Real-world treatment patterns and outcomes in patients with primary hemophagocytic lymphohistiocytosis treated with emapalumab.

ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome. Emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon gamma, is approved in the United States to treat primary HLH (pHLH) in patients with refractory, recurrent, or progressive disease, or intolerance with conventional HLH treatments. REAL-HLH, a retrospective study, conducted across 33 US hospitals, evaluated real-world treatment patterns and outcomes in patients treated with ≥1 dose of emapalumab between 20 November 2018 and 31 October 2021. In total, 46 patients met the pHLH classification criteria. Median age at diagnosis was 1.0 year (range, 0.3-21.0). Emapalumab was initiated for treating refractory (19/46), recurrent (14/46), or progressive (7/46) pHLH. At initiation, 15 of 46 patients were in the intensive care unit, and 35 of 46 had received prior HLH-related therapies. Emapalumab treatment resulted in normalization of key laboratory parameters, including chemokine ligand 9 (24/33, 72.7%), ferritin (20/45, 44.4%), fibrinogen (37/38, 97.4%), platelets (39/46, 84.8%), and absolute neutrophil count (40/45, 88.9%). Forty-two (91.3%) patients were considered eligible for transplant. Pretransplant survival was 38 of 42 (90.5%). Thirty-one (73.8%) transplant-eligible patients proceeded to transplant, and 23 of 31 (74.2%) of those who received transplant were alive at the end of the follow-up period. Twelve-month survival probability from emapalumab initiation for the entire cohort (N = 46) was 73.1%. There were no discontinuations because of adverse events. In conclusion, results from the REAL-HLH study, which describes treatment patterns, effectiveness, and outcomes in patients with pHLH treated with emapalumab in real-world settings, are consistent with the emapalumab pivotal phase 2/3 pHLH trial.

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.

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.

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.

Utilization of Genomic Tumor Profiling in Pediatric Liquid Tumors: A Clinical Series.

Hematologic tumors are mostly treated with chemotherapies that have poor toxicity profiles. While molecular tumor profiling can expand therapeutic options, our understanding of potential targetable drivers comes from studies of adult liquid tumors, which does not necessarily translate to efficacious treatment in pediatric liquid tumors. There is also no consensus on when profiling should be performed and its use in guiding therapies. We describe a single institution's experience in integrating profiling for liquid tumors. Pediatric patients diagnosed with leukemia or lymphoma and who underwent tumor profiling were retrospectively reviewed. Ten (83.3%) patients had relapsed disease prior to tumor profiling. Eleven (91.7%) patients had targetable alterations identified on profiling, and three (25%) received targeted therapy based on these variants. Of the three patients that received targeted therapy, two (66.7%) were living, and one (33.3%) decreased. For a portion of our relapsing and/or treatment-refractory patients, genetic profiling was feasible and useful in tailoring therapy to obtain stable or remission states. Practitioners may hesitate to deviate from the 'standard of therapy', resulting in the underutilization of profiling results. Prospective studies should identify actionable genetic variants found more frequently in pediatric liquid tumors and explore the benefits of proactive tumor profiling prior to the first relapse.

Molecular Tumor Boards: The Next Step towards Precision Therapy in Cancer Care.

The application of molecular tumor profiles in clinical decision making remains a challenge. To aid in the interpretation of complex biomarkers, molecular tumor boards (MTBs) have been established worldwide. In the present study, we show that a multidisciplinary approach is essential to the success of MTBs. Our MTB, consisting of pediatric oncologists, pathologists, and pharmacists, evaluated 115 cases diagnosed between March 2016 and September 2021. If targetable mutations were identified, pharmacists aided in the evaluation of treatment options based on drug accessibility. Treatable genetic alterations detected through molecular testing most frequently involved the cell cycle. For 85% of the cases evaluated, our MTB provided treatment recommendations based on the patient's history and results of molecular tumor testing. Only three patients, however, received MTB-recommended targeted therapy, and only one of these patients demonstrated an improved clinical outcome. For the remaining patients, MTB-recommended treatment often was not administered because molecular tumor profiling was not performed until late in the disease course. For the three patients who did receive MTB-recommended therapy, such treatment was not administered until months after diagnosis due to physician preference. Thus, the education of healthcare providers regarding the benefits of targeted therapy may increase acceptance of these novel agents and subsequently improve patient survival.

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.

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.

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.

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.

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.

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.

Therapeutic considerations for prevention and treatment of thrombotic events in COVID-19.

Thrombosis is a known complication of SARS-CoV-2 infection, particularly within a severely symptomatic subset of patients with COVID-19 disease, in whom an aggressive host immune response leads to cytokine storm syndrome (CSS). The incidence of thrombotic events coinciding with CSS may contribute to the severe morbidity and mortality observed in association with COVID-19. This review provides an overview of pharmacologic approaches based upon an emerging understanding of the mechanisms responsible for thrombosis across a spectrum of COVID-19 disease involving an interplay between immunologic and pro-thrombotic events, including endothelial injury, platelet activation, altered coagulation pathways, and impaired fibrinolysis.

Successful use of enteral nutrition for asparaginase-induced pancreatitis in children with acute lymphoblastic leukemia and lymphoblastic lymphoma: A case series.

Asparaginase-induced acute pancreatitis (AAP) is a concerning adverse effect in the treatment of pediatric acute lymphoblastic leukemia and lymphoblastic lymphoma. Typically, treatment of AAP follows a nil per os approach with or without parenteral nutrition (PN). However, with accounts of increased risk of adverse events, such as bacterial translocation and multiorgan failure when PN is used in lieu of enteral nutrition (EN), the recent literature has advocated for a change in practice to the early use of EN for children and adults with acute pancreatitis. Despite these recommendations, a gap remains in the literature regarding whether or not early enteral feedings are currently being used in pediatric oncology patients with acute pancreatitis. In our case series, we account for the successful use of EN to manage AAP in three pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma. Additionally, we describe the development of an early enteral feeding protocol for pediatric oncology patients with pancreatitis. To the best of our knowledge, this is the first case series chronicling the nutritional management of AAP using EN in the pediatric oncology population. The successful use of EN we have seen in our patients supports the shift in treatment practice to the use of EN in lieu of PN for this population.

Multidisciplinary Multiagent Treatment of Complex Lymphatic Anomalies with Severe Bone Disease: A Single-Site Experience.

Background: Complex lymphatic anomalies (CLA) are a group of conditions that pose diagnostic and therapeutic challenges due to their rarity and overlapping clinical findings. This case series describes the complex pathology and novel combination therapies of three patients diagnosed with various types of CLA. Methods and Results: A retrospective review of medical records was performed for three patients treated for CLA between 2011 and 2019. Diagnostics, imaging, treatment, and follow-up were reviewed in the electronic medical record and combined with the literature review within the analysis. One patient had involvement of her skull base and ear canals, diagnosed after ear canal abnormalities were detected on computed tomography following meningitis. The second patient had involvement of her posterior ribs and T7-T12 vertebral bodies, with thoracic instability requiring a back brace. The third patient had involvement of his left lower extremity and hemipelvis, necessitating a left above the knee amputation. Case 1 progressed on sirolimus and pamidronate but responded to zoledronic acid (ZA). She developed flares of coagulopathy and cellulitis that required reinforcement with vincristine and steroid pulses. Similarly, case 2 progressed on sirolimus and ZA alone, but achieved stable disease with added vincristine. Upon further disease progression, stabilization was obtained by the reinforcement of ZA. Case 3 required a combination of surgery as well as medical management with sirolimus and pamidronate. All three patients now have stable disease. Conclusion: This case series depicts a multidisciplinary and multiagent approach to the management of CLA with severe bony involvement using sirolimus, bisphosphonates, vincristine, and steroids.

The mechanistic basis linking cytokine storm to thrombosis in COVID-19.

It is now well established that infection with SARS-CoV-2 resulting in COVID-19 disease includes a severely symptomatic subset of patients in whom an aggressive and/or dysregulated host immune response leads to cytokine storm syndrome (CSS) that may be further complicated by thrombotic events, contributing to the severe morbidity and mortality observed in COVID-19. This review provides a brief overview of cytokine storm in COVID-19, and then presents a mechanistic discussion of how cytokine storm affects integrated pathways in thrombosis involving the endothelium, platelets, the coagulation cascade, eicosanoids, auto-antibody mediated thrombosis, and the fibrinolytic system.

An unusual case of late recurrence of bilateral retinoblastoma.

Recurrence of retinoblastoma usually occurs within the first few years after treatment. Despite complete tumor regression, delayed relapse of retinoblastoma can occur, predisposing patients to osteosarcoma as second malignancy. Our case was unique regarding the late relapse 13 years after treatment and recurrence at the femur. The initial tumor was treated with chemotherapy, enucleation of the right eye, and plaque radiotherapy. The relapsed tumor was treated with chemotherapy, consolidation, and autologous stem cell transplant. Our patient is currently in complete remission and continues to follow-up with oncology and ophthalmology. This report illustrates the possibility of late recurrence of retinoblastoma.