Increased Incidence of TdT-negative Pre-B Acute Lymphoblastic Leukemia Associated With Poor Prognostic Features Among Mexican Children in Central Mexico.

Mexican and Hispanic children in Mexico and the United States, respectively, have the highest incidence and worst outcomes of pre-B acute lymphoblastic leukemia (ALL) compared with other racial/ethnic groups. Terminal deoxynucleotidyl transferase (TdT) is an intranuclear DNA polymerase normally present on immature lymphocytes (TdT-positive) and distinguishes ALL from mature lymphoid malignancies. We performed a multisite retrospective study to determine the incidence of TdT-negative precursor B-cell acute lymphoblastic leukemia (pre-B ALL) among Mexican, Caucasian, and US-born Hispanic children to correlate TdT expression with patient characteristics and known prognostic factors. Fisher exact test was performed for categorical variables and the Wilcoxon rank-sum test was used for continuous variables. TdT-negative pre-B ALL was most frequently identified in patients with National Cancer Institute high-risk disease ( P =0.014). TdT-negative expression was also most frequently associated with hypodiploid pre-B ALL ( P =0.001) and KMT2A gene rearrangement ( P =0.0012). Mexican children had the highest incidence of TdT-negative ALL compared with Caucasians and US Hispanics ( P <0.001), with an increased incidence of poor prognostic features as well. This study demonstrates significant differences in TdT-negative expression, genomic alterations, and leukemic ploidy based on race and ethnicity.

Skin Toxicity Due to Mercaptopurine in Maintenance Therapy Among Children With Acute Lymphoblastic Leukemia.

Mercaptopurine is a crucial component in the treatment of acute lymphoblastic leukemia. It is associated with toxicities that can delay treatment. Mercaptopurine is metabolized into 6-thioguanine nucleotides and 6-methylomercaptopurine nucleotides (6MMPN). Accumulation of 6MMPN has previously been associated with hepatotoxicity, pancreatitis, and hypoglycemia. However, skin toxicity has rarely been reported. We report 5 cases of elevated 6MMPN levels associated with cutaneous manifestations.

A Pediatric Case of Treatment-related Myelodysplastic Syndrome While on Therapy for Pre-B Acute Lymphoblastic Leukemia.

BACKGROUND: Treatment-related myelodysplastic syndrome (t-MDS) is a rare late effect of cancer therapy. After alkylating agents, this typically occurs years after completion of therapy. Treatment of t-MDS in pediatrics is an allogeneic stem cell transplant, however, the prognosis remains poor. OBSERVATIONS: This case demonstrates t-MDS developing in a patient receiving treatment for pre-B acute lymphoblastic leukemia. This patient was treated with a combination of hematopoietic stem cell transplant and hypomethylating agents. CONCLUSIONS: These agents should be considered for use in patients with t-MDS, before transplant to limit additional chemotherapy and as maintenance therapy post-transplant to reduce the risk of relapse.

Therapeutic plasma exchange for multiorgan dysfunction among critically ill pediatric patients with leukemia: A single-institutional experience.

INTRODUCTION: Therapeutic plasma exchange (TPE) has well-documented applications in the adult population, outlined by the American Society for Apheresis (ASFA) 2019 guidelines. Limited data exist regarding the use of TPE in critically ill pediatric patients; however, these reports rarely include patients with oncological diseases. METHODS: We highlight the use of TPE in the acute management of seven pediatric patients with leukemia treated at Children's Mercy Hospital ICU from 2015 to 2020, including TPE specifications, baseline and interval laboratory evaluation, and outcome measures. Analysis compared those who did (n = 4) and did not (n = 3) survive 30 days post-TPE. RESULTS: Multiorgan failure (MOF) prompted the initiation of TPE in 85.7% of patients, 57.1% of whom were also diagnosed with hemophagocytic lymphohistiocytosis (HLH). Baseline laboratory evaluations prior to initiation of TPE were similar between the two groups. With subsequent TPE treatments, C-reactive protein (CRP) and lactic acid decreased. CRP and lactic acid following the last TPE treatment were significantly higher for those deceased 30 days post-TPE (P = .023 and .031, respectively). No TPE-associated adverse events necessitated discontinuation of TPE treatment. Several surviving patients required chemotherapy dose reductions or alterations. CONCLUSION: Our cohort demonstrated MOF and HLH consistently as indications for TPE, currently ASFA category III indications (optimal role of apheresis is not yet established). Recognition of this treatment modality earlier in the clinical course for critically ill oncological patients may lead to the development of formal protocols that may result in earlier initiation of TPE and improved outcomes.

MYOD1 as a prognostic indicator in rhabdomyosarcoma.

BACKGROUND/OBJECTIVES: Rhabdomyosarcoma (RMS) is characterized by the expression of the myogenic regulatory protein MYOD1. Histologic types include alveolar, embryonal (ERMS), and spindle cell sclerosing RMS (SRMS). SRMS harbors MYOD1 mutations in a subset of adult cases in association with poor prognosis. DESIGN/METHODS: To study the level of MYOD1 protein expression and its clinical significance, we have analyzed variable numbers of pediatric (<18 years of age) and adult (age range ≥18 to 35 years) ERMS and SRMS cases for presence or absence of MYOD1 immunoreactivity in correlation with clinical outcome and MYOD1 L122R mutations. RESULTS: Lack of MYOD1 immunoreactivity, identified in 23.8% of nonalveolar RMS (non-ARMS) cases, was more prevalent in SRMS (44%) than ERMS (17.2%) and was significantly associated with low overall survival and unfavorable tumor sites (p < .05). Lack of MYOD1 immunoreactivity was not associated with MYOD1 L122R mutations, which were identified in 3/37 (8%) cases including only two of 31 (6.5%) pediatric cases, one of 11 or 9% pediatric SRMS, and one case of infant ERMS. CONCLUSION: These studies highlight the prognostic role of MYOD1 in non-ARMS. Lack of MYOD1 immunoreactivity is associated with poor prognosis in ERMS and SRMS. MYOD1 gene mutations are generally infrequent in pediatric RMS. Although mutations are predominant in SRMS, they may exceptionally occur in infantile ERMS.

Neuroblastoma in Adolescents and Children Older than 10 Years: Unusual Clinicopathologic and Biologic Features.

Neuroblastoma (NB) in children older than 10 years is rare. We reviewed our archives for patients with NB aged 10 to 18 years and summarized their clinicopathologic/genetic records. Of 96 patients, 4 patients were identified in this age group. Four tumors were abdominal; 1 patient had 2 tumors at diagnosis, one of which was presacral. Tumor sizes ranged from 3 to 20 cm. All tumors were high risk at clinical stages 3 and 4, with metastasis to bone marrow and other areas. Four tumors were poorly differentiated with unfavorable histology and one patient with bilateral adrenal disease had an intermixed ganglioneuroblastoma on one side. Another tumor exhibited pheochromocytoma-like morphology. MYCN amplification was present in bone marrow metastasis in one case. Complex chromosomal gains and 19p deletions were common. Exome sequencing revealed ALK variants in 2 cases and previously unreported MAGI2, RUNX1, and MLL mutations. All patients received standard chemotherapy and 2 patients received ALK-targeted trial therapy. Three patients died of disease, ranging 18 to 23 months after diagnosis. One patient has active disease and is receiving trial therapy. In conclusion, NB in children older than 10 years may exhibit unusual clinicopathologic and genetic features with large tumors, bilateral adrenal disease, rare morphologic features, complex DNA microarray findings and novel mutations. Patients often have grim prognoses despite genomic profiling-guided targeted therapy.

Polypyrimidine Tract Binding Protein: A Universal Player in Cancer Development.

OBJECTIVES: Polypyrimidine tract binding protein is a 57-Kda protein located in the perinucleolar compartment where it binds RNA and regulates several biological functions through the regulation of RNA splicing. Numerous research articles have been published that address the cellular network and functions of PTB and its isoforms in various disease states. METHODOLOGY: Through an extensive PubMed search, we attempt to summarize the relevant research into this biomolecule. RESULTS: Besides its roles in embryonic development, neuronal cell growth, RNA metabolism, apoptosis, and hematopoiesis, PTB can affect cancer growth via several metabolic, proliferative, and structural mechanisms. PTB overexpression has been documented in several cancers where it plays a role as a novel prognostic factor. CONCLUSION: The diverse carcinogenic effect opens an argument into its potential role in inhibitory targeted therapy.

Perinucleolar Compartment (PNC) Prevalence as an Independent Prognostic Factor in Pediatric Ewing Sarcoma: A Multi-Institutional Study.

The perinucleolar compartment (PNC) is a small nuclear body that plays important role in tumorigenesis. PNC prevalence correlates with poor prognosis and cancer metastasis. Its expression in pediatric Ewing sarcoma (EWS) has not previously been documented. In this study, we analyzed 40 EWS tumor cases from Caucasian and Hispanic patients for PNC prevalence by immunohistochemical detection of polypyrimidine tract binding protein and correlated the prevalence with dysregulated microRNA profiles. EWS cases showed staining ranging from 0 to 100%, which were categorized as diffuse (≥77%, n = 9, high PNC) or not diffuse (<77%, n = 31) for low PNC. High PNC prevalence was significantly higher in Hispanic patients from the US (n = 6, p = 0.017) and in patients who relapsed with metastatic disease (n = 4; p = 0.011). High PNC was associated with significantly shorter disease-free survival and early recurrence compared to those with low PNC. Using NanoString digital profiling, high PNC tumors revealed upregulation of eight and downregulation of 18 microRNAs. Of these, miR-320d and miR-29c-3p had the most significant differential expression in tumors with high PNC. In conclusion, this is the first study that demonstrates the presence of PNC in EWS, reflecting its utility as a predictive biomarker associated with tumor metastasis, specific microRNA profile, Hispanic ethnic origin, and poor prognosis.

NanoString Digital Molecular Profiling of Protein and microRNA in Rhabdomyosarcoma.

PURPOSE: Rhabdomyosarcoma (RMS) exhibits a complex prognostic algorithm based on histologic, biologic and clinical parameters. The embryonal (ERMS) and spindle cell-sclerosing RMS (SRMS) histologic subtypes warrant further studies due to their heterogenous genetic background and variable clinical behavior. NanoString digital profiling methods have been previously highlighted as robust novel methods to detect protein and microRNA expression in several cancers but not in RMS. METHODS/PATIENTS: To identify prognostic biomarkers, we categorized 12 ERMS and SRMS tumor cases into adverse (n = 5) or favorable (n = 7) prognosis groups and analyzed their signaling pathways and microRNA profiles. The digital spatial profiling of protein and microRNA analysis was performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissue using NanoString technology. RESULTS: The detectable expression of several component members of the PI3K/AKT, MAPK and apoptosis signaling pathways was highlighted in RMS, including INPP4B, Pan-AKT, MET, Pan-RAS, EGFR, phospho-p90 RSK, p44/42 ERK1/2, BAD, BCL-XL, cleaved caspase-9, NF1, PARP and p53. Compared to cases with favorable prognosis, the adverse-prognosis tumor samples had significantly increased expression of INPP4B, which was confirmed with traditional immunohistochemistry. The analysis of microRNA profiles revealed that, out of 798 microRNAs assessed, 228 were overexpressed and 134 downregulated in the adverse prognosis group. Significant over-expression of oncogenic/tumor suppressor miR-3144-3p, miR-612, miR-302d-3p, miR-421, miR-548ar-5p and miR-548y (p < 0.05) was noted in the adverse prognosis group. CONCLUSION: This study highlights the utility of NanoString digital profiling methods in RMS, where it can detect distinct molecular signatures with the expression of signaling pathways and microRNAs from FFPE tumor tissue that may help identify prognostic biomarkers of interest. The overexpression of INPP4B and miR-3144-3p, miR-612, miR-302d-3p, miR-421, miR-548y and miR-548ar-5p may be associated with worse overall survival in ERMS and SRMS.

Tisagenlecleucel infusion in patients with relapsed/refractory ALL and concurrent serious infection.

BACKGROUND: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated durable efficacy and a manageable safety profile in pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) in the ELIANA pivotal trial and real-world experience. Experience from investigator-led studies prior to ELIANA suggests that infections and inflammatory conditions may exacerbate the severity of cytokine release syndrome (CRS) associated with CAR-T cell therapy, leading to extreme caution and strong restrictions for on-study and commercial infusion of tisagenlecleucel in patients with active infection. CRS intervention with interleukin (IL)-6 blockade and/or steroid therapy was introduced late in the course during clinical trials due to concern for potential negative effect on efficacy and persistence. However, earlier CRS intervention is now viewed more favorably. Earlier intervention and consistency in management between providers may promote broader use of tisagenlecleucel, including potential curative therapy in patients who require remission and recovery of hematopoiesis for management of severe infection. MAIN BODY: Patient 1 was diagnosed with B-ALL at 23 years old. Fourteen days before tisagenlecleucel infusion, the patient developed fever and neutropenia and was diagnosed with invasive Mucorales infection and BK virus hemorrhagic cystitis. Aggressive measures were instituted to control infection and to manage prolonged cytopenias during CAR-T cell manufacturing. Adverse events, including CRS, were manageable despite elevated inflammatory markers and active infection. The patient attained remission and recovered hematopoiesis, and infections resolved. The patient remains in remission ≥1 year postinfusion.Patient 2 was diagnosed with pre-B-ALL at preschool age. She developed severe septic shock 3 days postinitiation of lymphodepleting chemotherapy. After receiving tisagenlecleucel, she experienced CRS with cardiac dysfunction and extensive lymphadenopathy leading to renovascular compromise. The patient attained remission and was discharged in good condition to her country of origin. She remained in remission but expired on day 208 postinfusion due to cardiac arrest of unclear etiology. CONCLUSIONS: Infusion was feasible, and toxicity related to tisagenlecleucel was manageable despite active infections and concurrent inflammation, allowing attainment of remission in otherwise refractory pediatric/young adult ALL. This may lead to consideration of tisagenlecleucel as a potential curative therapy in patients with managed active infections.

Successful mobilization with AMD3100 and filgrastim with engraftment of autologous peripheral blood stem cells in a heavily pretreated pediatric patient with recurrent Burkitt lymphoma.

The authors report a case of a 13-year-old female with recurrent Burkitt lymphoma who was heavily pretreated with chemotherapy. During chemotherapy for relapse, she developed serious aspergillus infection of the palate and sinuses. Despite 10 microg/kg of filgrastim for 5 days, peripheral blood CD34(+) cells remained

Extracorporeal Membrane Oxygenation as a Bridge to Chimeric Antigen Receptor T-cell Therapy for Severe Refractory Sepsis in the Setting of Relapsed Refractory Pediatric Acute Lymphoblastic Leukemia: A Case Report.

Pediatric oncology patients with sepsis are at higher risk of morbidity and mortality compared with pediatric patients without malignancy. Historically, patients with relapsed and/or refractory disease were not considered candidates for aggressive life support strategies including extracorporeal membrane oxygenation support. CASE SUMMARY: We report a 4-year-old female with relapsed refractory pre-B cell acute lymphoblastic leukemia preparing for chimeric antigen receptor T cell therapy with tisagenlecleucel who was admitted with fever and neutropenia. She progressed to refractory septic shock secondary to Escherichia coli bacteremia and required escalation of hemodynamic support to venoarterial extracorporeal membrane oxygenation cannulation. She cleared her E. coli bacteremia, was decannulated, subsequently received her chimeric antigen receptor T-cell therapy, and was declared disease free 1 month from her initial presentation. CONCLUSION: The ability to provide chimeric antigen receptor T-cell therapy at designated institutions can augment extracorporeal membrane oxygenation candidacy discussions in oncology patients with relapsed disease and may make extracorporeal membrane oxygenation candidacy for oncology patients with refractory sepsis more favorable.

Successful treatment of fanconi anemia and T-cell acute lymphoblastic leukemia.

Fanconi anemia is associated with an increased risk of malignancy. Patients are sensitive to the toxic effects of chemotherapy. We report the case of a patient with Fanconi anemia who developed T-cell acute lymphoblastic leukemia. He experienced chemotherapy-related complications including prolonged neutropenia, grade IV vincristine neuropathy, and disseminated aspergillosis. He was successfully treated with modified dosing of cytarabine and intrathecal methotrexate followed by allogeneic bone marrow transplant. The aspergillosis was treated with systemic antifungal treatment and surgical resection. Now 30 months after bone marrow transplant the patient is without evidence of aspergillosis or leukemia.