- 1. By Shimaa Abd Alla Ahmed
2. defenition Progressiveaccumulation 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 CBCCLLSLL5;
B-cell Marker (CD19, 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. Recurrentinfection 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 1020% cases, warm
antibodyAIHA in 5.0109/L Neutropenia anaemia, thrombocytopenia and
absent in early stageCLL; autoimmune haemolysis occur at any
stage.thrombocytopenia may 11. 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; 12. Comparison
of CLL and PLL B-CLLCLL-PLLCLL slg CD19 CD20 CD5PLL+ ++ ++ ++++ ++
++ -/+Courtesy of Randy Gascoyne, MD. 1. Bennett JM, et al. J Clin
Pathol. 1989;42:567-584. 13. Immunophenotyping crucialto
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 14. Immunophenotype
scoring system Scoring system for B-CLL Points Membrane marker
Smlg10WeakModerate/strongCD5PositiveNegativeCD23PositiveNegativeFMC7NegativePositiveCD79b
(SN8)NegativePositive1. Matutes E, et al. Leukemia.
1994;8:1640-1645. 2. Moreau EJ, et al. Am J Clin Pathol.
1997;108:378-382. 15. Immunoglobulins: immuneparesis
(hypogammaglobulinaemia) common; monoclonal paraprotein (usually
IgM) 30% mature lymphocytes. Trephinebiopsy: provides prognostic
information: infiltration may be nodular (favourable);
interstitial; mixed; diffuse (unfavourable). Lymph node biopsy:
rarely required; appearances of lymphocytic lymphoma. 16. Bone
marrow 17. Prognosis: histologic bone Nodular Interstitial Diffuse
marrow patterns (low risk) (low risk) (high risk) Thedifferent bone
marrow patterns probably variations in amount of lymphoid
accumulation the natural course of the diseaseCourtesy of Randy
Gascoyne, MD. 1. Montserrat E, et al. Cancer.
1984;54:447-451.reflect during 18. Cytogenetics Conventional
chromosome banding can nolonger be recommended in the diagnostic
work up of CLL ( detects abnormalities in 40-50 % of CLL patients
only. 19. Cytogenetics prognostic value; abnormalities in >80%
using FISH: 13q(55%), 11q (18%), 12q+ (16%), 17p (7%), 6q (7%);
11q, 17q veryunfavourable; sole 13qfavourable,or6q ,normal
karotyping neutral out come ,Clonal evolution occurs over time. 11q
and 17q associated with advanced disease. 20. 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. 21. Other tests:
U&E; LFTs; LDH; Uric acide b2-microglobulin; imaging . Ct chest
and abdomine Pet scan(With richter transformation) 22. 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 15,000/mm3)0-150 months (12.5 years)Lymphocytosis
plus nodal involvementIALymphocytosis plus organomegalyIIBAnemia
(RBCs)III Hgb 50% increase or new Circulating lymphocytes : > 50
% increase.. Others: Richters syndrome SD: All 0ther than the
above. 26. Cll ttt acording to NCCN 2013 Chemotherapy reserved for
patients with symptomatic or progressive disease: 1. anaemia (Hb
6cm BCM, Autoimmune Disease Refractory To Steroids, 6. Repeated
Infections Hypogammaglobulinaemia. 27. Frail patient with
significant comorbidity Chlorampucil rituximab Rituximab Pulse
steriod 28. Cll patients indicated to tttFish T(11,14) Del 13 Del11
Del171-cll without del 17p,11q2-cll with del17p3-cll with del 11q
29. Cll without del 17p,11q>70 years ,significant comorbidiyy
Chlorampucil rituximab bendamastine Cyclophosphamide,predni sloneR
Rituximab Alemtuzumab FludarabineR Cladripine Lenalidomide70 years
,significant comorbidiyy Reduced dose FCR,PCR BendamastineR
Chlorampucilrituximab AlemtuzumabR LenalidomideR HDMP+R70 years
,significant comorbidiyy Chlorampucil rituximab Bendamastine
Cyclophosphamide,predni sloneR Rituximab Alemtuzumab FludarabineR
Cladripine Lenalidomide70 years ,significant comorbidiyy Reduced
dose FCR,PCR BendamastineR Chlorampucilrituximab AlemtuzumabR
LenalidomideR HDMP+R 50,000) patient may develop cytokine release
syndrome (fever, rigor, skin rash , nausea, vomiting, hypotension,
& dyspnea ) 38. 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 39.
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 40. 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) withlenalidomide
