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To study the mechanisms of relapse in KMT2A -rearranged ( KMT2A -r) acute lymphoblastic (ALL) and acute myeloid leukemia (AML), we performed whole-genome and exome sequencing of infants and children with relapsed ALL/AML ( n  = 36), and longitudinal deep-sequencing of 257 samples in 30 patients. Somatic alterations in drug-response genes, most commonly in TP53 and IKZF1 (64%), were highly enriched in early relapse ALL (79%, 9-36 months after diagnosis), but rare in very early relapse ALL (<9 months, 9%). A marked chemotherapy-exposure signature was detected for mutations in early relapse ALL but not in very early ALL or AML relapse, in line with different mechanisms of relapse. Longitudinal analyses could track residual leukemia cells, clonal drug responses, and the upcoming relapse. These results highlight that KMT2A -r ALL and AML evade therapy differently and provide insights into the mechanisms of relapse in this highly lethal form of pediatric acute leukemia. Infant KMT2A -rearranged acute lymphoblastic leukemia is associated with poor overall survival rates. Here, the authors use WGS and WES of 36 relapsed KMT2A -rearranged ALL and AML patients and find alterations in drug response genes in ALL, which may correspond with relapse time. Longitudinal analyses of >250 samples could track residual leukemia cells, clonal drug responses, and the upcoming relapse.

The clinical presentation of chronic myeloid leukemia (CML) at diagnosis differs in children compared to adults. At younger age, anemia appears to be frequent at diagnosis, but its prevalence and its impact on prognosis are not well known. In the International Registry of Childhood CML, we selected children and adolescents in chronic phase at diagnosis of CML and treated upfront with imatinib. We examined their hemoglobin level at diagnosis according to the WHO grades to assess the prevalence of anemia and its impact on response to tyrosine kinase inhibitors (TKIs). Data on 430 patients were included. Anemia at diagnosis was observed in 350 patients (81%), with a mean hemoglobin level of 96.4 g/l (SD 23.6). Among them, 182 patients (52%) presented with moderate anemia and 110 (31%) with severe anemia while 58 (17%) had mild anemia. Compared with mild and no anemia, moderate and severe forms were significantly associated with younger age at diagnosis, asthenia, splenomegaly, and increased leukocyte and basophil counts. Delays in achieving major and deep molecular responses were significantly increased for patients with moderate and severe anemia, and also failure of imatinib treatment was more frequent in these two sub-cohorts. However, hemoglobin level was not significantly associated with survival. Anemia at diagnosis of pediatric CML was frequent and may be considered as a prognostic factor.

The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1 ) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.

Background Interprofessional education in childhood cancer is a multifaceted field involving multiple healthcare professionals with general and specialised knowledge and skills. Complex treatment, care and rehabilitation require continuous professional development and maintenance of healthcare professionals’ competencies in their field of expertise. However, limited knowledge exists in comparing interprofessional and monoprofessional education. Only a few randomised studies have evaluated the effectiveness and efficiency of interprofessional education. The objective of this single-centre, investigator-initiated cluster randomised trial is to study the effect of interprofessional versus monoprofessional case-based learning on healthcare professionals’ knowledge of gastrointestinal side effects and attitudes towards team collaboration. Methods This study will randomise healthcare professionals to participate in either the experimental interprofessional group or the control monoprofessional group of case-based learning. The topic of the case-based intervention will be gastrointestinal side effects, one of six categories identified in a three-round Scandinavian Delphi study as relevant for interprofessional education in childhood cancer. The primary outcome is the self-reported questionnaire Assessment of Interprofessional Team Collaboration Scale. Secondary outcomes are measured by the self-reported questionnaires Readiness for Interprofessional Learning Scale Questionnaire, Safety Attitudes Questionnaire, and knowledge will be evaluated using a multiple-choice quiz. Participants will receive the self-reported questionnaires about 2 weeks before and 1 month after the intervention. On the day of the intervention, participants will answer a multiple-choice quiz before and after the case-based learning. Linear mixed models will be used to compare differences between the two groups in mean scores postintervention, adjusting for preintervention scores. Discussion This study will provide insight into the differences between interprofessional and monoprofessional case-based learning and how it affects healthcare professionals’ knowledge of gastrointestinal side effects and attitudes towards team collaboration. Trial registration The intervention was registered at Clinical Trials.gov : NCT04204109 on December 102,019 and with the National Committee on Health Research Ethics: H-19087506 December 112,019 and the Danish Data Protection Agency: P-2019-637 October 152,019.

Pediatric acute myeloid leukemia (AML) is a heterogeneous disease composed of clinically relevant subtypes defined by recurrent cytogenetic aberrations. The majority of the aberrations used in risk grouping for treatment decisions are extensively studied, but still a large proportion of pediatric AML patients remain cytogenetically undefined and would therefore benefit from additional molecular investigation. As aberrant epigenetic regulation has been widely observed during leukemogenesis, we hypothesized that DNA methylation signatures could be used to predict molecular subtypes and identify signatures with prognostic impact in AML. To study genome-wide DNA methylation, we analyzed 123 diagnostic and 19 relapse AML samples on Illumina 450k DNA methylation arrays. We designed and validated DNA methylation-based classifiers for AML cytogenetic subtype, resulting in an overall test accuracy of 91%. Furthermore, we identified methylation signatures associated with outcome in t(8;21)/RUNX1-RUNX1T1, normal karyotype, and MLL/KMT2A-rearranged subgroups (p < 0.01). Overall, these results further underscore the clinical value of DNA methylation analysis in AML.

Activating FLT3 and RAS mutations commonly occur in leukemia with KMT2A‐gene rearrangements (KMT2A‐r). However, how these mutations cooperate with the KMT2A‐r to remodel the epigenetic landscape is unknown. Using a retroviral acute myeloid leukemia (AML) mouse model driven by KMT2A::MLLT3, we show that FLT3ITD, FLT3N676K, and NRASG12D remodeled the chromatin accessibility landscape and associated transcriptional networks. Although the activating mutations shared a common core of chromatin changes, each mutation exhibits unique profiles with most opened peaks associating with enhancers in intronic or intergenic regions. Specifically, FLT3N676K and NRASG12D rewired similar chromatin and transcriptional networks, distinct from those mediated by FLT3ITD. Motif analysis uncovered a role for the AP‐1 family of transcription factors in KMT2A::MLLT3 leukemia with FLT3N676K and NRASG12D, whereas Runx1 and Stat5a/Stat5b were active in the presence of FLT3ITD. Furthermore, transcriptional programs linked to immune cell regulation were activated in KMT2A‐r AML expressing NRASG12D or FLT3N676K, and the expression of NKG2D‐ligands on KMT2A‐r cells rendered them sensitive to CAR T cell‐mediated killing. Human KMT2A‐r AML cells could be pharmacologically sensitized to NKG2D‐CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D‐ligand levels. Co‐treatment with LBH589 and NKG2D‐CAR T cells enabled robust AML cell killing, and the strongest effect was observed for cells expressing NRASG12D. Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation‐specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.

BackgroundComplex treatment, care and rehabilitation require continuous healthcare professional development and maintenance of competencies in collaboration with other professionals. Interprofessional education in childhood cancer involves several groups of healthcare professionals with both general and specific knowledge and skills.ObjectiveTo establish consensus on content and interprofessional learning objectives for an interprofessional education in childhood cancer.DesignA three-round Delphi survey in Scandinavian childhood cancer departments.ParticipantsHealthcare professionals appointed by their head of departments and head nurses based on their profession and their involvement in continuing professional development.Main outcome measuresA prioritised list of interprofessional learning objectives with a mean score of ≥3 on a five-point scale (1=not relevant, 5=extremely relevant).Results12 childhood cancer departments participated with 30 healthcare professionals: 11 nurses, 10 medical doctors, 5 social workers, 2 physiotherapists and 2 pedagogues. In total, 28 (93%), 25 (83%) and 22 (73%) completed the first, second and third round, respectively. In the first round, we asked open-ended questions and used directed content analysis to analyse 386 statements. We formulated 170 interprofessional learning objectives in six categories: (1) acute life-threatening situations, (2) gastrointestinal toxicities and side effects, (3) pain, (4) palliation, (5) play and activity, and (6) prescription and administration of medicine. The second round resulted in 168 interprofessional learning objectives receiving a mean score of ≥3 on a five-point scale. Final agreement in the third round resulted in a prioritised list of 168 learning objectives.ConclusionsConsensus on content and interprofessional learning objectives for an interprofessional education in childhood cancer was established across five groups of healthcare professionals in three countries. Some learning objectives are generic and can be applied in settings other than childhood cancer, where healthcare professionals collaborate to provide patients and families optimal treatment and care.

Background Associations between body mass index (BMI), outcome, and leukemia‐related factors in children with acute myeloid leukemia (AML) remain unclear. We investigated associations between pretherapeutic BMI, cytogenetic abnormalities, and outcome in a large multinational cohort of children with AML. Methods We included patients, age 2‐17 years, diagnosed with de novo AML from the five Nordic countries (2004‐2016), Hong Kong (2007‐2016), the Netherlands and Belgium (2010‐2016), and Canada and USA (1995‐2012). BMI standard deviations score for age and sex was calculated and categorized according to the World Health Organization. Cumulative incidence functions, Kaplan‐Meier estimator, Cox regression, and logistic regression were used to investigate associations. Results In total, 867 patients were included. The median age was 10 years (range 2‐17 years). At diagnosis, 32 (4%) were underweight, 632 (73%) were healthy weight, 127 (15%) were overweight, and 76 (9%) were obese. There was no difference in relapse risk, treatment‐related mortality or overall mortality across BMI groups. The frequency of t(8;21) and inv(16) increased with increasing BMI. For obese patients, the sex, age, and country adjusted odds ratio of having t(8;21) or inv(16) were 1.9 (95% confidence interval (CI) 1.1‐3.4) and 2.8 (95% CI 1.3‐5.8), respectively, compared to healthy weight patients. Conclusions This study did not confirm previous reports of associations between overweight and increased treatment‐related or overall mortality in children. Obesity was associated with a higher frequency of t(8;21) and inv(16). AML cytogenetics appear to differ by BMI status. In this multinational study of 867 pediatric AML patients diagnosed within the last two decades, we found no evidence of associations between BMI group and risk of relapse, treatment‐related, or overall mortality. We found associations of obesity and a higher frequency of t(8;21) and inv(16).

A total of 156 patients (age range 1.3–18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m2, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1−120) was 97% (95% CI, 94.2−99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.