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Università “La Sapienza”, Roma

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1 Università “La Sapienza”, Roma
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 ( %), AIHA ( %), 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 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 the pathophysiology of the disease For a more accurate diagnostic definition For a biologically-based prognostic stratification 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

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

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

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

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 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

12 FREQUENCY OF CHROMOSOME LESIONS IN CLL (comparison of CCA and FISH)
Aberration Cytogenetics (*) FISH (**) Clonal 30-50% 82% Normal 50-70% 18% del 13q14 single 7-11% 36-45% 12q trisomy 13-19% 11-14% del 11q22-23/ATM 6-13% 8-25% del 17p/p53 1-5% 3-7% del 6q21 1% 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 VH3-21 REPRESENT an UNFAVORABLE PROGNOSTIC SUBSET
of B-CLL with MUTATED IgVH 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 % CD p CD4/CD8 ratio wt n.d. wt 2 wt 1.2 wt 2.18 wt 1 wt 4 wt 2.5 wt 3 wt 2 wt 1.66 wt 2.28 wt 2.2 wt 2 wt 2 wt 1 wt 2.6 wt 1 wt 2.5 wt 4.5 wt 3.66 Guarini et al, Blood 2003

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

19 with two different features:
CLL is a unique disease with two different features: 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) Rosenwald et al (J Exp Med 2001)

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

21 Diagnosis How many diseases?
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 WAIT & SEE CHLORAMBUCIL CONSERVATIVE APPROACH 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 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) ??

25 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%)

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

27 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

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 Correct diagnostic definition & dd (ndr, should always take place!)
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

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

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

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 Changes in approach to CLL – From patients to genes
Last decades’ evolution in the understanding of CLL B NK T 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 T CLL B s 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 Immune defects Autoimmune phenomena Ig CD40 CD40L B-CLL cell accumulation genomic characterization, new drugs membrane and soluble mediator interactions

35 Acknowledgments: A. Guarini, S. De Propris, S. Chiaretti, I
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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