Allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma in Switzerland, 20 years of experience: 2001–2020

Abstract Despite the high cure rate with initial therapy, approximately 10% of Hodgkin lymphoma (HL) patients are refractory to initial treatment, and up to 30% of patients will relapse after achieving initial complete remission. Despite promising initial results of treatment by immune checkpoint inhibitors, most patients will eventually progress. We analyzed 62 adult patients with relapsed or refractory HL (rrHL) treated by allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in one of three University Hospitals of Switzerland (Zurich, Basel, and Geneva) between May 2001 and January 2020. The primary endpoint was overall survival (OS). Secondary endpoints were relapse‐free survival (RFS), non‐relapse mortality (NRM), and relapse incidence, which were assessed in univariate analysis. The median follow‐up was 61 months (interquartile range 59–139). The 2‐ and 5‐year OS was 54% (standard error (SE) ±12) and 50.2% (SE ±13.3), respectively, and the 2‐ and 5‐year RFS was 40.7% (SE ±16.3) and 34.4% (SE ±19.0), respectively. NRM was 23.1% (SE ±2.2) and 27.4% (SE ±2.5) at 2 and 5 years, respectively. The cumulative incidence of relapse was 36.1% (SE ±5.6) at 2 years and 38.2% (SE ±6.6) at 5 years. Our analysis of allo‐HSCT outcomes in the context of rrHL shows encouraging OS and RFS rates, with the mortality rate reaching plateau at 50% at 2 years after allo‐HSCT. This confirms that allo‐HSCT still remains as a potentially curative option for half of patients with rrHL.


INTRODUCTION
Despite the high cure rate with frontline therapy, up to 30% of Hodgkin lymphoma (HL) patients will relapse after achieving complete remission (CR) or will develop primary refractory disease (rrHL)  [1,2]. Targeted therapies such as checkpoint inhibitors (CPI) and anti-CD30 monoclonal antibodies (brentuximab vedotin, BV) yield promising results with high response rates in rrHL [3]. However, most patients with rrHL would eventually relapse or progress [2]. For eligible rrHL patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) currently remains the last potentially curative option, leading to sustainable remission in approximately 50% of these patients [2]. The role of allo-HSCT in rrHL patients has been controversial due to the high rates of non-relapse mortality (NRM) [4]. However, allo-HSCT represents the potentially curative treatment in this setting [1].
Here, we report a retrospective, multicenter, registry-based analysis (Swiss Blood Stem Cell Transplantation and Cellular Therapy, SBST) of the Swiss experience in allo-HSCT for HL from 2001 to 2020.

MATERIALS AND METHODS
We retrospectively collected the data from 62 patients with HL treated with allo-HSCT in three University Hospitals of Switzerland (Zurich, Basel, and Geneva) between May 2001 and January 2020. The primary endpoint was overall survival (OS). Secondary endpoints were relapse-free survival (RFS), NRM, and relapse incidence (RI), which were assessed by univariable analysis.

RESULTS
The  (Table 1 and Figure 1).

DISCUSSION
First reports on the outcomes of allo-HSCT in HL described quite discouraging results. In 1996, Gajewski et al. [5] reported a 3-year probability of survival at around 21% and a 3-year disease-free sur-vival rate as low as 15%. Since then, the introduction of RIC regimens, improvement of supportive care, and graft-versus-host disease (GvHD) prevention and treatment have contributed to better outcomes and lower NRM rates [6][7][8][9].
As for other hematologic diseases, the application of allo-HSCT in rrHL has been expanded in HL by alternative (haploidentical) donor's usage [10,11]. This was possible because of constant improvement of peri-transplant treatment, including lower toxicity by the usage of new agents such as BV and CPI and better GvHD control in early post-transplant period by cyclophosphamide and antithymocyte globulin usage [10,12,13]. Because of the high efficacy, BV and CPI and their combinations are now under extensive investigation for optimal bridging strategies prior to allo-SCT [13][14][15].
Thus, the constant improvement of peri-transplant settings allows the patient to obtain higher survival results than previously reported [1]. A previous analysis of disease outcome of 709 HL patients treated by allo-HSCT (EBMT register) published in 2020 showed a 3-year OS as high as 77% and a 3-year progression-free survival of 63% [11].
Our analysis of allo-HSCT outcomes in the context of rrHL also shows encouraging 5-year OS and RFS rates, with the mortality rate reaching a plateau at 50% at 2 years after allo-HSCT. Relatively high NRM rates in this young population could be explained by accumulated toxicities after multiple pre-transplant treatment lines.
This is the first study of allo-HSCT outcomes in patients with rrHL in Switzerland. The analysis is retrospective and register-provided (SBST), so it lacks some important details, for example, regarding the number and type of pre-transplant treatments as well as the full information about type and incidence of GvHD. We still believe that this brief survival extraction could be considered a very important message for allo-HSCT in the setting of rrHL.

CONCLUSION
The results of this retrospective study suggest that allo-HSCT may be a viable treatment option for the difficult-to-treat population of rrHL.