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Senior Staff Haematologist, Royal North Shore Hospital Sydney

Stephen Mulligan Senior Staff Haematologist, Royal North Shore Hospital; Adjunct Associate Professor, The University of Sydney, Australia. Senior Staff Haematologist, Royal North Shore Hospital Sydney Adjunct Associate Professor, University of Sydney

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Senior Staff Haematologist, Royal North Shore Hospital Sydney

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  1. Stephen MulliganSenior Staff Haematologist, Royal North Shore Hospital; Adjunct Associate Professor, The University of Sydney, Australia • Senior Staff Haematologist, Royal North Shore Hospital Sydney • Adjunct Associate Professor, University of Sydney • Director of Haematology, Symbion Pathology • Founder and Chairman, Chronic Lymphocytic Leukaemia Australian Research Consortium Royal North Shore Hospital

  2. CLL treatment today and tomorrow: the role of rituximab Stephen Mulligan Royal North Shore Hospital, Sydney, Australia

  3. CLL: indications for primary treatment • Progressive lymphocytosis • lymphocyte increase >50% in 2 months • lymphocyte doubling time <6 months • At least one of the following systemic symptoms • 10% weight loss over 6 months • extreme fatigue, persistent fevers, night sweats • Progressive marrow failure (anaemia or thrombocytopenia) • Massive or progressive splenomegaly • Massive or progressive lymphadenopathy • Autoimmune cytopenias Cheson B, et al. Blood 1996;87:4990–7 Hallek M, et al. Blood 2008. In press CLL = chronic lymphocytic leukaemia

  4. Treatment strategies for CLL • Treatment strategy decisions are influenced by disease, patient performance status and comorbidities • Palliative approach (traditional) • goals: obtain maximum control of symptoms, prevent complications and maintain quality of life • multiple intermittent treatment schedules • no survival advantage for tested treatments • Response-orientated approach • aim for complete remission (CR) • minimal residual disease (MRD) • improved response may improve survival

  5. Prognostic factors independent of disease stage • Chromosomal aberrations: 11q-, 17p- • Unmutated IgVH status • Expression of cytoplasmic ZAP-70 • Short lymphocyte doubling time • Elevated serum β2 microglobulin • Elevated serum levels of soluble CD23 • Elevated serum thymidine kinase activity • Leukaemia cell surface expression of CD38 Binet JL, Blood 2006;107:859–61

  6. First-line treatment for CLL: a brief historical perspective • Alkylating agents-treatment of choice until the 1990s • chlorambucil – introduced early 1950s • cyclophosphamide, adriamycin and prednisone (CAP) • cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) • Fludarabine superior to chlorambucil in randomised clinical trials Johnson S, et al. Lancet 1996;347:1432–8 Rai K, et al. N Engl J Med 2000;343:1750–7 Leporrier M, et al. Blood 2001;98:2319–25

  7. Fludarabine plus cyclophosphamide (FC versus F) in CLL *A further 387 patients were randomly assigned to receive chlorambucil†PFS at 5 years ORR = overall response rate PFS = progression-free survival 1Eichhorst B, et al. Blood 2005;107:885–912Flinn IW, et al. J Clin Oncol 2007;25:793–8 3Catovsky D, et al. Lancet 2007;370:230–9

  8. CLL4 trial: benefit of FC over F or chlorambucil in terms of PFS • 777 patients with CLL requiring treatment were randomised fludarabine (n=196), chlorambucil (n=387) or FC (194) Overall survival (OS) PFS Patients Events O/E 387 311 1.3 194 149 1.1 196 102 0.5 100 80 60 40 20 0 100 80 60 40 20 0 Chlorambucil Fludarabine FC Survival (%) PFS (%) FC Patients Events O/E 387 116 0.9 194 71 1.1 196 67 1.0 Fludarabine Chlorambucil 0 1 2 3 4 5 0 1 2 3 4 5 Time (years) Time (years) Catovsky D, et al. Lancet 2007;370:230–9

  9. B-cell tetraspan protein 33–37kDa non-glycosylated phosphoprotein Rituximab epitope conformationally-dependent and discontinuous epitope steric proximity with disulphide bond CD20 structure and epitope recognition • (170) ANPS (173) • (182) YCYS (185) From: Binder M, et al. Blood 2006;108:1975–1978 (original article) Jensen-Jarolim E, et al. Blood 2006;108:1794–1795 (commentary)

  10. Rituximab binding rapidly redistributes CD20 within lipid rafts • Signal transduction platforms • microdomains enriched in cholesterol and sphingolipid • outer membrane • complement defence proteins • inner membrane • Src-family kinases • Rituximab cross-linking • induces rapid redistribution in the plasma membrane • modifies cell function CD20 multitimers Raft domain Rituximab Cragg MS, et al. Curr Dir Autoimmun 2005;8:140–74

  11. Rituximab in CLL: rationale • Mechanism of action • antibody-dependent cellular cytotoxicity (ADCC)1 • complement-dependent cytotoxicity2 • induction of apoptosis3,4 • Good clinical activity in combination chemotherapy • synergistic with other cytotoxics3,5 • Generally well tolerated • potential for maintenance therapy 1Lefebvre ML, et al. J Immunother 2006;29:388–97; 2Golay J, et al. Blood 2001;98:3383–93Byrd J, et al. Blood 2002;99:1038–43; 4Hussain S, et al. Clin Cancer Res 2007;13:2144–505Alas S, et al. Clin Cancer Res 2001;7:709–23

  12. Synergy between rituximab and fludarabine Rituximab • Increases efficacy of fludarabine and other cytotoxics • independent of mechanism of cytotoxic action • occurs in CLL with incomplete antigen saturation1,2 • Activation of caspases and apoptosis3 • Downregulates Bcl-2 and Bcl-x(L) protein4 • Increased propensity to ADCC and complement activation • Altered cell signalling and calcium flux Fludarabine • Prevents DNA repair of alkylating agent cross links • Induction of apoptosis • Down-regulates CD46, CD55, CD59 (complement defence proteins)5 1Wierda W, et al. J Clin Oncol 2005;98:3383–9; 2Chow KU, et al. Haematologica 2002;87:33–43 3Byrd J, et al. Blood 2002;99:1038–43; 4Alas S, et al. Clin Cancer Res 2001;7:709–23 5Di Gaetano N, et al. Br J Haematol 2001;114:800–09

  13. The evolution toward immunochemotherapy for CLL • Single-agent therapy • fludarabine • Combination chemotherapy • FC • Combination with immunotherapy • rituximab plus FC (R-FC)

  14. Single-agent rituximab is active in CLL t.i.w. = three times weekly 1O’Brien S, et al. J Clin Oncol 2001;19:2165–702Byrd J, et al. J Clin Oncol 2001;19:2153–64 3Hainsworth J, et al. J Clin Oncol 2003;21:1746–53 4Thomas D, et al. Blood 2001;98:364a (Abstract 1533)

  15. Rituximab + fludarabine results in improved response rates OR = overall response Byrd J, et al. Blood 2005;105:49–53

  16. Rituximab + fludarabine results in prolonged PFS and increased OS PFS OS 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Rituximab + fludarabine (CALGB 9712) Rituximab + fludarabine (CALGB 9712) Probability Probability Fludarabine (CALGB 9011) Fludarabine (CALGB 9011) p=0.003 p<0.0001 0 20 40 60 80 100 120 140 0 20 40 60 80 100 120 140 Time (months) Time (months) Byrd J, et al. Blood 2005;105:49–53

  17. The R-FC study at MDACC, University of Texas • November 1999–January 2004 • n=300 • R-FC as first-line treatment • CR rate 72%; time-to-progression (TTP) 80 months • Treated every4 weeks to six cycles of R-FC • rituximab 375mg/m2 day 1 cycle 1 rituximab 500mg/m2 day 1 cycles 2–6 • fludarabine 25mg/m2 days 1–3 • cyclophosphamide 250mg/m2 days 1–3 MDACC = MD Anderson Cancer Center Keating M, et al. J Clin Oncol 2005;23:4079–88 Tam C, et al. J Clin Oncol 2007;25(Suppl. 18):359s (Abstract 7008)

  18. R-FC results in the highest OR and CR rates reported to date 95% nPR = nodular partial responsePR = partial response Tam C, et al. J Clin Oncol 2007;25(Suppl. 18):359s (Abstract 7008)

  19. First-line R-FC is well tolerated • Most toxicities were similar to FC • Grade 3/4 infusion-related reactions occurred in 6% • The infection rate was similar to historical FC alone • IgVH mutation status • no effect on the CR rate • most important determinate of remission duration • >90% mutated patients remain in CR at 5 years • unmutated patients median CR duration 5 years Keating M, et al. J Clin Oncol 2005;23:4079–88 Lin KI, et al. Blood 2007;110:232a (Abstract 753) Tam C, et al. J Clin Oncol 2007;25(Suppl. 18):359s (Abstract 7008)

  20. Improved OS with R-FC compared with historical MDACC fludarabine-containing regimens 1.0 0.8 0.6 0.4 0.2 0 R-FC FC/FM Proportion Fludarabine } p=0.001 0 12 24 36 48 60 72 84 96 Months M = mitoxantrone Tam C, et al. J Clin Oncol 2007;25(Suppl.18):359s (Abstract 7008)

  21. German CLL study group/international CLL8 study of FC versus R-FC R A N D O M I S E R ESTAGING • CLL • Binet B,C • 18 years • No prior therapy • Central histology review R-FC x 3 cycles (every 4 weeks) R-FC x 3 cycles (every 4 weeks) FC x 3 cycles (every 4 weeks) FC x 3 cycles (every 4 weeks) Recruitment closed March 2006 861 patients recruited Analysis anticipated 2008 Rituximab dose Cycle 1: 375mg/m2Cycles 2–6: 500mg/m2 SD, PD off study SD = stable disease PD = progressive disease

  22. Roche Media Release 25th January, 2008 Basel, 25 January 2008 “MabThera increases the time patients with (CLL) live... Pivotal Phase III study with MabThera reaches primary endpoint in first line treatment for patients with CLL The pivotal CLL8 trial, initiated by the German CLL study group, successfully met its primary endpoint, by showing that patients treated with MabThera in combination with the current standard chemotherapy achieved a significant improvement in progression free survival, compared to patients treated with chemotherapy alone The CLL8 study is an international study ... included 817 patients … at 203 study sites across 11 countries ... The study aimed to show a 35% increase in progression free survival when the MabThera-based combination was used”   http://www.roche.com/med-cor-2008-01-25

  23. Reduced dose R-FC: ‘R-FC-Lite’ • 6 x 4-weekly cycles of • fludarabine 20mg/m2 days 1–3 • cyclophosphamide 150mg/m2 days 1–3 • Rituximab 500mg/m2 days 1 and 14 • rituximab-maintenance therapy 500mg/m2 every 3 months until progression • 40 previously untreated patients evaluable for efficacy • ORR 100%, CR 85% • all CR patients CD5/19 flow negative in marrow • 42 patients evaluable for safety/toxicity • grade 3/4 neutropenia in 12% of courses • grade 3/4 thrombocytopenia in 3% of courses • grade 3/4 anaemia in 2.5% of courses Tarhini T, et al. Blood 2006;108:805a (Abstract 2844)

  24. CFAR frontline for high risk CLL*:doses and schedule Tumour lysis – allopurinol HSV/CMV – valacyclovir/valganciclovir PCP – SMX/TMP Neutropenia – pegfilgrastim *High risk CLL defined as 2M 4mg/LCFAR = cyclophosphamide, fludarabine, alemtuzumab, rituximab Wierda WG, et al. Blood 2007;110:194a (Abstract 628)

  25. CFAR frontline for high risk CLL*: responses (NCI-WG) (n=26) (96%) *High risk CLL defined as 2M 4mg/LNCI-WG = National Cancer Institute – Working Group Wierda WG, et al. Blood 2007;110:194a (Abstract 628)

  26. Rituximab, pentostatin, cyclophosphamide achieves high response rates in CLL CRu = unconfirmed CRECOG PS = Eastern Cooperative Oncology Group performance status Kay N, et al. Blood 2007;109:405–11Mena RR, et al. J Clin Oncol 2007;25 (Suppl. 18s):680s (Abstract 17508)

  27. International Scandinavian/Australian study in previously untreated CLL • Chlorambucil • 10mg2/day for 10 days orally • Fludarabine • 25mg2/day for 5 days i.v., or • 40mg2/day for 5 days orally • Cladribine • 5mg2/day for 5 days i.v./2 hours or sq, or • 10mg2/day for 5 days orally • All treatments repeated every 28 days x 6 • n=221: chlorambucil 76, fludarabine 73, cladribine 72 i.v. = intravenously Karlsson KA, et al. Blood 2007;110:194a (Abstract 630)

  28. Chlorambucil Chlorambucil Fludarabine Fludarabine Cladribine Cladribine Longer response duration with cladribine versus fludarabine and high dose chlorambucil TTP Time to start of second therapy 100 90 80 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 p=0.005 p=0.0003 Cumulative proportion surviving (%) Cumulative proportion surviving (%) 0 365 730 1,095 1,460 1,825 2,190 2,555 0 365 730 1,095 1,460 1,825 2,190 2,555 Days Days Karlsson KA, et al. Blood 2007;110:194a (Abstract 630)

  29. DCLLSG CLL5 protocol for elderly patients with advanced CLL CLL,>65 years, untreated, Binet stage C or symptomatic A/B Chlorambucil (up to a maximum of 12 months): chlorambucil 0.4mg/kg body weight increasing 0.1mg up to 0.8mg/kg body weight every 15 days 6 x fludarabine phosphate: fludarabine 25mg/m², days 1–5 every 28 days Eichhorst BF, et al. Blood 2007;110:194a (Abstract 629)

  30. Random ChlorambucilFludarabine Chlorambucil -censored Fludarabine -censored Random ChlorambucilFludarabine Chlorambucil -censored Fludarabine -censored Fludarabine versus chlorambucil in elderly patients: PFS and OS Median observation time = 42.7months 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Cumulative survival Cumulative survival p=0.166 p=0.071 0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84 PFS in months OS in months Median PFS: fludarabine 21.6 months; chlorambucil 16.2 months Median OS: fludarabine 52.6months; chlorambucil not reached Eichhorst BF, et al. Blood 2007;110:194a (Abstract 629)

  31. Chlorambucil + rituximab for patients with comorbidity (CLL208) PI: Peter Hillmen, Andrew Pettitt Trial outline • Untreated CLL unfit for fludarabine-based therapy • Chlorambucil (10mg/m2/day x 7) + rituximab (6 doses) • Single arm, phase II, 50 patients in total Trial objectives • 1o: safety analysis • 2o: assess response rate, MRD, PFS, OS Timelines • Investigator Meeting November 2007 – first patient recruited

  32. Rituximab maintenance therapy: improved duration of response • Induction therapy with rituximab plus fludarabine (n=79) followed by rituximab-maintenance therapy (n=35) or not (n=13) in patients with bone marrow or peripheral blood MRD • After a median follow-up of 38 months duration of response was • significantly longer in MRD-positive patients receiving rituximab-maintenance therapy compared with no further treatment (85% vs 20% at 5 years; p=0.0001) • superior in the subset (n=30) of high-risk patients (CD38+, unmutated, ZAP-70+) treated with rituximab-maintenance therapy (64% [n=11] vs 13% [n=9] at 2 years; p=0.006) 4, monthly cycles of rituximab 375mg/m2 followed by 12, monthly low doses of rituximab at 150mg/m2 Del Poeta G, et al. Haematologica 2007;92 (Suppl. 1) (Abstract 0361)

  33. Summary of rationale for rituximab in CLL • CD20 in lipid raft signal transduction platforms • Rituximab crosslinking leads to • redistribution of CD20 in lipid rafts in plasma membrane • altered cell signalling • altered calcium flux • altered complement defence • increased propensity to ADCC and complement activation • increased apoptosis • synergistic mechanism of action with fludarabine and other cytotoxics • Clinical evidence of synergism with fludarabine and other cytotoxics

  34. Conclusions • Immunochemotherapy is becoming standard therapy for CLL • the CLL8 trial will provide further information • data analysis in progress, scheduled completion mid-2008 • Rituximab is an eminently suitable combination partner for a variety of active agents in CLL • with purine analogues in patients with good performance status • possibly with less aggressive cytotoxic regimens in elderly or patients with comorbidity • Maintenance rituximab is a promising potential strategy in CLL

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