Patient 4 (sibling to patient 3) was well until he presented with inflammatory colitis and Hodgkin lymphoma (inguinal and para-aortic region) at age 16 years. Because of his sibling's history, CTLA4 ...haploinsufficiency was confirmed by both genetic and protein level testing, the only patient in this cohort to have an identified mutation before HSCT. In summary, 4 of 8 patients experienced GvHD despite having well-matched donors and receiving alemtuzumab in 3 out of 4 cases.\n9 (5.4-16.8)IgA 0.27 (0.74-2.61)IgM 0.84 (0.40-1.95)Preimmunoglobulin therapyPre-RTX 23 y Interstitial lung disease ("nodular lymphoid hyperplasia") Transverse myelitis Recurrent white matter and brainstem lesions with oligoclonal bands and elevated IgG index Arthritis Father:ITPSister:Patient no. 7 Table I Patients' characteristics ABVD, Adriamcyin (Doxorubicin), bleomycin, vinblastine, dacarbazine; naive CD4, CD3+CD4+CD27+CD45RA+; naive CD8, CD3+CD4-CD27+CD45RA+; Euronet PHL-C1, Euronet pediatric Hodgkin lymphoma-C1; F, female; IDDM, insulin-dependent diabetes mellitus; ITP, idiopathic thrombocytopenic purpura; M, male; NK, natural killer; PN, parenteral nutrition; RTX, rituximab.
Inherited deficiency of the C1q component of the classical complement pathway is a severe autosomal recessive immunodeficiency disease associated with a high risk of death from either fulminant ...bacterial infections or systemic lupus erythematosus-like autoimmunity.1 Indeed, C1q deficiency is the strongest disease susceptibility gene for the development of severe systemic lupus erythematosus in human subjects, with a 90% risk of skin disease and a 50% risk of renal disease.2 C1q is unusual in that it is synthesized by bone marrow-derived monocytes.3,4 Studies in mice suggest that C1q deficiency might be amenable to treatment with HSCT.5,6 We have previously reported on a consanguineous Pakistani family in which the father and 5 of 6 sons were affected by C1q deficiency.1 The father died of chronic glomerulonephritis at 38 years of age, and one of his sons died at 17 months of Streptococcus pneumoniae-induced meningitis. Since publishing this report in 2007, another son had an acute central nervous system vasculopathy at 17 years of age and remains in a "locked in syndrome" 18 months after the acute event.
Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan ...exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve AUC) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT.
In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUC
), non-compartmental analysis (AUC from 0 to infinity AUC
and to the next dose AUC
), and by individual centres using various approaches (AUC
). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease GvHD); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses.
790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUC
was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC
(r
=0·74), but the latter correlated poorly with AUC
(r
=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio HR 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73-2·33; p=0·37).
Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg × h/L using a new validated pharmacokinetic model for all indications.
Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.
Inherited metabolic disorders (IMD) or inborn errors of metabolism are a diverse group of diseases arising from genetic defects in lysosomal enzymes or peroxisomal function. These diseases are ...characterized by devastating systemic processes affecting neurologic and cognitive function, growth and development, and cardiopulmonary status. Onset in infancy or early childhood is typically accompanied by rapid deterioration. Early death is a common outcome. Timely diagnosis and immediate referral to an IMD specialist are essential steps in management of these disorders. Treatment recommendations are based on the disorder, its phenotype including age at onset and rate of progression, severity of clinical signs and symptoms, family values and expectations, and the risks and benefits associated with available therapies such as allogeneic hematopoietic stem cell transplantation (HSCT). This review discusses indications for HSCT and outcomes of HSCT for selected IMD. An international perspective on progress, limitations, and future directions in the field is provided.
We compared substrate reduction in patients with lysosomal storage disorder treated with hematopoietic stem cell transplant and found that it was significantly reduced compared with patients treated ...with pharmacological enzyme replacement therapy. These data might support the wider application of hematopoietic stem cell transplant in the treatment of lysosomal storage disorders.
We describe the use of enzyme replacement therapy in conjunction with hematopoietic stem cell transplantation in 18 consecutive patients with severe mucopolysaccharidosis type I. The survival and ...engraftment rate was 89% overall and 93% for the 15 patients who received full-intensity conditioning.
Lymphocyte functions triggered by antigen recognition and co-stimulation signals are associated with a rapid and intense cell division, and hence with metabolism adaptation. The nucleotide cytidine ...5' triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids. CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthases (or synthetases) 1 and 2 (CTPS1 with CTPS2); the respective roles of these two enzymes are not known. CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes. Here we report the identification of a loss-of-function homozygous mutation (rs145092287) in CTPS1 in humans that causes a novel and life-threatening immunodeficiency, characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. In contrast, proximal and distal T-cell receptor (TCR) signalling events and responses were only weakly affected by the absence of CTPS1. Activated CTPS1-deficient cells had decreased levels of CTP. Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine. CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation. These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the immune response. CTPS1 may therefore represent a therapeutic target of immunosuppressive drugs that could specifically dampen lymphocyte activation.
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