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Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT
Schuetz, C., Gerke, J., Ege, M. J., Walter, J. E., Kusters, M., Worth, A. J. J., Kanakry, J. A., Dimitrova, D., Wolska-Kusnierz, B., Chen, K., et al
Blood. 2022
Abstract
Patients with hypomorphic mutations in RAG1 and RAG2 genes present as either Omenn syndrome or atypical combined immunodeficiency (CID) with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% autoimmunity and 18% granulomas pre-transplant. These complications were frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3 - 42.9 years) from matched unrelated donors, matched sibling or matched family donors or mismatched donors (MMFD) in 48%, 22% and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5 and 67.5% (median follow-up 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft and transplant from a MMFD were predictive of worse outcome, while organ damage and T-cell depletion remained significant in multivariable analysis (HR=6.01, HR=8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences (CI) of acute and chronic GvHD were 35% and 22% respectively. CI of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T-cells was faster and more robust in patients transplanted before 3.5 years and without organ damage. These findings support the indication for early transplantation.
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Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome: an EBMT inborn errors working party analysis
Albert, M. H., Slatter, M. A., Gennery, A. R., Güngör, T., Bakunina, K., Markovitch, B., Hazelaar, S., Sirait, T., Courteille, V., Aiuti, A., et al
Blood. 2022
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients transplanted at EBMT centers between 2006 and 2017, who received conditioning as recommended by the inborn errors working party (IEWP): either busulfan (n=103) or treosulfan (n=94) combined with fludarabine ± thiotepa. After a median follow-up after HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7%, and chronic GVHD-free survival (CRFS; events: death, graft failure, severe chronic GVHD) of 81.7%. Overall survival and CRFS were not significantly impacted by conditioning regimen (busulfan- versus treosulfan-based), donor type (MSD/MFD vs MUD/MMUD vs. MMFD), and period of HSCT (2006-2013 vs. 2014-2017). Patients younger than 5 years at HSCT had a significantly better overall survival. The overall cumulative incidences of grade III-IV acute GVHD and extensive/moderate/severe chronic GVHD were 6.6% and 2.1%, respectively. Patients receiving treosulfan-based conditioning had a higher incidence of graft failure, mixed donor chimerism and more frequently received secondary procedures (2nd HSCT, unconditioned stem cell boost, donor lymphocyte infusion, or splenectomy). In summary, HSCT for WAS with conditioning regimens currently recommended by IEWP results in excellent survival and low rates of GVHD, regardless of donor or stem cell source, but age ≥5 years remains a risk factor for overall survival.
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EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity
Lankester, A. C., Albert, M. H., Booth, C., Gennery, A. R., Güngör, T., Hönig, M., Morris, E. C., Moshous, D., Neven, B., Schulz, A., et al
Bone marrow transplantation. 2021
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4.
Risk factors affecting outcome of unrelated cord blood transplantation for children with familial haemophagocytic lymphohistiocytosis
Furtado-Silva, J. M., Paviglianiti, A., Ruggeri, A., Boelens, J. J., Veys, P., Ahmari, A. A., Zecca, M., Locatelli, F., Michel, G., Volt, F., et al
British journal of haematology. 2018
Abstract
Allogeneic haematopoietic stem cell transplantation is still the only available curative option for Familial Haemophagocytic Lymphohistiocytosis (FHLH). Most studies report outcomes after bone marrow or peripheral blood stem cell transplantation. We analysed the outcomes of 118 children with FHLH undergoing single-unit umbilical cord blood transplantation performed from 1996 to 2014. Myeloablative conditioning regimen was given to 90% of the patients, and was mostly busulfan-based (n = 81, 76%), including anti-thymocyte globulin or alemtuzumab (n = 102, 86%). The cumulative incidence of Day 60 neutrophil engraftment was 85%; and that of non-relapse mortality and acute graft-versus-host disease (GvHD) was 21% and 33% at 100 days, respectively. The 6-year cumulative incidence of chronic GvHD was 17% and the 6-year probability of overall survival was 55%. In multivariate analysis, children receiving a graft with a total nucleated cell dose greater than 9.9 x 10(7) /kg had a better overall survival (hazard ratio [HR]: 0.49, 95% CI: 0.27-0.88, P = 0.02). Degree of human leucocyte antigen (HLA) matching was associated with improved disease-free survival (5/6 vs. 6/6 HR: 2.11, 95% confidence interval [CI]: 1.01-4.4, P = 0.05 and ≤4/6 vs. 6/6, HR: 2.82, CI: 1.27-6.23, P = 0.01). Umbilical cord blood transplantation with a high cell dose and good HLA match is a suitable alternative option to haematopoietic stem cell transplantation in children with FHLH who lack a HLA-matched donor.
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The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis
Hartz, B., Marsh, R., Rao, K., Henter, J. I., Jordan, M., Filipovich, L., Bader, P., Beier, R., Burkhardt, B., Meisel, R., et al
Blood. 2016;127(25):3281-90
Abstract
Reduced-intensity conditioning has improved survival after hematopoietic stem cell transplantation (HSCT) for hemophagocytic lymphohistiocytosis (HLH) at the cost of more frequent mixed chimerism. The minimum level of donor chimerism (DC) required to prevent HLH reactivation in humans remains to be determined. In a multicenter retrospective study, 103 patients transplanted for hereditary HLH (2000-2013) and DC permanently or transiently <75% (overall, CD3(+), CD56(+)) were analyzed regarding DC, specific immunologic function, occurrence of systemic reactivations (>5/8 HLH criteria), partial systemic flares (<5 criteria and HLH-directed treatment), isolated central nervous system reactivations, and management. Recurrence was reported in 18 patients (systemic reactivation n = 11, partial flare n = 3, isolated central nervous system reactivation n = 4). Ten events occurred during profound immune suppression before day 180 (median DC, 10%; range, 1-100%; CD3(+) if available, otherwise overall DC), which renders a differentiation between secondary post-HSCT HLH and HLH related to the genetic defect difficult. Eight events occurred between 0.5 and 6.7 years post-HSCT (median DC, 13%; range, 0-30%). In 5 patients, overall and lineage-specific DC were <10% for >6 months (median, 5.1; range, 1.1-10 years) without reactivation. A second HSCT was performed in 18 patients (median, DC 4%; range, 0-19%). Death from reactivation occurred in 4 patients (22% of recurrences). Six patients died of transplant complications following a second HSCT (33% of second HSCT). We conclude that a DC >20%-30% is protective against late reactivation. Lower levels do not, however, inescapably result in recurrences. The decision for or against second HSCT must be based on a thorough risk assessment. Copyright © 2016 by The American Society of Hematology.