Lessons from the CLL8 study Adapted from Hallek, oral presentation, ASH 2008 FCR is superior to FC in most cytogenetic subgroups with regard to: Response rates (CR, OR, MRD) Progression-free survival FCR is safe: more neutropenias not more infections or other severe side effects well tolerated in physically fit patients > 65 or 70 years FCR is the new standard treatment for physically fit CLL patients

Anagraphic age Biologic age! Patient-adapted therapy in chronic lymphocytic leukemia… Gribben, Blood 2009

CLL a disease of the elderly ≥ 65 years 55–64 years 20–54 years 72% 25% 3% Age at CLL diagnosis (years) ≤ 54 55–64 65– Mean no. of co-morbidities n/a Age at CLL diagnosis

Bendamustine in CLL therapy Reference PhaseRegime Pat. prev. ORR CR n= ther. (%) Kath et al., 2001IIB 5x60mg/m2 2310/ Bremer et al., 2002IIB 5x60mg/m2 15yes777 Aivado et al., 2002II B 2x100mg/m2 23yes6729 Köppler et al., 2004I/IIBM 2x75mg/m 2 22yes8627 Bergmann, 2005 I/II B 2x70mg/m2 16yes56 12,5 Lissitchkov, 2005I/IIB 2x100mg/m2 15yes6027 Less heavily pre-treated patients From: Wendtner, Mundipharma Symposium, Bari,

Phase III Randomized Study of Bendamustine Compared With Chlorambucil in Previously Untreated Patients With Chronic Lymphocytic Leukemia Wolfgang U. Knauf, Toshko Lissichkov, Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul Herbrecht, Gunnar Juliusson, Gerhard Postner, Liana Gercheva, Stefan Goranov, Martin Becker, Hans-Joerg Fricke, Francoise Huguet, Ilaria Del Giudice, Peter Klein, Lothar Tremmel, Karlheinz Merkle, and Marco Montillo Journal of Clinical Oncology 27:

B-CLL Binet stage B/C No pretreatment Age  75 years Bendamustine 100 mg/m 2 days 1+2, every 4 weeks for a maximum of 6 cycles Randomization 1:1 (open label) Chlorambucil 0.8 mg/kg (Broca´s normal weight) days 1+15, for a maximum of 6 cycles Primary endpoints: overall remission rate, progression-free survival Responses assessed in a blinded fashion by an Independent Committee for Response Assessment (ICRA) Bendamustine versus chlorambucil: the European Phase III ‘Intergroup’ CLL Study

Comparison of chlorambucil doses in recent CLL studies 1 Eichhorst B et al. Blood 2007;110(11)Part 1of2:194a,Abs 629; 2 Hillmen P et al. Blood 2006;108:11 Abs 301; 3 Rai K et al. N Engl J Med 2000;343:1750–7; 4 Catovsky D et al. Lancet 2007;370:230–9

European Phase III ‘Intergroup’ CLL Study: patient demographics

European Phase III ‘Intergroup’ CLL Study: response rates Difference in overall response rate: 37%, 95% CI (27%, 47%), p<0.0001

European Phase III ‘Intergroup’ CLL Study: response by Binet stage ICRA, Independent Committee for Response Assessment

European Phase III ‘Intergroup’ CLL Study: progression-free survival Median progression-free survival: bendamustine 21.6 months; chlorambucil 8.3 months; p< Survival distribution function Bendamustine (n=162) Chlorambucil (n=157) Censored observations Time (months) Median observation time: 35 months (range, 1-68) at the time of the analysis

European Phase III ‘Intergroup’ CLL Study: duration of response Median duration of response: bendamustine 21.8 months; chlorambucil 8.0 months CR, complete response; PR, partial response

European Phase III ‘Intergroup’ CLL Study: grade 3 or 4 toxicities Overall delievered dose: 90% (benda) vs 95% (chl)

Chlorambucil in first-line therapy of CLL

1st-line therapy with single-agent bendamustine in CLL Most patients with CLL are aged over 65 years and have at least 2 co-morbidities 1,2 A large proportion of patients are therefore not suitable for intensive chemotherapy Studies with bendamustine as first-line therapy for CLL show that it: –Provides significantly greater efficacy than chlorambucil both in terms of RR and PFS –Has a manageable toxicity profile 1. SEER Report Yancik R. Cancer 1997;80:1273–83

Comparison of fludarabine, bendamustine, alemtuzumab and chlorambucil as single agents Rai Hillmen Knauf Regimen N F Chl Al Chl Ben Chl Median age, years Rai Stage III-IV or Binet C, % Grade 3 / 4 ↓ ANC, % CR, % OR, % Med PFS (mo) Rai KR, et al. N Engl J Med Hillmen P, et al. J Clin Oncol Knauf WU, et al J Clin Oncol 2009.

Niederle et al, ICML Lugano 2008 Randomize Bendamustine 100 mg/m 2 day 1+2 q 4 weeks Fludarabine 25 mg/m 2 day 1-5 q4 weeks Treatment until best response for a maximum of 8 cycles Bendamustine vs Fludarabine as 2nd line treatment in CLL

Niederle et al, ICML Lugano 2008 ORR78%65% CR29%10% Median PFS83 weeks64 weeks Bendamustine vs Fludarabine as 2nd line treatment in CLL Bendamustine (n=46) Fludarabine (n=43)

Niederle et al, ICML Lugano 2008 Bendamustine vs Fludarabine as 2nd line treatment in CLL

Niederle et al, ICML Lugano 2008 Bendamustine vs Fludarabine as 2nd line treatment in CLL

Rituximab + bendamustine in relapsed CLL: the CLL2M study Fischer et al., 2008, Abs 330. Session: Chronic Lymphocytic Leukemia – Therapy, Excluding Transplantation MabThera Bendamustine Relapsed/ refractory 28 days 70 mg/m mg/m 2 70 mg/m mg/m 2 Bendamustine has shown considerable efficacy and an excellent safety profile This makes bendamustine a good candidate for combination therapy with MabThera in F-ineligible CLL patients FU q3 months, up to 3 years until PD Interim staging PD/unaccept. toxicity:  end of study Initial response assessment day 169 ± 7 Final staging day 225

81 patients 6 cycles BR Second to fourth-line therapy Bendamustine 70mg/m 2 day 1-2 q4wks, cycle 1-6 Rituximab 375 mg/m 2 day 0, cycle mg/m 2 cycle patients 6 cycles BR First-line therapy Protocol amendment 1 Bendamustine 90mg/m 2 day 1-2 q4wks, cycle 1-6 Rituximab 375 mg/m 2 day 0, cycle mg/m 2 cycle 2-6 closed German Phase II CLL2M study of bendamustine + rituximab (BR) in relapsed/refractory CLL Primary end point: ORR

CLL2M demographic data 33.3 % 30.9 % 35.8 % Age categories < ≥ 65 < 7025 ≥ 7029 Age in years Mean % 33.3 % Number of pts81 Male54 Female27 2nd to 4th line Fischer K et al. Blood 2008;112:Abs 330

CLL2M study : response rates (2 nd -4 th, n=62) Responsen% Overall response rate Complete response914.5 Partial response Stable disease Progressive disease34.8 Fischer K et al. Blood 2008;112:Abs 330 After a mean of 4.5 treatment cycles

CLL2M study (2nd-4th): toxicities Grade 3/4, % of courses Hematological adverse events Anemia6.1 Thrombocytopenia9.1 Leukopenia/neutropenia11.9 Non-hematological adverse events Infections4.9 Fischer K et al. Blood 2008;112:Abs 330

MarkernOverall response rate, n (%) Complete response, n 11q–1312 (92.3)1 17p–94 (44.4)– (100)1 IgV H unmutated3929 (74.4)– Fischer K et al. Blood 2008;112:Abs 330 CLL2M study (2 nd -4 th ): response by cytogenetics

48,7 % 21,0 % 30,3 % Age categories < ≥ 65 < 7025 ≥ 7036 Age in years Mean63,2 71,4 % 28,6 % Number of pts119 Male85 Female34 CLL2M study: demographic data 1st line Fischer K et al. Blood 2008;112:Abs 330

bendamustine plus rituximab is an effective regimen in R/R CLL major tolerable toxicities were myelosuppression and infections notable activity in high-risk CLL disease trial follow-up analysis will define response duration and long-term safety ongoing trial activity will determine the clinical efficacy and toxicity for 1st line treatment (ASH 2009) CLL2M conclusions

R Fludarabine Cyclophosphamide Rituximab (FCR) Bendamustine Rituximab (BR) Fludarabine 25 mg/m² i.v., d 1–3 Cyclophosphamide 250 mg/m², d 1–3, Rituximab: 375 mg/ m 2 i.v. d 0, c 1 Rituximab: 500 mg/m² i.v. d 1, c 2–6 Bendamustine 90mg/m² d 1–2 Rituximab 375 mg/m² d 0, c 1 Rituximab 500 mg/m² d 1, c 2–6 Similar efficacy of BR vs. FCR? Lower toxicity rate of BR? CLL10 protocol of GCLLSG Primary objective: progression-free survival patients with previously untreated CLL CIRS < 6 Non inferiority?

ADDITIONAL SLIDES

Recommended doses for bendamustine in CLL Pre-treated Patients: Bendamustine 70 mg/m2, day 1+2 every 4 weeks BR – Rituximab 375 mg/m2 day1 (2nd+ cy 500 mg/m2) + bendamustine 70 mg/m2 day 1+2 q4 weeks Primary therapy: Bendamustine 100 mg/m2, day 1+2 q4 weeks

Yancik R, Cancer 1997; 80:1273– Patients (%) Age (years) 55–65 65–74 > 75 > Co-morbidities The elderly patient’s burden of co-morbidity