W.J.F.M. van der Velden

Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: A multicenter survey

Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1–7) and SR-cGVHD (1–10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3–90.7%, 95% confidence interval (CI)) and 97.4% (92.3–100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

Search for purines and pyrimidines in the Murchison meteorite

Abstract A 1 g interior sample of the Murchison CII meteorite was examined for the presence of purines and pyrimidines by dual-column, ion-exclusion chromatography and ultraviolet spectroscopy. Xanthine, not previously reported in meteorites, was found to be the major purine liberated by extraction with formic acid, with a concentration corresponding to 2.3 μg/g of meteorite. Guanine (0.1 ppm) and hypoxanthine (0.04 ppm) were also tentatively identified. The presence of adenine could not be confirmed. No pyrimidines were detected at concentrations higher than the background level (0.01 ppm) in water, formic acid or strong acid extracts. Silylation of the water extract, however, resulted in the appearance of 4-hydroxypyrimidine, 4-hydroxy-2-methylpyrimidine and 4-hydroxy-6-methylpyrimidine. These compounds are-though to be formed during the silylation procedure from contaminants present in the reagent.

NOD2 polymorphisms predict severe acute graft-versus-host and treatment-related mortality in T-cell-depleted haematopoietic stem cell transplantation

Single nucleotide polymorphisms (SNPs) in the NOD2 gene have significant impact on both treatment-related mortality (TRM) and acute GVHD (aGVHD) in haematopoietic stem cell transplantation (HSCT). The effect of these polymorphisms when using T-cell-depleted grafts has been poorly studied. We retrospectively analysed NOD2 polymorphisms in a cohort of 85 patients and donors who received an HLA-identical sibling partially T-cell-depleted HSCT (0.5 × 106 CD3+ T cells per kg) following idarubicin-containing conditioning regimens. NOD2 polymorphisms were present in 14 of 85 (16.5%) of patients and 18 of 85 (21%) of donors. The risk of severe aGVHD (grade III–IV) and the 1-year TRM was significantly higher in the presence of NOD2 polymorphisms (hazard ratio (HR) 6.0, P=0.02 for severe aGVHD and HR 3.3, P=0.02 for TRM, respectively) and was most prominent in cases where patient and donor both had a polymorphism (HR 10.5, P=0.002 and HR 3.9, P=0.002). There was also a trend towards increased risk of bacteraemia due to coagulase-negative staphylococci in patients with an NOD2 polymorphism. We conclude that NOD2 polymorphism screening should be used to optimize donor selection and antimicrobial prophylaxis to reduce the occurrence of aGVHD and TRM following allogeneic HSCT.

Febrile mucositis in haematopoietic SCT recipients.

We undertook a retrospective analysis of a cohort of 67 patients with multiple myeloma who had received an autologous haematopoietic SCT (HSCT) following high-dose melphalan to explore the impact of mucositis on the systemic inflammatory response. A homogenous group of 16 patients without a documented infection and a group of 30 patients with bacteraemia were identified for whom complete data on neutropenia, an inflammatory response, infectious complications and mucositis were available. All patients showed a similar course of events with an inflammatory response coinciding with the occurrence of significant mucositis, regardless of the presence or absence of infection. The only differences between the two groups were significantly higher maximum C-reactive protein (CRP) levels and lower citrulline levels for patients with bacteraemia, suggesting a causative role for mucositis in the occurrence of bacteraemia. Statistical analysis showed a significant association over time between citrulline levels, to a lesser extent bacteraemia, but not neutropenia, and the inflammatory response measured by CRP. These data suggest that the inflammatory response after conditioning for a HSCT is the result of the chemotherapy-induced mucositis and independent of neutropenia. Though primary inflammation appeared due to mucositis, infections resulting from mucosal barrier injury and neutropenia aggravated the inflammatory response.

Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines.

Epstein-Barr virus-related post-transplant lymphoproliferative disorders are recognized as a significant cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation. To better define current understanding of post-transplant lymphoproliferative disorders in stem cell transplant patients, and to improve its diagnosis and management, a working group of the Sixth European Conference on Infections in Leukemia 2015 reviewed the literature, graded the available quality of evidence, and developed evidence-based recommendations for diagnosis, prevention, prophylaxis and therapy of post-transplant lymphoproliferative disorders exclusively in the stem cell transplant setting. The key elements in diagnosis include non-invasive and invasive methods. The former are based on quantitative viral load measurement and imaging with positron emission tomography; the latter with tissue biopsy for histopathology and detection of Epstein-Barr virus. The diagnosis of post-transplant lymphoproliferative disorder can be established on a proven or probable level. Therapeutic strategies include prophylaxis, preemptive therapy and targeted therapy. Rituximab, reduction of immunosuppression and Epstein-Barr virus-specific cytotoxic T-cell therapy are recommended as first-line therapy, whilst unselected donor lymphocyte infusions or chemotherapy are options as second-line therapy; other methods including antiviral drugs are discouraged.

Purines and Pyrimidines in Sediments from Lake Erie

Quantitative analyses of purines and pyrimidines in sequential sections of cores from the central and eastern basins of Lake Erie show steeply increasing concentrations in the youngest sediments. This may be related to increased loading of nutrients and recent cultural eutrophication of the lake. The purine and pyrimidine distributions suggest the operation of a specific degradative process for uracil at an extremely early stage in, or prior to, sediment formation.

Primary hepatic invasive aspergillosis with progression after rituximab therapy for a post transplantation lymphoproliferative disorder

We present a case of primary hepatic and possible splenic invasive aspergillosis (IA), which progressed under anti-CD20 B cell treatment for posttransplantation lymphoproliferative disease following allogeneic stem cell transplantation, to highlight the clinical value of a positive galactomannan-antigen test, an intestinal portal of entry of Aspergillus, and the detrimental effect of B lymphocyte depletion in IA.

Distribution of amino acids, amino sugars, purines and pyrimidines in a Lake Ontario sediment core

Abstract An irregular decrease of total amino acid contents in a Lake Ontario sediment core (0–160 cm) is contrasted with the uniform decrease of both organic C and N. The source of the amino sugars glucosamine and galactosamine has been attributed either to the chitinous exo-skeletons of lake organisms or to the mucopeptides of algae or bacterial membranes. In addition, substantial abundances of the D-enantiomers of alanine and glutamic acid are indicative of bacterial activity within the sediment. In direct contrast with earlier evidence, amino sugars were found to degrade more quickly than the amino acid contents. The relative order of the degree of racemisation of amino acids with depth is in agreement with previous results for the established order in older sediments and fossils. In contrast to amino acid and amino sugar N, which together account for about 50% of total organic N within the surface sediment, purine and pyrimidine N represent less than 2% of the organic nitrogen balance. At a depth of only 15 cm this contribution to the organic nitrogen balance has decreased ten-fold. Unlike the similarity between amino acid distributions in the sediment and zooplankton samples there is no apparent correlation between the purine and pyrimidine content of the sediment and that of the zooplankton sample. Below a depth of 60 cm hypoxanthine becomes the single most abundant base. Although kinetic experiments have indicated that purines and pyrimidines are moderately stable within the geological environment, their rapid disappearance in this core suggests that factors other than thermal stability are responsible for their extreme lability.

Reduced PTLD-related mortality in patients experiencing EBV infection following allo-SCT after the introduction of a protocol incorporating pre-emptive rituximab

The mortality associated with post-transplant lymphoproliferative disorder (PTLD) induced by EBV infection can be reduced by monitoring EBV by polymerase-chain-reaction and rituximab given pre-emptively. We performed a retrospective analysis of the risk factors for the occurrence of EBV infection/disease and EBV-related mortality among 273 consecutive recipients of a T-cell-depleted allo-SCT during two periods: (a) before the implementation of a comprehensive protocol (2006–2008) and (b) afterwards (2009–2011). EBV infection was detected in 61 (22%) cases, and 28 cases were considered to have had EBV disease. Treatment with antithymocyte globulin was the most important risk factor (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.3–4.2, P=0.001). After implementation of the protocol, in patients experiencing EBV infection, pre-emptive therapy was started more often and sooner (median 3 vs 6 days, P=0.002). Moreover, there were fewer cases of monomorphic PTLD (4/33 (12%) vs 11/28 (39%), P=0.01), and the EBV-related mortality was lower for patients experiencing EBV infection (2/33 (6%) vs 8/28 (29%), OR 0.2; 95% CI 0.05–0.9, P=0.03). The EBV protocol proved feasible and resulted in faster initiation of pre-emptive therapy, the diagnosis in an earlier stage of EBV disease, and decreased EBV-related mortality.

Citrulline and albumin as biomarkers for gastrointestinal mucositis in recipients of hematopoietic SCT

Gastrointestinal (GI) mucositis is a common side effect of intense chemotherapy to prepare patients for hematopoietic SCT. Measuring intestinal damage objectively remains difficult, and clinicians often rely on albumin levels as an indicator of GI mucositis, but citrulline might be a more specific marker, which has in the past been shown to correlate with clinical signs of GI mucositis. We evaluated the courses of albumin and citrulline following different conditioning regimens for SCT and studied their relatedness to the subsequent inflammatory response using C-reactive protein. Patterns of albumin and citrulline differed significantly between myeloablative and non-myeloablative conditioning regimens. After myeloablative regimens, decreasing citrulline levels preceded the occurrence of inflammation unlike albumin levels, which decreased thereafter. Albumin levels were greatly influenced by inflammation, confirming it to be a ‘negative acute-phase protein’, whereas citrulline levels were not. Citrulline appeared to be a better biomarker of GI mucositis than albumin. Measuring citrulline might prove useful in clinical decision making, in identifying GI mucositis, and it would also be of interest to see how it compares with other biomarkers in the setting of acute GI GVHD.