The 1 World Congress on Controversies in Hematology (COHEM) Rome, September 2010

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1 The 1 World Congress on Controversies in Hematology (COHEM) Rome, September 2010 Is the wait and watch philosophy still practical in the treatment of CLL even in younger patients? Expected to say NO Federico Caligaris-Cappio University Scientific Institute San Raffaele Dept Oncology, Div Molecular Oncology Milano, Italy

2 Figure 1. Overall survival of CLL patients relative to age-matched controls Shanafelt, T. D. Hematology 2009;2009: Copyright 2009 American Society of Hematology. Copyright restrictions may apply.

3 CLL: Proportion of patients diagnosed in early stage < % 20% Binet A 40% Binet B 60% 80% 100% Binet C EHFV, Barcelona

4 ..Catastrophes usually depend upon a combination of errors.as time goes by. FCC, Inside Blood, 2009 Natural History

5 ..Catastrophes usually depend upon a combination of errors.as time goes by. M.Twain: Age is an issue of mind over matter. If you don t mind, it doesn t matter

6 Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations RN Damle et al. BLOOD, 2004, 103, 375 Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status P Grabowski et al. BLOOD, 2005, 105, 4807

7 In vivo measurement of CLL cell kinetics by labeling dividing cells with deuterium (2H) H2O 2 Hydrogen Deuterium Newly synthesized DNA B-CLL cells Gas chromatography/ Mass spectrometry

8 Results of previous B-CLL cell kinetic studies using 2H2O Messmer B. et al, al, JCI 2005 Defoiche J. et al, al, BJH 2008 Van Gent R. et al, al, Cancer Res., 2008 CLL clones are definitely more dynamic than presumed Increased proliferation entails increased genetic risk (TIME MATTERS)

9 WHO TO TREAT? WHEN TO TREAT? The question is whether we may determine if an individual young CLL patient at presentation, with early stage disease, will have stable progression-free disease and long overall survival or progress rapidly, develop complications and die PROGNOSTIC FACTORS

10 Patient A.B. April 2002 Male 29 yrs old, excellent health conditions, physically fit Incidental diagnosis of CLL with WBC, lymphadenopathy June WBC, lymphadenopathy, palpable tip of spleen, no B signs. BM: 65% lymphocytes No molecular nor cytogenetic nor sophisticated cytofluorograph analysis BMT advised

11 Patient A.B. April 2002 Male 29 yrs old, excellent health conditions, physically fit Incidental diagnosis of CLL with WBC, lymphadenopathy June WBC, lymphadenopathy, palpable tip of spleen No molecular nor cytogenetic nor sophisticated cytofluorograph analysis June WBC, lymphadenopathy, palpable tip of spleen Excellent health conditions, physically fit Deletion 13q14, IGVH mutated, CD38 < 1%, ZAP70 neg No Treatment

12 Patient F.G. April 2005 Female 44 yrs old with sporadic fever Father died in 1997 of CLL. Aunt (father s sister) has stage 0 CLL Diagnosis of CLL with WBC, hypogammaglobulinaemia, microlymphadenopathy. BM: 80% lymphocytes Deletion 13q14, IGVH 3-53 Unmutated CD38 18% (PB; 35% BM), ZAP70 30% May WBC, lymphadenopathy slightly increased, palpable tip of spleen Weakness and unrelenting fever January 2007 CLL8 Protocol: FCR July 2010: Still Molecular Remission

13 Predicting outcome using Molecular Biological Factors IGVH Mutation Status CD38 ZAP70 Recurrent Cytogenetic Abnormalities Patient risk stratification in routine clinical practice Work in Progress

14 IgVH Mutation status is a Prognostic Marker in CLL Hamblin et al, 1999 Damle et al, 1999 Time from diagnosis

15 CD38 % surviving CD38 is a Prognostic Marker Independent of IgVH Mutation status CD5 Damle et al, 1999 Time from diagnosis

16 Which Cut-off Level for CD38? 100 CD38+ CLL Cells (%) Damle et al, 1999 Ibrahim et al, 2001 Krober et al, 2002

17 0.4% B 98.9% C 34.7% CD38 A CD19 Events D E 0.4% F 98.9% CD38 Ghia P et al, Blood %

18 CD38+ and bimodal patients have similar cumulative survival 1,2 Cumulative Survival 1,2 CD38-1,0 CD38 bimodal CD38+ 0,8 CD38 30% 0,8 0,6 0,6 0,4 0,4 0,2 0,2 0,0 0,0-0,2-0,2 0 CD38< 30% 1, Time (months)

19 Fraction of 2H labeled cells Results of previous B-CLL cell kinetic studies using 2H2O Defoiche J. et al, al, BJH 2008 Messmer B. et al, al, JCI 2005 Van Gent R. et al, al, Cancer Res., CD CD38-20 Intra-clonal kinetics heterogeneity. Within each clone CD38+ cells proliferate faster than those CD Time (days) 168 C. Calissano C. et al, Blood 2009

20 Zap-70 expression identifies patients at risk of progression and shorter survival Crespo et al, 2003

21 Zap-70 expression is a continuum M M M M UM UM Rassenti, L. Z. et al. 2004

22 Genomic Aberrations and Survival in CLL 100 Survival in % qn= n=47 13q- single n=117 17pn= H.Dohner et al, NEJM, Time in Months

23 A personal biased use of prognostic tests for young early stage (Rai 0-1) asymptomatic CLL patients FISH testing (17p-, 11q-) IGVH Mutational Status CD38 ZAP70 All Positive 17p- or 11qIGVH Unmutated CD38 Positive ZAP70 Positive All Positive High Risk Be Ready to Treat All Negative Absence of 17p- and 11qIGVH Mutated CD38 Negative ZAP70 Negative All Negative Low Risk W&W Variable Combinations 17p- or 11qIGVH Unmutated CD38 Positive ZAP70 Positive Variable Combinations (at least two markers) Intermediate Risk Careful Follow-Up

24 Unclear Issues The (wrong) concept of surrogate markers The confusing need of cut-off The prognostic significance of stereotyped receptors The prognostic significance of MBL The prognostic significance of microrna signatures

25 Subsets of patients carry a similar stereotyped HCDR3 H L The case of IGHV3-21-expressing CLL H L P. Ghia et al Blood 2005

26 Clinical implications: Homologous HCDR3 correlate with outcome QWL Survival Functions Stereotyped HCDR3 Cumulative events Heterogeneous HCDR3 1,2 Cum Survival Cumulative events IGHV3-21 Heterogeneous HCDR3 1,0,8,6 IGHV,4 Stereotyped HCDR3,2 2-cens 0,0 1 -,2 1-cens -100 Time (months) 2 T IME Time (months) Ghia et al, Blood 2005 Stamatopoulos et al, Blood 2007

27 MBL Monoclonal B-cell Lymphocytosis CLL-like MBL are frequent Rawstrom et al 2002, 2008, Ghia et al 2004, Dagklis et al, 2009 CD19 MBL virtually always precede the development of overt CLL (1.1% yr) Landgren et al 2009 CD5 Chronic Lymph Leukemia MBL is not relevant unless detected in first-degree relatives of CLL pts from high-risk families (17-fold higher in young adults (16-40 yrs) when MBL is virtually non-existing in the general population Rawstron, Blood 2002; de Tute, Leukemia 2006, Marti Cytometry 2003