This document provides information on chronic lymphocytic leukemia (CLL), including its definition, diagnosis, incidence, aetiology, clinical features, diagnostic tests, staging systems, prognostic factors, and treatment approaches. Some key points include: - CLL is defined as the progressive accumulation of long-lived, functionally incompetent B lymphocytes. - Diagnosis involves evaluating lymphocyte counts, immunophenotyping, bone marrow biopsy, and cytogenetic/molecular testing. - Incidence is highest in Western adults over age 65 and is more common in men. - Prognostic factors include genetic abnormalities, IgV gene mutation status, and response to initial therapy. - Treatment depends on

1. By
Shimaa Abd Alla Ahmed

2. defenition
 Progressive
accumulation of matureappearing, functionally incompetent,longlived B lymphocytes in peripheral blood,
bone marrow, lymph nodes,spleen, liver
and sometimes other organs.

3. Diagnosis: NCI guidelines for CLL
VARIABLE
CBC
CLL
SLL
≥5; B-cell
Marker (CD19, <5 B-Cell Marker
CD20, (CD19, CD20,
CD23) + CD5 CD23) + CD5
MBL
<5 B-Cell Marker
(CD19, CD20,
CD23) + CD5
Lymphadenopath
y+organomegaly
No aneamia
No
thrombocytobenia
BM >30% lymphocyte
STAGING
RIA,BINET
Ann Arpor

4. Incidence
 Commonest leukaemia in Western adults (25–30%
of all leukaemias).
 2.5/100,000 per year.
 Age
 Predominantly disease of elderly Median age at
diagnosis 65 years. (in over 70s,>20/100,000).
 m:f ratio ~2:1.
 Marked geographic difference e.g.
In China & Japan = 1/10 of Western world.

5. Aetiology
 Unknown. No causal relationship with radiation,
chemicals or viruses.
 Small proportion are familial. Genetic factors
suggested by low incidence in Japanese even after
emigration.
 Lymphocyte accumulation appears to result from
defects in intracellular apoptotic pathways: 90% of
CLL cases have high levels of BCL-2 which blocks
apoptosis.

6. Clinical features and presentation
 asymptomatic; lymphocytosis (>5.0 ¥ 109/L) on
routine FBC.
 Lymphadenopathy:
painless,
often
symmetrical,splenomegaly (66%), hepatomegaly
 BM failure due to infiltration causing
 anaemia,
 neutropenia and
 thrombocytopenia.
 Recurrent
infection
due
to
acquired
hypogammaglobulinaemia: esp.Herpes zoster.

7. Lymphadenopathy

8. Lymphadenopathy

9. • Patients with advanced disease:B-symptoms:
FUO.
Night sweats.
Wt loss.
general malaise.
 Autoimmune phenomena occur;
 DAT +ve in 10–20% cases, warm antibodyAIHA in <50%
of these cases.
 Autoimmune thrombocytopenia in 1–2%.

10. Diagnosis
 FBC:
 lymphocytosis >5.0
109/L
 Neutropenia
 anaemia,
 thrombocytopenia and
 absent in early stageCLL;
 autoimmune haemolysis
occur at any stage.
thrombocytopenia may

13. Morphology:
Peripheral Blood
•Absolute lymphocytosis > 5 X 109 /L.
Mature looking lymphocytes; characteristic artefactual damage to
cells in film preparation produces numerous ‘smear cells’
(Note:absence of smear cells should prompt review of diagnosis);
•Morphological subtypes:
Atypical or mixed CLL/PLL:
> 10% & < 54% prolymphocytes.
•Morphology is usually not enough to
differentiate from reactive lymphocytosis.
spherocytes,polychromasia
Increase retics if AIHA;

14. Comparison of CLL and PLL
B-CLL
CLL-PLL
CLL
slg
CD19
CD20
CD5
PLL
+
++
++
++
++
++
++
-/+
Courtesy of Randy Gascoyne, MD.
1. Bennett JM, et al. J Clin Pathol. 1989;42:567-584.

15. Immunophenotyping
 crucial
to differentiation from other
lymphocytoses
 First line panel: CD20; CD5; CD19; CD23;
FMC7; SmIg, CD22 or CD79b.
 CLL characteristically CD20 and FMC7 –
ve;
 CD5,CD19 and CD23 +ve;
 SmIg, CD22, CD79b weak;
 k or l light chain restricted.
 CD 38.Zab 70

16. Immunophenotype scoring
system
Scoring system for B-CLL
Points
Membrane
marker
Smlg
1
0
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.

17.  Immunoglobulins:
 immuneparesis
(hypogammaglobulinaemia)
common;
 monoclonal paraprotein (usually IgM) <5%.
 Bone marrow: >30% ‘mature’ lymphocytes.
 Trephine
biopsy:
provides
prognostic
information: infiltration may be
 nodular (favourable); interstitial; mixed;
diffuse (unfavourable).
 Lymph
node
biopsy:
rarely
required;
appearances of lymphocytic lymphoma.

18. Bone marrow

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

20. Cytogenetics
 Conventional chromosome banding can no
longer be recommended in the diagnostic
work up of CLL ( detects abnormalities in 40-50
% of CLL patients only.

21. Cytogenetics
 prognostic value; abnormalities in >80% using FISH:
 13q–(55%),
 11q– (18%),
 12q+ (16%),
 17p– (7%),
 6q– (7%);
 11q–, 17q– veryunfavourable; sole 13q–favourable,or
6q– ,normal karotyping neutral out come ,Clonal
evolution occurs over time.
 11q– and 17q– associated with advanced disease.

22. Molecular biology:
 IgV genes mutational status:
 Relates to stage of differentiation of malignant B-cells
 Accordingly there are 2 variants of CLL :
* Pre-germinal variant :
- Naive B-lymphocytes with no IgV gene mutation
(CD38+ve)
- Unfavorable clinical outcome .
* Post-germinal Variant :
- Originates from memory B-lymphocytes,
exhibiting IgV mutation (CD38 – ve)
- Favorable clinical outcome
• bcl-2:
> 85% of B-cell cases express high levels of bcl-2 which is a potent inhibitor
of apoptosis (programmed cell death).
p53:
• The p53 tumour suppressor gene is mutated
in 8 % B-cell cases.

23. Other tests:
 U&E; LFTs;
 LDH;
 Uric acide
 b2-microglobulin;
 imaging .
 Ct chest and abdomine
 Pet scan(With richter transformation)

24. Poor prognostic factors
 male sex.
 Advanced clinical stage.
 Initial lymphocytosis > 50 ¥ 109/L.
 >5% prolymphocytes in blood film.
 Diffuse pattern of infiltrate on trephine.
 Blood lymphocyte doubling time <12 months.
 Cytogenetic abnormalities 11q– or 17q–.
 serum b2-microglobulin.
 serum LDH.
 serum thymidine kinase.
 soluble CD23.
 Unmutated IgVH genes.
 Poor response to therapy.

25. Staging: Rai and Binet staging systems for CLL
Clinical staging systems for CLL
Stage
Value
Rai
Binet
Median survival
Lymphocytosis
(>15,000/mm3)
0
-
150 months
(12.5 years)
Lymphocytosis plus
nodal involvement
I
A
Lymphocytosis plus
organomegaly
II
B
Anemia (RBCs)
III
Hgb <11 g/dL
<3
node groups
>3
node groups
Hgb <10 g/dL
C
Lymphocytosis plus
IV
thrombocytopenia
PLT <100,000/mm3
1. Rai KR, et al. Blood. 1975;46:219-234.
(platelets)
2. Binet JL, et al. Cancer. 1981;48:198-206.
3. Binet JL, et al. Cancer. 1977;40:855-864.
PLT <100,000/mm3
101-108 months
(8.5-9 years)
60-71 months
(5-6 years)
19-24 months
(1.5-2 years)

26. Response criteria to NCI guidelines for CLL
Variable
Response criteria
CR
NCI
Physical exam
Symptoms
Lymphocytes (x 109/L)
Neutrophils (x 109/L)
Platelets (x 109/L)
Hemoglobin (g/dL)
Bone marrow lymphs (%)
Normal
None
≤4
≥1.5
>100
>11 (untransfused)
<30, no nodules
PR
Physical exam (nodes and/or liver, spleen)
Plus ≥1 of:
Neutrophils (x 109/L)
Platelets (x 109/L)
Hemoglobin (g/dL)
Duration of CR or PR
1. Cheson BD, et al. Blood. 1996;87:4990-4997.
≥50% decrease
≥1.5
>100
>11 or 50%
improvement
≥2 months

27. PD:
•Physical ex. (LN , liver , spleen):
> 50% increase or new
•Circulating lymphocytes : > 50 %
increase..
•Others: Richter’s syndrome
SD:
•All 0ther than the above.

28. Cll ttt acording to NCCN 2013
Chemotherapy reserved for patients with symptomatic or
progressive disease:
1. anaemia (Hb <10g/dL)
2. Thrombocytopenia (<100 ¥109/L),
3. Constitutional Symptoms Due To CLL (>10% Weight
Loss In 6 Months, Fatigue, Fever, Night Sweats),
4. Progressive Lymphocytosis: Doubling Time <6 Months,
5. SymptomaticLymphadenopathy>10cm
splenomegay>6cm
BCM,
Autoimmune
Disease
Refractory To Steroids,
6. Repeated Infections Hypogammaglobulinaemia.

29. Frail patient with significant
comorbidity
 Chlorampucil ±rituximab
 Rituximab
 Pulse steriod

30. Cll patients indicated to ttt
Fish
T(11,14)
Del 13
Del11
Del17
1-cll without del
17p,11q
2-cll with del17p
3-cll with del 11q

31. Cll without del 17p,11q
>70 years
,significant
comorbidiyy
 Chlorampucil ±rituximab
 bendamastine
 Cyclophosphamide,predni





slone±R
Rituximab
Alemtuzumab
Fludarabine±R
Cladripine
Lenalidomide
<70 years , no
significant
comorbidiyy




FCR
FR
PCR(Pentostatin)
bendamastine±R

32. Cll without del 17p,11q
Relapse, no response
>70 years
,significant
comorbidiyy
 Reduced dose FCR,PCR
 Bendamastine±R
 Chlorampucil
±rituximab
 Alemtuzumab±R
 Lenalidomide±R
 HDMP+R
<70 years , no
significant
comorbidiyy










FCR
PCR(Pentostatin)
bendamastine±R
F+Alemtuzemab
Alemtuzemab±R
R-CHOP
OFAR
R-HYPER CVAD
Lenalidomide±R
Then allogenic SCT

33. Cll with del 17p
short term
relapse,no
response
First line
therapy
 FCR
 FR
 Alemtuzumab±R
 HDMP+R
 Then allogenic SCT








Alemtuzumab±R
RCHOP
CFAR
OFAR
HDMP+R
R±hyper CVAD
Lenalidomide±R
Then allogenic SCT

34. Cll Without Del 11q
>70 years
,significant
comorbidiyy
 Chlorampucil ±rituximab
 Bendamastine
 Cyclophosphamide,predni





slone±R
Rituximab
Alemtuzumab
Fludarabine±R
Cladripine
Lenalidomide
<70 years , no
significant
comorbidiyy
 FCR
 PCR(Pentostatin)
 bendamastine±R
 Then allogenic SCT with
PR,opserve With CR

35. Cll without del 11q
Relapse, no response
>70 years
,significant
comorbidiyy
 Reduced dose FCR,PCR
 Bendamastine±R
 Chlorampucil
±rituximab
 Alemtuzumab±R
 Lenalidomide±R
 HDMP+R
<70 years , no
significant
comorbidiyy









FCR
PCR(Pentostatin)
bendamastine±R
F+Alemtuzemab
Alemtuzemab±R
R-CHOP
R-HYPER CVAD
Lenalidomide±R
Then allogenic SCT

36. Treatment of CLL
CHLORAMBUCIL:
•Still the primary therapy of choice for older patients.
•CR rates: 8-13%.
•Addition of steroids: No advantage except in
autoimmune cytopenias.
•Dose: 0.4 mg/kg day 1 (repeat every 2 weeks)
or 0.1 mg/kg day 1-14 (repeat every 4 weeks)
•For how long?: Till max. response (may take months).
•Maintenance treatment: No advatage in CLL.
•Progress after 12 months of max. response: You may
repeat the same dose.

37. Treatment of CLL
FLUDARABINE (Purine analog):
•Salvage treatment in older patients.
•Primary treatment in young patients who will
receive stem cell transplantaion.
•It is the most active single agent in CLL.
•CR rates: 25% (up to 20 months duration) even if
strict NCI WG criteria are used.
•Most CR cases occur in the first 3 months of
• treatment. Dose:
25 mg / m2 D 1-5 repeated every 4 weeks for 3 - 6 cycles.
Side effects:•Lymphocytopenia + opportunistic infections.
•AIHA (contraindicated if AIHA is already present).
•Tumour lysis syndrome in the first cycle if counts are very high
due to rapid response.
•Transfusion-associated GVHD (irradiate blood components).

38. Treatment of CLL
CLADARABINE (2CdA, Leustatin)
•Purine analog
•Same effect in CLL as Fludarabine
•Dose:
0.1 mg / kg D 1-7 repeated every 4 weeks
for 3-6 cycles.
•Side effects:-
Almost the same like Fludarabine.

39. Treatment of CLL
(MONOCLONAL AB)
2- Campath-1H
 Anti CD 52 antibody
(CD 52 present on most B &T cells )
 Response rates 50 %
 Toxicities : rigors,chills, fever,immunosuppression & lymphocytopenia .
 CMV re-activation is a problem
3- Rituximab ( anti-CD20)
 In CLL CD 20 is moderately expressed on the cells ( possible reason for
low response rates )
 With high counts (TLC > 50,000) patient may develop “cytokine
release syndrome” (fever, rigor, skin rash , nausea, vomiting,
hypotension, & dyspnea )

41. Stem Cell
Transplantation
• The only treatment modality that
resulted in PCR-negative CRs in
a substantial number of patients.
• Minitransplants can be applied to a
higher age range group.
 Cll with del 17p after first crif patient eligible with doner
 Cll with del11q after first pr if patient eligible with doner
 Cll with relapse after receiving high dose chemotherapy

42. Complications of cll
 Recurrent infection(neutropenia,immunoparesis)
 Ivig
 Antimicrobial agent
 Anti infective prophylaxis
 Herpes
 Sulfa(neumocystic)
 CMV(alemtuzemab)
 Autoimmune disease
 ITP,AIHA,PRCA
 steriod,rituximab,cyclosporine,splenectomy
 Fludarabine is contraindicated with AIHA

43. Complicatins of cll
 Vaccination
 Influanza
 Pneumococal vaccin
 Avoid live vaccine
 Blood products(irradiated blood)
 Tumour lysis syndrome
 Tumour flair syndrome(lenalidomide)
 Ttt steriod
 Thrompoprophylaxis(asprine81 mg/day) with
lenalidomide