge”
cells)
• Careful examination of the blood smear can
usually differentiate CLL, and the diagnosis
can be confirmed by immunophenotyping

10. Laboratory findings
• 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+
• Hypogammaglobulinemia or agammaglobulinemia
are often observed
• 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

11. The diagnostic criteria for CLL
1) A peripheral blood lymphocyte count of
greater than 5 G/L, with less than 55% of
the cells being atypical
2) The cell should have the presence of Bcell-
specific differentiation antigens (CD19,
CD20, and CD24) and be CD5(+)
3) A bone marrow aspirates showing greater
than 30% lymphocytes

12. 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

13. Investigations
• Pretreatment studies of patients with CLL should
include examination of:
– complete blood count
– peripheral blood smear
– reticulocyte count
– Coomb’s test
– renal and liver function tests
– serum protein electrophoresis
– immunoglobulin levels
– plasma 2 microglobulin level
• If available immunophenotyping should be carried
out to confirm the diagnosis
• Bone marrow biopsy and cytogenetic analysis is not
routinely performed in CLL

14. Staging (1)
• Rai Classification for CLL
– 0 - lymphocytosis (>5 G/L)
– I - lymphocytosis + lymphadenopathy
– II - lymphocytosis + splenomegaly +/-lymphadenopathy
– III - lymphocytosis + anemia (Hb <11g%) +/-
lymphadenopathy or splenomegaly
– IV - lymphocytosis + thrombocytophenia (Plt <100G/L) +/-
anemia +/-lymphadenopathy +/- splenomegaly

15. Staging (2)
• Binet Classification for CLL
– A. < 3 involved areas, Hb > 10g%, Plt > 100G/L
– B. > 3 involved areas, Hb > 10g%, Plt > 100G/L
– C. - any number of involved areas, Hb < 10g%,
Plt < 100G/L

16. CLL - Immunologic Complications
• Autoimmune hemolytic anemia
– Coombs’ positive
– Clinical hemolysis
• Pure red cell aplasia
• Immune-mediated thrombocytopenia
• Depressed immunoglobin levels
• Granulocytopenia
• Hypogammaglobulinemia  with advanced disease
• Long-term complications: autoimmune phenomena,
Richter’s transformation

17. CLL - Complications
• Severe systemic infections
• Bleeding
• Richter’s transformation
• Prolymphocytoid transformation
• Secondary malignancies
• Acute myeloid leukemia

18. Prognosis
• Rai classification
stage median survival
(years)
0 >10
I > 8
II 6
III 2
IV < 2
• Binet classification
stage median survival
(years)
A > 10
B 7
C 2

19. Markers of poor prognosis in CLL
• Advanced Rai or Binet stage
• Peripheral lymphocyte doubling time <12
months
• Diffuse marrow histology
• Increased number of prolymphocytes or
cleaved cells
• Poor response to chemotherapy
• High 2- microglobulin level
• Abnormal karyotyping

20. Transforming the way we approach
CLL therapy
• Traditional treatment goal: Palliation
– Age is a factor
– Treat to relieve symptoms
– Continuous/intermittent treatment
– No survival advantage for any tested treatment to date
• New advances may allow treatment for remission
and survival
– Treat to complete remission (CR)
– Eliminate minimal residual disease
– Response predicts for survival: More CRs

21. CLL – treatment (1)
• Watch and wait
• Monotherapy
– glucocorticoids
– alkylating agents (Chlorambucil,
Cyclophosphamide)
– purine analogues (Fludarabine, Cladribine)
• Combination chemotherapy
– Chlorambucil/ Cyclophosphamide + Prednisone
– Fludarabine + Cyclophosphamide +/- Mitoxantrone
– CVP, CHOP
• Monoclonal antibodies (monotherapy & combination)
– Alemtuzumab (anti-CD52)
– Rituximab (anti-CD20)
• Splenectomy
• Radiotherapy

22. CLL – treatment (2)
• Hematopoietic stem cell transplantation
– allogeneic with reduced intensity conditioning
– autologous
• New and novel agents
– Oblimersen – bcl2-directed antisense
oligonucleotide
– Lenalidomide
– Flavopiridol
– Anti-CD23, Anti-CD40
• Vaccine strategies
• Supportive therapy (allopurinol, G-CSF, blood and
platelet transfusion, immunoglobulins, antibiotics)

23. NCI-WG: Indications to Initiate
Treatment for CLL
• Constitutional symptoms referable to CLL
(B-symptoms)
• Progressive marrow failure
• Autoimmune anemia and/or thrombocytopenia
poorly
responsive to corticosteroids
• Massive or progressive splenomegaly
• Massive or progressive lymphadenopathy
• Rapid lymphocyte doubling time

24. Treatment of CLL

25. CLL – Treatment strategy
Gribben J G Blood 2010;115:187-197

26. Thank you