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Lessons from the CLL8 study

Lessons from the CLL8 study. 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

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Lessons from the CLL8 study

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  1. Lessons from the CLL8 study • 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 Adapted from Hallek, oral presentation, ASH 2008

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

  3. 20–54 years 3% ≥ 65 years 25% 55–64 years 72% Mean no. of co-morbidities n/a 2.9 4.2 3.6 CLL a disease of the elderly Age at CLL diagnosis

  4. Bendamustinein CLL therapy Reference Phase Regime Pat. prev. ORR CR n= ther. (%) Kath et al., 2001 II B 5x60mg/m2 23 10/23 75 30 Bremer et al., 2002 II B 5x60mg/m2 15 yes 77 7 Aivado et al., 2002 II B 2x100mg/m2 23 yes 67 29 Köppler et al., 2004 I/II BM 2x75mg/m222 yes 86 27 Bergmann, 2005 I/II B 2x70mg/m2 16 yes 56 12,5 Lissitchkov, 2005 I/II B 2x100mg/m2 15 yes 60 27 Less heavily pre-treated patients From: Wendtner, Mundipharma Symposium, Bari, 24.09.2008

  5. 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 27:4378-4384

  6. Bendamustine100 mg/m2 days 1+2, every 4 weeksfor 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 Bendamustine versus chlorambucil: the European Phase III ‘Intergroup’ CLL Study B-CLL Binet stage B/C No pretreatment Age £75 years • Responses assessed in a blinded fashion by an Independent Committee for Response Assessment (ICRA) • Primary endpoints: overall remission rate, progression-free survival

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

  8. European Phase III ‘Intergroup’ CLL Study: patient demographics

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

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

  11. European Phase III ‘Intergroup’ CLL Study: progression-free survival • Median observation time: 35 months (range, 1-68) at the time of the analysis Survival distribution function 1.0 0.9 Bendamustine (n=162) 0.8 Chlorambucil (n=157) 0.7 Censored observations 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 Time (months) Median progression-free survival: bendamustine 21.6 months; chlorambucil 8.3 months; p<0.0001

  12. Survival distribution function CR-Bendamustine (n=50, median=29.3) 1.0 CR-Chlorambucil (n=3, median=8.0) 0.9 PR-Bendamustine (n=60, median=17.4) 0.8 PR-Chlorambucil (n=45, median=8.0) 0.7 Censored observations 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 Time (months) 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

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

  14. Chlorambucil in first-line therapy of CLL

  15. 1st-line therapy with single-agent bendamustine in CLL • Most patients with CLL are aged over 65 years and have at least 2 co-morbidities1,2 • 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 2009 2. Yancik R. Cancer 1997;80:1273–83

  16. Comparison of fludarabine, bendamustine, alemtuzumab and chlorambucil as single agents 1. Rai KR, et al.N Engl J Med. 2000. 2. Hillmen P, et al. J Clin Oncol. 2007. 3. Knauf WU, et al J Clin Oncol 2009.

  17. Bendamustine vs Fludarabine as 2nd line treatment in CLL Bendamustine 100 mg/m2 day 1+2 q 4 weeks Randomize Fludarabine 25 mg/m2 day 1-5 q4 weeks Treatment until best response for a maximum of 8 cycles Niederle et al, ICML Lugano 2008

  18. Bendamustine vs Fludarabine as 2nd line treatment in CLL Bendamustine (n=46) Fludarabine (n=43) Niederle et al, ICML Lugano 2008

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

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

  21. Rituximab + bendamustinein relapsed CLL: the CLL2M study 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 500 mg/m2 500 mg/m2 500 mg/m2 500 mg/m2 375 mg/m2 500 mg/m2 28 days 28 days 28 days 28 days 28 days 28 days Relapsed/refractory 70 mg/m2 70 mg/m2 70 mg/m2 70 mg/m2 70 mg/m2 70 mg/m2 Final staging day 225 MabTheraBendamustine Interim staging PD/unaccept. toxicity:  end of study Initial response assessment day 169 ± 7 Fischer et al., 2008, Abs 330. Session: Chronic Lymphocytic Leukemia – Therapy, Excluding Transplantation

  22. German Phase II CLL2M study of bendamustine + rituximab (BR) in relapsed/refractory CLL Protocol amendment 1 Second to fourth-line therapy First-line therapy 81 patients 119 patients 6 cycles BR 6 cycles BR Bendamustine 70mg/m2 day 1-2 q4wks, cycle 1-6 Rituximab 375 mg/m2 day 0, cycle 1 500 mg/m2 cycle 2-6 Bendamustine 90mg/m2 day 1-2 q4wks, cycle 1-6 Rituximab 375 mg/m2 day 0, cycle 1 500 mg/m2 cycle 2-6 closed Primary end point: ORR

  23. Number of pts 81 Male 54 Female 27 66.7 %33.3 % Age in years Mean 66.7 33.3 %30.9 %35.8 % Age categories < 65 27 ≥ 65 < 70 25 ≥ 70 29 CLL2M demographic data 2nd to 4th line Fischer K et al. Blood 2008;112:Abs 330

  24. CLL2M study : response rates (2nd-4th, n=62) After a mean of 4.5 treatment cycles Fischer K et al. Blood 2008;112:Abs 330

  25. CLL2M study (2nd-4th): toxicities Fischer K et al. Blood 2008;112:Abs 330

  26. CLL2M study (2nd-4th): response by cytogenetics Fischer K et al. Blood 2008;112:Abs 330

  27. Number of pts 119 Male 85 Female 34 71,4 % 28,6 % Age in years Mean 63,2 Age categories < 65 58 ≥ 65 < 70 25 ≥ 70 36 48,7 %21,0 %30,3 % CLL2M study: demographic data 1st line Fischer K et al. Blood 2008;112:Abs 330

  28. CLL2M conclusions • 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)

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

  30. ADDITIONAL SLIDES

  31. Recommended doses for bendamustine in CLL Primary therapy: Bendamustine 100 mg/m2, day 1+2 q4 weeks 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

  32. > 5 4 3 2 1 0 The elderly patient’s burden of co-morbidity Co-morbidities 100 80 60 Patients (%) 40 20 0 65–74 55–65 > 75 Age (years) Yancik R, Cancer 1997; 80:1273–1283.

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