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Chronische lymphatische Leukämie – Was ist neu?

Chronische lymphatische Leukämie – Was ist neu?. Michael Hallek www.dcllsg.de. CLL: Stadium bestimmt Behandlung. CLL in frühen Stadien. CLL1: DESIGN AND STUDY POPULATION (n = 630). Binet stage A 877 pts. LDT <12/>12 months BM diffuse/non diffuse. Risk Stratification 804 pts.

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Chronische lymphatische Leukämie – Was ist neu?

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  1. Chronische lymphatische Leukämie – Was ist neu? Michael Hallek www.dcllsg.de

  2. CLL: Stadium bestimmt Behandlung

  3. CLL in frühen Stadien

  4. CLL1: DESIGN AND STUDY POPULATION (n = 630) Binet stage A 877 pts LDT <12/>12 months BM diffuse/non diffuse Risk Stratification 804 pts TK ≤/> 7 U/L ß2-MG ≤/> 3.5 mg/L Inclusion/Exclusion ok 728 pts LOW RISK 535 pts HIGH RISK W&W 95 pts n = 630 R HR Fludarabine 98 pts

  5. PFS AND OS RELATED TO RISK STRATIFICATION LR = 522; Events = 262 HR W&W = 94; Events = 75 LR = 527; Events = 42 HR W&W = 93; Events = 19 p<0.001 p<0.001

  6. PFS AND OS IN RELATION TO IGVH-STATUS + FISH p<0.001 p<0.001 p=0.054

  7. Conclusion: Top 10 variables predicting OS and PFS in untreated, early stage CLL

  8. Cox regression model (excluding cytogenetics): Overall survival

  9. Major factors predicting an unfavorable course in Binet stage A/Rai stage 0 CLL • Chromosomal aberrations 17p- and 11q- • Elevated serum thymidine kinase (> 10 U/L) • Lymphocyte doubling time < 12 months • Unmutated IgVH gene • Expression of cytoplasmic ZAP70 • Elevated surface expression of CD38?

  10. CLL7 protocol of the GCLLSG/FCLLSGPatients at Binet stage A or B without symptoms Aim and Rationale: Complete (MRD-) eradication of early high risk disease • Assessment of 4 prognostic factors: • 11q- or 17p- deletion • Unmutated IgVH-Status • Serum thymidine kinase > 10 U/L • Lymphocyte doubling time < 12 months Low risk: < 2 factors positive watch and wait 2/3 of patients FCR High risk: 2 or more factors positive watch and wait 1/3 of patients

  11. Ältere (komorbide) Patienten mit CLL in fortgeschrittenen Stadien

  12. CLL5 protocol for elderly patients with advanced CLL CLL,> 65 years, untreated, Binet stage C or symptomatic A/B 6 x Fludarabine phosphate F 25 mg/m², Days 1–5q 28 days Chlorambucil (up to a maximum of 12 months) Clb0.4 mg/kg body weight increasing 0.1 mg up to 0.8 mg/kg body weight q 15 days

  13. CLL5 protocol Overall Survival (OS) p = 0.15 Median OS: F 45.8 months; Clb 63.6 months

  14. CLL5 protocolCauseofdeath Clb arm: 32 patients died F arm: 42 patients died

  15. Jüngere (fitte) Patienten mit CLL in fortgeschrittenen Stadien

  16. p=0.16 p=0.10 p<0.01 p=0.12 First-line R-FC: improved OSfollowing CR 1.0 0.8 0.6 Probability 0.4 0.2 0 0 12 24 36 48 60 72 84 96 108 Time (months) nPR = nodular PRPR-i = met all criteria for CR except for incomplete recovery of blood countsPR-d = residual disease in blood, nodes, spleen, marrow or other sites Tam CS, et al. Blood 2008;112:975–80

  17. p<0.001 p=0.37 F±P vs F±M/C vs R-FC: improved survival with rituximab (historical comparison) 1.0 0.8 0.6 Probability 0.4 0.2 0 0 12 24 36 48 60 72 84 96 108 Time (months) Tam CS, et al. Blood 2008;112:975–980

  18. CLL8: first-line treatment of CLL 6 x FCR Final staging and follow-up 817 untreated patients with Binet B/C CLL randomised 6 x FC Final staging and follow-up • In January 2008, the DSMB concluded that the study had reached the primary endpoint (PFS, difference of at least 35% at 2 yrs) • FCR is the superior study arm

  19. 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 CLL2M study design II closed closed

  20. BR GCLLSG – FCR Wierda

  21. BR GCLLSG – FCR Wierda

  22. CLL 10 protocol of GCLLSG Fludarabin Cyclophosphamid Rituximab (FCR) Fludarabine 25 mg/m² i.v., days 1-3 Cyclophosphamide 250 mg/m², days 1-3, Rituximab: 375 mg/ m2 i.v. day 0, cycle 1 Rituximab: 500 mg/m² i.v. day 1, cycle 2-6 R Bendamustin Rituximab (BR) Bendamustine 90mg/m² day 1-2 Rituximab 375 mg/m² day 0, cycyle 1 Rituximab 500 mg/m² day 1, cycyle 2-6 Similar efficacy of BR in comparison to FCR? Lower toxicity rate of BR?

  23. 3rd generation of trials of the GCLLSG: Risk, stage and fitness adapted Inactive Binet A Active disease + all Binet C, not del(17p) CLL12 CLL10 CLL11 Which is the best score to define high risk? Go Go Slow go no yes W&W W&W treat BR FCR CLB CLB + R Disease (MRD) eradication? Longer survival? Symptom control? longer disease-free survival?

  24. CLL Treatment 2008

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