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While pre-emptive rituximab therapy for EBV has substantially reduced the incidence of post-transplant lymphoproliferative disorder, following allogeneic haematopoietic SCT (HSCT), cytomegalovirus (CMV) and adenovirus (ADV) still contribute to significant morbidity and mortality after HSCT. We therefore aimed to identify high-risk children who could benefit from recent advances in virus-specific immunotherapy, define the impact of viral reactivations on survival and estimate the economic burden of pre-emptive antiviral drug therapy. Between 2005 and 2010, prospective monitoring of 291 paediatric HSCT procedures revealed that reactivation of CMV (16%), ADV (15%) and EBV (11%) was frequent during period of CD4 T-cell lymphopenia (0.15 × 109 L−1; P<0.05). We report significant risk factors for reactivation, most notably the use of serotherapy and development of GVHD (grade II) in the presence of pre-existing infection (ADV) or donor and/or recipient seropositivity (CMV, EBV). Most interestingly, CMV and ADV viraemia were the major independent predictors of mortality (P<0.05). CMV, ADV or EBV viral reactivation caused prolonged hospitalization (P<0.05), accounted for 15% of all mortality and substantially increased the cost of transplantation by ∼£22 500 ($34 000). This provides an economic rationale for targeting high-risk HSCT recipients with interventions such as virus-specific cell therapy. [ABSTRACT FROM AUTHOR]

Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes (NOTCH1WTFBXW7WT), 38% single NOTCH1 mutant (NOTCH1SingleFBXW7WT), 3% just FBXW7 mutant (NOTCH1WTFBXW7MUT) and 24% either double NOTCH1 mutant (NOTCH1DoubleFBXW7WT) or mutant in both genes (NOTCH1MUTFBXW7MUT), hereafter called as NOTCH1±FBXW7Double. There was no difference between groups in early response to therapy, but NOTCH1±FBXW7Double patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1WTFBXW7WT patients (71% versus 40%, P=0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1WTFBXW7WT, NOTCH1SingleFBXW7WT and NOTCH1±FBXW7Double patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1±FBXW7Double patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy. [ABSTRACT FROM AUTHOR]

Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms ‘complete MRD response’, ‘MRD persistence’ and ‘MRD reappearance’. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplant is curative for haemophagocytic lymphohistiocytosis (HLH) and refractory Langerhans cell histiocytosis (LCH). However, patients frequently have significant pre-transplant morbidity and there is high TRM. Because HLH is caused by immune dysregulation, we surmised that a reduced-intensity conditioned (RIC) regimen might be sufficient for cure, while decreasing the TRM. In 2006, we reported the outcome of 12 patients treated with RIC SCT from a matched family/unrelated or haploidentical donor. Here we discuss the update of these patients, including a total of 25 patients treated with RIC SCT for HLH and three for LCH. Twenty-one of the twenty-five patients with HLH (84%) are alive and well with remission at a median of 36 months from SCT. Mortality included pneumonitis (n=3) and hepatic rupture (n=1). All three patients treated with RIC SCT for LCH remain alive and in remission at a median of 5.1 years from SCT. Seven of twenty-four survivors (one with LCH) have mixed chimerism but remain disease-free. These data are supported by other groups including 100% survival in seven patients with HLH and 78% survival of nine patients with LCH. In summary, RIC compares favourably with conventional SCT with long-term disease control in surviving patients with both HLH and LCL, despite a significant incidence of mixed chimerism.Bone Marrow Transplantation (2008) 42, S47–S50; doi:10.1038/bmt.2008.283 [ABSTRACT FROM AUTHOR]

We report successful outcome in 13 children (median age 2.2 years) with high-risk AML who received SCT from an unrelated (11) or identical sibling (2) donor after a preparative regimen consisting of BU, CY and melphalan. Three children were ‘poor’-risk in first CR, three in the second CR, five in PR and two had resistant disease. Immunotherapeutic strategies were employed to maximize a GVL response escalating through a reduced dose of alemtuzumab, early taper of CsA, donor lymphocyte infusion and treatment with α-IFN. Ten out of 13 (77%) children are alive in CR at a median of 41 months (range: 17–88) from SCT. There was no TRM, but three children relapsed and died 3, 4 and 17 months after SCT. These encouraging early results warrant further studies in children with very high-risk AML.Bone Marrow Transplantation (2008) 42, 253–257; doi:10.1038/bmt.2008.160; published online 16 June 2008 [ABSTRACT FROM AUTHOR]

Summary:Infective diarrhoea is common among allogeneic stem cell transplant (SCT) recipients, frequently caused by viruses and may be difficult to differentiate from acute graft-versus-host disease (GVHD). Viral pathogens may directly or indirectly impact upon transplant-related mortality. Rotavirus is one of the most common causes of diarrhoea worldwide, but one of the least studied causes of diarrhoea post SCT. In this retrospective study we describe 21 cases of confirmed rotavirus infection in allogeneic SCT recipients. Most of these cases may occur in clusters during the winter and spring period. Symptoms of rotaviral infection were diarrhoea (95%), vomiting (62%), abdominal pain (38%), weight loss and loss of appetite in 38 and 29% of the cases, respectively. Possible extraintestinal manifestations of rotavirus infection were observed. The duration of the symptoms in this series ranged from 4 days to 4 months with median of 15 days. Patients with rotavirus infection were invariably lymphopenic and/or on immunosuppression for GVHD. Of the patients diagnosed with rotavirus, 86% required hospitalisation. In 57% of the cases, other viral pathogens were isolated near to the rotavirus infection period. Rotavirus infection is an important cause of prolonged diarrhoea post SCT, causing significant morbidity and frequently requiring hospitalisation.Bone Marrow Transplantation (2005) 36, 691–694. doi:10.1038/sj.bmt.1705127; published online 22 August 2005 [ABSTRACT FROM AUTHOR]

Summary:CAMPATH-1H (C-1H) is widely used in vivo and / or in vitro for T cell depletion in hematopoietic SCT. This humanised monoclonal antibody is specific for CD52, a marker coexpressed on the majority of human lymphocytes with CD48 and other glycosylphosphatidyl-inositol (GPI) anchored proteins. We detected CD52 / CD48 dual expression on >99% of CD3+ lymphocytes from normal individuals and all 15 post-SCT patients whose transplants did not utilise C-1H. By contrast, 23 / 26 patients with transplants involving C-1H (in vivo, in vitro or both) exhibited populations lacking CD52 expression that accounted for 49.7% (4.2–86.2%) of the CD3+ lymphocytes (median and range) in samples evaluated at a median of 2 months post-SCT. Most CD52− cells also lacked CD48 expression. These GPI− T cells were of either donor or mixed donor / recipient origin. They were predominant in the early months after SCT at times of profound lymphopenia and inversely correlated with the recovery of the absolute lymphocyte count (r= − 0.663, P<0.0001). The presence of CD52− cells has been correlated previously with clinical outcome after CAMPATH therapy for both malignant and nonmalignant diseases.Bone Marrow Transplantation (2005) 36, 237–244. doi:10.1038/sj.bmt.1705049; published online 13 June 2005 [ABSTRACT FROM AUTHOR]

Leukemia (2003) 17, 247–251. doi:10.1038/sj.leu.2402759 [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes (CTL) are important for the recognition and lysis of virally infected cells, but their effectiveness can be limited by viral immune evasion mechanisms. We investigated the immunophenotype and function of human CD8+ T cells raised in response to herpes simplex virus (HSV). The expanded population contained cells of an activated and mature phenotype, as determined by the expressions of CD25, CD45RO, CD57, CD95 and HLA-DR. Cultured cells also expressed CD45RA. These cells lysed autologous and allogeneic HSV-infected lymphoblastoid cell line (LCL) targets via a non-major histocompatibility complex (MHC) restricted recognition pathway. Inhibition assays showed the mechanism of cytotoxicity to be calcium-dependent, granule exocytosis pathway, rather than the internal disintegration pathway. Cold target competition assays indicated that a common CTL population contributed to the recognition of autologous and allogeneic-infected targets. These effectors showed recognition of infected targets which was distinct from that of K562 cells. Non-MHC restricted lysis-associated molecule 2B4 (CD244) was upregulated on culturing and made a significant contribution to lysis of FcγR-bearing targets in a redirected killing assay. These findings suggest that CTL can recognize virally infected cells through a combination of non-MHC restricted mechanisms and may result in more efficient lysis than classical CD8+ T cells. [ABSTRACT FROM AUTHOR]

We have tested the hypothesis that functional dendritic cells (DC) may be generated from patients with acute lymphoblastic leukaemia (ALL). We evaluated the production of DC from blast cells taken at presentation from nine children with ALL. Blast cells were expanded in serum-free medium supplemented with Flt3L, G-CSF, GM-CSF, IL-3, IL-6 and SCF for 7 days and subsequently stimulated with Flt3L, GM-CSF and TGF-beta for a further 14 days, with the addition of TNF-alpha for the final 48 h of culture. Cultured cells had the morphological appearance of DC and expressed the DC-associated antigens CD1A (range 2-87%) and CD83 (15-44%). Expression of the co-stimulatory molecules CD80 and CD86 was increased and the majority of these cells retained their expression of CD34 (73+/-4%) and HLA-DR (79+/-5%). Seven of the nine ALL had a leukaemia-specific abnormality and DC generated from five of these seven cases were derived from the leukaemic clone. Leukaemic DC derived from four HLA-A*02-positive ALL pulsed with CMV-associated peptides could induce significant proliferation of peptide-specific CD8+ T cells. This specificity was verified using tetrameric complexes of HLA class l/antigenic peptide. DC could also be generated from cells taken at times of complete remission of ALL and from normal controls using these culture conditions. These findings show that functional DC can be generated both from ALL blasts and from patients in remission; these might be utilised in future for immunotherapeutic strategies in the treatment of ALL. [ABSTRACT FROM AUTHOR]

We conducted a retrospective review of the clinical features and outcome of adenovirus infection in 572 consecutive patients transplanted in a single centre over a 10 year period. One hundred patients (17%) had a total of 105 episodes of adenovirus infection diagnosed at a median of 18 days post transplant (range 2–150 days). The incidence was higher in children than adults (21% vs 9%, P < 0.001) and in unrelated donor vs matched sibling donor transplants (26% vs 9%, P < 0.001). Diarrhoea and fever were the most common presenting features. Reflecting these symptoms, the most common site of isolation was the stool. Serotypes 1, 2 and 7 were the most frequently seen (total of 41/68 or 60% of evaluable cases). In six patients (6%) adenovirus infection was the direct cause of death occurring at a median of 72 days post transplant (range 18–365 days). Five of these six patients had pulmonary involvement and four had associated graft-versus-host disease (GVHD). Three further patients were considered to have severe adenoviral disease (total incidence 9%). Isolation of virus from multiple sites correlated with a poor outcome (P < 0.001). Comorbid viral infection was common in this group with 50% of all patients having other viruses isolated (predominantly polyoma virus and cytomegalovirus). We conclude that adenovirus is commonly isolated after bone marrow transplant and is a cause of significant morbidity but was a rare cause of mortality (6/572 = 1%) in our patient group as a whole. The relative infrequency of severe infection will make it difficult for the transplant physician to decide which patients should receive experimental antiviral drugs such as ribavirin and cidofovir or immunomodulatory therapy with donor white cell infusions. Bone Marrow Transplantation (2000) 26, 1333–1338. [ABSTRACT FROM AUTHOR]

The biological activities of CD8+ that co-express CD57 remain poorly defined. It is unclear whether all CD8+ cells have the potential to become CD57+ or whether they represent a unique subset with distinct functions. Several studies have reported the association between elevated numbers of CD8+CD57+ and a wide range of clinical disorders such as viral reactivation of human cytomegalovirus (HCMV). In this study, we have investigated the relationship between viral reactivation and the effect of diminished interleukin (IL)-2 production. Using CD8+ cells isolated from patients at various times after allogeneic transplants and in vitro models of HCMV infection, we determined their combined effect on CD8+CD57+. Our results show that high numbers of CD8+CD57+ correlated with diminished killing of HCMV-infected targets. In addition, we showed a synergistic effect between IL-2 and HCMV in the expansion of CD8+CD57+ cells. Furthermore, these cells after anti-CD3 stimulation did not produce tumour necrosis factor (TNF)-α or interferon (IFN)-γ. Interestingly, IL-10 production was elevated in several patients which appeared to be associated with the time from transplant. [ABSTRACT FROM AUTHOR]

Two elderly male patients presented with similar, widespread, papular, granulomatous eruptions and developed myelodysplastic syndromes. The first showed histological features of diffuse granuloma annulare and had mild hypergammaglobulinaemia, slightly abnormal liver function and a leucoerythroblastic anaemia. He developed acute myeloid leukaemia (AML) secondary to a background myelodysplastic syndrome and was treated with combination chemotherapy during which his eruption settled; his AML and his skin are in remission 1 year later. The second developed a myelodysplastic syndrome and a similar rash with histological features of papular cutaneous sarcoidosis but no systemic abnormalities apart from mild hypergammaglobulinaemia, cutaneous anergy to multiple recall antigens and activation of circulating monocytes. He has remained well but his rash and myelodysplastic syndrome have persisted. These cases are interesting because of the striking similarity of their granulomatous eruptions and their associated haematological abnormalities. Patients with such disseminated, granulomatous cutaneous infiltrations should be investigated to exclude associated haematological abnormalities if there is any abnormality of their peripheral blood picture. [ABSTRACT FROM AUTHOR]

This article discusses research on the clinical spectrum of intrathecal methotrexate (IT MTX)-related stroke-like syndrome (SLS) in patients with acute lymphoblastic leukaemia (ALL) who were treated during the Medical Research Council UKALL 2003 trial in Great Britain. Researchers reviewed 203 investigator-generated reports of neurological serious adverse effects associated with IT MTX administration and learned that 31 cases are consistent with an SLS-type presentation.

Discusses the results of three major reports on the importance of minimal residual disease level prior to hematopoietic stem cell transplantation (HSCT) as a prognostic marker in pediatric acute lymphoblastic leukemia patients. Patient categories according to the minimal residual disease level prior to HSCT; Results of statistical analysis; Factors considered for the multivariate analysis.

Leukemia (2003) 17, 268–270. doi:10.1038/sj.leu.2402751 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding Omenn syndrome and β thalassaemia cure with mismatched unrelated donor transplantation.

An abstract of the article "An Exploration of Parents' and Professionals' Roles in Sharing Illness and Treatment Information With Children Who Have Cancer," by S. Kumpunen and colleagues is presented.

A correction to the article "Successful outcome of allo-SCT in high-risk pediatric AML using chemotherapy-only conditioning and post transplant immunotherapy," which was published on July 14, 2008 is presented.

Focuses on the clinical trials to established to explore the use of minimal residual disease (MRD). Aim of the exercise to stratify patients into different treatment therapies; Use of polymerase chain reaction to quantitate MRD; Likelihood of relapse by half of patients in the lowest treatment regimes; Suggestion for chemotherapy for patients with low MRD; Effectiveness of MRD detection as a prognostic tool.