Familiarità e Suscettibilità nella Leucemia Linfatica Cronica Paolo Ghia

Transcription

1 Familiarità e Suscettibilità nella Leucemia Linfatica Cronica Paolo Ghia Lab of B Cell Neoplasia - Division of Molecular Oncology Lymphoma Unit Department of Onco-Hematology Università Vita-Salute San Raffaele - Milano Istituto Scientifico San Raffaele - Milano

2 Epidemiology of CLL Rate per 100,000 Non-Hispanic White Black Asian/Pacific Islander CLL incidence: 5/ /year The incidence rates vary considerably in the world Incidence of disease remains stable in migrants of different ethnic groups Years of Diagnosis evidence for genetic susceptibility SEER

3 Familial CLL CLL patient with at least one affected relative is considered familial In population-based samples, approximately 5% of patients with CLL reported a family history of leukemia Over the last seven decades clustering of CLL have been reported in >100 families

4 Familial CLL Not explained by a simple mode of genetic transmission Likely shared genes explain the variant B-cell tumors Poligenic model of inheritance seems more likely Goldin L, European J Clin Med Oncol. 2010

5 RR of LPD in 1 st -degree relatives of LPD pts LP TUMOR IN RELATIVE CLL NHL LPL/WM MGUS Proband CLL 8.5* 1.9* 4.0* 1.4 NHL 1.6* 1.5* 3.1* 1.2 LPL/WM 4.0* 3.0* 20.0* 5.0* MGUS 2.0* * 2.8* Goldin L, European J Clin Med Oncol. 2010

6 RR of LPD in 1 st -degree relatives of CLL Outcome RR (95% CI) B-NHL 1.8 ( ) Indolent B-NHL 2.2 ( ) FL 1.6 ( ) MCL 1.1 ( ) HCL 3.3 ( ) LPL/WM 4.0 ( ) Aggressive B-NHL 1.0 ( ) Goldin L, European J Clin Med Oncol. 2010

7 CLL and Second Malignancies Variable O/E ratio (95% CI) Total 2.20 ( ) Sex Male 2.24 ( ) Female 2.14 ( ) Age, years < ( ) ( ) Site NHL 9.42 ( ) HL ( ) AML 7.09 ( ) Prostate 1.35 ( ) Lung 1.12 ( ) Breast (female) 1.59 ( ) % Melanoma 6.17 ( ) Tsimberidou A, JCO 2009

8 CLL and Second Malignancies 10.9% 0.5% 0.02% 88.4% Number of other malignancies 27.5% of CLL pts had a history of malignant neoplasm at the time of first visit or developed a second cancer during the study period Survival (%) Main causes of death in CLL pts: 1. Infectious complications (24.4%) 2. Progressive CLL (24%) 3. Other malignancies (14.6%) Time (years) Tsimberidou A, JCO 2009

9 Second Malignancies in CLL In CLL, particularly increased risk for Lung Cancer Melanoma Age Group In comparison to age-matched general population, especially in patients < 55 years old Morton LM, JCO 2010

10 Second Malignancies: Different Risk by Lymphoma Subtype p <0.001 p <0.05 Significantly different patterns of second malignancy after CLL/SLL, DLBCL, FL: elevated risks for lung cancer and melanoma after CLL/SLL and FL chemotherapy-related excesses of acute non-lymphocytic leukemia after DLBCL and FL Morton LM, JCO 2010

11 Second Malignancies: Different Risk by Lymphoma Subtype Increased Risk for Acute non lymphocytic leukemia in SLL but not in CLL patients Maybe due to more frequent use of chemotherapy for SLL than CLL (44 vs 25%) Morton LM, JCO 2010

12 Familial CLL Clinical Features Anticipation (= intensified clinical severity and earlier age of onset with each successive generation) not confirmed by recent studies (potential bias due to censoring or cohort effects) Sex ratio of familial CLL more equal than that of sporadic CLL (M:F ratio 1.4:1 vs 2:1) % of surviving Stage at diagnosis, need for treatment and overall survival comparable between familial and sporadic CLL cases Months Mauro FR et al, Haematologica 2010

13 Familial CLL Biological Features IN CONCLUSION: Familial CLL Elevated levels of B-lymphocyte stimulator in Familial CLL cases Sporadic CLL No consistent differences in familial vs sporadic CLL IGHV genes IGHV repertoire and frequency not significantly different Similar frequency of mutated cases in familial CLL Novak AJ et al, JCO 2006; Crowther-Swanepoel D et al, Blood 2008

14 Is there still an interest in Familial CLL? It might help simplify the identification of the genes involved in the pathogenesis of CLL

15 Linkage Studies Approaches to Finding Genes Chromosome 2 Chromosome 6 Chromosome 18 CXCR4? HLA? SMAD7? Sellick GS et al, Blood 2007 Association Studies: SNPs analyzed in Genome Wide Analysis studies IRF8? HLA? Slager S et al, Blood 2011

16 Familial CLL Genetic Models Multiple low-risk variants, with effect sizes of ~ could make an important contribution to the overall familial risk SNP Chr Risk allele Nearest gene OR rs q13 G ACOXL, BCL2L rs q37.1 G SP140, SP rs q37.3 A FIR 1.39 rs p25.3 G IRF rs q24.21 G rs q24.1 A GRAMD1B 1.45 rs q21.3 A RFX7, NEDD rs q23 A rs q24.1 T IRF rs q13.32 A PRKD2, STRN Crowther-Swanepoel D et al, Semin Cancer Biol 2010

17 NGS Studies in Sporadic CLL In most cases identified Genes associated with high-risk disease and chemorefractoriness Gene Chr Mechanism Frequency NOTCH1 9q34.3 SF3B1 2q33.1 BIRC3 MYD88 Disruption of the C-terminal PEST domain activated NOTCH1 Deregulated normal and alternative mrna splicing 11q22.2 Constitutive NF B activation 3p22 Increased TLR complex activity 4-10% at diagnosis 25% chemorefractory disease 30% Richter Syndrome 5-10% at diagnosis 25% chemorefractory disease 5% sindrome di Richter 4% at diagnosis 25% chemorefractory disease 3-5% at diagnosis

18 Hierarchical order of relevance of the genetic lesions in predicting survival in newly diagnosed CLL Recursive partitioning to divide patients into genetic subgroups with different OS Random survival forest validation of the stability of the recursive decision tree Amalgamation algorithm to merge terminal nodes showing homogenous survival Top variables Minimal depth HR TP53 DIS p<0.001 TP53 DIS BIRC3 DIS SF3B1 M NOTCH1 M del11q22-q NOTCH1 M p=0.042 No SF3B1 M p=0.017 Yes No BIRC3 DIS p<0.001 Yes No Yes del11q22-q23 p=0.030 No Yes Cumulative probability of OS Node 6 (n = 383) 1 Node 7 (n = 20) 1 Node 8 (n = 50) 1 Node 9 (n = 29) 1 Node 10 (n = 27) 1 Node 11 (n = 74) No Yes Years Years Years Years Years Years Rossi et al, Blood 2012 SF3B1 M and/or NOTCH1 M and/or del11q22-q23 TP53 DIS and/or BIRC3 DIS

19 CLL-like clones are present in otherwise healthy individuals Characteristic phenotype: CD5 +, CD23 +, CD20 low, sigm low CD19 CD5 CD5 CD20 CD79b Kappa CD19 CD5 CD5 CD20 CD79b Kappa Rawstron e AC et al, Blood 2002; Ghia P et al, Blood 2004

20 B-cells 5 x 10 9 /L (5,000/ µl) Monoclonal Kappa:Lambda <0.3:1 or >3:1 25% lacking surface immunoglobulin No other feature of a B- lymphoproliferative disorder CLL diagnosis: B cells > 5 x 10 9 /L Hallek et al, Blood 2008

21 MBL as Precursor Condition for CLL Virtually all cases of CLL are preceded by MBL. MBL progress into CLL requiring treatment at the rate of 1.5%/year 1.5% B-cell count <5 000/µl 5.2% B-cell count 5 000/µl Rawstron e AC et al, NEJM 2008; Landgren O et al, NEJM 2010, Scarfo et al, Leukemia 2012

22 MBL cluster in families 25 MBL in 5 families (28.0%) Dagklis et al, Blood 2010

23 MBL as Marker of Genetic Susceptibility for CLL On the overall population In different age groups with 4 or 6-Color Flow de Tute R et al, Leukemia 2006; Goldin LR et al, BJH 2010

24 Genetic Models in MBL Multiple low-risk variants, with effect sizes of ~ could make an important contribution to the overall familial risk SNP Chr Risk allele Nearest gene OR rs q13 G ACOXL, BCL2L rs q37.1 G SP140, SP rs q37.3 A FIR 1.38 rs p25.3 G IRF rs q24.21 G rs q24.1 A GRAMD1B 1.63 rs q21.3 A RFX7, NEDD4 NS rs q23 A - NS rs q24.1 T IRF8 NS rs q13.32 A PRKD2, STRN4 NS Crowther-Swanepoel D et al, Blood 2010

25 Should we screen CLL pt relatives for CLL? Baseline risk of CLL in the population is low Absolute risk of a relative of a CLL pt developing CLL is still very low CLL Incidence in General Population CLL Incidence in Relatives of CLL pts RR=3-7 Colon Cancer Incidence in General Population Colon Cancer Incidence in Relatives of Colon Cancer pts RR=2

26 Should we screen CLL pt relatives for CLL? Early detection of CLL is not likely to affect outcome since stage 0 CLL is usually not treated (studies have shown that treatment at an early stage is not associated with a better outcome) One exception to this conclusion may be the need to screen for MBL/CLL in a 1 st degree relative of a CLL patient who is a potential stem cell donor.

27 Clinical Applications: Should we screen related donors for MBL? MBL found in 2 out of 19 (15.4%) siblings of CLL patients candidate to Allo-SCT 2 cases of new CLL clones after related donor BMT with the same IGHV rearrangement in donors Recipient Donor Flandrin-Gresta et al, Blood 2010; Del Giudice I et al, Blood 2009; Perz JB et al, Bone Marrow Transplant 2008

28 Università Vita-Salute San Raffaele Istituto Scientifico San Raffaele Department of Oncology - Division of Molecular Oncology Laboratory of B Cell Neoplasia Maria Gounari, Andrea Agathangelidis, Benedetta Apollonio, Giorgia Simonetti, Claudia Fazi, Elisa ten Haken, Lydia Scarfò Laboratory of Lymphoid Malignancies Cristina Scielzo, Sabrina Bertilaccio, Pamela Ranghetti, Tania Veliz-Rodriguez, Federica Barbaglio, Eleonora Fonte, Marta Muzio, Federico Caligaris-Cappio Rete Ematologica Lombarda M. Montillo, P. Bertazzoni, A Cortelezzi, M. Motta, G. Nalli, E. Orlandi, F. Rossini, B. Sarina Unità Linfomi Lydia Scarfò, Gabriele Todisco, Silvia Govi, Marta Brunoventre, Marco Foppoli, Giovanni Donadoni, Giovanni Citterio, Simonetta Longoni, Maurilio Ponzoni, Andres Ferreri

29 CLL and Second Malignancies The Australian Experience SIR Is increased across all age groups Risk of Second Malignancies Persisted >9 y after CLL diagnosis Royle JA, BJC 2011

30 OS and Cancer-Specific Survival in CLL pts Increased OS and Cancer-Specific Survival for several common cancers in patients with pre-exisisting CLL Cancer Type Overall HR (95% CI) Survival Cancer-Specific HR (95% CI) Breast 1.7 ( ) 1.41 ( ) Colorectal 1.65 ( ) 1.64 ( ) Kidney 1.54 ( ) 1.41 ( ) Lung 1.19 ( ) 1.13 ( ) Ovarian 1.04 ( ) 0.88 ( ) Pancreatic 0.97 ( ) 0.91 ( ) Prostate 1.92 ( ) 1.18 ( ) Solomon BM, JCO 2013

31 Chronic Lymphocytic Leukemia? Trasforming events Microenvironment Interactions Sequential genetic abnormalities Step 1: Transformation Step 2: Accumulation Step 3: Autonomous Growth

32 Familial Risk of CLL and LPD Study Index case Familial relative risk RR (95% CI) Cohort Study Gunz et al Leukemia Leukemia in 1st degree relatives 2.4 ( ) Giles et al LPD LPD in 1st degree relatives 3.4 ( ) Goldgar et al CLL CLL in 1st degree relatives 5.7 ( ) Crowther-Swanepoel D et al, Semin Cancer Biol 2010

33 Familial Risk of CLL and LPD Study Cartwright et al Linet et al Pottern et al Goldin et al Goldin et al Index case Case-control Studies CLL CLL CLL CLL CLL Familial relative risk Lymphocytic leukemias Leukemia in parents and siblings Leukemia in parents and siblings CLL in 1st degree relatives CLL in 1st degree relatives RR (95% CI) 4.3 ( ) 2.6 ( ) 2.3 ( ) 7.5 ( ) 8.5 ( ) Crowther-Swanepoel D et al, Semin Cancer Biol 2010

34 Alternative Novel Approaches to Gene Identification Genome Wide Association Studies (GWA) Mouse Models Puente XS et al, Nature 2011

35 Mouse Models Transgenic Mice carrying MDR/Mir15a-16-1/13q14.3 deletions NZB Mice TCL1 Mice Klein U et al, Cancer Cell 2010 Salerno E et al, Cytometry Part B 2010 Bichi R et al, PNAS 2002

36 Chronic Lymphocytic Leukemia (CLL) DIAGNOSIS 1) Absolute B cell lymphocytosis >5000/ul for > 4 weeks 2) (>30% linfociti in MO) 3) Immunophenotype - Light chain (κ/λ) restriction - CD19 +, CD5 +, CD Low surface Ig CD19 CD5 CD5 CD20 CD79b Kappa Cheson et al, Blood 1996 Hallek et al, Blood 2008

37 Prevalence of monoclonal CLL-phenotype cells in relatives of familial CLL index cases compared with the general population.(a) Highly significant overall difference (P is ageadjusted). Rawstron A C et al. Blood 2002;100: by American Society of Hematology

38 Monoclonal B cell clones in relatives of familial CLL Prevalence 50yy 50-59yy 60-69yy >70yy Age group Rawstron et al, Blood 2002

39 CLL and Second Malignancies Independent Factors Predicting Development of Other Cancers (Cox Analysis): Factor RR 95% CI Older age Male sex microglobulin >3 mg/ l LDH>618 U/l Creatinine >1.6 mg/dl Tsimberidou A, JCO 2009

40 CLL and Second Malignancies: Early Studies Study Manusow et al, 1975 Incidence of Cancer RR=3 for the age- and sex-matched population Greene et al, 1978 O/E ratio 1.14 Santoro et al, 1980 Second cancers: 19.5% Mellemgaard et al, 1994 Suzuki et al, 1997 Mauro et al, 1999 SIR 2.0 for men and 1.2 for women Second malignancies 16% of all major causes of death Second cancers: 8.3% <55 y, 10.7% in > 55y Hisada et al, 2001 O/E ratio 1.20 ( ) Kyasa et al, 2004 SMR 2.97 ( )

41 OS by Cancer Type in CLL pts Colon Overall Survival (%) Breast Lung Prostate Time Since Cancer Diagnosis (years) Solomon BM, JCO 2013