Georg Hopfinger 3. Med.Abt and LBI for Leukemiaresearch and Haematology Hanusch Krankenhaus,Vienna, Austria

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1 Chronic lymphocytic Leukemia Georg Hopfinger 3. Med.Abt and LBI for Leukemiaresearch and Haematology Hanusch Krankenhaus,Vienna, Austria

2 CLL Diagnosis and Staging Risk Profile Assessment Choice of Therapy

3 Diagnosis is easy Lymphocytosis > 5000/ µl Cytology Immunology FISH

4 Staging according to Binet Lnd Hb Plt Spleen Liver A < 2 >10 > 100 B > 2 >10 > 100 C - < 10 < 100

5 Prognostic Factors Clinical Stage RAI or Binet Lymphocyte doubling time < 1 year Cytogenetics /molecularbiology 11q- or 17p- Deletion Unmutated IgV H -Status Labor/ Immunphenotype beta-2 Mikroglobulin Serum Thymidine Kinase CD 23 CD 38 ZAP 70

6 Clinical and molecular Parameters Questions : 1. Are they available? 2. Do they impact on therapy? 3. Predictive for Progression? 4. Predictive for Survival?

7 Survival according to Binet Stadium Probability of survival Binet stage A Binet stage B Binet stage C Time (Months)

8 Survival according to lymphocyte doubling time 1.0 Probability LDT > 12 months LDT < 12 months p< AD < 12 months Time (months) Mauro F, et al. Blood 1999;94:

9 Survival according to FISH and IGV H Mutation Status Genomic aberrations (n=325) 1 IgV H mutation status (n=211) 2, q del only 100 Survival (%) q del 12q trisomy Survival (%) Mutated p del Normal P < Unmutated Time (months) Time (months) 1. Dohner H, et al. N Engl J Med 2000;343: Rai K, et al. Hematology 2001: Krober A, et al. Blood 2002;100:

10 ZAP-70 Expression ZAP-70 expression and IgV H mutation status ZAP-70 expression and survival probability ZAP-70-positive cells (%) IgV H Mutated Unmutated 0 ZAP-70-positive cells (%) <95% 95 98% >98% Probability of survival (%) < 20% ZAP -70-positive cells 20% ZAP -70-positive cells p= IgV H Homology Year after diagnosis Crespo M, et al. N Engl J Med 2003;348:

11 PFS for del(17p) and del(11q) Grever, M. R. et al. J Clin Oncol; 25:

12 Therapy General considerations When? No: Asymptomatic Binet A ( only trials) Yes:Symptomatic Binet A &B, Binet C How? Performance Status? Aim? Cytogenetics?

13 Overall Survival Binet A chlorambucil vs no treatment Dighiero G et al. N Engl J Med 1998;338:

14 Mono Chemotherapy

15 Fludarabin 1st line n response(%) OS Rai FD vs CLB vs vs 56 NEJM 2000 (p=0.0001) French Cooperative FD vs CAP vs vs 24.5 Group Lancet 1996 Leporrier FD vs CHOP vs 71 vs vs 67 vs Blood 2001 CAP (p=0.0001) 70 Mo

16 Combination Chemotherapy

17 F vs FC Concerning CR % and Overall -Response % Fludarabin Fludarabin PFS Cyclophosphamide German trial 7/ / vs 48 Mo Eichhorst, Blood 2006 Uk trial 15/ / %vs 36% at 5 Yrs Catovsky,Lancet 2007 US trial 4,6/ / vs 31.6 Mo Flinn, JCO 2007

18 F vs FC PFS Eichhorst Blood 2006 Flinn,JCO 2007

19 Einfluss von 17p - nach F/FC Stilgenbauer ASH 2005

20 How can we further improve?

21 Monoclonal Antibodies in CLL HLA-DR CD52 slg CD20 CD23 MoAbs: Lymphocyte Anti CD 20 Rituximab Anti CD 52 Alemtuzumab Anti CD 23 Lumiliximab Adapted from Press O, et al. Cancer J Sci Am. 1998:4(suppl 2):s19 s26.

22 Rituximab monotherapy in CLL

23 Rituximab in relapsed CLL Huhn, D. et al. Blood 2001;98:

24 Lower ORR in CLL Patienten P=0.01 Possible causes: ORR (%) lower CD20 Expression lower Rituximab Serum levels higher Lymphocyte counts 0 FL SLL (CLL-type) Patients McLaughlin et al. J Clin Oncol. 1998;16:2825.

25 Dose Escalation 50 PatientS, CLL (with prior therapy) + other Rai III-IV Rai I-II with B Symptoms Dose 1 Dose 2-4 Kohorts n (mg/m2) (mg/m2) weekly A B C D E F O Brien et al. J Clin Oncol. 2001;19:2165.

26 Dose Escalation ORR CLL Patients 100 Response Rate (%) All CLL Patients (n=39)* (n=24)* (n=7)* (n=9)* * Evaluable patients. O Brien et al. J Clin Oncol. 2001;19:2165.

27 Rituximab + Chemo in relapsed /refractory CLL

28 FCR in relapsed CLL ORR: 73% CR: 25% PR (npr): 32% (16%) Molecular CR in 32% of CR Patients Fludarabin sensitive (n=108) Fludarabin resistant (n=37) ORR CR 31 5 npr PR Wierda et al., J Clin Oncol 2005;23:4070 8

29 FCR in relapsed CLL : TTP and OS No. of patients OS Died TTP Relapsed Probability Median OS 39 months Median TTP 28 months OS TTP Time (months) Wierda W, et al. J Clin Oncol 2005;23:4070 8

30 Rituximab in CLL first line

31 FR versus F in first -line CLL restrospective Comparison of 2 trials FR (CALGB 9712) vs F (CALGB 9011) F FR Patients (CALGB (CALGB 9011) 9712) N M Age (years) Rai III/IV (%) ECOG PS ORR (%) CR (%) p= p= 0.02 Byrd J, et al. Blood 2005;105:49 53.

32 FR vs F (retrospective) in first -line CLL PFS OS Probability FR Probability FR p< Time (months) F p= Time (months) F Byrd J, et al. Blood 2005;105:49 53.

33 FC-R first line in CLL 300 Patients 6 cycles R -FC every 4 weeks Keating M, et al. J Clin Oncol 2005;23: Response CR npr PR No response Early death 6-Year OS: 77% 6-Year FFS: 51% Patients (n) % % Tam C, et al. Blood 2008;15:112:

34 Overall survival and time to progression by treatment response Tam, C. S. et al. Blood 2008;112:

35 OS: historical Comparison R-FC 0.6 FC/FM Proportion F 0 Patients Died Treatment Fludarabine FC/FM R-FC Months Tam C, et al. Blood 2008;15:112:

36 CLL-8: R-FC vs FC in first line CLL untreated B -CLL Binet B with need for treatment or Binet C ECOG 0 1 N = 817 R A N D O M I S E R-FC q4wk 3 FC q4wk 3 R E S T A G E R-FC q4wk 3 CR, PR FC q4wk 3 MabThera Cycle 1: 375 mg/m 2 Cycle 2 6: 500 mg/m 2 Fludarabin 25 mg/m 2 iv, day 1 3 Cyclophosphamid 250 mg/m 2 iv, day 1 3 SD, PD off study

37 CLL-8: R-FC vs FC in first line CLL untreated B -CLL Binet B with need for treatment or Binet C ECOG 0 1 N = 817 R A N D O M I S E R-FC q4wk 3 FC q4wk 3 R E S T A G E R-FC q4wk 3 CR, PR FC q4wk 3 MabThera Cycle 1: 375 mg/m 2 Cycle 2 6: 500 mg/m 2 Fludarabin 25 Primary mg/m 2 iv, endpoint day 1 3 reached: > 35% SD, PD off study Cyclophosphamid PSF Benefit at two years! Data will be presented 250 mg/m 2 iv, at day ASH ,San Francisco EMEA accreditation pending

38 Future perspectives

39 Current Concepts of the DCLLSG CLL Binet A Asymptomatic CLL Binet C Symtomatic A and B CLL 7 CLL 2O CLL 10 17pwww.dcllsg.de

40 CLL7 Trial of the DCLLSG and French CLL Group Patients with Binet Stage A Aim and Rationale: complete eradication in high-risk patients Determination of risk factors: 1. 11q- or 17p- Deletion 2. Unmutated IgV H -Status 3. Serum TK > 10 U/L 4. LDT < 12 Mo Low risk: <2 Factors High risk:> 2 Faktors Observation FC+Rituximab Observation