Title: Emerging Therapeutic Options for Sickle Cell Anemia: Enhancing the Current Predominant Treatment

Comment on: Viral infections in pediatric brain tumor patients treated with targeted therapiesAimen Waqar KhanDepartment of Medicine, Jinnah Sindh Medical University, Karachi, PakistanDear Dr. Newburger,We have read with great enthusiasm the article titled Viral infections in pediatric brain tumor patients treated with targeted therapies by Lisa Mayr et al [1]. We commend the authors’ efforts in collating epidemiologic data and investigating infectious outcomes between pediatric patients being treated with targeted therapy versus conventional therapies. It was a pleasure to read such a well-written paper. We concur with the conclusion that patients receiving targeted therapies are made more susceptible to developing viral infections than those receiving conventional treatment. However, we would like to draw attention to some key points regarding the study following a thorough appraisal.To begin with, the retrospective nature of the study adds several unavoidable biases such as recollection bias and incorrect data retrieval, which may have been mitigated had the investigators included current cases at the time. The study is also limited in its single-centered scope making it difficult to generalize the findings to this particular pediatric demographic. Moreover, the comparison between the two subsets of brain tumor patients is also subject to several partialities. For instance, it is noted that those receiving targeted therapies were managed in an outpatient setting and by extension, exposed to greater environmental stressors than those being managed on conventional chemotherapy. As a result, a greater proportion of virological infections were reported in children receiving targeted therapy than those being managed conventionally. Further, due to the lack of available data correlating disease severity with treatment option, the possibility that patients receiving conventional chemotherapy simply had a lower disease grade than those on targeted therapies and vice versa exists. Knowing this is pertinent as the body’s ability to fight off infections is greatly influenced by the grade of cancer and hence degree of inflammation [2]. Next, it remains to be seen what the baseline nutritional status of the participants was as nutrition and metabolism are known to have a bearing on immune status and hence infectious susceptibility [3]. Finally, the deduction that patients treated with bevacizumab or mTOR (mechanistic target of rapamycin) inhibitors suffered more infections than those treated with other targeted therapeutic drugs cannot be made with certainty as not enough patients were treated with drugs other than bevacizumab or mTOR inhibitors for a fair and accurate comparison.In conclusion, multi-centered prospective studies are required to better lay claims regarding infectious outcomes and attention to potential influencers of immunity must be given to minimize bias in future studies.

Calcineurin inhibitors (CNI), cyclosporine and tacrolimus, are commonly used for pharmacotherapeutic prophylaxis of Graft-vs.-Host disease after hematopoietic cell transplantation (HCT). Unfortunately, their use is associated with significant toxicities. While intolerance to CNI is well defined, there is very little data on how they impact outcomes after HCT in children. Our retrospective study in a cohort of 82 children, shows a high intolerance rate of 39% in this population associated with lower event free survival and a higher transplant-related mortality.

Background: Methotrexate is widely recommended as a first-line treatment for the intensive systemic and consolidation phases of childhood acute lymphoblastic leukemia. However, methotrexate-induced nephrotoxicity is a severe adverse reaction, of which the mechanism remains unclear. Methods: An untargeted metabolomics analysis of serum from childhood acute lymphoblastic leukemia with delayed methotrexate excretion with or without acute kidney injury was performed to identify altered metabolites and metabolic pathways. An independent external validation cohort and in vitro assays further confirmed the candidate metabolites and the mechanisms underlying the nephrotoxicity of methotrexate. Results: Four metabolites showed significant differences between normal excretion and delayed excretion, seven metabolites reflected the differences between groups with or without acute kidney injury, and six pathways were finally enriched. In particular, oxidized glutathione is confirmed as an candidate metabolite involved in the toxicity of methotrexate. Based on the depletion of glutathione mediated cell death, it was found that methotrexate overload significantly reduced cell viability, triggered reactive oxygen species and intracellular Fe 2+ accumulation, and altered the expression of ferroptosis-related proteins in HK-2 cells. These methotrexate-induced changes were alleviated or reversed by the administration of a ferroptosis inhibitor, further suggesting that ferroptosis promoted methotrexate-induced cytotoxicity in HK-2 cells. Conclusions: Our findings revealed complex metabolomic profiles and provided novel insights into the mechanism by which ferroptosis contributes to the nephrotoxic effects of methotrexate.

Gorham-Stout disease (GSD) and generalized lymphatic anomaly (GLA) are subtypes of complex lymphatic malformations (CLMs) with osseous involvement that cause significant complications in children, including pain and pathologic fractures. Mutations in cellular growth pathways are common, and the mTOR inhibitor sirolimus alleviates symptoms in some, but not all, patients. We describe two patients, one with GSD and one with GLA, who were found to have EML4::ALK fusions. This report of a targetable, oncogenic fusion in vascular malformations expands our understanding of the genetic basis for CLMs and suggesting additional targeted therapies could be effective.

In optic pathway glioma (OPG), bevacizumab-based therapy (BBT) has promising effects on radiographic tumor burden, but impact on vision is less clear. This single-institution study characterized visual acuity (VA) and visual field (VF) outcomes in 17 pediatric OPG patients treated with BBT. VA was stable or improved in 14 patients. Nine patients had evaluable VF data, 6 of whom experienced stability or improvement. Among 6 patients with vision deterioration as a treatment indication, stable or improved was observed for both VA and VF in 5 patients. In summary, BBT was associated with favorable visual outcomes in most patients with OPG.

Stroke in Sickle Cell Revascularization Surgery Retrospective Study (SiSCRS) in this issue reports retrospective data from 15 medical centers to examine the benefit of cerebral revascularization surgery (CRS) in children with sickle cell disease (SCD) who also have Moyamoya Syndrome (SCD-MMS). The American Society of Hematology guidelines “suggests evaluation for revascularization surgery in addition to regular blood transfusion” for treating SCD-MMS combined with a history of stroke or transient ischemic attack but categorizes this as a “conditional recommendation based on very low certainty in the evidence about effects”. The research presented in this article is aimed at reducing the uncertainty surrounding revascularization surgery as a treatment using retrospective data from 15 medical centers with expertise in CRS for SCD-MMS. Even with the 78 children with CRS (Surgery group) and 63 children in the non-surgery (Conservative group), the differences between the two groups had mixed statistical significance in multivariate analyses. SiSCRS is an important retrospective analysis but must be interpreted with caution. The benefit of CRS attains statistical significance only in some of the comparisons. The rate of stroke in pediatric SCD decreases with age, creating a bias in favor of the older group (i.e., the Surgery Group) to have fewer CVEs, The additional role of aspirin and the bias of patient selection for surgery also weaken the ability to make definitive statements. The SiSCRS results suggest a likely retrospective benefit of CRS, but the benefit must be demonstrated with more rigorous studies in the future.

Lactate dehydrogenase reflects the status of ultra-high-risk neuroblastoma in a child under treatmentAkinori Yaguchi, Junya Fujimura, Ayane Yakabe, Megumi Fujiwara, Takeshi Ishibashi, Osamu Tomita, Toshiaki ShimizuDepartment of Pediatrics, Juntendo University Faculty of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

Background Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. Procedure The Children’s Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug reinduction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m 2/dose) was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently combined with reinduction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) followed by an expansion pharmacokinetic (PK) cohort. Results Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m 2/dose orally for 21 days. No additional DLTs were observed in the dose determination or PK expansion cohorts and overall rates of grade 3/4 non-hematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Conclusions Palbociclib in combination with reinduction chemotherapy was well tolerated with a RP2D of 50 mg/m 2/day for 21 days. Complete responses were observed among heavily pretreated patients.

Title : Cutaneous presentation of Candida krusei fungemia refractory to amphotericin BAuthors : Michelle Toker, BS1, Carson Kirkpatrick, MD1, Pooja Srivastava, MD1,2, Bijal Amin, MD1,2, Benedict Wu, DO, PhD1Affiliations :1- Division of Dermatology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA2- Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USACorresponding author :Michelle Toker, BSAlbert Einstein College of Medicine, Montefiore Medical Center1300 Morris Park Avenue, Bronx, New York, 10461Email: michelle.toker@einsteinmed.eduTelephone: 516-946-4726Funding and support : NoneConflicts of Interest : NoneManuscript word count : 599Reference count : 5Figure count : 2Table count : 0Key words : disseminated fungemia, candida, oncology, leukemia, cutaneous fungal infection, rash, pathology, infectious disease

In low- and middle-income countries, malignancies remain underreported due to lack of quality data. This study outlines the histopathological pattern of pediatric solid malignancies in children aged 0-15yrs at the largest referral hospital in Ethiopia. 432 solid malignancies were evaluated. The most common malignancies were Lymphoma (21.8%), Retinoblastoma (19.4%), and Wilms tumor (13.9%). Burkitt lymphoma accounted for 2.1%, despite being the most reported pediatric malignancy in sub-Saharan Africa in published literature. Definitive diagnosis could not be made in 7% of cases, related to the lack of confirmatory testing. The study highlights the need for improvements in diagnostic capabilities in LMIC.

TITLE PAGETitle: Comment on: evaluating age and sex-specific rates of gall bladder disease in children with sickle cell diseaseArticle type: Letter to the editorCorrespondence : 1. Ifra Eeman Ahmed contact : 03335890003 Email : ifraeemanahmed786@gmail.comInstitution : Federal medical & dental college,IslamabadAddress: House#2,Street#15g,Sector A,Bahria Enclave,IslamabadCo-author : 2. Satesh KumarContact: +92-3325252902 Email:Institute: Shaheed Mohtarma Benazir Bhutto Medical College Liyari, KarachiAddress: Parsa citi Garden east, KarachiWord count: 391Conflict of interest : NoneDeclaration : NoneAcknowledgment : None

Daratumumab induced Minimal Residual Disease Negative Remission in CD 38 (dim) Positive Pediatric Acute Myeloid LeukemiaPronamee Borah1, Dinah Ng1, Nitin Dayal2, Sangeeta Pathak3, Rahul Naithani11Hematology and Bone Marrow Transplant Division, Max Superspecialty Hospital, Delhi, India2Department of Lab Medicine, Max Superspecialty Hospital, Delhi, India3Department of Transfusion medicine, Max Superspecialty Hospital, Delhi, IndiaConflicts of interest: None to declare.No financial support was obtained in this study.Text word count 815Brief running title: Daratumumab in Pediatric AMLKey Words: Daratumumab, AML, ChildrenTables: 0; Figures: 0

Background/Purpose Stage at diagnosis is an important metric in treatment and prognosis of cancer, and also in planning and evaluation of cancer control. In sub-Saharan Africa (SSA), for the latter, the only data source is the population-based cancer registry (PBCR). For childhood cancers, the “Toronto Staging Guidelines” have been developed to facilitate abstraction of stage by cancer registry personnel. Although the feasibility of staging using this system has been shown, there is limited information on the accuracy of staging. Methods A panel of case records of 6 common childhood cancers was established. 51 cancer registrars from 20 SSA countries staged these records, using Tier 1 of the Toronto guidelines. The stage that they assigned was compared with that decided by two expert clinicians. Results The registrars assigned the correct stage for 53-83% of cases (71% overall), with the lowest values for acute lymphocytic leukaemia (ALL), retinoblastoma and non Hodgkin lymphoma (NHL), and the highest for osteosarcoma (81%) and Wilms tumour (83%). For ALL and NHL, many unstageable cases were mis-staged, probably due to confusion over the rules for dealing with missing data; for the cases with adequate information, accuracy was 72-73%. Some confusion was observed over the precise definition of three stage levels of retinoblastomas. Conclusions A single training in staging resulted in an accuracy, for solid tumours, that was not much inferior to what has been observed in high income settings. Nevertheless, some lessons were learned on how to improve both the guidelines, and the training course.

A 19 year-old adolescent girl with Dravet syndrome, characterized by complex seizure disorder and global developmental delay, presented with B-cell acute lymphoblastic leukemia. The genetic basis for her Dravet syndrome was a pathogenic variant in SCN1A, a sodium channel subunit. SCN1A is chiefly expressed in neuronal tissue, but bioinformatic analysis demonstrated its presence in B cell lineage. One estimate suggested that 10% of children with pediatric cancer have a germline predisposition involving proto-oncogenes or tumor suppressors. This number might be even higher should non-classical genetic variants, such as that encoding a sodium channel subunit, be considered.

Background While racial disparities in the clinical outcomes of hematopoietic stem cell transplant (HSCT) patients have been explored, racial disparities in quality of life (QoL) during the readjustment phase after transplant has yet to be investigated in pediatric patients. The objective of this study was to examine the role of patient race in QoL at least two years after pediatric HSCT. Procedure We conducted a retrospective chart review of patients under 21 years of age at diagnosis that received an allogeneic transplant at our institution between January 2007 and December 2017. Patient QoL was assessed using the PedsQL TM 4.0 at least two years post-transplant. Patient demographic, treatment, and transplant outcome data were obtained for subsequent analysis, where patient race was categorized as either Black, White, Hispanic, or Native American. Results Data were collected on 86 pediatric patients who underwent HSCT. Forty patients (46.5%) were non-Hispanic White, 29 (33.7%) Hispanic, 10 (11.6%) Black, and 7 (8.1%) Native American. Where preliminary analyses indicated a difference in QoL by patient race, there were no significant differences in physical, emotional, social, and school functioning by patient race after adjusting for transplant characteristics (age at transplant, sex, diagnosis, donor type and conditioning regimen) and determinants of socioeconomic status (insurance type, estimated household income). Conclusions Pediatric patients had comparable QoL, regardless of race, at a median of three years after HSCT in our study cohort.

Background Based on previous reports of disparities in financial burden following cancer, this study aims to characterize mechanisms of disparities experienced by caregivers of children with cancer, including the impact of work flexibility and social support. Methods Cross-sectional survey (in English or Spanish) of caregivers of children with cancer that assessed household material hardship (HMH), financial toxicity and income change. Results Of 156 caregivers surveyed, 32% were Hispanic and 32% were low income. Hispanic caregivers were more likely to report HMH and financial toxicity compared to non-Hispanic White and Asian (HMH 57% v. 21% v. 19%, p<0.001; financial toxicity 73% v. 52% v. 53%, p=0.07). Low and middle income caregivers were more likely to experience HMH and financial toxicity compared to high income (HMH: 68% low v. 38% middle v 8.7% high, p<0.001; financial toxicity: 81% v. 68% v. 44%, p<0.001). All income categories demonstrated significant increases in HMH one year after diagnosis. Seventeen percent reported >40% income loss, more of whom were low income than high income (27% v. 12%, p=0.20). Work flexibility and social support were associated with income and financial toxicity. Conclusion HMH, financial toxicity, and income loss are prevalent after a child’s cancer diagnosis, suggesting that screening should be incorporated into routine care. This financial burden disproportionately affects low income and Hispanic caregivers. Further research is underway to understand how safety net services are utilized by families, how best to support families with HMH, and how the financial burden of cancer has been impacted by COVID-19.

Letter to the editor