Explore the vast range of titles available.

Almost half of patients with acute myeloid leukemia (AML) do not have detectable cytogenetic abnormalities. This study of more than 870 such patients determined the frequencies of mutations of the NPM1, FLT3, CEBPA, and MLL genes that affect the growth and differentiation of hematopoietic stem cells and showed that these mutations are associated with the treatment outcome. The authors propose that these mutations constitute a new basis for refining the risk classification of AML. This study of patients with cytogenetically normal AML determined the frequencies of mutations of genes that affect the growth and differentiation of hematopoietic stem cells and showed that these mutations are associated with the treatment outcome. Acute myeloid leukemia (AML) is a genetically heterogeneous disease in which somatic mutations that disturb cellular growth, proliferation, and differentiation accumulate in hematopoietic progenitor cells. The karyotype at the time of diagnosis provides the most important prognostic information in adults with AML, 1 – 3 but 40 to 50% of patients do not have clonal chromosomal aberrations. 1 – 3 All such cases of cytogenetically normal AML are currently categorized in the intermediate-risk group, yet this group is quite heterogeneous. 4 , 5 In recent years, acquired gene mutations, as well as deregulation of gene expression, have been identified. 6 – 8 Somatic mutations in AML include partial . . .

Mutations in the nucleophosmin 1 ( NPM1 ) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition of NPM1 mutated ( NPM1 mut ) AML, we assess mutation status of five recurrently mutated oncogenes in 129 paired NPM1 mut samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1 mut loss ( n  = 11). To better understand these NPM1 mut loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1 mut loss patients (pts) feature distinct mutational patterns that share almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways. In contrast, profiles of pts with persistent NPM1 mut are reflected by a high overlap of mutations between diagnosis and relapse. Our findings confirm that relapse often originates from persistent leukemic clones, though NPM1 mut loss cases suggest a second “de novo” or treatment-associated AML (tAML) as alternative cause of relapse. NPM1 gene mutation is a founding event in acute myeloid leukaemia. Here, the authors find that at relapse, some patients lose the NPM1 mutation and show distinct mutational and gene expression patterns, highlighting a potential route for relapse.

Up to 40% of donor-recipient pairs in SCT have some degree of ABO incompatibility, which may cause severe complications. The aim of this study was to describe available options and survey current practices by means of a questionnaire circulated within the EBMT Pediatric Diseases Working Party investigators. Major ABO incompatibility (donor’s RBCs have antigens missing on the recipient’s cell surface, towards which the recipient has circulating isohemagglutinins) requires most frequently an intervention in case of bone marrow grafts, as immediate or delayed hemolysis, delayed erythropoiesis and pure red cell aplasia may occur. RBC depletion from the graft (82%), recipient plasma-exchange (14%) were the most common practices, according to the survey. Graft manipulation is rarely needed in mobilized peripheral blood grafts. In case of minor incompatible grafts (donor has isohemagglutinins directed against recipient RBC antigens), isohemagglutinin depletion from the graft by plasma reduction/centrifugation may be considered, but acute tolerability of minor incompatible grafts is rarely an issue. According to the survey, minor ABO incompatibility was either managed by means of plasma removal from the graft, especially when isohemagglutinin titer was above a certain threshold, or led to no intervention at all (41%). Advantages and disadvantages of each method are discussed.

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.

Background Integrative medicine is used frequently alongside chemotherapy treatment in pediatric oncology, but little is known about the influence on toxicity. This German, multi-center, open-label, randomized controlled trial assessed the effects of complementary treatments on toxicity related to intensive-phase chemotherapy treatment in children aged 1–18 with the primary outcome of the toxicity sum score. Secondary outcomes were chemotherapy-related toxicity, overall and event-free survival after 5 years in study patients. Methods Intervention and control were given standard chemotherapy according to malignancy & tumor type. The intervention arm was provided with anthroposophic supportive treatment (AST); given as anthroposophic base medication (AMP), as a base medication for all patients and additional on-demand treatment tailored to the intervention malignancy groups. The control was given no AMP. The toxicity sum score (TSS) was assessed using NCI-CTC scales. Results Data of 288 patients could be analyzed. Analysis did not reveal any statistically significant differences between the AST and the control group for the primary endpoint or the toxicity measures (secondary endpoints). Furthermore, groups did not differ significantly in the five-year overall and event-free survival follow up. Discussion In this trial findings showed that AST was able to be safely administered in a clinical setting, although no beneficial effects of AST between group toxicity scores, overall or event-free survival were shown.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Charlotte Niemeyer, Mignon Loh and colleagues report that germline mutations at CBL are associated with developmental abnormalities and predispose individuals to juvenile myelomonocytic leukemia. CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.

We performed a retrospective analysis on 124 patients with transfusion-dependent thalassemia who were registered in the German pediatric registry for stem cell transplantation. All patients underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 2011 and 2020 and belonged mainly to Pesaro risk class 1–2. Four-year overall (OS) and thalassemia-free survival (TFS) were 94.5% ± 2.9% and 88.0% ± 3.4% after treosulfan-fludarabine-thiotepa- and 96.9% ± 3.1% (P = 0.763) and 96.9% ± 3.1% (P = 0.155) after busulfan-fludarabine-based conditioning. Mixed chimerism below 75% occurred predominantly in treosulfan-based regimens (27.5% versus 6.2%). OS and TFS did not differ significantly between matched sibling, other matched family and matched unrelated donor (UD) HSCTs (OS: 100.0%, 100.0%, 96.3% ± 3.6%; TFS: 96.5% ± 2.4%, 90.0% ± 9.5%, 88.9% ± 6.0%). However, mismatched UD-HSCTs performed less favorable (OS: 84.7% ± 7.3% (P = 0.029); TFS: 79.9% ± 7.4% (P = 0.082)). We generated a scoring system reflecting the risk to develop mixed chimerism in our cohort. The main risk-reducing factors were a high CD3+ cell count (≥6 × 107/kg) in the graft, busulfan-conditioning, pre-conditioning therapy and low-targeted ciclosporin A trough levels. Acute GvHD grade III-IV in treosulfan-based concepts predominantly occurred in patients with UD and reduced GvHD prophylaxis but not in the context of high CD3+ cell doses. Taken together, this information might be used to develop more risk-adapted HSCT regimens for thalassemia patients.