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Chronic lymphocytic leukemia

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  • 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
  • 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-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.
  • 13. 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
  • 14. 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.
  • 15.  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.
  • 16. Bone marrow
  • 17. 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
  • 18. 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.
  • 19. 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.
  • 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 <12 months.  Cytogenetic abnormalities 11q– or 17q–.  serum b2-microglobulin.  serum LDH.  serum thymidine kinase.  soluble CD23.  Unmutated IgVH genes.  Poor response to therapy.
  • 23. 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)
  • 24. 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
  • 25. PD: •Physical ex. (LN , liver , spleen): > 50% increase or new •Circulating lymphocytes : > 50 % increase.. •Others: Richter’s 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 <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.
  • 27. Frail patient with significant comorbidity  Chlorampucil ±rituximab  Rituximab  Pulse steriod
  • 28. 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
  • 29. 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
  • 30. 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
  • 31. 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
  • 32. 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
  • 33. 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
  • 34. 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.
  • 35. 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).
  • 36. 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.
  • 37. 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 )
  • 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) with lenalidomide