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Robin Foà Ematologia Università “ La Sapienza ”, Roma Rieti, 27 Ottobre 2006

PARALLELISMO TRA PROFILO GENETICO-MOLECOLARE ED ETEROGENEITA’ FENOTIPICA, CLINICA E PROGNOSTICA DELLA LLC. Robin Foà Ematologia Università “ La Sapienza ”, Roma Rieti, 27 Ottobre 2006. CHRONIC LYMPHOCYTIC LEUKEMIA.

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Robin Foà Ematologia Università “ La Sapienza ”, Roma Rieti, 27 Ottobre 2006

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  1. PARALLELISMO TRA PROFILO GENETICO-MOLECOLARE ED ETEROGENEITA’ FENOTIPICA, CLINICA E PROGNOSTICA DELLA LLC Robin Foà Ematologia Università “La Sapienza”, Roma Rieti, 27 Ottobre 2006

  2. CHRONIC LYMPHOCYTIC LEUKEMIA • Most frequent leukemia in Western countries (30% of all leukemias vs 2-5% in Asian countries). • Median age at diagnosis: c65 yrs • M/F ratio 1.5:1 • Familial cases (4-5% first-degree relatives?) • Diagnosis usually made in asymptomatic individuals • Lymphadenopathy, splenomegaly, infections • Immune disturbances hypogammaglobulinemia (20 - 40%), AIHA (10 - 20%), T and NK cell defects

  3. CLL: WHY RELATIVE INTERESTIN THE PAST YEARS? A disease of the ‘elderly’; median age c65 yrs A disease with a chronic, often indolent, clinical course No grips on the heterogeneous clinical course Limited therapeutic options, namely chlorambucil A conservative, often ‘wait and watch’ management has been the treatment of choice

  4. CHANGE IN ATTITUDE TOWARDS CLL • Increased prevalence due to extended life expectancy • Biologic age who is old nowadays?? • Increasingly diagnosed in younger individuals c20% of patients under 55 yrs • Increased diagnosis due to broader use of routine blood tests • Identification of biologic features of prognostic relevance • New therapeutic options, including auto and allotransplantation procedures, MoAb and new drugs • Concept of living (and working) with leukemia quality of life and overall expectations

  5. CLL - EXTENDED BIOLOGIC CHARACTERIZATION • For a better understanding of thepathophysiology of the disease • For a more accurate diagnostic definition • For a biologically-based prognosticstratification of patients • For the definition of markers for MRD monitoring • For an optimal therapeutic (or non-therapeutic) algorythm • ? For the design of innovative therapeutic strategies

  6. Approaches Utilized for a Modern Characterization of CLL • Morphology dd, typical vs atypical CLL • Immunophenotype dd, typical vs atypical CLL, CD38 expression, degree of antigen expression • Cytogenetics for prognostic stratification • Mutated or unmutated IgVH profile for prognostic stratification • ZAP-70 expression for prognostic stratification • Further biologic properties of leukemic cells, cell-to-cell interplay and cytokine network(s) • Host immune status T cells, NK cells, DC, etc • Gene profiling

  7. PHENOTYPE OF B-CELL CHRONIC LYMPHOPROLIFERATIVE DISORDERS (TdT-/CD19/20+) CLL PLL HCL SLVL MCL FL

  8. SIg+ CD23++ CD5+ CLL CD19+ FMC-7-/+ CD20+ CD22-/+

  9. SIg++ CD5+ CD23-/+ MCL CD20++ FMC7+ CD22++

  10. "ATYPICAL" CLL • On morphological grounds: cases with a typical immunophenotypic profile, but with more than 10% of large lymphocytes and/or prolymphocytes and/or cells with nuclear clefts • On immunophenotypic grounds: cases with a typical morphology, but with the expression of FMC7 and/or of bright sIg ‘Atypical’ CLL account for c20% of cases, have a more advanced disease and a worse prognosis

  11. FREQUENCY OF CHROMOSOME LESIONS IN CLL(comparison of CCA and FISH) (*) % total abnormal (**) Dohner et al, 2001 EHA

  12. Survival and specific chromosome aberrations Dohner et al, NEJM (2000)

  13. SURVIVAL BASED on IgV MUTATION STATUS and CD38 EXPRESSION among B-CLL of RAI INTERMEDIATE RISK Damle et al. Blood 1999;94:1840

  14. B-CLL UTILIZING VH3-21 REPRESENT an UNFAVORABLE PROGNOSTIC SUBSET of B-CLL with MUTATED IgVH GENES Blood 99:2262, 2002

  15. “SUPERSTABLE” CLL PATIENTS Guarini et al, Blood 102, 1035, 2003

  16. IgVH, CD38, p53 & CD4/CD8 IN ‘SUPERSTABLE’ CLL Case% Mutated IgV% CD38p53 CD4/CD8 ratio 1 4.7 1 wt n.d. 2 7.6 3 wt 2 3 3.3 48 wt 1.2 4 5.0 1 wt 2.18 5 3.6 2 wt 1 6 7.0 1 wt 4 7 11.4 1 wt 2.5 8 6.0 1 wt 3 9 6.1 1 wt 2 10 3.6 1 wt 1.66 11 12.7 1 wt 2.28 12 7.5 1 wt 2.2 13 8.4 1 wt 2 14 1.3 1 wt 2 15 10.7 1 wt 1 16 7.5 9 wt 2.6 17 3.8 4 wt 1 18 4.0 6 wt 2.5 19 4.7 2 wt 4.5 20 10.8 1 wt 3.66 Guarini et al, Blood 2003

  17. Germinal Center and Lymphomagenesis Schroeder & Dighiero. Immunol Today, 1994 Hamle et al. Blood, 2000 Hamblin et al. Blood, 2000 CLL GC cells Apoptosis MZ Naive B-cell Memory B-cells IgV hypermutation Ig isotype switch Plasma cells CLL MCL FL BL DLCL MM IgV mutations - - + + BCL-6 Syndecan

  18. NON MUTATED MUTATED HIGH & LOW NON MUTATED MUTATED HIGH & LOW Rosenwald et al (J Exp Med 2001) Klein et al (J Exp Med 2001) DLBCL OTHER CLL CLL is a unique disease with two different features: Rosenwald et al (J Exp Med 2001)

  19. ZAP70 expression and IgVH mutational status Survival probability according to ZAP70 expression (A stage) <20% ZAP70   20% ZAP70 Crespo et al., NEJM 2003

  20. Diagnosis • CLL is a heterogeneous disease, not only from the clinical standpoint • Morphology • Immunophenotype • IgV mutated vs IgV unmutated • Zap-70+ vs Zap-70- • Cytogenetic/genetic -clinical correlates • Gene profile How many diseases?

  21. CHRONIC LYMPHOCYTIC LEUKEMIA PRESENT * Fludurabine  CR * Combined chemotherapy (eg Fluda+Cyclo) * MoAb (Rituximab, Campath) * Chemo + MoAb (FCR, FluCam) * Other purine analogs (2-CdA, DcF) *Transplantation programs (auto, allo, ric allo) *Allografting/minitransplant ± DLI * New drugs and compounds HEMATOPOIETIC TOXICITY ASSOCIATED WITH IMMUNE DEPRESSION (DEFICIT T, NK, DC) PAST WAIT & SEE CHLORAMBUCIL CONSERVATIVE APPROACH

  22. A Few Concepts to be Considered for the Optimal Management of CLL Patients • Age-dependent treatment (taking into account biologic age) • Early and aggressive treatment maybe curative • Change in definition of remission • High remission rate after first-line therapy associated with longer PFS • Choice of first-line treatment is very important

  23. MODERN APPROACH TO THE MANAGEMENT OF CLL • An integrated biologic work-up at diagnosis • A biologically-based prognostic stratification and possible design of a new scoring system • A biologically-based therapeutic (and non-therapeutic) algorythm • Change in “therapeutic” approach for “younger” patients with poor prognostic factors? • Early and aggressive treatment? • Aim at disease eradication (MRD monitoring) ??

  24. CD38 EXPRESSION FREQUENCY IN B-CELL CHRONIC LYMPHOPROLIFERATIVE DISORDERS AT DIAGNOSIS PATIENTS CD38+>10% CD38+ >20% CLL (N° 110) 19 (17.2%) 15 (13.6%) CD5+ NHL (N° 46) 25 (54%) 19 (41.3%) NHL (CD5-) (N° 51) 8 (15.6%) 6 (11.7%)

  25. Treatment-Free Survival CD38+ pts: cut-off=20% CD38 neg CD38 pos p<.0001 Gentile et al, BJH 2005

  26. Treatment-Free Survival in Rai Stage 0 Patients According to CD38 Positivity (cut-off=20%) CD38 neg CD38 pos p<.0001 Gentile et al, BJH 2005

  27. Change over Time of Remission Criteria • Moving away from palliative treatment clearance of blood major marker • Moving towards a curative approach clearance of bone marrow • No longer on a morphologic definition of remission, but the use of immunophenotypic and genetic monitoring of minimal residual disease

  28. BIOLOGICAL WORK-UP FOR ‘YOUNGER’ CLL Correct diagnostic definition & dd (ndr, should always take place!) • High risk • 17p13 deletions or p53 mutations, 11q22-q23 deletions and unmutated IgVH • unmutated IgVH ± 12q trisomy • ± ZAP-70 ± CD38+ Standard risk

  29. Phase II pilot study to evaluate a therapeutic strategy diversified accoring to the biologic profile of patients with CLL with advanced stage and/or progressive disease aged <60 yearsLLC0405 GIMEMA Protocol

  30. “YOUNG” CLL PATIENTS WITH PROGRESSIVE DISEASE • HIGH RISK Fludarabine + Campath-1H MCR CR PR NR age donor age donor PBSC Off Study Auto, Allo Transplantation or Further Campath W & W

  31. “YOUNG” CLL PATIENTS WITH PROGRESSIVE DISEASE Standard risk Fludarabine + Cyclophosphamide x 4 NR PR CR-CIR MCR W & W FC x 2 Campath PBSC NR CR CIR PR W & W W & W Off study

  32. PROBLEMATICHE • Ottimale inquadramento diagnostico e diagnosi differenziale • Stratificazione prognostica alla diagnosi su base biologica almeno fino a 65 anni problema di numerosità, di tecnologie e competenze, di riproducibilità, di costi • Possibilità di monitorizzare la MRM (immunologica e molecolare)

  33. T NK B Immune defects Changes in approach to CLL – From patients to genes Last decades’ evolution in the understanding of CLL 1970s → 80s 1980s → 90s clinical immunedeficiency cellular and humoral immune impairment Inhibition of CD40L expression Stimulation of Ig production NEW THERAPIES BIOLOGICALLY-BASED PROGNOSTIC STRATIFICATION 1995 00s T CLL B IL-4 IL-4 IL-4 IL-4 CLL Inappropriate production of autoreactive antibodies Impaired interactions with B and APC 2000 → Tumor cell activation, proliferation and inhibition of apoptosis Autoimmune phenomena Ig CD40 B-CLL cell accumulation CD40L genomic characterization, new drugs membrane and soluble mediator interactions

  34. Acknowledgments:A. Guarini, S. De Propris, S. Chiaretti, I. Dalla Starza, E. Ghia, F. Mancini, R. Maggio, M. Mancini, I. Del Giudice, F.R. Mauro – RomeG. Castoldi, A. Cuneo – FerraraG. Gaidano, D. Capello – NovaraJ. Ritz – BostonGIMEMA network

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