Allogeneic Hematopoietic Stem Cell Transplantation for Congenital Immune Dysregulatory Disorders

Abstract

Primary immunodeficiency disorders that predominantly affect immune regulation and mechanisms of self-tolerance have come into the limelight, because at least for a subgroup of monogenetic disorders, a targeted therapy has become available. Nevertheless, their management often involves the treatment of severely compromising, refractory, multi-organ autoimmunity, leading to further increased susceptibility to infections and complications of long-term immune suppressive treatment, including the risk of malignancy. While evidence for allogeneic hematopoietic stem cell transplantation (alloHSCT) as a curative treatment option for severely affected patients by this disease category accumulates, clear indications, and guidelines for alloHSCT are lacking. Predictive and stratification-relevant tools such as disease activity scores are largely missing and often there is not a consistent genotype-phenotype correlation within the same family to facilitate the decision whether to transplant or not. In this review, we provide a literature-based update on indications and outcomes of alloHSCT for congenital immune dysregulative inborn errors of immunity according to the IUIS classification 2017.

EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity

“…Background. An increasing number of diseases of immune dysregulation are emerging which may be amenable to treatment with HSCT [13,86]. These include T regulatory cell defects such as IPEX syndrome and CTLA4 deficiency and immune dysregulation with colitis.…”

“…Targeted biological agents such as abatacept or ruxolitinib are increasingly available and can result in significant reduction in disease activity, but the complications of long-term use of these agents could be significant. Use of these agents as a bridging therapy to optimize condition of the patient prior to transplant is recommended [ 86 ]. Molecular diagnosis is important particulary in Very-early-onset Inflammatory Bowel Disease, as HSCT is not indicated for an enteropathy due to an epithelial defect [ 95 , 96 ].…”

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey

“…The results suggest that a large proportion of these rare diseases have required HCT and provide preliminary overview of HCT outcomes. While previous reports of HCT survival in selected PIRD genotypes have ranged from 40 to 80%, this is the first attempt to gain a broader overview of HCT outcomes for clinical features of "immune dysregulation" (2,3,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). For this reason, the study was intentionally broad in scope and captured only a limited data set of key clinical features and outcomes from these patients.…”

Germline STAT3 gain-of-function mutations in primary immunodeficiency: Impact on the cellular and clinical phenotype

“…Out of 6 published patients 4 have died from complications after HSCT. In a recent survey by the EBMT 11/18 patients survived HSCT [ 93 ]. However, these numbers are still too small to judge the risks associated with HSCT and to appropriately weigh these risks against the spontaneous evolution of the disease including long-term immunosuppressive therapies.…”