To the Editor:
Autologous hematopoietic stem cell transplantation (HSCT) is a therapeutic option for severe/refractory autoimmune diseases (AD) [1, 2] and is now considered standard of care for highly active relapsing-remitting multiple sclerosis (MS) failing disease modifying therapies and early severe diffuse-cutaneous systemic sclerosis (SSc) [3,4,5]. While multiple conditioning regimens exist, EBMT guidelines recommend Cyclophosphamide-anti-thymocyte globulin (Cy-ATG) and BEAM-ATG [1].
Polyclonal anti-thymocyte globulin (ATG) is commonly used in most conditioning regimens. Other monoclonal antibodies such as alemtuzumab and rituximab are also used, sometimes in combination with ATG [6, 7]. The use of ATG reflects a form of in vivo T-cell depletion, which concomitantly depletes host T-cells, along with other immune cells of lymphoid linage, that have survived the conditioning regimen while similarly depleting T-cells that are reinfused with the graft, contributing to the immune resetting [8] related to HSCT procedure.
To date, the choice of anti-T cell serotherapy largely depends on availability, center preference, and/or enrollment in clinical trials. Through a collaborative initiative of the ADWP, we evaluated the current real-word clinical practice among EBMT centers on the use of ATG and other serotherapy in conditioning regimens for HSCT in AD. Such information may allow to optimize and harmonize ATG administration schemes across centers, with the goal of maximizing benefits of HSCT while reducing adverse effects.
This study followed the EBMT study guidelines. All EBMT centers having performed more than 5 HSCT for AD in adult patients since 2015 were invited to the survey. A web-based limited/closed questionnaire (Supplementary Materials) has been developed and sent to leaders of centers for completion directly or by delegates. Data collection and statistical analysis were performed by the ADWP Data Office (Paris). The answers given by centers were summarized using descriptive statistics.
Forty-six EBMT centers (66%) from 18 countries responded to the survey. Among responding centers, 11 (23.9%) perform HSCT for neurological AD indications, 7 (15.2%) for rheumatological ADs, 1 (2.2%) for hematological ADs and 27 (58.7%) for multiple indications. All centers use ATG. Twelve centers (26.1%) use rituximab in addition to ATG, none of the centers currently uses alemtuzumab.
The conditioning regimens, serotherapy type and total dose (TD) used by centers are shown in Table 1.
Twenty-seven centers (58.7%) use the same conditioning regimen for all AD indications. Cy-ATG is the most frequently used regimen across EBMT centers, followed by BEAM-ATG, whereas reduced-intensity conditioning regimens like cyclophosphamide-fludarabine-ATG are used less frequently. Most centers (93.5%) use ATG for all AD indications. Only one center uses a serotherapy-free regimen (cyclophosphamide only), for neurologic indications.
Several types of ATG exist, including rabbit ATG of various brands (Thymoglobulin®/Sanofi-Genzyme and Grafalon®/Neovii), horse-ATG and goat-ATG [7]. Moreover, timing and dosage of administration of ATG in the conditioning scheme can vary considerably [7]. Thymoglobulin is the most commonly used ATG type (41 centers, 89.1%). Among centers using Thymoglobulin, 32.6% administer a TD of 7.5 mg/kg, while 53.6% administer <7.5 mg/kg and 4.3% >7.5 mg/kg. Four centers report using Grafalon, each center a with a different TD, and one center uses Atgam. ATG administration is always fractionated over multiple days, 3 days for 15 centers or 5 days for 17 centers; half of the centers divide the TD equally for each day of administration.
Twenty-nine centers administer ATG during chemotherapy (63%), especially if Cy-ATG is used, while rituximab is administered before chemotherapy in 3 centers, during chemotherapy in 1 center, after HSCT infusion in 2 centers, or before chemotherapy and after cell infusion in 6 centers.
A test dose is used by 16 centers before ATG administration (ranges 0.28–25 mg or 0.5–1 mg/kg). None of the centers uses a rituximab test dose. The variability of reported doses for ATG test dose shows that some centers administer a lower ATG dose in the first day of administration and reported it as “test dose”. ATG administration is slow: 22 centers (48.9%) administer it over 12 h, 7 (15.6%) over 8 hours, 7 (15.6%) over 6 h. Rituximab is mainly administered over 4 hours (5 centers) or 6 h (5 centers).
Class-related adverse effects of serotherapy include acute infusion-associated reactions, consistent with cytokine-release syndrome, anaphylaxis and other allergic phenomena [9, 10]. Premedication is used to prevent serotherapy-related adverse events, including antihistamines (100% of centers), paracetamol (91.1%) and steroids (98%); details are shown in Table 1. Fifteen centers repeat the premedication at fixed times during a single infusion, typically every 4 h (7 centers) or 8 h (3 centers).
In 37 (80.4%) centers, the planned TD of ATG is successfully administered to all patients. Nine out of 12 centers administer the TD of rituximab to all patients. Our survey revealed that most centers experience transient disease-related symptoms during serotherapy and conditioning. Among 36 centers performing HSCT for neurological ADs, pseudo-relapse [11] was reported by 12 centers treating MS, by 4 centers treating neuromyelitis optica (NMO) and by 5 centers treating chronic inflammatory demyelinating neuropathy (CIDP). Only one center treating MS reported Uhthoff’s phenomenon, ie short-term and stereotyped worsening of neurological function among MS patients in response to increases in core body temperature. Centers treating myasthenia gravis reported various symptoms typical of this disease: ptosis (2 centers), respiratory failure (2 centers), dysphagia (1 center), limb weakness (1 center). Among fourteen centers treating gastroenterological ADs, 3 centers reported clinical signs of disease activity during serotherapy when treating Crohn’s disease. Among twenty-nine centers performing HSCT for rheumatological diseases, in particular SSc, cardiac toxicity was reported by 14 centers, renal crises by 8, interstitial pneumonitis by 10 and pulmonary failure by 10. Few centers have performed HSCT in systemic lupus erythematosus, but 2 of them reported disease relapse involving a vital organ during serotherapy. Steroids have been associated with renal crises, however, with the limits of a survey-based study, we found no difference in steroid dose used by centers treating rheumatological diseases reporting renal crises and centers not reporting them.
Interestingly, some centers reported no experience of neurological disease-specific complications (4 centers treating MS, 2 centers treating NMO, 2 centers treating CIDP) while all centers treating SSc reported complications during serotherapy and conditioning. This may reflect the complexity of performing HSCT in SSc patients, whose fitness is crucial for the safety of the procedure [12].
In the management of serotherapy-related adverse events, 28 (62.2%) centers collaborate with Intensive Care, most frequently transferring some patients to the ICU and managing other patients in the Transplant Ward with Intensive care staff assistance (21 centers).
Serotherapy, most commonly including ATG, is a key component of conditioning regimens, contributing to the restoration of immunologic self-tolerance and to induce long term-remissions [7, 8]. This survey reveals a high degree of consistency across EBMT centers regarding the choice of rabbit ATG and Cy-ATG regimen. There is still a high variability in doses, both TD and schemes to fractionate the doses, in current practice, with a general trend towards low ATG-TD. Moreover, different medications, in particular different types of ATG, are not equally available in different countries. Supportive care measures, including slow infusion and premedication with high dose steroids, allow most centers to infuse the planned TD to all patients, although the optimal premedication and infusion scheme allowing to maximize the number of patients receiving the planned TD is still open to debate. Even though ATG dosing is based on ATG type, body weight and schedule of administration, ATG pharmacokinetics also depends on the number of lymphocytes in the blood, lymph nodes, and bone marrow at the time of treatment. In the setting of allogeneic transplant for hematologic malignancies, suboptimal ATG exposure has been associated with the main transplant outcomes [13]. Similarly, ATG exposure in SSc patients treated with autologous HSCT was shown to be higher in HSCT responders than in non-responders, even with the same weight-based ATG dose and administration schedule [14]. How to modulate ATG administration schemes in order to optimize ATG exposure, also according to the specific disease indication, is still an open research question.
Few centers use rituximab, all in addition to ATG, mainly in rheumatological diseases (75% of centers), though not exclusively. Interestingly, alemtuzumab is currently not used by centers in the context of HSCT for ADs.
In conclusion, these results suggest the need for improved reporting and communication between centers performing HSCT in ADs to foster collaborative and comparative research studies in the future, including patient-level studies starting from the EBMT registry and expanding to multicenter, prospective trials, detailing serotherapy administration schemes in relation to serotherapy-related adverse events and patient outcomes, including ATG pharmacokinetics. These include a larger heterogenous cohort of treated patients allowing more robust statistical analysis, wider generalization and pooling of protocols and costs. The aim is to identify commonalities and opportunities to reduce variations and inequalities in practice across healthcare systems, with the goal of offering similar treatment schemes to similar patients. The results of these studies may translate into consensus guidelines (developed in cooperation between transplant and disease specialists) to best standardize practice on serotherapy administration and improve patients’ outcomes.
Data availability
The final analysis dataset will be available upon specific request to the Working Party chair.
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Acknowledgements
We are grateful for the support by EBMT and ADWP without which this work would not have been possible. The authors thank the EBMT Paris Office, EBMT centers for their contributions to the EBMT registry and those active in the ADWP. We are grateful to the all the EBMT affiliated centers contributing to this survey: St. Vincent’s Hospital, Kinghorn Cancer Centre, Sydney, Australia; Antwerp University Hospital (UZA), Antwerp Edegem, Belgium; FOSCAL Internacional of the FOSUNAB Foundation, Floridablanca, Colombia; Instituto de Cancerologia S.A, Medellin, Colombia; University Hospital Ostrava, Ostrava, Czech Republic; North Estonia Medical Centre, Tallinn, Estonia; Tartu University Hospital, Tartu, Estonia; CHU Lapeyronie, Montpellier, France; Hôpital Saint-Louis, APHP, Université Paris, Paris, France; Hopital Saint Antoine, Paris, France; Hopital La Miletrie, Poitiers, France; ICANS - Institut de cancérologie Strasbourg Europe, Strasbourg, France; CHU - Institut Universitaire du Cancer Toulouse, Toulouse, France; Medizinische Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany; University Hospital Eppendorf, Hamburg, Germany; Universitaet Tuebingen, Tuebingen, Germany; Universitaetsklinikum Wuerzburg, Wuerzburg, Germany; Rambam Medical Center, Haifa, Israel; ASST Papa Giovanni XXIII, Bergamo, Italy; Ospedale Policlinico, Catania, Italy; Azienda Ospedaliera Universitaria Careggi, Firenze, Italy; Fondazione IRCCS - Ca Granda, Milano, Italy; IRCCS Ospedale San Raffaele, Milano, Italy; U.O.D Trapianti di midollo osseo, Palermo, Italy; Unità Operativa di Ematologia, Ravenna, Italy; Hospital C. Panico, Tricase Lecce, Italy; Leiden University Hospital, Leiden, The Netherlands; Nijmegen Medical Centre, Nijmegen, The Netherlands; University Medical Centre, Utrecht, The Netherlands; Haukeland University Hospital, Bergen, Norway; Oslo University Hospital, Rikshospitalet, Oslo, Norway; RM Gorbacheva Research Institute, Pavlov University, St Petersburg, Russia; King Abdul - Aziz Medical City, Riyadh, Saudi Arabia; Singapore General Hospital, Singapore, Singapore; Wits Donald Gordon Medical Centre, Johannesburg, South Africa; Hospital Clinic, Barcelona, Spain; Hospital Universitario Central de Asturias, Oviedo, Spain; Clínica Universitaria de Navarra, Pamplona, Spain; Hospital Clínico de Valencia, Valencia, Spain; University Hospital La Fe, Valencia, Spain; Skanes University Hospital, Lund, Sweden; University Hospital | Uppsala, Uppsala, Sweden; London Bridge Hospital, London, United Kingdom; Kings College Hospital London, London, United Kingdom; St. Bartholomew’s Hospital London, London, United Kingdom; Sheffield Royal Hallamshire, Sheffield, United Kingdom.
Funding
The EBMT provided resources via the working party, data office and registry. Other than EBMT support there is no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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AI, RN, JAS and RG led on concept and design, provided expert and analytical feedback, and worked as a writing committee. MB and PA prepared and conducted survey and prepared data. ML analyzed the data. All authors contributed to the analysis and interpretation of data. All authors critically reviewed first a preliminary and then the final version of the manuscript.
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RG discloses speaking honoraria from Biotest, Pfizer, Medac, Neovii and Magenta. TA received study support from Amgen, Janssen and honoraria from Neovii, GSK, Astra-Zeneca, Abbvie. JAS discloses consultancy for Vertex, Medac and Jazz, and advisory board from Kiadis. None of the mentioned conflicts of interest were related to financing of the content of this manuscript. The remaining authors have nothing to declare.
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Ismail, A., Nitti, R., Sharrack, B. et al. ATG and other serotherapy in conditioning regimens for autologous HSCT in autoimmune diseases: a survey on behalf of the EBMT Autoimmune Diseases Working Party (ADWP). Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02383-3
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DOI: https://doi.org/10.1038/s41409-024-02383-3