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PARALLELISMO TRA PROFILO GENETICO-MOLECOLARE ED ETEROGENEITA FENOTIPICA, CLINICA E PROGNOSTICA DELLA LLC PARALLELISMO TRA PROFILO GENETICO-MOLECOLARE ED.

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Presentation on theme: "PARALLELISMO TRA PROFILO GENETICO-MOLECOLARE ED ETEROGENEITA FENOTIPICA, CLINICA E PROGNOSTICA DELLA LLC PARALLELISMO TRA PROFILO GENETICO-MOLECOLARE ED."— Presentation transcript:

1 PARALLELISMO TRA PROFILO GENETICO-MOLECOLARE ED ETEROGENEITA FENOTIPICA, CLINICA E PROGNOSTICA DELLA LLC 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 INTEREST IN THE PAST YEARS? A disease of the elderly; median age c65 yrs A disease of the elderly; median age c65 yrs A disease with a chronic, often indolent, clinical course A disease with a chronic, often indolent, clinical course No grips on the heterogeneous clinical course No grips on the heterogeneous clinical course Limited therapeutic options, namely chlorambucil Limited therapeutic options, namely chlorambucil A conservative, often wait and watch management has been the treatment of choice 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 Increased prevalence due to extended life expectancy Biologic age who is old nowadays?? Biologic age who is old nowadays?? Increasingly diagnosed in younger individuals c20% of patients under 55 yrs 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 Identification of biologic features of prognostic relevance New therapeutic options, including auto and allotransplantation procedures, MoAb and new drugs 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 Concept of living (and working) with leukemia quality of life and overall expectations

5 CLL - EXTENDED BIOLOGIC CHARACTERIZATION For a better understanding of the pathophysiology of the diseaseFor a better understanding of the pathophysiology of the disease For a more accurate diagnostic definitionFor a more accurate diagnostic definition For a biologically-based prognostic stratification of patientsFor a biologically-based prognostic stratification of patients For the dFor the definition of markers for MRD monitoring For an optimal therapeutic (or non-therapeutic) algorythmFor an optimal therapeutic (or non-therapeutic) algorythm ? For the design of innovative therapeutic strategies? 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

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

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

10 SIg++ CD5+ FMC7+ CD22++ CD20++ CD23-/+ MCL

11 "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 cleftsOn 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 sIgOn 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 Atypical CLL account for c20% of cases, have a more advanced disease and a worse prognosis

12 FREQUENCY OF CHROMOSOME LESIONS IN CLL (comparison of CCA and FISH) AberrationCytogenetics (*)FISH (**) Clonal30-50%82% Normal50-70%18% del 13q14 single7-11%36-45% 12q trisomy13-19%11-14% del 11q22-23/ATM6-13%8-25% del 17p/p531-5%3-7% del 6q211%2% (*) % total abnormal (**) Dohner et al, 2001 EHA

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

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

15 B-CLL UTILIZING V H 3-21 REPRESENT an UNFAVORABLE PROGNOSTIC SUBSET of B-CLL with MUTATED IgV H GENES Blood 99:2262, 2002

16 SUPERSTABLE CLL PATIENTS Guarini et al, Blood 102, 1035, 2003

17 IgVH, CD38, p53 & CD4/CD8 IN SUPERSTABLE CLL Case% Mutated IgV% CD38 p53 CD4/CD8 ratio 1 4.7 1 wt n.d. 1 4.7 1 wt n.d. 2 7.6 3 wt 2 2 7.6 3 wt 2 3 3.3 48 wt 1.2 3 3.3 48 wt 1.2 4 5.0 1 wt2.18 4 5.0 1 wt2.18 5 3.6 2 wt 1 5 3.6 2 wt 1 6 7.0 1 wt 4 6 7.0 1 wt 4 7 11.4 1 wt 2.5 7 11.4 1 wt 2.5 8 6.0 1 wt 3 8 6.0 1 wt 3 9 6.1 1 wt 2 9 6.1 1 wt 2 10 3.6 1 wt1.66 10 3.6 1 wt1.66 11 12.7 1 wt2.28 11 12.7 1 wt2.28 12 7.5 1 wt 2.2 12 7.5 1 wt 2.2 13 8.4 1 wt 2 13 8.4 1 wt 2 14 1.3 1 wt 2 14 1.3 1 wt 2 15 10.7 1 wt 1 15 10.7 1 wt 1 16 7.5 9 wt 2.6 16 7.5 9 wt 2.6 17 3.8 4 wt 1 17 3.8 4 wt 1 18 4.0 6 wt 2.5 18 4.0 6 wt 2.5 19 4.7 2 wt 4.5 19 4.7 2 wt 4.5 20 10.8 1 wt3.66 20 10.8 1 wt3.66 Guarini et al, Blood 2003

18 Plasma cells Germinal Center and Lymphomagenesis Naive B-cell GC cells Memory B-cells BCL-6 Syndecan CLL MCLFLBL Apoptosis IgV mutations DLCLMM -++ IgV hypermutation Ig isotype switch CLL - MZMZ Schroeder & Dighiero. Immunol Today, 1994 Hamle et al. Blood, 2000 Hamblin et al. Blood, 2000

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

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

21 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?

22 CHRONIC LYMPHOCYTIC LEUKEMIA PAST PAST WAIT & SEE CHLORAMBUCIL CONSERVATIVE APPROACH PRESENT 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)

23 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 may be 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

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

25 CD38 EXPRESSION FREQUENCY IN B-CELL CHRONIC LYMPHOPROLIFERATIVE DISORDERS AT DIAGNOSIS PATIENTSCD38+>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%)

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

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

28 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

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

30 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 years LLC0405 GIMEMA Protocol

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

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

33 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)

34 clinicalimmunedeficiency cellular and humoral immune impairment Inhibition of CD40L expression Stimulation of Ig production TB CLL Impairedinteractions with B and APC Immune defects Tumor cell activation, proliferation and inhibition of apoptosis B-CLL cell accumulation Inappropriate production of autoreactive antibodies Autoimmune phenomena IL-4 IL-4 IL-4 IL-4 Ig CD40 CD40L membrane and soluble mediator interactions genomic characterization, new drugs Changes in approach to CLL – From patients to genes Last decades evolution in the understanding of CLL B NK T 1970s 80s 1970s 80s 1980s 90s 1980s 90s 2000 2000 1995 00s NEW THERAPIES BIOLOGICALLY- BASED PROGNOSTIC STRATIFICATION

35 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 – Rome G. Castoldi, A. Cuneo – Ferrara G. Gaidano, D. Capello – Novara J. Ritz – Boston GIMEMA network


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