0
selected
-
1.
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.
-
2.
Epigenetic age is a cell-intrinsic property in transplanted human hematopoietic cells
Soraas, A., Matsuyama, M., de Lima, M., Wald, D., Buechner, J., Gedde-Dahl, T., Soraas, C. L., Chen, B., Ferrucci, L., Dahl, J. A., et al
Aging cell. 2019;:e12897
Abstract
The age of tissues and cells can be accurately estimated by DNA methylation analysis. The multitissue DNA methylation (DNAm) age predictor combines the DNAm levels of 353 CpG dinucleotides to arrive at an age estimate referred to as DNAm age. Recent studies based on short-term observations showed that the DNAm age of reconstituted blood following allogeneic hematopoietic stem cell transplantation (HSCT) reflects the age of the donor. However, it is not known whether the DNAm age of donor blood remains independent of the recipient's age over the long term. Importantly, long-term studies including child recipients have the potential to clearly reveal whether DNAm age is cell-intrinsic or whether it is modulated by extracellular cues in vivo. Here, we address this question by analyzing blood methylation data from HSCT donor and recipient pairs who greatly differed in chronological age (age differences between 1 and 49 years). We found that the DNAm age of the reconstituted blood was not influenced by the recipient's age, even 17 years after HSCT, in individuals without relapse of their hematologic disorder. However, the DNAm age of recipients with relapse of leukemia was unstable. These data are consistent with our previous findings concerning the abnormal DNAm age of cancer cells, and it can potentially be exploited to monitor the health of HSCT recipients. Our data demonstrate that transplanted human hematopoietic stem cells have an intrinsic DNAm age that is unaffected by the environment in a recipient of a different age.
-
3.
Low burden of minimal residual disease prior to transplantation in children with very high risk acute lymphoblastic leukaemia: The NOPHO ALL2008 experience
Ifversen, M., Turkiewicz, D., Marquart, H. V., Winiarski, J., Buechner, J., Mellgren, K., Arvidson, J., Rascon, J., Korgvee, L. T., Madsen, H. O., et al
British journal of haematology. 2019
Abstract
The population-based Nordic/Baltic acute lymphoblastic leukaemia (ALL) Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol combined minimal residual disease (MRD)-driven treatment stratification with very intense first line chemotherapy for patients with high risk ALL. Patients with MRD ≥5% at end of induction or ≥10(-3) at end of consolidation or following two high risk blocks were eligible for haematopoietic cell transplantation (HCT) in first remission. After at least three high risk blocks a total of 71 children received HCT, of which 46 had MRD ≥5% at end of induction. Ten patients stratified to HCT were not transplanted; 12 received HCT without protocol indication. Among 69 patients with evaluable pre-HCT MRD results, 22 were MRD-positive, one with MRD ≥10(-3) . After a median follow-up of 5.5 years, the cumulative incidence of relapse was 23.5% (95% confidence interval [CI]: 10.5-47.7) for MRD-positive versus 5.1% (95% CI: 1.3-19.2), P = 0.02) for MRD-negative patients. MRD was the only variable significantly associated with relapse (hazard ratio 9.1, 95% CI: 1.6-51.0, P = 0.012). Non-relapse mortality did not differ between the two groups, resulting in disease-free survival of 85.6% (95% CI: 75.4-97.2) and 67.4% (95% CI: 50.2-90.5), respectively. In conclusion, NOPHO block treatment efficiently reduced residual leukaemia which, combined with modern transplant procedures, provided high survival rates, also among pre-HCT MRD-positive patients.
-
4.
Cost-utility of allogeneic hematopoietic stem cell transplantation in Norway
Diep, P. P., Melberg, H. O., Brinch, L., Buechner, J., Fløisand, Y., Gedde-Dahl, T., Loge, J. H., Tjønnfjord, G. E., Ruud, E.
Bone marrow transplantation. 2018;53(5):657-660