Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71% and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) GVHD. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and with higher HCT-CI scores. On multivariable analysis EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71% and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) GVHD. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and with higher HCT-CI scores. On multivariable analysis EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.

Allogeneic Hematopoietic Stem Cell Transplantation Activity in Inborn Errors of Immunity in Russian Federation

“…Сertainly, this comparison is limited by expected underreporting of IEI by the Russian registry [ 9 ] and purely pediatric patients included in the current analysis, whilst other registry data included adults. For many years, HSCT in adult patients has not been a common practice for IEI, although this practice has been changing and HSCT became a treatment option for adult patients with IEI [ 30 ]. Unfortunately, HSCT is still limited for adult patients with IEI in Russia.…”

How to optimize outcome of patients undergoing HLA‐matched related haematopoietic stem cell transplantation in acquired and inherited bone marrow failure syndromes

“…Conversely, in iBMFs associated with immunodeficiency/immune dysregulation, a higher myeloablative effect in preparative regimen, preferring reduced-toxicity profile chemotherapy, is commonly pursued as in classical primary immunodeficiencies. 6 The standard conditioning regimen of MRD HSCT in aSAA includes higher dose of Cy (200 mg/kg cumulative) and ATG with or without Flu, 7 while a low dose (200-300 cGy) of total body irradiation (TBI) is suggested in the context of HSCT from alternative donor to reduce the risk of graft failure that is notably higher in immunized aSAA patients. 8 In their paper, the authors emphasize the prominence of immunosuppressive conditioning regimen, including in vivo recipient T-depletion with ATG although in a context of HSCT from MRD, with reducing Cy-dose in both aSAA and non-FA iBMFs of which 7/13 were TBDs.…”

“…Since extra‐haematological complications remain in TBDs a well‐known cause of late mortality post‐HSCT, a careful selection of preparative regimens aimed to minimize the risk of toxicity and improve the long‐term outcome is recommended. Conversely, in iBMFs associated with immunodeficiency/immune dysregulation, a higher myeloablative effect in preparative regimen, preferring reduced‐toxicity profile chemotherapy, is commonly pursued as in classical primary immunodeficiencies 6 …”

The impact of Treosulfan‐based conditioning for inborn errors of immunity: Is dose monitoring crucial?

“…Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative treatment for infants and children with inborn errors of immunity (IEI). 1 The curative potential of allogeneic HSCT was first demonstrated in 1968 and 1969 in patients with severe combined immunodeficiency (SCID). 2,3 The role of HSCT in children with genetically confirmed IEI known to have a poor prognosis with conservative treatment alone is well recognized and supported by clear evidence.…”

“…Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative treatment for infants and children with inborn errors of immunity (IEI) 1 . The curative potential of allogeneic HSCT was first demonstrated in 1968 and 1969 in patients with severe combined immunodeficiency (SCID) 2,3 .…”