BEAM Vs Cyclophosphamide-Based Conditioning Regimen in Aggressive Multiple Sclerosis: A Retrospective Analysis of European Blood and Marrow Transplantation Society
Authors: Saccardi Riccardo , Badoglio Manuela , Burman Joachim , Helbig Grzegorz , Kazmi Majid A. , Mancardi Giovanni , Mielke Stephan , Moore John , Muraro Paolo , Sanz Jaime , Sharrack Basil , Smilowski Marek , Sormani Maria Pia , Snowden John A 
Published: November 2019

Background
Multiple Sclerosis (MS) is a chronic, immuno-mediated disease of Central Nervous System (CNS), mostly affecting young adults and frequently resulting in a progressive, irreversible disability despite the administration of approved Disease Modifying Treatments (DMTs). Autologous HSCT was shown to induce a high rate of sustained, treatment-free remissions in cases of aggressive MS, seldom associated to a partial reversal of disability. Toxicity of Conditioning Regimen is still a major concern. We retrospectively analyzed the outcome of 926 MS patients reported to the EBMT Registry who underwent autologous HSCT following the two most frequent CRs for this indication in the last 20 years.
Patients and Methods
Patient data were extracted from both the EBMT database and a disease-specific database developed by the EBMT Autoimmune Diseases Working Party (ADWP). Patients were selected for having received either BEAM + ATG (BEAM) or HD-Cyclophosphamide + ATG (CYC) as conditioning regimen. Hematological toxicity was assessed through Neutrophil (PMN) engraftment and 100-days (early) mortality (eTRM). MS forms at HSCT were reported as Relapsing-Remitting (RR), Secondary Progressive (SP), Primary Progressive (PP) and Progressive-Relapsing (PR). The impact of variables related to both patients (age, gender, year of HSCT, EDSS at HSCT) and disease characteristics (MS form, interval diagnosis-HSCT) at HSCT in the two groups were also evaluated.
Results
The utilization of conditioning regimens along the observed time period (1998-2018) was variable, with an increase of the HSCT activity in general after 2010 (230 vs 697 procedures) and a prevalence of BEAM before 2010 (205 BEAM vs 25 CYC) and of CYC thereafter (205 BEAM vs 492 CYC, p=0.001). Also, RR forms of MS prevailed over Progressive forms after 2010 (p=0.001) which is reflected in the different distribution across the two regimens, with RR significantly more frequently treated with CYC-based regimen (p<0.001). Gender distribution and age at HSCT was similar in the two groups (p=ns), whilst the interval between diagnosis and HSCT was longer in BEAM group than CYC (8.47 years ± 5.9 vs 7.57 ±5.5, mean ± SD, p=0.012). PMN engraftment in BEAM/ATG- and CYC/ATG-treated patients occurred at +11.0 (8-42) and +10.9 (8-95) days, respectively (median and range, p=ns). Overall eTRM was low (1.4%), but slightly higher in BEAM over CYC (8/402, 2% vs 5/517, 1%, p=ns).
Discussion
Although autologous HSCT is increasingly used as a treatment in highly active MS, toxicity remains a principal concern in the neurological community despite a marked decrease of TRM over time. The intensity of conditioning regimens has varied in the literature, but the best toxicity/efficacy ratio remains unclear. The non-myeloablative regimen CYC-ATG has become the most common conditioning regimen despite a lack of comparative data with more intense regimens. In our large retrospective analysis of the two most frequent conditioning regimens in the EBMT Registry, there was no significant difference in major toxicity indicators despite differences in chronological period and patients characteristics in the two groups. Comparative analysis of neurological efficacy is currently ongoing and will inform the toxicity/efficacy ratio and clinical choice of conditioning regimen in autologous HSCT in MS.

Disclosures
Mielke: Bellicum: Consultancy, Honoraria, Other: Travel (via institution); Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; IACH: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; DGHO: Other: Travel support; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; ISCT: Other: Travel support; EBMT/EHA: Other: Travel support.