1. HANAN.A.ELTIB 2014 Chronic lymphocytic leukemia

3. OVERVIEW The most prevalent type of adult leukemia in western countries Median age of diagnosis of CLL is ~ 72 years, with only 10% of patients younger than 50 years of age CLL morbidity rapidly increases with age More common in men than women (2:1 ratio)

4. Pathophysiology Historically CLL considered disease of accumulation due to defect in apoptosis CLL more proliferative disease than previously thought CLL cells up regulate gene signature consistent with BCR and NF-KB pathway activation

5. Diagnosis CBC: at least 5000 monoclonal B-lymphocytes/cml in the peripheral blood Morphologically :small mature lymphocytes N.B :Fewer clonal B-Cells LNS less 1.5 cm no anemia or thromocytopenia +/_ the immunophenotybe of the CLL ALymphoproliferative disorders :monoclonal B- lymphocytosis(MPL)

6. CLL/SLL  Different manifestation of the same disease managed in the same way The major difference SLL: the abnormal lymphocytes are predominantly found in the LNS-diagnosis mainly by LN biopsy-no more than 5000 clonal B-cells in the peripheral blood CLL: significant number of the abnormal lymphocytes are also found in the BM and blood

7. Initial Work-up of CLL Patients Flow cytometry of the peripheral blood Kappa/lambda CD5 + CD19 + CD23 + CD10 - CD20 dim Surface IG dim Cycline D1 – Atypical CLL : t(11;14) by FISH :LN biopsy with IHC CD3 CD5 CD10 CD20 CD23 Cyclin D1

8. Anemic pt : RC count - direct combs‘ test LN biopsy only if diagnosis not confirmed by flowcytometry Bone marrow aspirate and biobsy not necessary in absence of cytopenias No CT scan unless symptoms are present; PET scan can be helpful if Richter’s suspected Informative for prognostic and/or therapy determination flowcytometry or IHC: CD38-CD70 cytogenetics analysis : +12, del(13q), del(17p)and del(11q) mollecular analysis : IGVH gene status assessment-TP53 serum level : β2-microglobulin Initial Work-up of CLL Patients

9. Physical Exam LNs : size-symptoms liver-spleen size B-symptoms Performance Useful under certain circumstaces  haptoglobin  Serum QIG level  uric acid  LDH  HBV Initial Work-up of CLL Patients

10. RAI’s CLINICAL STAGING SYSTEM StageClinical Features at DiagnosisMedian Survival (years) 0 Low risk Blood lymphocytosis>5000/mcl, Bone marrow lymphocytosis>30% >12,5 I Intermediate risk Stage 0 and enlarged lymph node(s) 8 II Intermediate risk Stage 0-I and enlarged spleen and/or liver 6 III High risk Stage0-II and anemia (Hb < 11g/dl) 1,5-2 IV High risk Stage0-III and thrombocytopenia(< 100 000 /mcl) 1,5-2

11. When to Treat CLL Patient No advantage to treating CLL until symptoms develop  Constitutional symptoms due to disease (fatigue, B symptoms)  Enlarging, symptomatic lymph nodes (> 10 cm)  Enlarging, symptomatic spleen (> 6 cm BCM)  Cytopenias due to CLL (hemoglobin < 11 g/dL, platelets < 100,000 cells/μL)  Poorly controlled AIHA or ITP  Absolute lymphocytic count alone is not indication for treatment unless above 200-300×109/L Or symptoms related to leukostasis

12. Treatment options  Alkylating agents  Purine anologue vs Alkylators Higher RR and PFS Better QOL Not OS  Purine/alkylator combo vs. purine: Higher RR and PFS Not OS

13. Treatment options  CLL8 study ;chemoimmunotherpy : FCR VS FC More neutropenia A better therapy for young –physically fit pt Significantly improves ORR and CR Significantly improves PFS Significantly improves OS 7% Most genetic groups benefit from FCR therapy except for del(17p13)

15. Treatment options CLL10 study; FCR VS BR  Bendamastin: An Alkylator agent with apurine like benzimidazole ring component  Identical ORR  Higher CR rates observed with FCR  PFS significantly longer with FCR  Acute (and long-term?) toxicity greater with BR PCR  Pentostatin: purine analog  No advantage over FCR  Cyclophoshamide is an important component Alemtuzumab  Huminazied Monoclonal Ab target CD52  Not as afirst line treatment option except in the setting of del (17p)

16. In elderly: Treatment options FCR not well tolerated –less effective by pts  70 ys Fludrabine vs chloreambucil  65 ys Better ORR CR TTTF QOL analysis favoured fludrabine NO PFS OS difference SO Chloreambucil is avalid option

17. In elderly: Treatment options Bendamastin vs chlorambucil Higher RR/PFS Higher toxicity CLL11 study :Obinituzumab + chlorambucil is an effective, well-tolerated therapy  Most appropriate for elderly  ? question of whether obinituzumab is superior to rituximab in other clinical contexts

18. First line therapy Fit patient Chemoimmunotherapy e.g FCR/FR/BR/PCR Elderly pt-comorbidity Chlorambucil+/- R Fludarabine+/- R Cyclophosphamide, prednisolone+/-R Bendamastin+/-R Rituximab

19. First line therapy Frail pt Chlorambucil Pulse steroides Rituximab

20. Molecular guided therapy Pt with del(17p)  Trial  FCR  HDM+R  Alemtuzumab+/-R  Ibrutinib for patients with relapsed/refractory disease  Pt with del(11q)  Regimens containing an alkylator

21. Considerations for Relapsed CLL  Outcome of patients at time of relapse dependent on: – Interphase cytogenetics, β2-microglobulin, and stage – Previous therapy (ie, monotherapy or chemoimmunotherapy) – Time of remission with last treatment  Treat relapsed patients when symptomatic only  Interphase cytogenetics should be repeated prior to initiating salvage therapy  All patients with cytopenias should have repeat bone marrow to assess for MDS if prior FCR given  Transplant evaluation should be considered early in this population if any unfavorable features present

23. Salvage therapy Ibrutinib Chemoimmunotherapy Ofatumab Lenalidomide+/- R Alemtuzumab+/- R

26. Supportive Care for pts with CLL 1-Recurrent infection Antimicrobials as appropriate IVIG, if <500mg/dl 2-Antinfective prophylaxis PCP-Herpes virus CMV HBV 3-vaccination Annual INFLUENZA vaccine Pneumococcal vaccine/5y

27. Supportive Care for pts with CLL Blood product :irradiate all blood product Tumor lysis syndrome Tumor flare reaction :lenalidomide Thromboprophylaxis :lenalidomide Autoimmune cytopenias - Steroides - IVIG - Cyclosporin A - Rituximab - Splenectomy

29. In clinical practice)) Follow up Constitutional symptoms Physical Examination Organomegally LNS Blood parameters blood counts +/_BM

30. Richter's syndrome))Histological Transformation DLBCL or HL 2-5 % Increase with NO. of prior regimens Poor prognosis Extra nodal involvement, Sharp rise in LDH Chemoimmunotherapy e.g R-CHOP/ R-HYPERCYVAD Allogeneic HSCT, considered following initial therapy Prolymphoctic leukemia.  > 55% increase in prolymphocytes  Progression of splenomegaly & cytopenias  Refractoriness to treatment.