Successful Outcome Following Allogeneic Haematopoietic Stem Cell Transplantation in Adults with Inherited Primary Immunodeficiency (PID)
Authors: Morris Emma C , Fox Thomas Andrew , Burns Siobhan , Carpenter Ben , Thomson Kirsty J , Lowe David , Fielding Adele K. , Peggs Karl S , Kottaridis Panagiotis , Grandage Victoria , Denovan Shari , Grace Sarah , Dahlstrom Julia , Workman Sarita , Symes Andrew , Mackinnon Stephen , Chakraverty Ronjon , Hough Rachael 
Published: October 2019

Abstract
The primary immunodeficiencies (PID) are rare inherited diseases characterised by severe dysfunction of adaptive and/or innate immunity. Over 200 distinct PIDs have been described, with 20 of them accounting for > 90% cases. The 3 most common PIDs are severe combined immunodeficiency (SCID), Wiskott Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). Many have been successfully treated by allogeneic hematopoietic stem cell transplantation (Allo-HSCT), however, almost all published series to date have focussed on paediatric patients. In the largest published series, the median age at transplant is < 1 year for SCID, 12.7 years for CGD, and 3 years for WAS.
Early Allo-HSCT is preferred for PID patients, but not always possible. Delayed diagnosis and 'milder' clinical phenotypes may delay treatment with curative intent. With improved supportive care PID patients are more likely to survive to early adulthood without Allo-HSCT, despite serious co-morbidities. Furthermore, for several PIDs, controversy surrounding optimal timing of Allo-HSCT remains due to rarity of disease and lack of experience. Furthermore, Allo-HSCT for older adolescents and adults with PID has previously been avoided due to severe TRM and poor outcomes.
Here we report the largest group of consecutive adult PID patients described to date (n=27) who underwent Allo-HSCT in the adult HSCT programme of University College London. The mean age was 24 years (range 17-50) at transplant. Of these, 11 patients had X-linked or autosomal recessive CGD and 16 had other inherited PID, including CVID (1 with T-NHL, 1 with HLH, 1 with GLILD) (n=3), autoimmune LPD (1 Fas mutation) (n=2), X-linked LPD (n=1), DCML +/- Gata2 mutation (n=2), Gata2 Defic (n=1), Cg-SCID (n=1), CID with CD27 Defic (1 with HL and DLBCL, 1 with HL) (n=2), NK Defic (n=1), AR IL12 Recb Defic (n=1), XIAP with Crohn's and HLH (n=1) and Rag2 compound heterozygote with red cell aplasia (n=1). Stem cell donors were matched unrelated (MUD) (n=14), mismatched unrelated (MMUD) (n=5, all 1 Ag mismatch) or matched related donors (MRD) (n=8). Stem cell source was PBSC (n=20) and BM (n=7).
Reduced intensity conditioning was used in 26 patients including Flu/Mel/Alemtuzumab (n=17), Flu/Bu/Alemtuzumab (n=8) and Flu/Bu/ATG (n=1). One patient underwent myeloablative conditioning with Flu/Cy/TBI. Additional GVHD prophylaxis with cyclosporine was used in all patients. Reverse isolation, antimicrobial and antifungal prophylaxis were used to reduce the risk of infectious complications. Acute and chronic GVHD incidence and severity and time to engraftment, lineage specific chimerism, immune reconstitution and discontinuation of immunoglobulin replacement therapy were recorded.
Overall survival (OS) at 2 years for all patients was 85.6%, and by donor was 75% for MRDs (n=8) and 89.5% for MMUD/MUD (n=19) with a mean follow up of 35 months (range: 7 to 11 years 1 month). Analysis of outcome by diagnosis demonstrated OS at 2 years of 81.8% for CGD patients (n=11) and 87.5% for other PIDs (n=16).
TRM was low with only four deaths observed at a median follow-up of 22 months (n=27). 2 patients died of multi organ failure and sepsis prior to engraftment, one at 7 months post-HSCT of granulomatous meningitis and grade III aGVHD and one at 28 months post-HSCT of sepsis in the context of chronic extensive GVHD.
8 patients developed grades I-II aGVHD (6 skin only, 1 involving the gut and 1 progressing to chronic lung GVHD). GVHD had resolved in all but one patient at last follow up. For all patients, neutrophil and platelet engraftment occurred after a median of 12 and 14 days respectively.
Peripheral blood chimerism was available for 22 of the 23 surviving patients at last follow up. Multilineage full donor chimerism was observed in 8 (36%) with mixed chimerism observed in at least one cell lineage tested for the remainder. At 1-year post transplant, 80% of those tested had achieved a normal lymphocyte count (1.0-2.8 x 109/L), 47% had normalization of absolute CD3+ count (0.7-2.1 x 109/L), 40% had a normal CD4+ count (0.3-1.4 x109/L) and 87% had normalisation of their CD8+ cell count (0.2-0.9 x109/L).
Allo-HSCT is well tolerated in this patient group and should be considered as an alternative therapeutic option in PID patients not transplanted in childhood where an appropriate donor is available. Triggers for referral should include life threatening infections, malignancy, severe autoimmunity and refractory disease.

Disclosures
Fielding: Baxalta: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.