Treatment of Stage I-II A Non-Bulky Hodgkin's Lymphoma (HL): An Individual Patient-Data Comparison of German Hodgkin Study Group (GHSG) HD10 and HD11 Combined-Modality Therapy (CMT) and NCIC Clinical Trials Group (NCIC CTG) HD.6 ABVD Alone
Authors: Hay Annette E. , Klimm Beate , Chen Bingshu E. , Goergen Helen , Shepherd Lois E. , Fuchs Michael , Gospodarowicz Mary , Borchmann Peter , Connors Joseph M. , Markova Jana , Crump Michael , Lohri Andreas , Winter Jane N. , Dörken Bernd , Pearcey Robert G. , Diehl Volker , Horning Sandra J. , Eich Hans Theodor , Engert Andreas , Meyer Ralph M. 
Published: October 2019

Abstract
Abstract 548

Background:
Excellent results are seen in HL patients with stage I-IIA disease treated with CMT that includes involved field radiation therapy (IFRT), as per GHSG HD10 [Engert NEJM 2010] and HD11 [Eich JCO 2010] or with ABVD alone, as per NCIC CTG/ECOG HD.6 [Meyer NEJM 2012]. Comparing these reports is complicated by differences in eligibility, staging, endpoints and follow-up duration. Our objectives were to use individual patient data from these 3 trials to compare outcomes after standardizing patient eligibility.

Methods:
Potentially eligible patients were those treated with 2 cycles of ABVD/20 Gy IFRT on GHSG HD10, 4 cycles of ABVD/30 Gy IFRT on GHSG HD11 and 4–6 cycles of ABVD alone on NCIC CTG HD.6. To be included in analysis, patients were required to be eligible for GHSG HD10 or HD11 and NCIC CTG HD.6. Eligibility of HD10/11 patients for HD.6 was determined by the GHSG by applying HD.6 protocol criteria. Anonymized individual patient data of eligible patients was forwarded to NCIC CTG along with reasons for ineligibility of other patients. Eligibility of HD.6 patients for HD10/11 was determined by NCIC CTG by applying HD10/11 protocol criteria with listing of reasons for ineligibility. Eligibility questions were resolved through consensus. Patients meeting mutually inclusive eligibility criteria were stratified by a propensity score (PSc) based on age, gender, stage, ESR and number of disease sites. Outcomes were based on Revised Response Criteria for Malignant Lymphoma [Cheson JCO 2007]; no trial incorporated PET scanning. The primary outcome measure was progression-free survival (PFS), which includes disease progression and death from any cause as events. Secondary outcomes included overall survival (OS) and time to progression (TTP), which includes disease progression and death from HL as events. A priori subsets for analysis included eligibility for HD10 vs. HD11 and CR/CRu status after 2 cycles of ABVD among those eligible for both HD10 and HD.6. Cox models stratified by PSc were used to obtain hazard ratios (HR) for PFS, OS and TTP; HRs are expressed as GHSG HD10/11 relative to NCIC CTG HD.6.

Results:
Of 655 patients eligible for selected arms of HD10/HD11, 406 were eligible when applying the inclusion criteria for HD.6 (HD10 = 254; HD11 = 152). Most common reasons for ineligibility were B symptoms (n=127) and large mediastinal mass (n=80). Of 196 HD.6 patients, 182 were eligible for HD10 (n=110) or HD11 (n=71; 1 patient not assignable). Median follow-up for both HD10 and HD11 was 91 months and for HD.6 was 134 months. Results that include all eligible patients are shown in table; TTP was superior in GHSG trials.
In the HD10/HD.6 subset, 8-yr PFS was 87% vs 82% (HR=0.58; 95% CI=0.32–1.05) and OS was 96% vs 94% (HR=0.65; 95% CI=0.25–1.72). Among those with CR/CRu after 2 cycles of ABVD, 8-yr PFS was 87% vs 95% (HR=2.8; 95% CI=0.64–12.5) and OS was 96% vs 100%. Among those without CR/CRu after 2 cycles of ABVD, 8-yr PFS was 88% vs 74% (HR=0.35; 95% CI=0.16–0.79) and OS was 95% vs 91% (HR=0.42; 95% CI=0.12–1.44). In the HD11/HD.6 subset, 8-yr PFS was 91% vs 91% (HR=1.15; 95% CI=0.45–2.97) and OS was 95% vs 97% (HR=2.03; 95% CI=0.53–7.79). Among 406 HD10/11 patients, there have been 19 deaths; 7 were attributed to HL or immediate treatment toxicity and 12 to other causes. Among 182 HD.6 patients, there have been 10 deaths; 5 were attributed to HL or immediate treatment toxicity and 5 to other causes.

Conclusions:
In this non-randomized cohort comparison, TTP was superior and PFS trended to being superior in patients treated with CMT on HD10/11. No differences in OS are evident; longer follow-up is needed to assess trade-offs between disease control and risks of late treatment effects. The role of IFRT in attaining long-term disease control appears to be especially important in those who do not attain CR/CRu status after 2 cycles of ABVD. As outcomes of those eligible for HD10/HD.6 and treated with 4–6 cycles of ABVD alone were excellent if CR/CRu was attained after 2 cycles of ABVD, these data support more recent strategies evaluating response-adapted approaches for use of IFRT.

Disclosures:
Borchmann: Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other. Horning:Genentech: Employment; Roche: Equity Ownership. Engert:Millenium The Takeda Oncology Company: Honoraria. Meyer:Lilly: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen Canada: Research Funding; Ariad Pharma: Research Funding; Astex Therapeutics: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; GlaxoSmithKline: Research Funding; Janssen Ortho: Research Funding; Novartis: Research Funding; Oncothyreon: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Sanofi-Aventis: Research Funding; Schering Canada: Research Funding.