2. defenition
Progressive
accumulation of matureappearing, functionally incompetent,longlived B lymphocytes in peripheral blood,
bone marrow, lymph nodes,spleen, liver
and sometimes other organs.
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.
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
11.
12.
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.
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.
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 )
40.
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