The Clinical Landscape of NRAS- mutated Juvenile Myelomonocytic Leukemia-like Myeloproliferation Includes Children With Costello Syndrome.

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive pediatric disorder characterized by pathologic myeloproliferation because of alterations in RAS pathway genes. NRAS -mutated JMML encompasses a broad range of clinical severity. Herein we describe 4 unique cases of NRAS -mutated JMML and JMML-like myeloproliferation, 2 with somatic mutations and 2 with germline mutations. These cases illustrate the diverse clinical and hematologic presentation of this subtype of JMML, including a very unusual example presenting with Auer rods. Lastly, this is the first report of patients with phenotypic Costello syndrome presenting with JMML-like myeloproliferation, highlighting an important clinical phenomenon that has not been previously described.

Hodgkin lymphoma involving the extra-axial CNS: an AHOD1331, PHL-C1, and PHL-C2 report from the COG and EuroNet-PHL.

ABSTRACT: Hodgkin lymphoma (HL) involving the central nervous system (CNS) is exceedingly rare. Information regarding the presentation, management, treatment, and outcome of patients with CNS HL is limited to case reports or small series. We describe 45 pediatric patients with 55 extra-axial CNS lesions at diagnosis with HL from a cohort of 4995 patients enrolled on Children's Oncology Group AHOD1331 and the European Network for Pediatric Hodgkin lymphoma C1 and C2 trials, with an overall incidence of 0.9%. Up to 82.2% of patients had a single CNS lesion in the thoracic, lumbar, or sacral spine. In the evaluated cohort, HL did not occur within the CNS parenchyma. Lesions extended into the extra-axial CNS space from adjacent soft tissue or bone and never directly infiltrated through the dura into the brain or spinal cord. Patients with CNS involvement had a twofold greater incidence of extranodal lesions than previously reported cohorts without CNS involvement. After 2 cycles of chemotherapy, 89.1% of CNS lesions demonstrated a complete metabolic response and >75% decrease in volume. Thirteen CNS lesions (23.6%) received irradiation; none were sites of disease relapse. Relapse occurred at the site of 2 lesions involving the CNS, both of which had an adequate interim response to chemotherapy. In summary, we present, to our knowledge, the largest reported cohort of systemic HL involving the CNS at diagnosis, demonstrating that these lesions originate from surrounding tissues, extend into the extra-axial CNS space, and respond similarly to other nodal and extranodal disease. The trials were registered at www.clinicaltrials.gov as #NCT02166463, #NCT00433459, and #NCT02684708.

Rationale and design of the Children's Oncology Group study AAML1831 integrated cardiac substudies in pediatric acute myeloid leukemia therapy.

Background: Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in de novo pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of de novo pediatric AML. Methods/design: Children (age <22 years) with newly diagnosed AML were enrolled and randomized to CPX-351-containing induction 1 and 2 (Arm A) or standard daunorubicin and dexrazoxane-containing induction (Arm B). Embedded cardiac correlative studies aim to compare the efficacy of this liposomal anthracycline formulation to dexrazoxane for primary prevention of cardiotoxicity by detailed core lab analysis of standardized echocardiograms and serial cardiac biomarkers throughout AML therapy and in follow-up. In addition, AAML1831 will assess the ability of early changes in sensitive echo indices (e.g., global longitudinal strain) and cardiac biomarkers (e.g., troponin and natriuretic peptides) to predict subsequent LVSD. Finally, AAML1831 establishes expert consensus-based strategies in cardiac monitoring and anthracycline dose modification to balance the potentially competing priorities of cardiotoxicity reduction with optimal leukemia therapy. Discussion: This study will inform diagnostic, prognostic, preventative, and treatment strategies regarding cardiotoxicity during pediatric AML therapy. Together, these measures have the potential to improve leukemia-free and overall survival and long-term cardiovascular health in children with AML. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04293562.

Training for Wellness in Pediatric Oncology: A Focus on Education and Hidden Curricula.

Pediatric oncologists have the privilege of caring for children and families facing serious, often life-threatening, illnesses. Providing this care is emotionally demanding and associated with significant risks of stress and burnout for oncologists. Traditional approaches to physician burnout and wellbeing have not emphasized the potential roles of education and training in mitigating this stress. In this commentary, we discuss the contribution that education, particularly in the areas of palliative and psychosocial oncology, can make in preparing oncologists for the work that they do. We argue that by adequately providing oncologists with the skills they need for their work, we can reduce their risk of burning out. We also discuss the importance of paying attention to hidden and formal curricula to ensure that messages provided in formal education programs are supported by informal training experiences.