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BACKGROUND: Short telomere syndrome (STS) in children may result in phenotypically heterogenous clinical spectrum ranging from completely asymptomatic to typical dyskeratosis congenita (DC). Patients with this cancer predisposition syndrome may have multiple organ dysfunctions including pulmonary fibrosis, liver cirrhosis, and bone marrow failure. Not all mutations in telomerase or telomere genes have been identified, and STS may pose a diagnostic and management challenge. METHODS: A retrospective chart review and literature search were done for this report. RESULTS: Here, we report a case of atypical DC with a heterozygous germline missense mutation in the postmeiotic segregation increased 2 (PMS2) gene, exon 5, (c.466A>G (p. Thr156Ala)). The PMS2 (a mismatch repair protein) gene is known to be an important mediator of telomere-induced aging. The patient was transfusion dependent and underwent successful umbilical cord blood transplant using a non-myeloablative regimen with alemtuzumab, fludarabine, cyclophosphamide, and total body irradiation. CONCLUSION: In this case of atypical DC with a previously unreported germline missense mutation in PMS2, the patient was successfully treated with an umbilical cord blood transplant with a non-myeloablative regimen.
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Trasplante de Células Madre de Sangre del Cordón Umbilical , Disqueratosis Congénita/genética , Disqueratosis Congénita/terapia , Alemtuzumab/administración & dosificación , Antineoplásicos/administración & dosificación , Preescolar , Ciclofosfamida/administración & dosificación , Femenino , Mutación de Línea Germinal , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados , Irradiación Corporal TotalRESUMEN
While advancements in cellular therapy have improved outcomes for patients with refractory leukemia, severe infections may hinder access. Granulocyte transfusions, in combination with anti-microbial therapy, may be a safe option to facilitate candidacy for chimeric antigen receptor T-cell therapy in patients with leukemia and prolonged immune-compromised status.
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Leucemia , Receptores Quiméricos de Antígenos , Tratamiento Basado en Trasplante de Células y Tejidos , Granulocitos , Humanos , Inmunoterapia Adoptiva , Receptores de Antígenos de Linfocitos TRESUMEN
Non-relapse mortality due to GVHD and infections represents a major source of morbidity and mortality in pediatric HSCT recipients. Post-transplant cyclophosphamide (PTCy) has emerged as an effective and safe GVHD prophylaxis strategy, with improved GVHD and relapse-free survival in matched (related and unrelated) and mismatched haploidentical HSCT adult recipients. However, there are no published data in pediatric patients with acute myeloid leukemia who received matched-donor HSCT with PTCy. We demonstrate, in this case series, that the use of PTCy in this population is potentially safe, effective in preventing acute GVHD, does not impair engraftment, is associated with reduced non-relapse mortality, and does not hinder immune reconstitution post HSCT.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Adulto , Niño , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Recurrencia , Estudios Retrospectivos , Hermanos , Donante no EmparentadoRESUMEN
PURPOSE OF REVIEW: To provide an update on risk factors associated with adenovirus (ADV) infection in patients after hematopoietic cell transplant (HCT) and on options for ADV monitoring and treatment in the setting of HCT. RECENT FINDINGS: Among patients undergoing HCT, ADV infection continues to be more common amongst those receiving a T-cell-depleted or graft other than from a matched-related donor. Among children undergoing HCT, reactivation in the gastrointestinal tract appears to be the most common source, and the virus is detectable by quantitative PCR in the stool before it is detectable in the blood. Thus, screening for the virus in the stool of these children may allow for preemptive therapy to reduce mortality. Brincidofovir, although still not approved by any regulatory agency, remains a potential agent for preemptive therapy and for salvage in cases not responding to cidofovir. Rapidly generated off-the-shelf virus-specific T cells may facilitate adoptive cell therapy in populations with a special need and previously not eligible for adoptive cell therapy, such as cord blood recipients. SUMMARY: ADV infection continues to adversely affect survival in HCT recipients. Screening stool in children and preemptive therapy may reduce mortality. Brincidofovir and adoptive T-cell therapy remain potential options for treatment.
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Infecciones por Adenoviridae/etiología , Susceptibilidad a Enfermedades , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Receptores de Trasplantes , Infecciones por Adenoviridae/diagnóstico , Infecciones por Adenoviridae/epidemiología , Infecciones por Adenoviridae/terapia , Antivirales/farmacología , Antivirales/uso terapéutico , Manejo de la Enfermedad , Humanos , Técnicas de Diagnóstico Molecular , Factores de Riesgo , Resultado del TratamientoAsunto(s)
Anticuerpos Biespecíficos , Protocolos de Quimioterapia Combinada Antineoplásica , N-Metiltransferasa de Histona-Lisina , Inmunoterapia Adoptiva , Proteína de la Leucemia Mieloide-Linfoide , Piperazinas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Piridinas , Humanos , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/administración & dosificación , Proteína de la Leucemia Mieloide-Linfoide/genética , N-Metiltransferasa de Histona-Lisina/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Piperazinas/uso terapéutico , Piridinas/uso terapéutico , Piridinas/efectos adversos , Piridinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Masculino , Femenino , Reordenamiento Génico , Acrilamidas/uso terapéutico , Niño , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/etiologíaAsunto(s)
Leucemia Mieloide Aguda , Mastocitosis Sistémica , Pirazoles , Pirroles , Triazinas , Humanos , Niño , Decitabina , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Factores de Unión al Sitio Principal , Proteínas Proto-Oncogénicas c-kit/genética , MutaciónAsunto(s)
Neoplasias de la Mama/terapia , Terapia Combinada/métodos , Síndrome de Liberación de Citoquinas/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia Combinada/efectos adversos , Resultado Fatal , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Radioterapia/efectos adversos , Radioterapia/métodos , Receptores Quiméricos de Antígenos , Inducción de Remisión , Adulto JovenRESUMEN
Background: Sinusoidal obstruction syndrome is a potentially fatal complication following hematopoietic cell transplantation, high-intensity chemotherapies and increasingly seen with calicheamicin based leukemia therapies. Paediatric specific European Society for Blood and Marrow Transplantation (pEBMT) diagnostic criteria have demonstrated benefit in single center studies compared to historic criteria. Yet, the extent to which they have been universally implemented remains unclear. Methods: We conducted a retrospective multi-centre study to examine the potential impact of the Baltimore, modified Seattle and pEBMT criteria on the incidence, severity, and outcomes of sinusoidal obstruction syndrome among paediatric hematopoietic cell transplantation patients. Findings: The incidence of sinusoidal obstruction syndrome in this cohort (n = 488) was higher by pEBMT (21.5%) vs historic modified Seattle (15.6%) and Baltimore (7.0%) criteria (p < 0.001). Application of pEBMT criteria identified 44 patients who were not previously diagnosed with sinusoidal obstruction syndrome. Overall, 70.5% of all patients diagnosed with sinusoidal obstruction syndrome ultimately developed very severe disease and almost half of diagnosed patients required critical care support. Overall survival was significantly lower in patients who were diagnosed with sinusoidal obstruction syndrome vs those who were not. Interpretation: Taken together, pEBMT criteria may be a sensitive method for prompter diagnosis of patients who subsequently develop severe/very severe sinusoidal obstruction syndrome. To our knowledge, this is the first multi-centre study in the United States (US) to demonstrate that pEBMT guidelines are associated with earlier detection of sinusoidal obstruction syndrome. Since early initiation of definitive treatment for sinusoidal obstruction syndrome has been associated with improved survival in paediatric patients and implementation of pEBMT criteria appears feasible in the US, universal adoption should facilitate prompter diagnosis and lead to improved outcomes of children with sinusoidal obstruction syndrome. Funding: None.
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BACKGROUND: The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression, metastasis, and the poor response of many solid tumors to immunotherapy. CAF-targeted chimeric antigen receptor-T cell therapy cannot infiltrate ECM-rich tumors such as osteosarcoma. METHOD: In this study, we used RNA sequencing to assess whether the recently invented membrane-anchored and tumor-targeted IL-12-armed (attIL12) T cells, which bind cell-surface vimentin (CSV) on tumor cells, could destroy CAFs to disrupt the ECM. We established an in vitro model of the interaction between osteosarcoma CAFs and attIL12-T cells to uncover the underlying mechanism by which attIL12-T cells penetrate stroma-enriched osteosarcoma tumors. RESULTS: RNA sequencing demonstrated that attIL12-T cell treatment altered ECM-related gene expression. Immunohistochemistry staining revealed disruption or elimination of high-density CAFs and ECM in osteosarcoma xenograft tumors following attIL12-T cell treatment, and CAF/ECM density was inversely correlated with T-cell infiltration. Other IL12-armed T cells, such as wild-type IL-12-targeted or tumor-targeted IL-12-T cells, did not disrupt the ECM because this effect depended on the engagement between CSV on the tumor cell and its ligand on the attIL12-T cells. Mechanistic studies found that attIL12-T cell treatment elevated IFNγ production on interacting with CSV+ tumor cells, suppressing transforming growth factor beta secretion and in turn upregulating FAS-mediated CAF apoptosis. CAF destruction reshaped the tumor stroma to favor T-cell infiltration and tumor inhibition. CONCLUSIONS: This study unveiled a novel therapy-attIL12-T cells-for targeting CAFs/ECM. These findings are highly relevant to humans because CAFs are abundant in human osteosarcoma.
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Neoplasias Óseas , Fibroblastos Asociados al Cáncer , Osteosarcoma , Animales , Humanos , Interleucina-12 , Xenoinjertos , Osteosarcoma/terapia , Membrana Celular , Matriz Extracelular , Modelos Animales de Enfermedad , Neoplasias Óseas/terapia , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
ABSTRACT: Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Although increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with posttransplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single-center analysis of adult patients aged ≥18 years undergoing allo-SCT (N = 1561) using predominately PTCy as graft-versus-host disease (GVHD) prophylaxis (72%). We found a higher rate of VOD at 16.8% (20 of 119) in those aged ≤25 years compared with 3.8% (55 of 1442) in those aged >25 years, with unique predictors of VOD within each cohort. Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD. Among patients aged 18 to 25 years, disease risk index (DRI; 31% with high/very high DRI vs 12% low/intermediate DRI; P = .03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1; P = .03) were the strongest predictors of VOD. Incidence of VOD in patients aged >25 years of age consistently ranged between 3% and 5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase, alanine aminotransferase) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared with those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors of VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Enfermedades Vasculares , Humanos , Adolescente , Adulto , Anciano , Estudios Retrospectivos , Incidencia , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Factores de Riesgo , Ciclofosfamida/efectos adversos , Enfermedades Vasculares/etiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/complicacionesRESUMEN
Tumors of the central nervous system (CNS) are the most common and lethal childhood malignancy. Detection of residual disease and longitudinal monitoring of treatment response in patients are challenging and rely on serial imaging. This current standard of care fails to detect microscopic disease or provide molecular characteristics of residual tumors. As such, there is dire need for minimally invasive liquid biopsy techniques. We have previously shown the high specificity of using cell surface vimentin (CSV) to identify circulating tumor cells (CTCs) from patients bearing various types of cancers. Here, we describe the first report of CTCs captured from peripheral blood samples in 58 pediatric CNS tumor patients. In this study, we used a CSV-coated cell capture chip, the Abnova CytoQuest automated CTC isolation system, to boost the CTC capture from pediatric patients with CNS tumors. We successfully isolated CTCs in six glioma patients using immunostaining of histone H3 lysine27-to-methionine (H3K27M) mutations which are highly expressed by this tumor. We show that CSV is a viable marker for CNS CTC isolation and that this is a feasible method for detecting microscopic disease. Larger-scale studies focusing on CTCs in pediatric CNS tumors to explore their diagnostic and prognostic value are warranted.
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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that can involve the bone marrow, peripheral blood, skin, lymph nodes, and the central nervous system. Though more common in older adults, BPDCN has been reported across all age groups, including infants and children. The incidence of pediatric BPDCN is extremely low and little is known about the disease. Pediatric BPDCN is believed to be clinically less aggressive but often with more dissemination at presentation than adult cases. Unlike adults who almost always proceed to a hematopoietic stem cell transplantation in first complete remission if transplant-eligible, the majority of children can be cured with a high-risk acute lymphoblastic leukemia-like regimen. Hematopoietic stem cell transplantation is recommended for children with high-risk disease, the definition of which continues to evolve, or those in relapse and refractory settings where outcomes continue to be dismal. Novel agents used in other hematologic malignancies and CD123 targeted agents, including chimeric antigen receptor T-cells and monoclonal/bispecific antibodies, are being brought into research and practice. Our goal is to provide a comprehensive review of presentation, diagnosis, and treatment by review of pediatric cases reported for the last 20 years, and a review of novel targeted therapies and therapies under investigation for adult and pediatric patients.
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Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Trastornos Mieloproliferativos , Neoplasias Cutáneas , Niño , Humanos , Adolescente , Adulto Joven , Anciano , Células Dendríticas/patología , Neoplasias Hematológicas/patología , Neoplasias Cutáneas/patología , Trastornos Mieloproliferativos/patologíaRESUMEN
Interleukin 12 (IL-12) is a naturally occurring cytokine that plays a key role in inducing antitumor immune responses, including induction of antitumor immune memory. Currently, no IL-12-based therapeutic products have been approved for clinical application because of its toxicities. On the basis of this review of clinical trials using primarily wild-type IL-12 and different delivery methods, we conclude that the safe utilization of IL-12 is highly dependent on the tumor-specific localization of IL-12 post administration. In this regard, we have developed a cell membrane-anchored and tumor-targeted IL-12-T (attIL12-T) cell product for avoiding toxicity from both IL-12 and T cells-induced cytokine release syndrome in peripheral tissues. A phase I trial using this product which seeks to avoid systemic toxicity and boost antitumor efficacy is on the horizon. Of note, this product also boosts the impact of CAR-T or TCR-T cell efficacy against solid tumors, providing an alternative approach to utilize CAR-T to overcome tumor resistance.
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Neoplasias , Receptores Quiméricos de Antígenos , Citocinas , Humanos , Interleucina-12 , Linfocitos TRESUMEN
Non-Hodgkin lymphoma (NHL) is a broad entity which comprises a number of different types of lymphomatous malignancies. In the pediatric and adolescent population, the type and prognosis of NHL varies by age and gender. In comparison to adults, pediatric and adolescent patients generally have better outcomes following treatment for primary NHL. However, relapsed/refractory (R/R) disease is associated with poorer outcomes in many types of NHL such as diffuse large B cell lymphoma and Burkitt lymphoma. Newer therapies have been approved in the use of primary NHL in the pediatric and adolescent population such as Rituximab and other therapies such as chimeric antigen receptor T-cell (CAR T-cell) therapy are under investigation for the treatment of R/R NHL. In this review, we feature the characteristics, diagnosis, and treatments of the most common NHLs in the pediatric and adolescent population and also highlight the differences that exist between pediatric and adult disease. We then detail the areas of treatment advances such as immunotherapy with CAR T-cells, brentuximab vedotin, and blinatumomab as well as cell cycle inhibitors and describe areas where further research is needed. The aim of this review is to juxtapose established research regarding pediatric and adolescent NHL with recent advancements as well as highlight treatment gaps where more investigation is needed.
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Chimeric antigen receptor T-cell (CAR T) therapy is a revolutionary treatment for pediatric, adolescent and young adult patients (AYA) with relapsed/refractory B-cell acute lymphoblastic leukemia. While the landscape of immunotherapy continues to rapidly evolve, widespread use of CAR T therapy is limited and many questions remain regarding the durability of CAR T therapy, methods to avoid CAR T therapy resistance and the role of consolidative stem cell transplant. Modified strategies to develop effective and persistent CAR T cells at lower costs and decreased toxicities are warranted. In this review we present current indications, limitations and future directions of CAR T therapy for ALL in the pediatric and AYA population.
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Endothelial dysfunction underlies many of the major complications following hematopoietic cell transplantation (HCT), including transplant-associated thrombotic microangiopathy (TA-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), and engraftment syndrome (ES). Emerging evidence similarly implicates endothelitis and microangiopathy in severe COVID-19-related multi-system organ dysfunction. Given the overlap in these two illness states, we hypothesize that prior COVID-19 infection may increase risk for HCT-related endotheliopathies. This retrospective, multicenter study included patients aged 0-25 years who underwent autologous or allogeneic HCT for any indication between January 1, 2020 and September 21, 2021, with close attention to those infected with COVID-19 in either the six months prior to transplant or twelve months following transplant. Incidences of TA-TMA, VOD/SOS, and ES were compared among patients with COVID-19 infection pre-HCT and post-HCT, as well as with historical controls who were never infected with SARS-CoV-2. Those who underwent HCT following COVID-19 infection displayed significantly increased rates of TA-TMA compared to those who were never infected. Additionally, our data suggests a similar trend for increased VOD/SOS and ES rates, although this did not reach statistical significance. Therefore, a history of COVID-19 infection prior to undergoing HCT may be a nonmodifiable risk factor for endothelial-related complications following HCT. Further studies are warranted to better clarify this relationship among larger cohorts and in the era of the Omicron SARS-CoV-2 variants.
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Tisagenlecleucel is associated with remarkable outcomes in treating patients up to the age of 25 years with refractory B-cell acute lymphoblastic leukemia (ALL). Yet, due to unique and potentially life-threatening complications, access remains limited to higher-resource and certified centers. Reports of inequity and related disparities in care are emerging. In this multicenter study of ALL patients admitted for anti-leukemia therapy, who required pediatric intensive care (ICU) support (n = 205), patients receiving tisagenlecleucel (n = 39) were compared to those receiving conventional chemotherapy (n = 166). The median time to ICU transfer was 6 (0-43) versus 1 (0-116) days, respectively (p < 0.0001). There was no difference in the use of vasopressor, ionotropic, sedating, and/or paralytic agents between groups, but use of dexamethasone was higher among tisagenlecleucel patients. Patients receiving tisagenlecleucel were more likely to have cardiorespiratory toxicity (p = 0.0002), but there were no differences in diagnostic interventions between both groups and/or differences in ICU length of stay and/or overall hospital survival. Toxicities associated with tisagenlecleucel are generally reversible, and our findings suggest that resource utilization once admitted to the ICU may be similar among patients with ALL receiving tisagenlecleucel versus conventional chemotherapy. As centers consider improved access to care and the feasibility of tisagenlecleucel certification, our study may inform strategic planning.
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Isolated extramedullary relapse of acute lymphoblastic leukemia (ALL) occurs in soft tissues and various organs outside the testis and central nervous system. Treatments such as hematopoietic stem cell transplantation and more novel modalities such as immunotherapy have eradicated ALL at extramedullary sites. In some instances, survival times for relapsed ALL at these sites are longer than those for relapsed disease involving only the bone marrow. Isolated relapse of ALL in the myocardium is rare, especially in children, making diagnosis and treatment of it difficult. More recent treatment options such as chimeric antigen receptor T-cell therapy carry a high risk of cytokine release syndrome and associated risk of worsening cardiac function. Herein we present the case of an 11-year-old boy who presented with relapsed symptomatic B-cell ALL in the myocardium following allogeneic hematopoietic stem cell transplantation. This is an unusual presentation of relapsed ALL and this case demonstrates the associated challenges in its diagnosis and treatment. The case report is followed by a literature review of the advances in treatment of pediatric leukemia and their application to extramedullary relapse of this disease in particular.
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BACKGROUND: Despite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as < 35%. Currently, there are no biomarkers available to assess disease status in patients with sarcomas and as such, disease surveillance remains reliant on serial imaging which increases the risk of secondary malignancies and heightens patient anxiety. METHODS: Here, for the first time reported in the literature, we have enumerated the cell surface vimentin (CSV+) CTCs in the blood of 92 sarcoma pediatric and adolescent and young adult (AYA) patients as a possible marker of disease. RESULTS: We constructed a ROC with an AUC of 0.831 resulting in a sensitivity of 85.3% and a specificity of 75%. Additionally, patients who were deemed to be CSV+ CTC positive were found to have a worse overall survival compared to those who were CSV+ CTC negative. We additionally found the use of available molecular testing increased the accuracy of our diagnostic and prognostic tests. CONCLUSIONS: Our findings indicate that CSV+ CTCs have prognostic value and can possibly serve as a measure of disease burden.