Allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency

Abstract

With recent advances in genetic sequencing and its widespread adoption for clinical diagnostics, the identification of a primary immunodeficiency (PID) as the underlying cause of diseases presenting to hematologists including refractory autoimmunity, cytopenias, immune dysregulation, and hematologic malignancy, is increasing, particularly in the adult population. Where the pathogenic genetic variants are restricted to the hematopoietic system, selected patients may benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although it is generally accepted that early allo-HSCT (ie, in infancy or childhood) for PID is preferable, this is not always possible. The clinical phenotype of non–severe combined immune deficiency forms of PID can be very heterogeneous, in part because of the high number of genetic and functional defects affecting T, B, and natural killer cells, neutrophils, and/or antigen presentation. As a result, some patients have less severe disease manifestations in childhood and/or a later de novo presentation. For others, a delayed diagnosis, lack of a genetic diagnosis, or a previous lack of a suitable donor has precluded prior allo-HSCT. Specific issues which make transplantation for adult PID patients particularly challenging are discussed, including understanding the natural history of rare diseases and predicting outcome with conservative management alone; indications for and optimal timing of transplant; donor selection; conditioning regimens; and PID-specific transplant management. The role of gene therapy approaches as an alternative to allo-HSCT in high-risk monogenic PID is also discussed.

A Case of Two Adult Brothers with Wiskott-Aldrich Syndrome, One Treated with Gene Therapy and One with HLA-Identical Hematopoietic Stem Cell Transplantation

“…The following are members of the San Raffaele Hospital Consortium: Pina Brianti 4 , Jacopo Peccatori 5 , Sarah Markel 2,5 , Fabio Giglio 5 , Saverio Ladogana 6 , Lucia Dora Notarangelo 7 , Maria Ester Bernardo 1,2,3 , Fabio Ciceri 2,3,5 , Antonio Bognanni 3 , Maddalena Migliavacca 1,2 , Federica Barzaghi 1,2 , Valeria Calbi 1,2 , Francesca Tucci 1,2 , Vera Gallo 1,2 , Francesca Dionisio 2 , Stefania Giannelli 2 , Sabina Cenciarelli 1,3 , Francesca Ciotti 1 , Federico Fraschetta 1,2 , Miriam Casiraghi 1,2 , Giovanni Paolino 4 , Santo Raffaele Mercuri 4 . 4 Unit of Dermatology, IRCCS San Raffaele Scientific Institute, Milan, Italy 5 Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy 6 Department of Hematology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 7 Children's Hospital, ASST-Spedali Civili, Brescia, Italy…”

“…Indeed, despite the great improvement in transplantation procedures, allogeneic HSCT for WAS aged > 5 years is still associated with less favorable outcomes. As a consequence, HSCT is now evaluated individually for each patient [ 7 ] and HSPC-GT is emerging as a tailored therapeutic alternative with a potentially more favorable benefit/risk ratio.…”

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

“…6 HSCT for older adolescents and adults with IEI was uncommon until recently, mainly due to perceived high risks of transplantrelated mortality, and was reserved as a last resort for patients with excessive morbidity. [7][8][9] Indeed, initial publications on HSCT for adults with common variable immunodeficiency (CVID) reported disappointing survival rates of ~50% in patients who had acquired significant organ damage pre-HSCT. 10 In contrast, adolescents and very young adults with limited IEIrelated morbidity can expect excellent outcomes very similar to their pediatric counterparts.…”

Tailored treatments in inborn errors of immunity associated with atopy (IEIs-A) with skin involvement

“…Full chimerism seems to decrease the incidence of post-HSCT autoimmune diseases and chronic inflammation. Of note, some clinical features of the syndrome, such as AD, may persist in a percentage of patients after transplantation ( 17 ).…”