Late Events in Patients with Relapsed or Refractory Hodgkin’s Lymphoma Treated with an Autologous Stem Cell Transplantation.
Authors: Sieniawski Michal , Josting Andreas , Canals Carmen , Goldstone Anthony H. , Gramatzki Martin , Blaise Didier , Gisselbrecht Christian , Crawley Charles , Colombat Philippe , Harousseau Jean-Luc , Johnson Peter , Carella Angelo Michele , Sureda Anna , Socie Gerard , Schmitz Norbert 
Published: October 2019

Abstract
Background: Autologous stem cell transplantation (ASCT) has been used as a standard treatment in the management of patients (pts) with relapsed/refractory Hodgkin’s lymphoma (HL) in the last few decades. Long-term side effects of this treatment such as secondary malignancies (SM), organ failure and infertility attract scientific interest. Very little data is available on late events among pts with HL treated with ASCT.
Material and Methods: We retrospectively analysed HL pts treated with an ASCT and registered in the European Group for Blood and Marrow Transplantation (EBMT) Database. Further inclusion criteria were: age at ASCT ≥ 18 years and time of transplantation between 1985 and 1995. Additionally, pts treated with tandem protocols have been excluded. The frequency of late events including incidence of secondary malignancies and non-relapse related mortality (NRM) was evaluated. Univariate and multivariate analyses of risk factors for SM and NRM were performed.
Results: 2289 pts (median age at ASCT 30 years, range 18 – 70) were evaluated; 1408 (61.5%) pts were male. Most patients (76.9%) were in complete or partial remission at the time of transplantation and 23.1% of pts were transplanted with refractory or progressive disease. BEAM was the conditioning regimen most frequently used (57.3%) followed by CBV (29.4%) and other chemotherapy regimens (8.7%); TBI was given to 4.7% of pts. Median follow-up for all pts was 47 months (range 0 – 240). Progression free survival and overall survival at 5 years for the whole series were 39.9% and 46.8%, respectively. 988 pts (43.3%) relapsed after a median time of 8.5 months post-ASCT, 787 of them died and 201 are alive after a relapse. 312 pts died without previous relapse or progression (NRM). The main causes of death were relapse/progression (34%), transplant related mortality (11.4%) and SM (1.5%). Cumulative risk at 10 years for NRM was 14.4%. Sex, disease status at ASCT, year of ASCT (1985 – 1990 vs. 1990 – 1995), stem cell source (BM vs. PB), age > 40 years, conditioning with CBV, conditioning including TBI and time of ASCT after diagnosis > 48 months were significant prognostic factors in multivariate Cox regression analysis for NRM. SM were diagnosed in 74 pts (3.2%): solid tumours in 33 pts (1.4%), MDS/acute leukaemias in 35 pts (1.5%) and NHL in 6 pts. Cumulative risk at 10 years for SM was 4.4%, for solid tumours 2.2% and for MDS/acute leukaemia 1.7%. The significant risk factors in multivariate Cox regression analysis for SM were age at ASCT > 40 years, time from diagnosis to ASCT > 48 months and conditioning with CBV (p<0.05). Age > 40 years was the only significant risk factor for solid tumours and MDS/acute leukaemias in Cox multivariate analysis.
Conclusions: ASCT remains the standard treatment for patients with refractory/relapsed HL. The cumulative risk at 10 years for NRM and for SM was 14.4% and 4.4%, respectively. The cumulative risk for SM among evaluated patients is higher compared with that reported among HL patients after first line treatment and is expected to increase over time due to the rather short median observation time and the slow progression of solid malignancies.