1. Integrazione del profilo clinico-biologico con le nuove opzioni terapeutiche Francesca R Mauro Dipartimento di Biotecnologie Cellulari ed Ematologia Università “ La Sapienza” Roma

3. FCR the golden standard therapy for all patients? Age Cytogenetic abnormalities &

4. CLL8: Genetic effect on PFS FC FCR 17p- 13q- normal 11q- +12 11q- +12 normal 13q-

5. Outcome of 11q- patients: FCR vs FC p <.001 p <.05 PFS OS FCR FC %CR FCRFC 61.514 p<.001 FCR FC

6. Outcome of 17p- patients: FCR vs FC p <.001 PFS OS %CR FCRFC 194.5 p= ns FCR FC 53% vs 41% p=ns 30% vs 0% p<0.05 FCR FC

7. FCM-R for Previously Untreated CLL % ORR93 CR MRD -46 CR MRD +36 PR11 Response 82% MTX 6 mg/m 2 FAMP 25 mg/m 2 CTX 200 mg/m 2 Rituximab 375 (1°) 500mg/m2 (2°-6°) R D1D2D3 CR/PR Rituximab 375mg/m2 every 3 months % CR % MRD- CR 13q-8250 +1210050 11q-8762 17p-260 Bosh, JCO 2009

8. Response ORR77% CR14.5% 81 patients with relapsed or refractory CLL Fischer et al., ASH 2008 Toxicity Leucopenia 12% Infections 5% Rituximab 375 mg/m 2 (course 1) 500 mg/m 2 (courses 2-6) X 6 courses Bendamustine 70 mg/m 2 d1-2 11q-92%8% 17p-44%- Bendamustine and Rituximab (BR) for Patients with Relapsed CLL: a Multicentre Phase II Trial of the German CLL Study Group (GCLLSG- CLL2M Study) ORR CR

9. Ofatumumab (HuMax-CD20), a Novel CD20 Monoclonal Antibody, is an Active Treatment for Patients with CLL Refractory to Both Fludarabine and Alemtuzumab or Bulky Fludarabine-Refractory Disease: Results from the Planned Interim Analysis of an International Pivotal Trial Österborg et al. ASH 2008 DR %OR BFR %OR 11q- (40) 6364 17p- (31)4114

10. 17p Deletion Predicts for Inferior Overall Survival after Fludarabine ± CTX First Analysis of Genetics in the CLL4 Trial of the GCLLSG 17p- significant adverse impact on: Response (p=0.001) PFS (P=0.001) Survival (P<0.001) 17p-: 4.9% of CLL patients Stilgenbauer et al., ASH 2005 no 17p- 17p-

11. CLL4 study: effect of FISH abnormalities SurvivalProportion of 17p-cells and response

12. p53+ fludarabine-refractory CLL: Campath-1H Short response duration (4-8 months) regimenNo pts %OR (CR) Lozanski et al., Blood 2004 Campath-1H1540 (0) Stilgenbauer et al., CLL2H GCSG Blood 2004 [Abstr. #478 Campath-1H1354 (0) Osuji et al., Haematologica 2005 Campath-1H850 (0) Sayala et al., ASH 2006, abstr.#34 Campath-1H3858 Pettitt et al., Leukemia 2006 Campath-H - HDMP5100 (3/7) Wierda et al., ASH 2005 abstr.#31 CFAR3244 Mauro et al., ASH 2006 abstr.#2830 FandCam43/4

13. Sc Campath-1H for fludarabine refractory CLL patients GCLLSG-CLL2H study Stilgenbauer et al., JCO 2009

14. NCRI- UKCLL206- CamPred regimen PI: A Pettitt – 50% ORR - Relapse  post-remissional therapy p53 deletion ≥ 20% of cells HMP

15. Campath T-cell depletion: the only significant adverse factor for PFS at multivariate analysis EBMT transplant consensus: allogeneic SCT reasonable option for CLL patients with p53+ abnormalities requiring treatment Allogeneic Hematopoietic SCT for CLL with 17p deletion: a retrospective analysis of the EBMT Schetelig et al., JCO 2008

16. Sc Campath and oral Dexamethasone, followed by Campath maintenance or Allogeneic SCT in CLL associated with 17p deletion or refractory to fludarabine (CLL2O protocol) GCLLSG – FCLLSG- sc Campath: 30 mg TTW oral Dexamethasone 40 mg d 1–4 40 mg d15–18 sc Campath 30 mg/14 days max. 2 years CR or max. 3 cycles F-refractory (11) 17p- (19) OR4 (36%)17 (84%) CR- 4 (21%) Allo/maintenance4/37/10 CMV react,4/143/33 Grade 3-4 infections6/1411/33 % DFS at 16 mos60% Allogeneic SCT

17. NCRI- UKCLL210 - CamPred regimen Lenalidomide p53+ CLL patients

18. EFFICACY AND SAFETY OF A FIRST-LINE COMBINED THERAPEUTIC APPROACH FOR YOUNG CLL PATIENTS STRATIFIED ACCORDING TO THE BIOLOGIC PROGNOSTIC FEATURES: GIMEMA MULTICENTER LLC0405 STUDY

21. Low Risk patients: PFS FC 23% FCR 45%

22. High Risk patients: PFS High Risk patients: post-induction therapy

23. FCR: median age of patients 1st-line (CLL8)  61 yrs 2nd-line (REACH)  62 yrs FCR and age

24. 193 previously treated patients - median age 70 yrs 100 pts  fludarabine 25 mg/m2 d1-d5 x 6 courses 93 pts  chlorambucil 0.4 mg/kg d1-d15, 0.8 mg/kg increase every 15 days, x 12 months Fludarabine Chlorambucil p= ns FluCB OR72%52%<.01 CR7%0%<.05 mPFS19 m18 m First-line fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced CLL Eichhorst et al., Blood 2009 Multivariate analysis shorter PFS and OS: 1.elevated β2 microglobulin 2. ≥ 2 comorbidities R

25. FCR. median age of patients 1st-line  61 yrs 2nd-line  62 yrs

26. Chlorambucil + CD20 Mab for elderly CLL patients UK: CLL207 study ITALY: ML21445 study GCLLSG CLL11 studyOMB110911 study

27. Lenalidomide-based therapies for elderly CLL patients >

28. FCR the new standard treatment for physically fit patients Specific treatments for patients with selected cytogenetic entities. Specific treatments for elderly patients under investigation Conclusions