Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09 Lorenz Trümper Universitätsmedizin Göttingen

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1 Treatment of aggressive B-Cell Lymphomas in the Elderly Lorenz Trümper Abteilung Hämatologie & Onkologie Göttingen Comprehensive Cancer Center Universitätsmedizin Göttingen Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09 Lorenz Trümper Universitätsmedizin Göttingen 1

2 2

3 Diffuse large B-cell lymphoma, not otherwise specified (NOS) Centroblastic Immunoblastic 3

4 NHL im Alter NHL 10 most frequent Diagnose Häufigkeit in %

5 NHL im Alter Lymphoma Characteristics Diagnose 5 Jahre nach Diagnose % Chronische lymphatische Leukämie Follikuläres LymphomDiffus großzelliges B urkitt-lymphom Ly mphom Therapieerfolg Überleben

6 NHL im Alter Treatment strategies Therapie Lymphoma Involvement Indolent Lymphoma CLL Aggressive Lymphoma Limited Radiation Watch & wait Chemotherapy Chemotherapy Advanced ± Moab (+) Moab ± Radiation Chemotherapy ± Moab ± Radiation Trials/single cases Transplantation Radioimmunthx Moab Transplantation Transplantation Radioimmunthx

7 Prognosis of aggressive NHL: IPI Risk Score CR (%) 5- year OS (%) Risk Group # Factors 5-y OS Age > 60 y Low 0,1 73 ECOG PS > 1 Low-Intermed 2 51 Stage III or IV High Intermed 3 43 Extr sites > 1 High 4,5 26 LDH > normal International Prognostic Factors Group NEJM

8 Primary Treatment of aggressive B-NHL: CHOP 100% 80% 60% ProMACE-CytaBOM m-bacod CHOP MACOP-B At Risk Events Year Estimate 37% 35% 34% 32% 40% 20% 0% Years from Registration Fisher et al. NEJM 1993 Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09 Lorenz Trümper Universitätsmedizin Göttingen 8

9 NHL im Alter Life expectancy RKI data Basis

10 Aggressive NHL in elderly Treatment outcome and prognosis Sonnen & Kuse, DMW 1998

11 Treatment of aggressive lymphomas in the elderly Tx with less intensity no anthracycline? Autor, Jahr Therapie n Alter CR OAS nach Gruppe Median % % Tirelli, 1998 EORTC CHOP * VMP J Bastion, 1997 CTVP 233 > 69 47* 27* GELA CVP J Sonneveld, 1995 DHOSG CHOP CNOP * 31 42* 26 3 J Meyer, 1995 Ontario CHOP CHOPw > * 51 2 J Osby, 2003 (NLG) CHOP * 57* CNOP J

12 NHL im Alter CHOP: Bad in old age? Therapie J-Überleben % VMP CHOPw CNOP CHOP "Alters-CHOP"

13 Improvement 1 over CHOP: Rituximab CHOP (elderly) 1.0 LN98-5 Event-free survival : Interim analysis (ASH 2000) : Update of interim analysis (EHA 2001) : Analysis at end of study (NEJM 2002) : 3-year follow-up analysis : 5-year analysis (Feugier JCO) Years GELA / Coiffier et al. Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09 Lorenz Trümper Universitätsmedizin Göttingen 13

14 Improvement 2: Dose density, G-CSF supported (CHOP-14) CHOP-14 56% CHOEP-14 (n=169) CHOEP-21 (n=170) CHOP-21 (n=178) CHOP-14 (n=172) CHOP-21 42% months Pfreundschuh, Trümper et al (Blood 2004) Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09 Lorenz Trümper Universitätsmedizin Göttingen 14

15 RICOVER-60 Study Design 6 x CHOP Gy (Bulk, E) CD20 + DLBCL Stages I-IV 61 to 80 years Random 2x2 Factorial Design 8 x CHOP Gy (Bulk, E) 6 x CHOP Gy (Bulk, E) + 8 x Rituximab 8 x CHOP Gy (Bulk, E) + 8 x Rituximab

16 RICOVER-60 - Event-free survival x R-CHOP x R-CHOP 14 Proportion : 6 x CHOP 14 (n=307) 2: 8 x CHOP 14 (n=305) 3: 6 x R-CHOP 14 (n=306) 4: 8 x R-CHOP 14 (n=304) 1, 2: p= , 3: p< , 4: p< , 4: p= x CHOP 14 6x CHOP 14 3-years rate: 66.5% 63.1% 53.0% 47.2% Months Pfreundschuh et al. Lancet Oncology 2008

17 NHL im Alter Pre-Phase Treatment Diagnose Sick due to NHL Pre Phase Treatment Reassessment

18 RICOVER-60: Conclusion CHOP-14 plus Rituximab is safe and feasible EFS significant increase! No significant difference between 6 or 8 cycles of R-CHOP-14 6 x CHOP x Rituximab is the new standard less toxicity and cost, same efficacy as 8 cycles Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09 Lorenz Trümper Universitätsmedizin Göttingen 18

19 III. Elderly Patients Is further Improvement possible?

20 DENSE-R-CHOP-14 Study Design CD20 + DLBCL Stages I-IV 61 to 80 years C H O P C HOP C HOP C HOP C HOP C HOP W e e k s

21 DENSE-R-UP-CHOP-14 Study Design CD20 + DLBCL Stages I-IV to 80 years Rituximab 375 mg/m 2 2 Rituximab 500 mg/m W e e k s

22 DENSE-R-CHO/MP-60 UNFAVORABLE Study Design CD20 + DLBCL IPI 2-4 IPI 1 Bulky 61 to 80 years Random 2x2 Factorial Design R-CHOP Gy IN-RT* DENSE-R-CHOP Gy IN-RT* R-CHMP Gy IN-RT* * Except Interim-PET-neg. DENSE-R-CHMP Gy IN-RT*

23 Denser Rituximab Conclusion Pharmakokinetics.. Also important for MoAb Tx Phase III for early densification planned Significant sex-related differences Increased rate of opportunistic infections prophylaxis in the elderly like in AML etc!!! Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09 Lorenz Trümper Universitätsmedizin Göttingen 23

24 RICOVER-Trials Follow up: EFS of patients in PR Depending on Consolidative Radiation % 6xR-CHOP-14 + Rx bulk (n=117) Proportion % 6xR-CHOP-14 / no Rx bulk (n=47) p= m o n t h s Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09 Lorenz Trümper Universitätsmedizin Göttingen

25 RICOVER-Follow up Trial: PFS of patients in CR xR-CHOP-14 + Rx bulk (n=33) Proportion xR-CHOP-14 / no Rx bulk (n=20) 0.1 p= Median time of observation: 18/34 months Months Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09 Lorenz Trümper Universitätsmedizin Göttingen

26 Role of Radiation Tx in elderly Aggressive NHL pts Consolidation (36-40 Gy GHD) In initial bulky disease pts only when remaining lymphoma on CT Dto. In extranodal Contralateral testis in testis lymphoma Palliative Decreased Chemo-Tx + Radiation not superior to full dose chemotherapy Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09 Lorenz Trümper Universitätsmedizin Göttingen 26

27 Bias in clinical trials: KML results Radioimmuntherapie bei Lymphomen Onkologische Aspekte Lorenz Trümper Universitätsmedizin Göttingen 27

28 DSHNHL Elderly Trial - BR Open, non-randomized phase II Elderly non-fit pts (not fit for R-CHOP-14) Geriatric assessment Dose-dense Rituximab + Bendamustin PI U. Wedding / DSHNHL trial office Radioimmuntherapie bei Lymphomen Onkologische Aspekte Lorenz Trümper Universitätsmedizin Göttingen 28

29 Acknowledgements DSHNHL M. Pfreundschuh, N. Schmitz, L. Trümper B. Glaß, G. Wulf, M. Ziepert, S. Zeylanova, M. Loeffler UMG C. Binder, K. Hohloch, G. Wulf, E. Stitz, J. Hasenkamp, A. Borgerding D S H N H L Radioimmuntherapie bei Lymphomen Onkologische Aspekte Lorenz Trümper Universitätsmedizin Göttingen 29