Antifungal Prophylaxis and Risk for Invasive Mold Infections in Children with Hematologic Malignancies

Introduction: Invasive mold infections (IMI) are a leading cause of mortality in immunocompromised hosts. Children diagnosed with hematologic malignancies experience profound, prolonged neutropenia following intensive chemotherapy, and are at increased risk for infection-related outcomes. Depending on the anticipated therapeutic intensity, antimicrobial prophylaxis may be employed to mitigate risk for infection. We conducted a retrospective review of children diagnosed with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or lymphoma between 2006-2015 and determined the incidence of IMI to be 4.8% (47/976), with an exceptionally high incidence observed in patients with AML (8.1%). This observation prompted a change in clinical practice that broadened prophylaxis for high risk patients to include coverage of molds, and resulted in development of a risk-stratified algorithm for antifungal prophylaxis in children with hematologic malignancies. The objective of this study was to evaluate the change in IMI incidence post-implementation of this algorithm, and to identify host factors contributing to risk for IMI in children with hematologic malignancies. Objective: The objective was to compare the incidence of IMI pre/post implementation of antifungal prophylaxis decision tree. Also, it was planned to evaluate the impact of race/ethnicity on the development of IMI in children with hematologic malignancies. Methods: We conducted a retrospective review of children ≤ 21 years old and diagnosed with ALL, AML, or lymphoma between 2016-2019, and were treated for IMI between 2016 and June 2020. To identify potential cases, we employed a strategy identical to the one used in the 2006-2015 review, specifically, a search of the electronic medical record utilizing ICD9 codes broadly inclusive of relevant cancer and fungal diagnoses. Each potentially eligible case was then reviewed for the following inclusion/exclusion criteria (also identical to the prior review): diagnosis and treatment of ALL, AML, or lymphoma at Texas Children’s Hospital, diagnosis of IMI that met criteria for ‘proven’ or ‘probable’ per the European Organization for Research and Treatment of Cancer/Mycoses Study Group and occurring prior to stem cell transplant, and no underlying immunodeficiency or history of solid organ transplant. Host and disease-related factors, as well as IMI incidence, were compared for 2006-2015 vs. 2016-2020 using a Chi-square, Fisher, or Student t-test as appropriate, and host factors predictive of IMI were assessed by multivariable linear regression. Results: The overall incidence of proven/probable IMI in children diagnosed with hematological malignancies between 2006-2019 was 4.2% (61/1456). The incidence of IMI decreased from 4.8% to 2.9% between 2006-2015 and 2016-2020. For specific diagnoses, the rate of IMI decreased from 5.0% to 3.6% (ALL, 35/705 vs. 10/276), from 1.9% to 1.4% (lymphoma, 47/976 vs. 14/480), and from 8.1% to 3.2% (AML, 9/111 vs. 2/62). No significant differences in host factor or disease-related characteristics were noted when comparing IMI cases in 2006-2015 vs. 2016-2020, nor were there differences in the proportion of patients in relapse at the time of IMI or taking antifungal prophylaxis. Substantial differences in representative mold species were noted between the two-time periods, e.g. Aspergillus spp. accounted for 19/47 IMI from 2006-2015, but accounted for none of the IMIs diagnosed 2016-2020. In 2016-2020, 5/14 IMI were due to Trichosporon spp., with 4/14 Rhizopus spp., 2/14 Fusarium spp., 1/14 Curvularia spp., 1/14 Histoplasma spp., and 1 that met criteria for probable IMI. In multivariable analyses (Table 1), Hispanics were more likely to develop an IMI than non-Hispanics (p=0.04, OR 1.94, CI 1.03-3.66), and those with lymphoma were less likely to develop an IMI than those with ALL (p=0.03, OR 0.33, CI 0.12-0.87). Patients diagnosed between 2016- 2019 were substantially less likely to develop IMI than those diagnosed 2006-2015 (p=0.003, OR 0.33, CI 0.16-0.69). Discussion and Conclusion: In this single institution study, risk for IMI in children with hematologic malignancies declined significantly after implementation of an antifungal prophylaxis algorithm that broadened coverage for high risk populations. Hispanics were at higher risk for IMI than non-Hispanics, suggesting a need to investigate relevant factors contributing to this disparity. This project can be used to further investigate the factors that contributed to invasive mold infections using a larger study populations. We can then continue to explore the potential contributing factors to the racial and ethnic disparities by including potential contributing factors such as socioeconomic factors and genetic risk

Down syndrome and leukemia: from basic mechanisms to clinical advances

Children with Down syndrome (DS, trisomy 21) are at a significantly higher risk of developing acute leukemia compared to the overall population. Many studies investigating the link between trisomy 21 and leukemia initiation and progression have been conducted over the last two decades. Despite improved treatment regimens and significant progress in iden - tifying genes on chromosome 21 and the mechanisms by which they drive leukemogenesis, there is still much that is unknown. A focused group of scientists and clinicians with expertise in leukemia and DS met in October 2022 at the Jérôme Lejeune Foundation in Paris, France for the 1st International Symposium on Down Syndrome and Leukemia. This meeting was held to discuss the most recent advances in treatment regimens and the biology underlying the initiation, progression, and relapse of acute lymphoblastic leukemia and acute myeloid leukemia in children with DS. This review provides a summary of what is known in the field, challenges in the management of DS patients with leukemia, and key questions in the field

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondria) apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, FED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1. These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response

HEART: heart exercise and remote technologies: A randomized controlled trial study protocol

<p>Abstract</p> <p>Background</p> <p>Cardiovascular disease (CVD) is the leading cause of death worldwide. Cardiac rehabilitation (CR) is aimed at improving health behaviors to slow or reverse the progression of CVD disease. Exercise is a central element of CR. Technologies such as mobile phones and the Internet (mHealth) offer potential to overcome many of the psychological, physical, and geographical barriers that have been associated with lack of participation in exercise-based CR. We aim to trial the effectiveness of a mobile phone delivered exercise-based CR program to increase exercise capacity and functional outcomes compared with usual CR care in adults with CVD. This paper outlines the rationale and methods of the trial.</p> <p>Methods</p> <p>A single-blinded parallel two-arm randomized controlled trial is being conducted. A total of 170 people will be randomized at 1:1 ratio either to receive a mHealth CR program or usual care. Participants are identified by CR nurses from two metropolitan hospitals in Auckland, New Zealand through outpatient clinics and existing databases. Consenting participants are contacted to attend a baseline assessment. The intervention consists of a theory-based, personalized, automated package of text and video message components via participants' mobile phones and the Internet to increase exercise behavior, delivered over six months. The control group will continue with usual CR. Data collection occurs at baseline and 24 weeks (post-intervention). The primary outcome is change in maximal oxygen uptake from baseline to 24 weeks. Secondary outcomes include post-intervention measures on self-reported physical activity (IPAQ), cardiovascular risk factors (systolic blood pressure, weight, and waist to hip ratio), health related quality of life (SF-36), and cost-effectiveness.</p> <p>Discussion</p> <p>This manuscript presents the protocol for a randomized controlled trial of a mHealth exercise-based CR program. Results of this trial will provide much needed information about physical and psychological well-being, and cost-effectiveness of an automated telecommunication intervention. If effective, this intervention has enormous potential to improve the delivery of CR and could easily be scaled up to be delivered nationally (and internationally) in a very short time, enhancing the translational aspect of this research. It also has potential to extend to comprehensive CR (nutrition advice, smoking cessation, medication adherence).</p> <p>Trial Registration</p> <p><a href="http://www.anzctr.org.au/ACTRN12611000117910.aspx">ACTRN12611000117910</a></p

Dasatinib in pediatric patients with chronic myeloid leukemia in chronic phase:results from a phase II trial

PurposeSafe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I study determined suitable dosing for children with Philadelphia chromosome-positive (Ph+) leukemias.MethodsCA180-226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients < 18 years of age receiving dasatinib. There are three cohorts: (1) imatinib-resistant/intolerant CML-CP, (2) imatinib-resistant/intolerant CML in accelerated/blast phase or Ph+ acute lymphoblastic leukemia (n = 17), and (3) newly diagnosed CML-CP treated with tablets or powder for oral suspension. Major cytogenetic response > 30% for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest.ResultsOf 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, respectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial hypertension were reported. Bone growth and development events were reported in 4% of patients.ConclusionIn the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported