Rearrangements of the KMT2A gene are characteristic of infantile acute lymphoblastic leukemia (ALL) and are associated with increased lineage plasticity and resistance to therapy. Here, we describe the case of a 9-month-old infant with infantile ALL who experienced multiple immunophenotypic switches in her leukemia throughout therapy and ultimately achieved remission with the combination of CPX-351 and Inotuzumab. This case highlights the unique clinical challenges infantile ALL poses on monitoring therapeutic response with current methods of measuring minimal residual disease as well as the challenges in treating infantile B-ALL.

A document by Paul Meyers. Click on the document to view its contents.

Introduction: The risk of relapse in retinoblastoma is currently determined by the presence of high-risk histopathologic factors in the enucleated eye. However, the probability of developing metastatic disease is heterogeneous among these patients. Evaluating a biological marker to identify high-risk patients could be useful in clinical setting. This study aims to evaluate whether the expression of TFF1, a surrogate for subtype 2 retinoblastoma, is a prognostic marker for relapse and death. Methods: This multicenter cohort study included 273 patients, 48 of whom had extraocular disease. Immunohistochemical staining were performed for CRX, ARR3, TFF1 and Ki67. Tumors were classified as histological subtype 1 (HS1) if they had low or no expression of TFF1 (quick score (QS) ≤ 50) and as histological subtype 2 (HS2) if they expressed TFF1 diffusely (QS > 50). We studied the association between HS classification and outcome. Results: Of 273 patients, 35.9% were classified as HS1, 59.3% as HS2 and 4.8% were not evaluable. In multivariate analysis, patients with HS2 tumors had a higher probability of relapse and death than those with HS1 ( P < 0.0001 and P = 0.00020, respectively). We identified a higher-risk subgroup among HS2 tumors, presenting non-mutually exclusive expression of ARR3 and TFF1 and had an increased risk of relapse and death compared to tumors that displayed mutually exclusive expression ( P = 0.012 and P = 0.027, respectively). Conclusions: Expression of TFF1, especially when it is not-mutually exclusive with ARR3, is an independent prognostic marker of poor outcome in retinoblastoma.

Standard management of pediatric Non-Hodgkin’s Lymphoma (NHL) patients have included an initial assessment of the disease at presentation to establish it’s extent. This “staging” process has historically assigned patients using traditional classifications which were established decades ago when, like other pediatric malignancies, the more extensive involvement of the cancer for a patient directly correlated with the patient’s long term survival[[1]](#ref-0001). Advances in radiologic technology have evolved in the way the disease extent was evaluated, moving from conventional radiographs, to computerized tomography (CT) to magnetic resonance imaging (MRI) to most recently positron emission tomography (PET)[[2]](#ref-0002). Despite the development and use of PET scans for decades for various cancer diagnoses, the role of PET scans for NHL remains unclear[[3]](#ref-0003). Indeed, its value for many conditions is its ability to assess the response to initial therapy and establish the patient’s risk stratification guiding the remaining treatment plan[[4]](#ref-0004). Such efforts have not occurred in clinical trials of NHL and thus we are left to examine case series and try to discern its value for this disease.

Purpose Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma. Methods Oral cabozantinib (25mg/m 2) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75mg/m 2) and cyclophosphamide (250mg/m 2) were administered IV on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation. Results Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (7 with Ewing sarcoma; 5 with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis; grade 3 transaminitis; prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease. Conclusions The recommended phase 2 doses and schedules for this combination are topotecan 0.75mg/m 2 IV days 1-5, cyclophosphamide 250mg/m 2 IV days 1-5, and cabozantinib 25mg/m 2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity while allowing for potential disease control.

PARANEOPLASTIC JUVENILE IDIOPATHIC ARTHRITIS AS A MANIFESTATION OF A BENIGN TERATOMA IN A FIVE-YEAR-OLD GIRL

LETTER TO THE EDITORTITLE: Sarcoid-like reaction in a child following prolonged therapeutic exposure to dabrafenib and trametinib for BRAF V600E mutated hypothalamic/ chiasmatic gliomaAuthors : Mari Wilhelmsson MD, PhD1,2; Foo Jen Chun MD1; Rae S M Yeung MD, PhD3; Fiona Krtizinger MBChB, MMed4; Tata McKeown, MSc1; Ailish Coblentz, MD5; Birgit Ertl-Wagner, MD5; Uri Tabori MD, PhD1, Ute Bartels MD, PhD 1; Anirban Das MBBS, MD, DM 1AFFILIATIONS: 1. Division of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada; 2. Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden. 3. Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada. 4. Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. 5. Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada.WORD COUNT:   853FIGURES:  1RUNNING TITLE: Sarcoid-like reaction with BRAF/MEK-inhibitionKEYWORDS : MEK-inhibitor, BRAF inhibitor, sarcoidosis/sarcoid‑like reaction (S/SLR), Low-grade glioma, pediatric

Background: Anaplastic large cell lymphoma (ALCL) is an uncommon form of Non-Hodgkin Lymphoma (NHL) in younger patients, accounting for less than 15% of cases. The median age at presentation is 12 years and is exceedingly rare in infants. Various prognostic factors, risk stratification and novel treatment strategies have been studied in pediatric ALCL. There is no separate data available on the disease biology, treatment regimens and prognostic factors among infantile ALCL. Outcomes for infants with ALCL have been reported to be inferior to that of older children. The long-term Event Free Survival (EFS) in general among pediatric patients is approximately 70% regardless of the treatment approach. We report a case of an 8month old infant diagnosed with ALK positive ALCL with visceral organ involvement stratified as high risk and treated according to ALCL 99 protocol with excellent clinical response, on regular follow up and is disease free since 2years.

The value of reporting on end-of-treatment outcome of patients in low-income settingsTrijn Israels MD PhD1,2, Ramandeep Singh Arora DCH, MD3, Lillian Sung MD PhD41 Collaborative African Network for Childhood Cancer Care and Research (CANCaRe Africa), 2 Kamuzu University of Health Sciences, Blantyre, Malawi, 3 Max Super Speciality Hospital, New Delhi, India, 4 Sick Children’s Hospital, Toronto, CanadaCorresponding author:Dr Trijn Israels, CANCaRe Africa, Department of Paediatrics, Kamuzu University of Health Sciences (KuHES), Blantyre, Malawi. Email: cancareafrica@gmail.comWord count: 1256 wordsNumber of Tables: 0Number of Figures: 0Short running title: End-of-treatment outcome reportingKey words: childhood cancer, survival, LIC, indicatorsLIC Low-income countryHIC High-income countryGICC Global Initiative for Childhood CancerEFS Event-free survivalOS Overall survivalTRM Treatment related mortalityDRM Disease related mortalityCANCaRe Africa Collaborative African Network for Childhood Cancer Care and Research

Cure rates for acute lymphoblastic leukemia (ALL), the most common childhood cancer have steadily improved over the past five decades. This is due to intensifying systemic therapy, recognizing and treating the central nervous system as a sanctuary site, and implementing modern risk stratification to deliver varying intensities of therapy based on age, presenting white blood count (WBC), sentinel somatic genetics, and therapy response. Recently, numerous Children’s Oncology Group trials have demonstrated the lack of benefit of intensifying traditional chemotherapy, providing evidence that new approaches are needed to cure the patients for whom cure has been elusive. Distinguishing those who require intensive or novel therapeutic approaches from others who will be cured with minimal therapy is key for future trials. Incorporating new genomic biomarkers and more sensitive measures of minimal/measurable residual disease (MRD) provide opportunities to achieve these goals.

Since the publication of the last Cellular Therapy and Stem Cell Transplant blueprint in 2013, Children’s Oncology Group cellular therapy-based trials for advanced the field and created new standards of care across a wide spectrum of pediatric cancer diagnoses. Key findings include that tandem autologous transplant improved survival for patients with neuroblastoma and atypical teratoid/rhabdoid brain tumors, one umbilical cord blood (UCB) donor was safer than two UCB donors, killer immunoglobulin receptor (KIR) mismatched donors did not improve survival for pediatric acute myeloid leukemia when in vivo T cell depletion is used and the depth of remission as measured by next-generation sequencing based minimal residual disease assessment pre-transplant was the best predictor of relapse for acute lymphoblastic leukemia. Plans for the next decade include optimizing donor selection for transplants for acute leukemia/myelodysplastic syndrome, using novel engineered cellular therapies to target a wide array of malignancies, and developing better treatments for cellular therapy toxicities such as viral infections and graft-vs-host disease.

The Children’s Oncology Group (COG) Rare Tumor committee includes the Infrequent Tumor and Retinoblastoma subcommittees, encompassing a wide range of extracranial solid tumors that don’t fall within another COG disease committee. Current therapeutic trial development focuses on nasopharyngeal carcinoma, adrenocortical carcinoma, pleuropulmonary blastoma, colorectal carcinoma, melanoma, and thyroid carcinoma. Given the rarity of these tumors, novel strategies and international collaborative efforts are necessary to advance research and improve outcomes.

Cost effectiveness of support with out-of-pockets costs to prevent treatment abandonment in Malawi and sub-Saharan Africa; lessons learnt and the way forward – a report from CANCaRe Africa Junious Sichali1, Avi Denburg2, Harriet Khofi3, Cecilia Mdoka1, Deborah Nyirenda4, Yamikani Chimalizeni3, George Chagaluka3, Elizabeth Molyneux3, Marc Y. R. Henrion4,5, Sumit Gupta2, Trijn Israels11 Collaborative African Network for Childhood Cancer Care and Research (CANCaRe Africa), 2Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Canada,3 Kamuzu University of Health Sciences (KUHeS), Blantyre, Malawi, 4 Malawi Liverpool Wellcome Research Programme, Blantyre, Malawi, 5Liverpool School of Tropical Medicine, Liverpool, UKCorresponding author:Dr Trijn Israels, CANCaRe Africa, Department of Paediatrics, Kamuzu University of Health Sciences (KuHES), Blantyre, Malawi. Email: cancareafrica@gmail.comWord count: 1189 wordsNumber of Tables: 0Number of Figures: 0Short running title: Cost-effectiveness of treatment abandonment preventionKey words: childhood cancer, treatment abandonment, cost-effectiveness,LMIC Low- and middle-income countryGICC Global Initiative for Childhood CancerCANCaRe Africa Collaborative African Network for Childhood Cancer Care and ResearchALL Acute lymphoblastic leukaemiaGDP Gross Domestic ProductDALY Disability Adjusted Life Year

Children’s Oncology Group’s 2023 Blueprint For ResearchDouglas S. Hawkins,1 Lia Gore2Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WADepartment of Pediatrics, University of Colorado School of Medicine and Center for Cancer and Blood Disorders, Children’s Hospital Colorado,, Aurora, CO

As survival rates for childhood cancer have improved, there has been increasing focus on identifying and addressing adverse impacts of cancer and its treatment on children and their families during treatment and into survivorship. The Behavioral Science Committee (BSC) of the Children’s Oncology Group (COG), comprised of psychologists, neuropsychologists, social workers, nurses, physicians, and clinical research associates, aims to improve the lives of children with cancer and their families through research and dissemination of empirically supported knowledge. Key achievements of the BSC include enhanced interprofessional collaboration through integration of liaisons into other key committees within COG, successful measurement of critical neurocognitive outcomes through standardized neurocognitive assessment strategies, contributions to evidence-based guidelines, and optimization of patient-reported outcome measurement. The collection of neurocognitive and behavioral data continues to be an essential function of the BSC, in the context of therapeutic trials that are modifying treatments to maximize event-free survival, minimize adverse outcomes, and optimize quality of life. In addition, through hypothesis-driven research and multi-disciplinary collaborations, the BSC will also begin to prioritize initiatives to expand the systematic collection of predictive factors (e.g., social determinants of health) and psychosocial outcomes, with overarching goals of addressing health inequities in cancer care and outcomes, and promoting evidence-based interventions to improve outcomes for all children, adolescents, and young adults with cancer.

Severe Refractory Hemorrhagic Cystitis after Hematopoietic Cell Transplantation Responds to Recombinant Human Keratinocyte Growth Factor (KGF) - A Case Report and Review of the LiteratureCatherine Hughes1*, Anora Harris1*, Benjamin Watkins1, Muna Qayed1, Suhag Parikh1, Edwin Horwitz1, Elizabeth Stenger1, Kirsten M Williams1, Michelle L Schoettler1

Children with transfusion dependent thalassemia have an impaired ability to synthesize alpha or beta globin which results in anemia. Packed red blood cell (PRBC) transfusions are required to increase hemoglobin which supports appropriate growth and development. PRBC transfusions must be completed with 4 hours however infusion rates vary across institutions. Our institution infuses PRBC’s up to 10mL/kg/hr. A descriptive study of 21 children who received a total of 276 transfusions during 2021 demonstrated that this rate is safe and well tolerated. Shorter transfusion times support patients’ and families’ time, resources, and quality of life and aptly utilize institutional resources.

Reply to: Clinical trials: A plea to cooperative groups, consortia,