German Hodgkin Study Group Deutsche Hodgkin Studiengruppe Managing Risk in advanced-stage HL Andreas Engert, MD Chairman, German Hodgkin Study Group University Hospital of Cologne
Managing risk in advanced stage HL Key issues • Background • Advanced Stages • PerspecEves • Summary
GHSG Risk Allocation for HL Stage (Ann Arbor) Risk factors IA, IB, IIA IIB IIIA, IIIB IVA, IVB Early favorable None ≥ 3 LK- Areas Advanced Early Elevated ESR unfavor- Large Med Mass able Extranodal disease
Hodgkin Lymphoma Late side effects a=er treatment • 2nd NPL AML NHL Solid tumours • Organ damage Lung Heart Thyroid • Others FerElity OPSI FaEgue Psycho-social
GHSG HD9 trial FFTF by treatment arm 1.0 0.9 0.8 18% 0.7 Percentage 0.6 0.5 0.4 A (64%) 0.3 B (70%) p <0,001 0.2 C (82%) 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years Engert et al; JCO 2009
HD15 in advanced HL Freedom from Treatment Failure (FFTF) 1.0 0.9 Freedom from Treatment Failure 0.8 0.7 A: 84.4% 0.6 B: 89.3% C: 85.4% 0.5 0.4 p-value 60 months difference 0.3 A vs. B: 0.009 4.9% 97.5%-CI: [ 0.5%, 9.3%] 0.2 A vs. C: 0.5 1.1% 97.5% CI: [-3.7%, 5.8%] C vs. B: 0.04 (n.s.) 3.9% 97.5% CI: [-0.5%, 8.2%] 0.1 0.0 0 12 24 36 48 60 72 Time [months] Engert A et al, Lancet 2012
TRM of BEACOPP escalated* Multivariate model ECOG 2 or Age>40 Age>50 Patients TRM rate Karn.<80 - - - 2156 0.7 + - - 590 1.7 - - + 108 0.9 + + - 445 5.6 + - + 40 13.3 + + + 45 15.0 *Pts treated in HD9, 12, 15 (64/3565; 1.9%) Wongso et al, JCO 2013 7
UK RATHL: Impact of Bleomycin PFS for PET-negative patients (ITT) HR: 1.11 (0.79 – 1.54), p = 0.53 Johnson et al; NEJM 2016
Hodgkin Lymphoma ECHELON-1: modified PFS Connors et al., NEJM 2017
Hodgkin Lymphoma ECHELON-1: Side effects A+AVD ABVD Neutropenia (%) 58 45 InfecEon grade ≥3 (%) 18 10 Peripheral neuropathy (PN: all) (%) 67 43 Peripheral neuropathy (PN), grade 11 2 ≥3 (%) Lungtox grade ≥3 <1 3 Neutropenia associated deaths 7 9 (no G-CSF prophylaxis) Lungtox associated deaths 11 13 Connors et al., ASH 2017: A6
HD18 for PET-2-negaLve paLents Overall Survival 1.0 ╵ ╵ ╵╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵╵ ╵╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵╵ ╵╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵╵ ╵╵ ╵ ╵╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵╵╵╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ ╵ ╵╵ ╵ ╵ ╵ ╵ ╵ 0.9 0.8 3-year esEmate 5-year esEmate Overall Survival rate 0.7 8/6x eBEACOPP: 95.9% [94.1-97-7] 95.4% [93.4-97.3] 4x eBEACOPP: 98.7% [97.6-99.7] 97.6% [96.0-99.2] 0.6 Difference: +2.7 [+0.6-+4.8] +2.2% [-0.3-+4.7] 0.5 0.4 Hazard RaEo 0.36 [0.17 to 0.76], 0.3 log-rank test p=0.006 0.2 Median observaEon Eme 56 months 0.1 PET-, 8/6x eBEACOPP PET-, 4x eBEACOPP 0.0 0 12 24 36 48 60 Time [months] Pts. at risk 504 476 438 363 298 207 501 479 459 370 292 227 Borchmann et al, Lancet 2017
Managing risk in advanced stage HL Key issues • Background • Advanced Stages • PerspecEves • Summary
The GHSG perspecLve HD21: BV in advanced stage HL 2 x BEACOPP esc 2 x BrECADD Centrally reviewed PET 4x 4x BEACOPP esc BrECADD End of therapy and residual nodes > 2.5 cm: PET posiEv: Rx PET negaEve: Follow up
Nivolumab for r/r cHL PFS in CheckMate 205 trial 100 CR: 22 (19, NE) months 9 0 8 0 7 0 Probability of PFS 6 0 PR: 15 (11, 19) months 5 0 SD: 11 (6, 18) months 4 0 3 0 2 PD: 2 (2, 2) months 0 1 Median (range) follow-up: 18 (1, 27) ms 0 0 0 3 6 9 12 15 18 PFS (months) Fanale M et al. ICML 2017
CheckMate 205 Cohort D Newly Diagnosed cHL Monotherapy Combotherapy (4 doses) (6 combocycles; 12 doses) Follow- up/ Nivolumab Nivolumab 240 mg IV + AVD (N-AVD) observaE 240 mg IV Q2W Q2W on Max 2 yrs ~8 wks ~22 wks • 51 untreated advanced stage cHL pts (IIB, III, IV) • Median follow-up 11.1 months (cut-off 31.8.17) • Bleomycin excluded due to potenEal overlapping pulmonary toxicity • Primary EP: G3-5 safety and tolerability • Primary endpoint: safety and tolerability (G3–5 treatment-related AEs )
Nivo-AVD in advanced stage cHL End of Combotherapy 75 FDG-PET scan at end of therapy or last ReducEon from baseline in target lesion (%) 50 prior radiographic assessment PET-negaEve 25 0 –25 –50 –75 –100 PaEents Ramchandren et al, ASH 2017: A651 46/51 paLents had available response data. Response assessed by IWG 2007 criteria
Managing risk in advanced stage HL Key issues • Background • Advanced Stages • PerspecEves • Summary
Advanced stage HL Summary • Advanced-stage HL became curable with mulE-agent chemo • B.esc gave 15-20% beoer PFS and 10-15% beoer OS than ABVD or variants; more hematotox and inferElity • B.esc not to be used in pts >40 ys and poor performance • HD15: 6xB.esc: tumour control 89%, OS 95% • HD18: only 4 cycles B.esc in PET- pts (3y FFTF 94.8%; OS 98.7%) • ECHELON1 showed 4.9% beoer modified PFS for BV-AVD as compared with ABVD • New trials evaluate targeted therapy including BV (HD21) and PD1 inhibitors
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