Hodgkin Lymphoma Review of characteristics and treatment of elderly patients

Transcription

1 Hodgkin Lymphoma Review of characteristics and treatment of elderly patients Boris Böll M.D. German Hodgkin Study Group (GHSG) University Hospital Cologne

2 OS of HL patients in all stages Courtesy of Volker Diehl

3 Classical Hodgkin Lymphoma - Histology Nodular Sclerosis Mixed Cellularity Lymphocyte Depleted

4 1996: Proof of clonality and origin Kanzler H, Küppers R, Hansmann ML, Rajewsky, K et al: J Exp Med 184: , 1996

5 Age distribution in GHSG trials (HD5-HD9) median age: 32 years 15.0 Percent Age (years) HD5,6: yrs, HD8: yrs, HD9: yrs, HD9elderly: yrs

6 Population based data on age distribution (N = 6949), median age: 45y 20-30% of HL patients are 60 years old Sjöberg J et al.; Blood 119 (4): , 2012

7 GHSG Risk stratification Early favourable Early unfavourable Advanced stages Eichenauer DA et al.: Annals of Oncology 25 Suppl 3:iii70 5, 2014

8 GHSG Standards: young patients Early favourable stages (I-II without RF*): 2 x ABVD + 20Gy IF-RT 1 Early unfavourable stages (I-II with RF*): 2 x BEACOPP esc + 2xABVD + 30Gy IF-RT Advanced Stages (IIB+RFa,b*, III-IV): 6 x BEACOPP esc + PET-based RT *Risk Factors: a) large mediastinal mass; b) extranodal HL; c) elevated ESR; d) 3 LN areas involved 1 Engert et al: NEJM 363: , 2010; 2 von Tresckow et al:j Clin Oncol 30: , Engert et al: The Lancet, 11: , 2012

9 Prognosis of advanced HL in year OS for 6 BEACOPPescalated (N=711): 95.3 (95% CI: 93.4 to 97.2) Engert et al., Lancet 2012; 379:

10 Prognosis (OS) of elderly HL patients (GHSG) GHSG trials HD5-HD9 < 60 n= 3879; > 60 n= year FFTF: 80 % v.s. 60% 5-year OS: 85% v.s. 65% Engert A et al: J Clin Oncol 23: , 2005

11 real world elderly HL (Sweden) Courtesy of Magnus Björkholm 2010; Sjöberg J et al.; Blood 119 (4): , 2012

12 Characteristics of elderly HL Lymphoma MC subtype more common Risk factors more common ESR elevated B-symptoms EBV infection more common and disadvantageous Patients Performance (WHO/ECOG-PS) Comorbidities Therapy-associated toxicity Jarrett et al. Blood 2005; 106(7): Van Spronsen et al. Ann Hematol. 1999; 78(7):315-9

13 Which Chemotherapy for elderly HL? Do we need anthracyclins? What is the role of dose intensity? n = 88, > 60y HL ( ) CT: ABVD vs. MOPP (-variant) RDI >65% vs. RDI 65% ABVD RDI 65% Anthracyclins indispensable Dose density important MOPP or ABVD RDI 65% Landgren et al. Haematologica 2003;88(4):438-44

14 GHSG trials for HL 60 years COPP/ABVD vs. BEACOPP baseline Treatment-related mortality = 21% Ballova V et al: Annals of Oncology 16: , 2005 BACOPP = BEACOPP - etoposide, doxorubicin PVAG = ABVD bleomycin/dacarbazine + prednisone/gemcitabine Treatment-related mortality = 11% Halbsguth TV et al: Blood 116: , 2010 III/IV Toxicity = 75 % (TRM 2%) Böll B et al: Blood 118: , 2011 How about ABVD???

15 ABVD in HL 60 years UK SHIELD Study (n= 35) 1 Few advanced-stage patients Feasibility? III/ IV Toxicity 70%; TRM about 15% US Intergroup Trial E2496 (n= 22) 2 Feasibility? III/ IV Toxicity 70% Bleomycin-tox.: 10/22patients (lethal in 2); TRM about 9% GHSG HD 10 and HD 11 (n= 117) 3 No advanced stage patients RDI 0.8: 59%; III/ IV Toxicity 68%; TRM about 5% 1 Proctor SJ et al: Blood 119: , 2012; 2 Evens AM et al: British J of Haematology 161:76 86, 2013; 3 Böll B et al: J Clin Oncol 31: , 2013; Stamatoullas A et al: British J of Haematology 170: , 2015

16 Bleomycin in HL 60 years: France n= 147, 3 French centers median: 6 cycles ABVD Stamatoullas A et al: British Journal of Haematology 170: , 2015

17 4x or 2x Bleomycin in HL 60 years GHSG HD10 and HD13 trials; age 60 years Excessive toxicity including severe bleomycin-induced lung toxicity occurred in older HL patients receiving 4 cycles ABVD HD10 HD13 4*ABVD 2*ABVD 2*ABVD 2*AVD N=69 N=65 N=62 N=77 Pulmonary tox 9% 2% 2% TOTAL grade 3 65% 37% 42% 40% Behringer K et al.: The Lancet, 385 (9976) , 2015 Böll B et al.: Blood, 2016 in press

18 Potential Targets in HL H-RS cells Microenviroment Aldinucci D et al., J Pathol. 2010

19 Lenalidomide in relapsed/refractory Hodgkin Lymphoma Reference Key Inclusion Criteria Kuruvilla et al. ASH 2008 # 3052 Böll et al. Br J Haem 2009 ASH 2010 # 2828 Relapsed/refractory HL Fehniger et al. Blood 2011 Patients (n) Median prior therapies Prior SCT 71% 78% 87% Refractory to last prior therapy 66% (83%) 55% ORR 13% (CR:0%, PR: 13%) 28 % (CR: 6%, PR: 22%) 19 % (CR: 3%, PR: 16%) ORR in heavily pretreated rel/ref HL 15-20% well tolerated, main AEs: neutropenia, fatigue

20 AVD-Rev in elderly HL Lenalidomide I I I I day 1 day 8 day 15 day 22 Pause First line chl > 60 75, early unfavorable and advanced stages Phase I/II dose escalation (continual reassessment), n 30 pts. Primary EP: Dose limiting toxicity Secondary EP: ORR, QoL, AEs

21 AVD-Rev patient characteristics N= 25 patients Age, years Median (Range) Mean + STD 68 (61-76) N % Gender male GHSG stage advanced Clinical stage CS III+IV B-symptoms ECOG performance status Comorbidity (CIRS-G score, n=22) N %

22 AVD-Rev acute chemo-toxicities All 6 patients at 20 mg and all 14 patients at 25 mg had III/IV toxicities 20 mg, N=6 25 mg, N=14 CTC GRADE III/IV IV III/IV IV TERM % % % % Haematological 83% 50% 100% 86% Infection 21% 7% Hair loss 17% 17% 29% Respiratory 21% 7% Venous thromb. 17% 17% 7% Grade III-IV: Anemia: 76% Thrombocytopenia: 28% Leukopenia: 56% 36% did not receive (peg-)filgastrim

23 AVD-Rev efficacy: highest dose levels Dose level of lenalidomide 25 mg N=16 20 mg N=21 all pts. N=25 Final treatment outcome CR/CRr PR PRO Overall response rate 94 % 86% 80% 95%-CI [70% - 100%] [65% - 97%] [60% - 93%]

24 Relapsed HL in older patients Limited data available no trial, lack of clear guideline-recommendations (NCCN, German S3-guidelines) Recent single center analysis suggesting similar outcome 60y, n=15 < 60y, n= 137 Puig et al., Bone Marrow Transplant. 2011

25 Relapsed/Refractory HL in pat. 60y GHSG clinical trials: HD 7-12, PVAG, BACOPP Patients 60y with relapse or progression (n=105): update information on treatment and survival/remission status High-dose approaches (DHAP/ICE/DexaBEAM ) 22 %* PolyCTX/RX (COPP/ABVD/BEACOPP ) 39 % Palliative approaches (Gemcitabine/Vinorelbine ) 34 % Unknown 5 % * ASCT conducted in 5 % Böll B et al: J Clin Oncol 31: , 2013

26 Survival after relapse/progression Survival after first progression/relapse No 0.7 benefit of aggressive treatment (HDCT) for any patient in our 0.6 Polychemotherapy 0.5 as ABVD or Total BEACOPP 20.9 [16.8 can to induce 25.7] long-term Median observation time after progression/relapse: 72 months Simple Score allows distinction of high-risk vs. low-risk patients (early relapse, stage III or IV at relapse, anemia) analysis remissions in selected patients Median survival [95%-CI] Total 12 months [8 to 19] Standardized Mortality Ratio* [95%-CI] AVOIDING relapse is the key! Total Total Böll B et al: J Clin Oncol 31: , 2013

27 Perspective: Potential Targets in HL CD30 Aldinucci D et al., J Pathol Kanzler H et al: J Exp Med 184: , 1996

28 Brentuximab vedotin (Adcetris, SGN-35) Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), potent antitubulin agent protease-cleavable linker anti-cd30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex traffics to lysosome MMAE is released MMAE disrupts Microtubule network G2/M cell cycle arrest Apoptosis

29 BV in elderly HL n=27 Patients ineligible for or refusing Chemotherapy median age 78y Forero-Torres A et al: Blood 126: , 2015

30 BV in elderly HL median treatment: 8 cycles (3-23) no related grade 4 AEs 26% grade 3 PNP ORR 92%, CR 73% median PFS 10.5 months median DOR 9.1 months (2.8 to 20.9) Forero-Torres A et al: Blood 126: , 2015

31 Current trial: B-CAP (NLG, GHSG) day 1: Brentuximab Cyclophosphamide 750mg/m 2 Doxorubicine 50mg/m 2 day 2-6: Predniso(lo)ne 100 mg repeat on day 22 WEEK 1 WEEK 2 WEEK 3 IIT GHSG + Nordic lymphoma Group B-CAP-arm: advanced stage HL; N = 50 SGN-35 mono: all stages, N 20 Prephase: Predniso(lo)n 100 mg/d d -7 to d-1

32 Conclusions About 20-30% of all HL patients are 60 years Inferior survival aggressive lymphoma co-morbidities high therapy-related toxicity and mortality No standard therapy, avoid relapse and TRM! Inclusion in clinical trials Stratified by co-morbidities (e.g. CIRS-G)? Early stages: 2-4 cycles polychemo + IF-RT Advanced stages: 6 cycles polychemo +/- RT Relapse: Brentuximab???? PD-1??? Regimens: A(B)VD, PVAG, AVD-Rev? 32

33 International Hodgkin Symposium , Köln, Gürzenich

34 Comprehensive geriatric assessment statt Geburtsdatum Courtesy of Michael Hallek 34