1. Chronic lymphocytic leukemia Prognosis and treatment Emili Montserrat Institute of Hematology and Oncology. University of Barcelona ESH - Hammamet, 28 October 2010

2. Chronic Lymphocytic Leukemia Most frequent form of leukemia in Western world. Incidence: 3-20/100,000 Median age at diagnosis: 72 yrs Heterogeneous disease –Clinically –Biologically Accumulation of B lymphocytes –SmIg weak, CD5+, CD19+, CD20 weak, CD23+ Immune disturbances Genetic background No curative treatment

3. CLL diagnosis > 5,000 monoclonal lymphocytes in peripheral blood Characteristic immunophenotype –SmIg weak, CD5+, CD19+, CD20 weak, CD23+ Not necessary (but useful on many occasions) –Bone marrow aspirate/biopsy –Lymph node histology

4. CLL: Age at diagnosis Adapted from SEER (1975-2005) 43% 22% 35%

5. Prognostic Factors in CLL: Why? No curative therapy for CLL Heterogeneous clinical couse

6. CLL: natural history Lymphocytosis Good prognosis Intermediate prognosis Bad prognosis Survival Normal Months Anemia, thrombocytopenia Lymphadenopathy, enlarged spleen, liver

7. Overall survival in CLL Probability Time (years) 0.8 0.6 0.4 0.2 0 1.0 051015202530 40 Low risk High risk Intermediate risk

8. Relevant Prognostic Factors in CLL Classical –Clinical stages –Tumor burden (e.g. WBC count) –LDT New –Serum markers (Beta-2 microglobulin) –Cytogenetics –CD38 –IGVH mutations –ZAP-70 expression

9. Prognostic factors vs. Response predictors Prognostic factors –predict the natural history of the disease upon no therapy or no effective therapy –highly dependent on response to therapy (response to therapy by itself is the most important prognostic factor) Response predictors –factors (mainly biological) that predict response to a given therapy

10. CLL: Most important biologic response predictors 17p-Resistance to fludarabine, alkylators, rituximab 11q-RR (F< FC < FCR) Early relapse

11. From Prognostic Factors to Response Predictors Diagnosis Prognostic Factors Valuable information (i.e. risk, frequency of f/u) No disease activity Disease activity (Need for therapy) Response predictors Risk adapted & Targeted therapy C. Moreno, E. Montserrat Blood Rev. 2008

12. Prognostic factors in real life At diagnosis Clinical stages LDT B2 microglobulin are more than enough! Before starting treatment FISH (TP53 and ATM abnormalities) (17p-, 11 q-)

13. CLL treatment: when to treat General symptoms Lymphadenopathy or splenomegaly increasing in size or causing symptoms Decreasing hemoglobin levels or platelet counts Rapid doubling time Autoimmune hemolytic anemia not responsive to corticosteroids Hypogammaglobulinemia with infections

14. CLL treatment: when to treat General symptoms Lymphadenopathy or splenomegaly increasing in size or causing symptoms Decreasing hemoglobin levels or platelet counts Rapid doubling time Autoimmune hemolytic anaemia not responsive to corticosteroids Hypogammaglobulinemia with infections Biological markers (e.g. cytogenetics, CD38, ZAP-70, IgVH mutations) NOT an indication to start therapy outside clinical trials

15. Chemoimmunotherapy (rituximab-based) is the new gold standard for CLL therapy

16. Days of course Drug Dose (mg/m 2 ) Course 1 Courses 2–6 Rituximab375–500 Day 1 (375 mg/m 2 ) Day 1 (500 mg/m 2 ) Fludarabine252–41–3 Cyclophosphamide2502–41–3 First-line FCR: Dose and schedule Allopurinol 300 mg/day Tam CS, et al. Blood 2008; 112: 975-980

17. First-line R-FC: improved OS following CR Time (months) 12024364860728496108 Probability 0.8 0.6 0.4 0.2 0 1.0 nPR = nodular PR PR-i = met all criteria for CR except for incomplete recovery of blood counts PR-d = residual disease in blood, nodes, spleen, marrow or other sites Outcomenp value CR217 nPR31 PR-i21 PR-d16 Fail15 p=0.12 p<0.01 p=0.16 p=0.10 Tam CS, et al. Blood 2008; 112: 975-980

18. Time (months) 12024364860728496108 Probability 0.8 0.6 0.4 0.2 0 1.0 Protocoln6-year OSp value R-FC30077% F±M/C14059% F19054% p=0.37 Improved OS with R-FC in first-line CLL (historical comparison) p<0.001 Tam CS, et al. Blood 2008; 112: 975-980

19. Confirmatory phase III trials REACH Study –Robak et al. J Clin Oncol 2009 German CLL Study Group CLL8 trial –Hallek et al. Lancet 2010

20. The CLL-8 trial: R-FC vs. FC in previously untreated CLL RANDOMISERANDOMISE R-FC q4wk  3 FC q4wk  3 RESTAGERESTAGE R-FC q4wk  3 FC q4wk  3 SD, PD off study CR, PR Rituximab Cycle 1: 375mg/m 2 Cycles 2–6: 500mg/m 2 Fludarabine 25mg/m 2 iv, day 1–3 Cyclophosphamide 250mg/m 2 iv, day 1–3 Untreated B-CLL Binet B requiring treatment or Binet C ECOG PS 0–1 n=817 Hallek et al. German CLL Study Group. Lancet 2010; 376 (2): 1164-1174 ECOG PS = Eastern Cooperative Oncology Group performance status; q4wk = every 4 weeks SD = stable disease; progressive disease

21. FCFCR Evaluable patients 409408 ORR (%)8090 CR (%)2244 PFS (median) ~33 m.~ 52 m. OS @ 5 yrs60%75% The CLL-8 trial: R-FC vs. FC in previously untreated CLL Hallek et al. German CLL Study Group. Lancet 2010; 376 (2): 1164-1174

22. FCR: some caveats Abnormalities of TP53 (10%) Patients > 70 years-old (>40%!) Impaired renal function Viruses (B, C) AIHA, DAT-positivity

23. FCR: some caveats All patients progress Abnormalities of TP53 (10%) Patients > 70 years-old (>40%!) Impaired renal function Viruses (B, C) AIHA, DAT-positivity FCR is good treatment for many, but not all, patients with CLL

24. CLL: Treatment of special situations TP53 abnormalities/refractory disease (1) –Allogeneic stem cell transplantation –Alemtuzumab (corticosteroids) –Flavopiridol (1)Patients not responding or progressing shortly (24-48 m.) after chemoimmunotherapy

25. CLL: Treatment of special situations Elderly patients or patients with comorbidities precluding chemoimmunotherapy –Chlorambucil –Bendamustine –Lenalidomide –Rituximab + steroids –Trials!

26. CLL: Treatment of special situations Elderly patients or patients with comorbidities precluding chemoimmunotherapy –Chlorambucil (+ Rituximab) –Bendamustine (+ Rituximab) –Lenalidomide (+ Rituximab) –Rituximab + steroids –Trials!

27. CLL Therapy 1960-2010 Many things have changed… From chlorambucil (<10% CR) to chemoimmunotherapy (60%-70% CR) Chemoimmunotherapy new gold-standard for CLL therapy MRD- negativity CRs correlates with better outcome Improved PFS and OS

28. Individual, risk-adapted therapy –11q- FCR (better than F and FC) –17p- Refractory to fludarabine-based therapies. Alternatives: - alemtuzumab - flavopiridol - allogeneic stem cell tx

29. Individual, risk-adapted therapy –Patients failing to chemo-immunotherapy have very poor prognosis (median s. < 24 m.) Allogeneic stem cell transplantation

30. Others have not… CLL continues being an incurable disease!

31. Others have not… CLL continues being an incurable disease! –Why? –How to improve on current therapy?

33. CLL Therapy: not a single target B-cells T-cells Microenvironment

34. CLL Therapy: not a single target B-cells T-cells Microenvironment

35. CLL Therapy: not a single target B-cells T-cells Microenvironment

36. New agents for CLL 1 MoAb –Anti-CD20 –Other –Biclonal Immunomodulators –Lenalidomide Anti Bcl-2 –Oblimersen –Obatoclax –ABT-263 CDK inhibitors –Flavopiridol SMIP –TRU-016 (anti-CD37) Syk inhibitors –Fostamatinib PI3K p110δ inhibitor –CAL-101 CXCR4/CXCL12 axis inhibitors (1) List does not intend to be comprehensive (among others, aspirine, valproic acid, green-tea, and ging-seng not included)

37. New agents in CLL therapy New chemotherapies –Bendamustine New anti CD20 monoclonal antibodies –Ofatumumab, GA101 Immunomodulators –Lenalidomide

38. CLL survival: patients ≤ 65 years Hospital Clinic, Barcelona Median survival 1980–89 (n = 116): 10.0 yrs 1990–99 (n = 197): 11.4 yrs 2000–08 (n = 128): NR p = 0.008 p = NS p = 0.05 2000–2008 1990–1999 1980–1989 Abrisqueta et al. Blood 2009 1086420 Years 1.0 0.8 0.6 0.4 0.2 0.0 Survival probability