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Chronic lymphocytic leukemia Prognosis and treatment

Chronic lymphocytic leukemia Prognosis and treatment. Emili Montserrat Institute of Hematology and Oncology. University of Barcelona. ESH - Hammamet, 28 October 2010. Chronic Lymphocytic Leukemia. Most frequent form of leukemia in Western world. Incidence: 3-20/100,000

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Chronic lymphocytic leukemia Prognosis and treatment

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  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 22% 43% 35% Adapted from SEER (1975-2005)

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

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

  7. 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 30 40 Overall survival in CLL Low risk Probability Intermediate risk High risk Time (years)

  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 No disease activity Diagnosis Prognostic Factors Valuable information (i.e. risk, frequency of f/u) 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. First-line FCR: Dose and schedule Tam CS, et al. Blood 2008; 112: 975-980 Allopurinol 300 mg/day

  17. p=0.16 p<0.01 p=0.12 p=0.10 First-line R-FC: improved OSfollowing CR 1.0 0.8 0.6 Probability 0.4 0.2 0 0 12 24 36 48 60 72 84 96 108 Time (months) nPR = nodular PRPR-i = met all criteria for CR except for incomplete recovery of blood countsPR-d = residual disease in blood, nodes, spleen, marrow or other sites Tam CS, et al. Blood 2008; 112: 975-980

  18. p<0.001 p=0.37 Improved OS with R-FC in first-line CLL(historical comparison) 1.0 0.8 0.6 Probability 0.4 0.2 0 0 12 24 36 48 60 72 84 96 108 Time (months) 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. R-FC q4wk  3 R-FC q4wk  3 FC q4wk  3 FC q4wk  3 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 R A N D O M I S E R ESTAGE • Untreated B-CLL • Binet B requiring treatment or Binet C • ECOG PS 0–1 • n=817 CR, PR Rituximab Cycle 1: 375mg/m2Cycles 2–6: 500mg/m2 Fludarabine 25mg/m2 iv, day 1–3 Cyclophosphamide 250mg/m2 iv, day 1–3 SD, PD off study ECOG PS = Eastern Cooperative Oncology Group performance status; q4wk = every 4 weeks SD = stable disease; progressive disease

  21. 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 • 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 1960-2010Many 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?

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

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

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

  35. 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 New agents for CLL1 (1) List does not intend to be comprehensive (among others, aspirine, valproic acid, green-tea, and ging-seng not included)

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

  37. CLL survival: patients ≤ 65 yearsHospital Clinic, Barcelona 1.0 2000–2008 0.8 1990–1999 1980–1989 0.6 Survival probability 0.4 • Median survival • 1980–89 (n = 116): 10.0 yrs • 1990–99 (n = 197): 11.4 yrs • 2000–08 (n = 128): NR p = NS 0.2 p = 0.008 p = 0.05 0.0 0 2 4 6 8 10 Years Abrisqueta et al. Blood 2009

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