Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders.

The standard treatment for Langerhans cell histiocytosis (LCH) is chemotherapy, although the failure rates are high. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEK-inhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and there are no data on the use of these inhibitors as first-line therapy. We treated 34 patients (26 with LCH, 2 with juvenile xanthogranuloma, 2 with Rosai-Dorfman disease, and 4 with presumed single site-central nervous system histiocytosis) with dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients, aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, nine of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients, aged 0.2-45 years, received an inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated central nervous system/pituitary stalk histiocytosis had stabilization or improvement of their disease. Overall, inhibitors were well tolerated. Five patients with single-system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all four patients with multisystem disease who discontinued therapy had to restart treatment. Our data suggest that children suffering from histiocytoses can be treated safely and effectively with dabrafenib or trametinib. Additional studies are, however, needed to determine the long-term safety and optimal duration of therapy.

Success of Trametinib in the Treatment of Langerhans Cell Histiocytosis With Novel MAPK Pathway Mutations.

Approximately a third of patients with Langerhans cell histiocytosis (LCH) experience recurrence of disease. Genomic analysis has revealed that this condition is often driven by oncogenic mutations in the MAP kinase (MAPK) pathway, and agents that target components of this pathway have been explored as a second-line treatment for LCH. Here, we examine 2 pediatric patients with LCH and confirmed but rarely reported MAPK pathway mutations treated with trametinib, a MAP2K inhibitor approved to treat several cancers with a BRAFV600E mutation. Each patient achieved or maintained complete resolution of disease and remain on the drug with no adverse effects.

Lessons Learned: Utilization of a Reference Laboratory for Targeted Sequencing of Pediatric Tumors at a Single Institution.

Our study aims to report the prevalence of potentially actionable oncogenic variants in a sample of pediatric tumors from a single institution using a reference laboratory for tumor profiling. We investigated genomic alterations and immunotherapy biomarkers such a tumor mutation burden, microsatellite instability, and programmed death-ligand 1. Patients treated in the Cook Children's Health Care System who had tumor profiling performed by Foundation Medicine between January 1, 2013, and May 1, 2019, were included. Demographic variables, results of tumor profiling, and subsequent use of targeted therapies were captured. Eighty-one patients were in our final data set; patients had diagnoses of central nervous system tumors (n=5), leukemia and lymphoma (n=4), neuroblastoma (n=32), and other solid tumors (n=40). One or more genomic alterations were identified in 68 (84%) of patients, 34 of which had potential targeted therapies available. In all, 44/51 patients tested for tumor mutation burden had low tumor burden, and the rest had intermediate burden. All 41 patients tested for microsatellite instability status were microsatellite stable. Six of 34 patients tested for programmed death-ligand 1 status were positive. Twelve patients received targeted therapy. This study highlights a subset of pediatric tumors harboring targetable genetic alterations and describes the use of a reference laboratory for tumor profiling.

Characterization of Febrile Neutropenia in Pediatric Patients With Cancer Before and After Implementation of Coronavirus Disease 2019 Precautions.

Historically, febrile neutropenia (FN) has constituted a common but life-threatening emergency in pediatric oncology patients. As such, hygiene precautions have consistently been recommended for immunosuppressed patients. These precautions, however, were more strictly and widely adopted during the coronavirus disease 2019 pandemic. Universal mask mandates, emphasis on hand hygiene, and encouragement of social distancing were some of the many initiatives introduced in an effort to reduce transmission of the virus. There is little data available regarding whether the universal adoption of these precautions was associated with any changes in the incidence of hospitalizations for FN in pediatric oncology patients. A retrospective chart review was utilized to evaluate newly diagnosed patients admitted for FN in the first 14 months of the pandemic compared with the same time period during the previous year. During the pandemic, the admission rate for FN was 28.9%, compared with 29.1% prepandemic ( P = 0.97). There was no significant difference in causative organisms when comparing time periods. In addition, the presence of a state government-enforced mask mandate was associated with an increased admission rate for FN during the pandemic period.

Multimodal Management With Immunotherapy, Radiation, and Surgery of Histiocytic Sarcoma Following Acute Lymphoblastic Leukemia: An Unusual Presentation of a Rare Disease.

Histiocytic sarcoma (HS) is a rare neoplasm with no known cause. This sarcoma is characterized by morphology similar to that demonstrated by mature tissue histiocytes and mostly afflicts adults. HSs typically have a poor prognosis due to a rapidly progressive clinical course. Our patient's case was unique due to its presentation four years after completion of treatment for B-cell acute lymphoblastic leukemia. The patient experienced progression with initial therapy for HS. With dual immunotherapy and radiation, however, the patient has remained clinically stable without detectable disease. Immunotherapy may be a successful and tolerable therapeutic option for histiocytic disease.

Intracranial Relapse in Pediatric Sarcoma.

Advances in local control techniques, chemotherapy regimens, and imaging modalities have led to improvements in both morbidity and mortality in pediatric sarcoma patients. However, approximately one-third of patients develop disease relapse and intracranial metastasis was considered rare. The incidence of sarcoma brain metastasis is thought to have increased and is associated with grim outcomes. This was a retrospective study of 3 deidentified patient charts illustrating the possibility of the central nervous system as a potential site for pediatric sarcoma relapse and investigate the patterns of such relapses. We note this is the first report of infantile fibrosarcoma brain metastasis and a rare report of sarcoma lymph node metastasis. In addition, each patient was treated with targeted therapies, including entrectinib, Ruxolitnib, and pazopanib. Caregivers in cases 2 and 3 reported new-onset neurological manifestations before identification of new brain metastasis, indicating a lag in detection of new intracranial relapse in asymptomatic sarcoma patients. We suggest implementing a brief review of systems screening tool focused on concerning neurological manifestations to screen for new brain metastasis.

Factors Affecting Presentation and Treatment of Pediatric/Adolescent Cancer Patients Diagnosed With SARS-CoV-2.

BACKGROUND: It is thought that the clinical course of actively treated pediatric/adolescent cancer patients diagnosed with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is more severe than experienced by the general pediatric population. We describe the clinical course, risk factors affecting presentation, and management of coronavirus disease 2019 (COVID-19) infection for these patients. METHODS: Patients at a single institution receiving cancer therapy while diagnosed with SARS-CoV-2 between January 2020 and June 2021 were retrospectively reviewed. Data collected included age at SARS-CoV-2 diagnosis, sex, ethno-race, adjusted body mass index, and active therapies. RESULTS: Twenty-nine patients met inclusion criteria, with 16 (55.2%) experiencing symptoms. Twenty-three (79.3%) patients required no institutional support; 10 (34.4%) required hospitalization, of which 80.0% required oxygen, 30.0% required intensive care, and 10.0% required intubation. Three (10.3%) patients developed MIS-C. Obesity increased odds of hospitalization (odds ratio=25.5; P =0.002) and oxygenation (odds ratio=14.88; P =0.012). CONCLUSIONS: Hospitalization and MIS-C rates were significantly higher than, whereas mortality rates and symptom presentations were consistent with, rates in the general pediatric population. Obesity was the only risk factor predictive of clinical severity. Cancer treatment modifications and pre-emptive administration of COVID-19 treatment did not modify clinical course.

Pediatric Hemophagocytic Lymphohistiocytosis: Formation of an Interdisciplinary HLH Working Group at a Single Institution.

Fever of unknown origin is a common presentation in children with an extensive differential diagnosis that encompasses multiple specialties. From a hematologic standpoint, the differential includes hyperinflammatory syndrome, such as hemophagocytic lymphohistiocytosis (HLH), among others. Due to the rarity of HLH and nonspecific symptoms at initial presentation, specialists are often consulted later in the disease progression, which complicates disease evaluation further. Cook Children's Medical Center (CCMC) has recently developed a multidisciplinary histiocytic disorder group that is often consulted on cases presenting with fever of unknown origin to increase awareness and potentially not miss new HLH cases. In this study, we examine the clinical presentation and workup of 13 patients consulted by the HLH work group at a single institution and describe the clinical course of 2 patients diagnosed with HLH. The goal of this project was to describe the formation of a disease-specific team and the development of a stepwise diagnostic approach to HLH. A review of the current diagnostic criteria for HLH may be warranted given findings of markers such as soluble IL2 receptor and ferritin as nonspecific and spanning multiple disciplines including rheumatology, infectious disease, and hematology/oncology.

Strategies for the Treatment of Infantile Soft Tissue Sarcomas With BCOR Alterations.

BCOR alterations are described in ultra-rare infantile soft tissue sarcomas including primitive myxoid mesenchymal tumor of infancy and undifferentiated round cell sarcoma (URCS). Previous reports often describe dismal outcomes. Thus, we undertook a retrospective, multi-institutional study of infants with BCOR -rearranged soft tissue sarcomas. Nine patients aged 6 weeks to 15 months were identified. One tumor carried a BCOR :: CCNB3 fusion, whereas 7 tumors harbored internal tandem duplication of BCOR , including 4 cases classified as primitive myxoid mesenchymal tumor of infancy, 1 case as URCS, and 2 cases characterized by a "hybrid morphology" in our evaluation. Four patients underwent upfront surgery with residual disease that progressed locally after a median of 2.5 months. Locoregional recurrences were observed in hybrid patients, and the URCS case recurred with brain metastases. Complete radiographic responses after chemotherapy were achieved in patients treated with vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide (regimen I), and ifosfamide/carboplatin/etoposide. Seven patients received radiotherapy. With a median of 23.5 months off therapy, 8 patients are with no evidence of disease. In our study, observation was inadequate for the management of untreated postsurgical residual disease. Tumors demonstrated chemosensitivity with anthracycline-based regimens and ifosfamide/carboplatin/etoposide. Radiotherapy was required to achieve durable response in most patients.

Implementing a Disease-specific Multidisciplinary Team and Order Set for Hemophagocytic Lymphohistiocytosis in a Pediatric Hospital.

OBJECTIVE: To improve outcomes of hemophagocytic lymphohistiocytosis (HLH), prompt recognition and treatment are necessary. A HLH multidisciplinary team was implemented at our institution, and we established an electronic order set to foster uniformity in the diagnostic approach. The goal of this study is to capture the impact of this diagnostic tool. METHODS: This is a retrospective study analyzing the utilization of a HLH-specific order set since time of implementation in June 2019 through December 2022. The trends in the utilization of the order set by providers were analyzed to evaluate the awareness and effectiveness of this tool. RESULTS: The order set was utilized 50 times, most commonly by hematology/oncology (50%) and infectious disease (26%). Utilization by providers on newly presenting patients included 4 times in the year 2019, 12 times in 2020, 16 times in 2021, and 18 times in 2022. Utilization was associated with the diagnosis of HLH in 9 patients (18%). CONCLUSION: Implementation of an HLH-specific order set facilitated a systematic method to approach patients with suspected HLH. The utilization of the order set displayed an upward trend over time, indicating support of this tool among these providers. This tool can increase awareness and early identification of HLH.

Transient Pancytopenia Subsequently Diagnosed With Acute Leukemia: A Report of 4 Cases of Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia.

A transient pancytopenic phase has been described in pediatric leukemia. The characteristic complete recovery of peripheral counts can obscure a clinician's suspicion for malignancy and may impact subsequent follow-up care. The authors describe 4 pediatric patients that had transient pancytopenia with an initial abnormal marrow finding. These patients were subsequently diagnosed with acute leukemia within 5 months of presentation. Awareness of this phenomenon by the provider and education of families may help with the appropriate and timely diagnosis of subsequent leukemia.

Mutation of CEP72 Gene May Predispose Patients to Hepatotoxicity.

Drug toxicities during treatment of acute lymphoblastic leukemia play a pivotal role in influencing the outcome as certain toxicities may impair treatment compliance. Polymorphisms in CEP72 have been linked to increased incidence of vincristine-induced toxicities, namely peripheral neuropathy. We hypothesize that polymorphisms in the same gene may increase a patient's risk of developing hepatotoxicity when receiving potentially hepatotoxic agents during chemotherapy. This report describes hepatotoxicity that first developed during consolidation in a patient homozygous for the CEP72 risk alleles. Bilirubin levels normalized following dose reduction of 6-mercaptopurine. The patient continues to tolerate maintenance therapy at a reduced dose of 6-mercaptopurine.

Response to Pazopanib in Patients With Relapsed Osteosarcoma.

Axial skeleton primary tumor, metastatic disease at presentation, incomplete surgical resection, and <90% tumor necrosis have all been known to influence prognosis adversely in osteosarcoma. Relapse of osteosarcoma, typically occurring within the first 18 months of therapy, with an incidence rate of 50% is treated with surgery, chemotherapy, and targeted therapy. Here, we discuss 2 patients treated with pazopanib, a multi-tyrosine kinase inhibitor presently approved to treat renal cell carcinoma and soft tissue sarcomas. Case 1 achieved positive response and remains on pazopanib. Case 2 sustained gastrointestinal toxicity requiring suspension of drug, despite achieving stable disease.

Clotam enhances anti-proliferative effect of vincristine in Ewing sarcoma cells.

Current therapeutic strategies used in Ewing sarcoma (ES) especially for relapsed patients have resulted in modest improvements in survival over the past 20 years. Combination therapeutic approach presents as an alternative to overcoming drug resistance in metastatic ES. This study evaluated the effect of Clotam (tolfenamic acid or TA), a small molecule and inhibitor of Specificity protein1 (Sp1) and survivin for sensitizing ES cell lines to chemotherapeutic agent, vincristine (VCR). ES cells (CHLA-9 and TC-32) were treated with TA or VCR or TA + VCR (combination), and cell viability was assessed after 24/48/72 h. Effect of TA or VCR or TA + VCR treatment on cell cycle arrest and apoptosis were evaluated using propidium iodide, cell cycle assay and Annexin V flow cytometry respectively. The apoptosis markers, caspase 3/7 (activity levels) and cleaved-PARP (protein expression) were measured. Cardiomyocytes, H9C2 were used as non-malignant cells. While, all treatments caused time- and dose-dependent inhibition of cell viability, interestingly, combination treatment caused significantly higher response (~ 80% inhibition, p < 0.05). Cell viability inhibition was accompanied by inhibition of Sp1 and Survivin. TA + VCR treatment significantly (p < 0.05) increased caspase 3/7 activity which strongly correlated with upregulated c-PARP level and Annexin V staining. Cell cycle arrest was observed at G0/G1 (TA) or G2/M (VCR and TA + VCR). All treatments did not cause cytotoxicity in H9C2 cells. These results suggest that TA could enhance the anti-cancer activity of VCR in ES cells. Therefore, TA + VCR combination could be further tested to develop as safe/effective therapeutic strategy for treating ES.

Expression of carcinoma, apoptosis, and cell-death-related genes are determinants for sensitivity of pediatric cancer cell lines to lysis by natural killer cells.

Natural killer (NK) cells have potential utility in pediatric cancer immunotherapy for their ability to lyse diverse tumor targets, lack of dependence on mutation-associated tumor antigens, and for their relative safety demonstrated so far in clinical trials. Here, we evaluate the cytotoxic potential of expanded NK cells against a well-characterized panel of pediatric cancer cell lines representing Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, lymphoma, leukemia, and brain tumors. We correlate their sensitivity NK cell lysis with tumor phenotypic, transcriptomic, and genetic determinants, and correlate known immunogenetic determinants with donor NK cell potency. Although ligand expression on cell lines stratified according to hematologic versus nonhematologic cancer types, the sensitivity to NK cell lysis varied widely and did not correlate with cancer type, expression of individual activating or inhibitory ligands, gene-expression clusters of NK cell ligands, disease status (newly diagnosed or relapsed), or MYCN amplification. Rather, sensitivity to NK cell-mediated lysis was associated with a novel 96-gene cluster of predominantly carcinoma-, apoptosis-, and cell death-related pathways, and with functional p53 status. NK cell potency was strongly associated with activating KIR gene content, but not with KIR/KIR-ligand mismatch. This study suggests that adoptive immunotherapy with expanded NK cells has the potential for a wide range of pediatric cancers, identifies potential biomarkers of efficacy and response, and establishes a foundation for using this cell line panel for the preclinical evaluation of immunotherapies.

Sinus Histiocytosis With Massive Lymphadenopathy (Rosai Dorfman Disease): Diagnostic and Treatment Modalities for this Rare Entity Revisited.

Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy is a rare non-Langerhans' cell histiocytic disease resulting from the proliferation and accumulation of sinus histiocytes within lymph nodes. Extranodal involvement frequently occurs, which increases the morbidity and mortality of the disease. There is no clear consensus with regard to the most effective diagnostic and treatment modalities. This report will focus on the diagnostic imaging, treatment, and outcomes for 3 cases of Rosai-Dorfman disease. Imaging has typically utilized computed tomography (CT)/magnetic resonance imaging to detect extranodal involvement. However, the addition of fluorodeoxyglucose positron emission tomography/CT scans has shown value in identifying lesions unidentified or ambiguous on other modalities. Fluorodeoxyglucose positron emission tomography/CT detected disease involvement in 2 instances either not reported or not felt to be significant on correlative CT imaging. Areas of involvement included the stomach/liver in case 1, and the paranasal sinus in case 3. In addition, previously utilized chemotherapy regimens have not consistently displayed regression of the disease, which lends credence to the pursuit of more successful treatment. Notably, Clofarabine has shown promise in its use against histiocytic disorders. Our study concluded that Clofarabine demonstrates the ability to decrease lesion size and should be considered as an effective chemotherapeutic treatment method.

Therapeutic leukocytapheresis in infants and children with leukemia and hyperleukocytosis: A single institution experience.

BACKGROUND: Hyperleukocytosis, defined as white blood cell (WBC) count above 100 × 109 /L, has high early morbidity and mortality from leukostasis-related complications, namely intracranial hemorrhage and pulmonary distress. Initiating chemotherapy without prior leukocytoreduction may lead to tumor lysis syndrome (TLS). Therapeutic leukocytapheresis (TL) is used as one leukocytoreductive intervention; however, its safety and efficacy in pediatric leukemia has not been established. The purpose of this study is to evaluate safety of TL in pediatric patients and assess the efficacy of TL in reducing WBC count in pediatric leukemia. METHODS: Retrospective chart review was conducted on 14 patients with acute lymphoblastic leukemia (ALL) and 5 with acute myeloid leukemia (AML) who underwent TL during the period 2000-2014 at a single institution. RESULTS: Mean WBC count of 19 patients who received TL was 483.2 × 109 /L (547.1 in ALL, 304.3 in AML); a portion of patients presented with central nervous system symptoms (15%), respiratory symptoms (10%), or both (10%). TL reduced WBC count (mean 50.7% reduction after a single TL procedure; additional 17.1% reduction after a second TL procedure in 6 patients). Short-term survival immediately following TL was 100% without any major procedural complication. Mean survival time in patients with AML was 1.5 years and with ALL was 6.5 years. CONCLUSIONS: TL significantly reduces WBC number in pediatric leukemia patients as young as 22 days old. In our retrospective study, TL was not associated with any significant complications and suggests that TL is a safe initial procedure in pediatric leukemia.

Targeting specificity protein 1 transcription factor and survivin using tolfenamic acid for inhibiting Ewing sarcoma cell growth.

Transcription factor Specificity protein 1 (Sp1) and its downstream target survivin (inhibitor of apoptosis protein), play major roles in the pathogenesis of various cancers. Ewing Sarcoma (ES) is a common soft tissue/bone tumor in adolescent and young adults. Overexpression of survivin is also linked to the aggressiveness and poor prognosis of ES. Small molecule Tolfenamic acid (TA) inhibits Sp1 and survivin in cancer cells. In this investigation, we demonstrate a strategy to target Sp1 and survivin using TA and positive control Mithramycin A (Mit) to inhibit ES cell growth. Knock down of Sp1 using small interfering RNA (siRNA) resulted in significant (p < 0.05) inhibition of CHLA-9 and TC-32 cell growth as assessed by CellTiter-Glo assay kit. TA or Mit treatment caused dose/time-dependent inhibition of cell viability, and this inhibition was correlated with a decrease in Sp1 and survivin protein levels in ES cells. Quantitative PCR results showed that Mit treatment decreased the mRNA expression of both survivin and Sp1, whereas TA diminished only survivin but not Sp1. Proteasome inhibitor restored TA-induced inhibition of Sp1 protein expression suggesting that TA might cause proteasome-dependent degradation. Gel shift assay using ES cell nuclear extract and biotinylated Sp1 consensus oligonucleotides confirmed that both TA and Mit decreased DNA-binding activity of Sp1. These results demonstrate that both Mit and TA reduce expression of Sp1 and survivin, disrupt Sp1 DNA-binding and inhibit ES cell proliferation. This investigation suggests that targeting Sp1 and survivin could be an effective strategy for inhibiting ES cell growth.