Primary Progressive Disease in Hodgkin Lymphoma Patients: A Retrospective Analysis from the German Hodgkin Study Group
Authors: Kreissl Stefanie , Goergen Helen , von Tresckow Bastian , Behringer Karolin , Markova Jana , Lohri Andreas , Meissner Julia , Zijlstra Josée M , Greil Richard , Topp Max S. , Sökler Martin , Döhner Hartmut , Diehl Volker , Engert Andreas , Borchmann Peter 
Published: October 2019

Abstract
Background: Primary progressive disease still remains an unmet medical need in Hodgkin Lymphoma (HL). Due to missing data on treatment effects and survival there is no established standard of care. We thus performed a retrospective analysis using the German Hodgkin Study Group (GHSG) database to improve the knowledge on the course of primary progressive HL patients.
Methods: Patients aged between 18 and 60 years treated within the GHSG first-line trials HD13-HD15 were screened for primary progressive HL. Primary progression was defined as progressive disease during ongoing therapy, within 3 months after the end of treatment, or up to 6 months after the end of treatment in patients with partial response or stable disease in the final restaging. We investigated types and outcome of second-line treatment approaches and overall survival, which was calculated from first diagnosis of HL (OS) and from diagnosis of first progression or relapse (OSp).
Results: We analyzed 5,126 patients, of whom 112 (2.2%) were identified with primary progressive disease. Of those, 62 (55%) patients had initially been treated for advanced-stage HL with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) variants, 30 (27%) for early-stage unfavorable HL with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)- or BEACOPP-like regimens (24 and 6 patients, respectively) and 20 (18%) for early-stage favorable HL with ABVD variants. The median age at the time of progression was 33 years.
3 patients (3%) died before a salvage therapy was started. Second-line treatment strategies included reinduction with intensified salvage regimens (77%), conventional chemotherapy (14%), and radiotherapy (8%). Autologous stem cell transplantation (ASCT) was performed in 76% of the patients who had received intensified reinduction chemotherapy, and allogeneic stem cell transplantation in ten (9%) patients. After the first salvage therapy, 42% of all patients achieved a complete remission (CR) and did not require further treatment. In total, 66% of the patient cohort achieved a CR after one or more second-line approaches. Median duration of the first CR was 61 months.
After a median observation time of 7 years, 55 of the patients with primary progressive disease (49%) had died, mostly from progressive or relapsed HL (n=36) or toxicity of salvage treatment (n=10). The majority of the 57 survivors was in CR at the time of analysis; 2 were under treatment for HL and there was no information available for one patient. Median OSp for the entire cohort was 83 months, 5-year OSp was 55.4% (95%-CI, 46% to 65%). Since OSp differed among patients of different initial stages and types of pre-treatment (early-stage favorable and unfavorable patients treated with ABVD variants, OSp 74.2% [61%-87%] vs. higher-stage patients treated with BEACOPP variants, OSp 42.9% [31% - 55%]), treatment groups were analyzed for survival separately. In both groups, patients responding to the first salvage therapy had a significantly better OSp compared to those not responding (each p<0.001). OS was significantly worse in patients with primary progressive disease when compared to the complementary study cohort in both treatment groups (each p<0.001). When comparing patients with primary progressive disease with those patients with a relapse of HL (n=272), there were significant advantages of the latter regarding OS and OSp within the BEACOPP-pre-treated subgroup (each p<0.001). In patients pre-treated with ABVD variants, there was also a significant difference in OS (p=0.007), but no detectable difference regarding OSp (5-year OSp 74% vs. 78%, p=0.3).
Conclusion: Overall, the 5-year OSp in this unselected patient cohort of primary progressive HL patients is encouraging and supports the use of aggressive salvage regimens and consolidating high-dose chemotherapy in general. However, this approach is known to induce severe long-term toxicities and has limited efficacy in patients failing first-line treatment for advanced stage disease. We conclude that there is a need to develop different treatment approaches in primary progressive HL patients.

Disclosures
von Tresckow: Novartis: Consultancy, Other: Travel and accomodation, Research Funding; Amgen: Other: honoraria for preparation of scientific educational events; Celgene: Other: honoraria for preparation of scientific educational events; Takeda: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Engert:Takeda: Consultancy, Research Funding. Borchmann:Millennium: Research Funding.