Aktuelle Therapiestandards und neue Entwicklungen bei der CLL Primärtherapie und Risikostratifikation Dr. med. Petra Langerbeins Universitätsklinik Köln Deutsche CLL Studiengruppe (DCLLSG)
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Objektiv messbare biologische Merkmale, die prognostische, diagnostische RISK ASSESSMENT oder prädiktive Aussagekraft haben. BIOMARKER
Biomarker Prognostic vs. predictive Treatment and outcome Prognostic marker both Predictive marker Risk of death infections Richter transformation Eichhorst B. ASH Educational. 2016
Biomarker TP53-disruptions RESONATE-17: Ibrutinib 420mg/d Stilgenbauer S. et al. Blood. 2014 Burger JA. et al. Lancet Oncol. 2014
Biomarker NOTCH1 mutations NOTCH1 wildtype Median PFS FCR 57 mo. FC 33 mo. NOTCH1 mutated Median PFS FCR 34 mo. FC 34 mo. Stilgenbauer S et al. Blood 2014. Pozzo F et al. Leukemia. 2016
Biomarker IGHV status FCR300 CLL8-Studie Thompson et al. Blood. 2016. Fischer K et al. Blood. 2016 Guo A et al. Oncotarget. 2016
Biomarker Clinical stage Binet A Binet B Binet C Binet JL et al. Cancer.1981 Rai KR et al. Blood. 1975 Pflug & Bahlo et al. Blood. 2014
Cumulative Survival Biomarker Duration of remission 6 yrs 3 5.9 yrs 1 2.9 yrs <1 yr Months Tam CS et al. Blood. 2014. Fischer K et al. unpublished.
Biomarker MRD status Peripheral blood Progression-free survival Bone marrow Overall survival Böttcher S et al. J Clin Oncol. 2012 Strati P et al. Blood. 2014
Biomarker Comorbidity Goede V et al. Haematologica. 2014 Stauder et al. Annals of Oncol. 2017
Biomarker Comorbidity Stauder et al. Annals of Oncol. 2017
Biomarker Age Patients 65 years: P < 0.001 FCR 53.6 months BR 38.5 months Patients > 65 years: P = 0.170 FCR not reached BR 48.5 months Eichhorst B et al. Lancet Oncol. 2016
Multivariates, statistisches Verfahren zur Analyse hierarchisch strukturierter Daten. RISK ASSESSMENT HIERARCHIAL MODELS
Hierarchical model FISH Döhner et al. N Engl J of Med. 2000
Integrated cytogenetic model NOTCH1, SF3B1, BIRC3 Rossi D et al. Blood. 2013
comorbidity IGHV status age clinical stage FISH MRD NOTCH1 duration of remission RISK ASSESSMENT SCORING SYSTEMS
Scoring systems MDACC-score / GCLLSG-score Biomarker Score Age [years] < 50 1 50-65 2 > 65 3 Sex Female 0 Male 1 ß2-microglobulin < ULN 0 1-2 x ULN 1 > 2 ULN 2 Rai stage 0-II 0 III-IV 1 Lymphocyte count [10 9 /L] < 20 0 20-50 1 >50 2 Involved nodal areas 3 0 3 1 Risk group Low 1-3 Intermediate 4-7 High >7 Biomarker Score Age [years] 60 0 > 60 1 Sex Female 0 Male 1 ß2-microglobulin [mg/dl] 1.7 0 1.7-3.5 1 > 3.5 2 ECOG PS 0 0 > 0 1 Thymidine kinase [U] 10 0 > 10 2 IGHV Mutated 0 Unmutated 1 11q Non-deleted 0 Deleted 1 17p Non-deleted 0 Deleted 6 Risk group Low 1-2 Intermediate 3-5 High 6-10 Very high 11-14 Wierda WG et al. Blood. 2007 Pflug N and Bahlo J et al. Blood. 2014
Scoring systems CLL-IPI International CLL-IPI working group. Lancet Oncol. 2016
Scoring systems CLL-IPI Biomarker Score Age [years] 65 0 > 65 1 Stage Rai 0/Binet A 0 ß2-microglobulin [mg/dl] Rai I-IV/Binet B-C 1 3.5 0 > 3.5 2 IGHV Mutated 0 Unmutated 1 TP53 No abnormalities 0 Deletion ± mutation 4 CLL-IPI category OS at 5 ys (%) Low risk 93.2 Do not treat Intermediate risk Potential clinical consequence 79.3 Do not treat except symptomatic High risk 63.3 Treatment indicated except asymptomatic Very high risk 23.3 Do not use chemotherapy (use novel agents or treat within a clinical trial) Risk group Low 0-1 Intermediate 2-3 High 4-6 Very high 7-10 International CLL-IPI working group. Lancet Oncol. 2016
???????? RISK ASSESSMENT FIRST LINE TREATMENT
Biomarker Guideline recommendations Clinical stage Disease activity Age Comorbidities TP53 / del17p IGHV Duration of remission IWCLL. International Workshop on CLL ESMO. European Society for Medical Oncology NCCN. National Comprehensive Cancer Network
Fit, no TP53-disruption ( 65 years) Rituximab plus FC Binet A, B, C Symptomatic Age 65 CIRS 6 No TP53 / del17p IGHV Duration of remission Wendtner CM et al. Onkopedia. 2017
Fit, no TP53-disruption (> 65 years) Rituximab plus Bendamustin Binet A, B, C Symptomatic Age > 65 CIRS 6 No TP53 / del17p IGHV Duration of remission Wendtner CM et al. Onkopedia. 2017
Fit, no TP53-disruption FLAIR Binet A, B, C Symptomatic Age CIRS 6 No TP53 / del17p IGHV - irrelevant Duration of remission Patient population Treatment-naive CLL Fit R A N D O M I Z E FCR IR ibrutinib + rituximab I ibrutinib IV ibrutinib + venetoclax Collett L et al. Trials. 2017
Fit, no TP53-disruption CLL13 trial Clinical Binet A, stage B, C Disease Symptomatic activity Age Comorbidities CIRS 6 TP53 No TP53 / del17p / del17p IGHV - irrelevant Duration of remission Patient population Treatment-naive CLL Fit R A N D O M I Z E FCR/BR* RV rituximab + venetoclax GV GA-101 + venetoclax GIV GA-101 + ibrutinib + venetoclax
Unfit, no TP53-disruption Chlorambucil + CD20-mAb Binet A, B, C Symptomatic Age CIRS > 6 No TP53 / del17p IGHV - irrelevant Duration of remission Wendtner CM et al. Onkopedia. 2017
Unfit, no TP53-disruption ( 65 ys) Ibrutinib Binet A, B, C Symptomatic Age 65 CIRS > 6 No TP53 / del17p IGHV - irrelevant Duration of remission Wendtner CM et al. Onkopedia. 2017
Unfit, no TP53-disruption illuminate trial Binet A, B, C Symptomatic Age CIRS > 6 No TP53 / del17p IGHV - irrelevant Duration of remission
Unfit, no TP53-disruption CLL14 trial Binet A, B, C Symptomatic Age CIRS > 6 No TP53 / del17p IGHV - irrelevant Duration of remission Patient population Treatment-naive CLL Unfit R A N D O M I Z E Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax Fischer K. et al., Blood 2017
Fit, TP53-disruption Ibrutinib Binet A, B, C Symptomatic Age CIRS 6 TP53 / del17p IGHV - irrelevant Duration of remission Wendtner CM et al. Onkopedia. 2017
Unfit, TP53-disruption Ibrutinib Binet A, B, C Symptomatic Age CIRS > 6 TP53 / del17p IGHV - irrelevant Duration of remission Wendtner CM et al. Onkopedia. 2017
High risk CLL GIVe trial Binet A, B, C Symptomatic Age CIRS TP53 / del17p IGHV - irrelevant Duration of remission Patient population Treatment-naive del17p / TP53 Obinutuzumab Cycle 1-6 Venetoclax Cycle 1-12 Ibrutinib Cycle 1-12 induction consolidation maintenance
Biomarker in CLL Summary A variety of prognostic and predictive biomarkers is available. Prognostic scores help to combine multiple biomarkers. TP53 remains the strongest biomarker. For high risk patients (TP53-disruption) ibrutinib is the first choice. CIT remains the standard of care (FCR, BR, CLB + mab). Comorbidity defines fit, unfit and fragile subgroups. Consider ibrutinib in patients with IGHV unmutated CLL. Combination studies will clarify the role of novel drugs compared to CIT.
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