Introduction:
Inborn errors of immunity (IEI) are a group of rare heterogeneous diseases. Currently, more than 400 monogenetic IEI have been identified and increasingly a genetic diagnosis can be made in patients with an immune deficiency disorder [1]. Patients may present with a variety of clinical symptoms including a broad spectrum of infections, inflammatory manifestations, auto-immune phenomena and malignant diseases. Treatment by hematopoietic stem cell transplantation (HSCT) is increasingly successful [2,3,4,5,6,7,8,9,10] and the joint EBMT/ESID Inborn Errors Working Party (IEWP) has played a pivotal role designing and developing common HSCT guidelines, which have contributed to this success.
The wide clinical heterogeneity of patients, together with the fact that outcome data are based on observational rather than prospective studies, means that it is not yet possible to recommend strictly defined protocols for transplanting IEI patients. The current guidelines provide recommendations based on published data, center experience and expert opinions. Whenever possible, the individual transplant protocol should follow these guidelines, but modifications may be necessary according to the particular variant of the IEI and/or the patient’s clinical condition. For all these reasons the IEWP strongly recommends that all patients with primary immunodeficiency are transplanted in an experienced center that regularly transplants such patients, and also actively participates in the IEWP, as only in this way continuous improvement in outcomes can be achieved.
The prognosis of survival for some patients with IEI extends for years and even decades with conservative therapy alone. In those, the decision in favor or against HSCT or other cellular therapies can be extremely challenging. This decision needs to consider multiple factors such as clinical presentation, past and current infections, immunophenotype, genotype, autoimmune manifestations, current and anticipated future organ damage, family history and family experience with the disease, psychological and social factors such as quality of life and fertility, and informed consent not only of caregivers but also patients themselves. In case of a decision for a conservative treatment strategy, this should be re-evaluated on a regular basis by a team, which is informed about and experienced in all currently available therapeutic options. Centers are strongly advised to register their transplanted patients in the EBMT, ESID, and SCETIDE registries, which will allow continuous evaluation of the outcomes in transplanted IEI patients treated in line with IEWP guidelines.
Patients with IEI frequently present with or develop autoimmune or inflammatory complications eg, autoimmune cytopenias and inflammatory bowel disease as their sole clinical phenotype [11]. In recent years, monogenetic defects are increasingly identified in patients with primary immune regulation disorders (PIRD [12]). Awareness of the possibility that a monogenetic IEI may be the underlying defect in patients with aforementioned disease manifestations is pivotal in their clinical management and may provide the rationale for allogeneic HSCT as a curative approach [13].
In recent years, stem cell gene addition therapy (GT) has been explored for a limited number of IEI, including ADA-SCID, X-linked SCID, XL-CGD, and WAS. A retroviral ADA GT product (Strimvelis®) is licensed by the European Medicines Agency, and recently excellent results have been reported with lentiviral-based ADA GT [14]. There are ongoing clinical studies in a variety of other IEI [15]. GT offers the potential advantage of avoiding the negative consequences of alloreactivity (GVHD), but concerns remain about the curative potential of a mixed chimeric state in non-SCID IEI, which is inherent to current GT approaches, and the possible risk for insertional mutagenesis (although no vector related adverse events have been reported with lentiviral vectors). However, in the absence of comparative studies it is extremely difficult to make firm recommendations on the hierarchial position of GT in comparison to conventional HSCT. It has to be considered that: (a) long-term safety and efficacy data of GT are still limited, and (b) comparing outcome data from prospective single- or oligocentre studies (as is the case for GT) with retrospective multi-center studies (as most of the evidence for HSCT) does not meet the scientific standard and is therefore suboptimal. Currently, participation in a GT study may be considered for patients lacking a matched donor and able to travel to a respective study center.
The IEWP guidelines are reviewed periodically and retrospective studies are regularly performed on behalf of IEWP to evaluate and compare clinical outcomes of patients with specific disease entities treated according to these guidelines [3, 9, 16]. These studies are instrumental to periodically revise and update the guidelines for specific conditions.
EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity. Bone Marrow Transplant 56, 2052–2062 (2021). https://doi.org/10.1038/s41409-021-01378-8
