RESUMO
Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21(10%) with Hodgkin lymphoma and eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% CI 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (p=.76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI 19.5-32.4). Germline ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n=110) were classified as having absent (n=81) or residual (n=29) ATM kinase activity. Four-year EFS was 39.4% (95% CI 29-53.3) vs 78.7% (95% CI 63.7-97.2), (p<.001), and TRM rates were 37.6% (95% CI 26.4-48.7) vs 4.0% (95% CI 0-11.8), (p=.017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR=0.362, 95% CI 0.16-0.82; p=.009) and increased TRM (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.
RESUMO
BACKGROUND: Spinal cord compression is a rare presentation of non-Hodgkin lymphoma (NHL) in children. We aimed to describe the prevalence, histological subtypes, clinical presentation, therapy, and outcome of those children in a population-based cohort. The chemotherapy regimen remained comparable over time. METHODS: We retrospectively identified all children and adolescents with paresis as initial manifestations of the NHL between January 1990 and December 2020 from the NHL-BFM database. Characteristics, therapy, and outcome data were gathered from the database and patient files. RESULTS: Fifty-seven of 4779 children (1.2%) presented with initial paresis due to spinal cord compression. The median age was 10.3 years (range, 3.1-18.0 years), and 33% were female. Initial symptoms were paresis/weakness (n = 50, 88%), back pain (n = 33, 58%), paresthesia (n = 23, 40%), and bladder dysfunction and/or constipation (n = 22, 39%), persisting for a median of 14 days before diagnosis. Subtype distribution was mature B-NHL (n = 41, 72%), precursor B-lymphoblastic lymphoma (LBL) (n = 12, 21%), anaplastic large cell lymphoma (ALCL) (n = 3, 5%), and T-LBL (n = 1, 2%). Initial emergency therapy included surgery (70%) and/or chemotherapy/steroids (63%). Five-year event-free survival and overall survival (80% ± 5% and 82% ± 5%, respectively) were comparable with all other NHL patients. Neurological symptoms persisted in approximately one-third of surviving patients at the last follow-up. CONCLUSION: 1.2% of pediatric NHL patients presented with paresis from spinal cord compression mainly due to B-cell lymphomas. Neurological sequelae were observed in one-third of surviving patients.
Assuntos
Linfoma não Hodgkin , Compressão da Medula Espinal , Humanos , Feminino , Masculino , Criança , Adolescente , Estudos Retrospectivos , Pré-Escolar , Compressão da Medula Espinal/etiologia , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/epidemiologia , Taxa de Sobrevida , Prognóstico , SeguimentosRESUMO
BACKGROUND: Myeloid neoplasms account for 50% of cases of pediatric leukemias in infants. Approximately 25%-50% of patients with newborn leukemia have cutaneous extramedullary disease (EMD). In less than 10% of patients, aleukemic leukemia cutis or isolated extramedullary disease with cutaneous involvement (cEMD) occurs when skin lesions appear prior to bone marrow involvement and systemic symptoms. Interestingly, in acute myeloid leukemia with cutaneous EMD (AML-cEMD) and cEMD, spontaneous remissions have been reported. METHOD: This is a multicentric retrospective cohort study aiming to describe characteristics, treatment, and outcome of infants with either cEMD or presence of cutaneous disease with involvement of the bone marrow (AML-cEMD). This study included patients born between 1990 and 2018 from Italy, the Netherlands, Switzerland, and the United States, diagnosed between 0 and 6 months of life with cEMD or AML-cEMD. Descriptive statistics, Fisher's exact test, Kaplan-Meier method, and log rank test were applied. RESULTS: The cohort consisted of n = 50 patients, including 42 AML-cEMD and eight cEMD patients. The most common genetic mutation found was a KMT2A rearrangement (n = 26, 52%). Overall 5-year event-free survival (EFS) and overall survival (OS) were 66% [confidence interval (CI): 51-78] and 75% [CI: 60-85], respectively. In two patients, complete spontaneous remission occurred without any therapy. Central nervous system (CNS) involvement was found in 25% of cEMD patients. No difference in outcomes was observed between the AML-cEMD and cEMD groups, but none of the latter patients included in the study died. KMT2A rearrangements were not associated with poorer prognosis. CONCLUSION: In the largest cohort to date, our study describes the characteristics of infants with cutaneous involvement of myeloid neoplasms including cytomolecular findings and survival rates. Further prospective biologic and clinical studies of these infants with myeloid neoplasms will be required to individualize therapy for this rare patient population.
Assuntos
Leucemia Mieloide Aguda , Neoplasias Cutâneas , Humanos , Estudos Retrospectivos , Feminino , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Lactente , Masculino , Recém-Nascido , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/genética , Seguimentos , Taxa de Sobrevida , PrognósticoRESUMO
BACKGROUND: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. METHODS: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1-5; prednisone 60 mg/m2 orally on days 1-15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006-000995-33) and is completed. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1-69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3-89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8-92·5), for which the 95% CI included the 90% target rate. The most common grade 3-4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. INTERPRETATION: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.
Assuntos
Doença de Hodgkin , Adolescente , Criança , Feminino , Humanos , Recém-Nascido , Masculino , Doxorrubicina , Etoposídeo , Prednisona , Qualidade de Vida , VincristinaRESUMO
BACKGROUND: Children with relapsed acute lymphoblastic leukemia (ALL) in low-income and middle-income countries rarely survive. The Pediatric Hematology-Oncology Association of Central America (AHOPCA) developed the AHOPCA-ALL REC 2014 protocol to improve outcomes in resource-constrained settings without access to stem cell transplantation. METHODS: The AHOPCA-ALL REC 2014 protocol was based on a modified frontline induction phase 1A, a consolidation therapy with six modified R-blocks derived from the ALL-Berlin-Frankfurt-Munster REZ 2002 protocol and intermittent maintenance therapy. Children with B-lineage ALL were eligible after a late medullary relapse, an early or late combined relapse, or any extramedullary relapses. Those with T-lineage ALL were eligible after early and late extramedullary relapses, as were those with both B-lineage and T-lineage relapses occurring at least 3 months after therapy abandonment. RESULTS: The study population included 190 patients with T-lineage (n = 3) and B-lineage (n = 187) ALL. Of those with B-lineage ALL, 25 patients had a very early extramedullary relapse, 40 had an early relapse (32 extramedullary and 8 combined), and 125 had a late relapse (34 extramedullary, 19 combined, and 72 medullary). The main cause of treatment failure was second relapse (52.1%). The 3-year event-free survival rate (± standard error) was 25.9% ± 3.5%, and the 3-year overall survival rate was 36.7% ± 3.8%. The 3-year event-free survival rate was 47.2% ± 4.7% for late relapses. The most frequently reported toxicity was grade 3 or 4 infection. Mortality during treatment occurred in 17 patients (8.9%), in most cases because of infectious complications. CONCLUSIONS: Selected children with relapsed ALL in Central America can be cured with second-line regimens even without access to consolidation with stem cell transplantation. Children in low-income and middle-income countries who have lower risk relapses of ALL should be treated with curative intent.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Países em Desenvolvimento , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Protocolos de Quimioterapia Combinada Antineoplásica , PobrezaRESUMO
Chimeric antigen receptor (CAR) T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional CRS, a comprehensive characterization of CAR T-cell-associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Among 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase, and occasionally hemophagocytosis. Development of carHLH was associated with preinfusion natural killer(NK) cell lymphopenia and higher bone marrow T-cell:NK cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK cell lymphopenia amplified preinfusion differences in those with carHLH without evidence for defects in NK cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.
Assuntos
Síndrome da Liberação de Citocina/etiologia , Imunoterapia Adotiva/efeitos adversos , Linfo-Histiocitose Hemofagocítica/etiologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Adulto , Linfócitos T CD8-Positivos/imunologia , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/imunologia , Feminino , Humanos , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. METHODS: After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. RESULTS: After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. CONCLUSION: Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.
Assuntos
Doença de Hodgkin , Linfoma , Hiperplasia do Timo , Neoplasias do Timo , Humanos , Criança , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/complicações , Hiperplasia do Timo/diagnóstico por imagem , Hiperplasia do Timo/etiologia , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/tratamento farmacológico , Linfoma/tratamento farmacológico , Tomografia Computadorizada por Raios X , Tomografia por Emissão de Pósitrons/métodos , Neoplasias do Timo/diagnóstico por imagem , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/complicações , Fluordesoxiglucose F18/uso terapêutico , Compostos RadiofarmacêuticosRESUMO
Despite the progress in cure rates for pediatric cancers, several challenges remain, such as the management of diseases with poor prognosis. The efficacy of intensified chemotherapies is also accompanied by increased risks of severe acute and chronic toxicities. Thus, therapies specifically targeting tumor cells, or inhibiting oncogenic molecular aberrations, could provide more effective and less toxic treatments for pediatric cancers. Personalization of chemotherapies through pharmacogenetics and precision dosing could also improve the efficacy and toxicity of chemotherapies. In this review, we describe precision medicine strategies implemented or undergoing clinical evaluation in the treatment of pediatric cancers.
Malgré les progrès sur les taux de guérison des cancers pédiatriques, plusieurs défis restent à relever, comme la prise en charge des maladies à mauvais pronostic. L'efficacité des chimiothérapies intensives s'accompagne aussi de risques accrus de toxicités aiguës et chroniques graves. Ainsi, les thérapies ciblant spécifiquement les cellules tumorales, ou inhibant les aberrations moléculaires oncogéniques, pourraient offrir des traitements plus efficaces et moins toxiques pour les cancers pédiatriques. La personnalisation des chimiothérapies grâce à la pharmacogénétique et au dosage de précision pourrait également améliorer l'efficacité et la toxicité des chimiothérapies. Dans cet article de revue, nous décrivons les stratégies de médecine de précision implémentées ou en cours d'évaluation clinique dans le traitement des cancers pédiatriques.
Assuntos
Neoplasias , Medicina de Precisão , Criança , Humanos , Neoplasias/tratamento farmacológico , Farmacogenética , Terapia de Alvo MolecularRESUMO
Immunotherapy with the adoptive transfer of T cells redirected with CD19-specific chimeric antigen receptors (CARs) for B-lineage acute lymphoblastic leukemia (ALL) can salvage >80% of patients having relapsed/refractory disease. The therapeutic index of this emerging modality is attenuated by the occurrence of immunologic toxicity syndromes that occur upon CAR T-cell engraftment. Here, we report on the low incidence of severe cytokine release syndrome (CRS) in a subject treated with a CAR T-cell product composed of a defined ratio CD4:CD8 T-cell composition with a 4-1BB:zeta CAR targeting CD19 who also recieved early intervention treatment. We report that early intervention with tocilizumab and/or corticosteroids may reduce the frequency at which subjects transition from mild CRS to severe CRS. Although early intervention doubled the numbers of subjects dosed with tocilizumab and/or corticosteroids, there was no apparent detrimental effect on minimal residual disease-negative complete remission rates or subsequent persistence of functional CAR T cells compared with subjects who did not receive intervention. Moreover, early intervention therapy did not increase the proportion of subjects who experience neurotoxicity or place subjects at risk for infectious sequelae. These data support the contention that early intervention with tocilizumab and/or corticosteroids in subjects with early signs of CRS is without negative impact on the antitumor potency of CD19 CAR T cells. This intervention serves to enhance the therapeutic index in relapsed/refractory patients and provides the rationale to apply CAR T-cell therapy more broadly in ALL therapy. This trial was registered at www.clinicaltrials.gov as #NCT020284.
Assuntos
Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Síndrome da Liberação de Citocina/etiologia , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Adolescente , Corticosteroides/administração & dosagem , Corticosteroides/farmacologia , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Criança , Pré-Escolar , Síndrome da Liberação de Citocina/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Incidência , Lactente , Masculino , Gradação de Tumores , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Adulto JovemRESUMO
BACKGROUND: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging. PATIENTS, MATERIALS, AND METHODS: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from 18 F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment. RESULTS: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient. CONCLUSIONS: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.
Assuntos
Doença de Hodgkin/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Feminino , Fluordesoxiglucose F18/análise , Humanos , Imageamento por Ressonância Magnética , Masculino , Imagem Multimodal , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios XRESUMO
A 2.5-year-old boy presented to his pediatrician with progressive pallor, asthenia, fever, splenomegaly, and hematomas. Leukemia was suspected, and a bone marrow aspirate confirmed acute lymphoblastic leukemia. Before chemotherapy induction, the child developed a vesicular rash and was diagnosed clinically with chickenpox. Acyclovir treatment was initiated immediately, whereas induction chemotherapy was postponed by 10 days. At the time of chickenpox resolution, a spontaneous partial recovery of his blood counts and a 50% decrease of blastic bone marrow infiltration were noted. After a brief nonsystematic review, we discuss the potential beneficial effect of acyclovir and chickenpox infection in children with leukemia.
Assuntos
Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Varicela/complicações , Varicela/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Pré-Escolar , Herpesvirus Humano 3/efeitos dos fármacos , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Remissão EspontâneaRESUMO
Fighting leukemia using the immune system (antibodies, lymphocytes) is an old idea, which has already been fulfilled in allogeneic bone marrow transplantation. Indeed, the effectiveness of the transplant depends on the action of the donor lymphocytes. To limit the adverse effects on bystander organs (graft-versus-host disease), autologous T cells can be engineered to express synthetic chimeric antigen receptors (CARs) with artificially redirected antigen specificity. Autologous T cells engineered to express a CAR targeting CD19 have shown unprecedented efficacy in clinical trials for relapsed/refractory B-cell leukemias and lymphomas. In this review article, we describe the therapeutic strategies, clinical trial results, side effects and future direction of CAR T cell therapy in B cell acute lymphoblastic leukemia and other pediatric cancers and its future role in the Swiss setting.
Combattre la leucémie en utilisant les armes immunologiques, via les anticorps et les lymphocytes, est une idée ancienne, qui a déjà connu un accomplissement dans la greffe de moelle osseuse. Pour limiter les effets néfastes sur d'autres organes (maladie du greffon contre l'hôte), des cellules T autologues peuvent être modifiées pour exprimer des récepteurs d'antigènes chimères synthétiques (CAR) avec spécificité antigénique. Dans le cadre d'essais cliniques, les cellules CAR-T anti-CD19 ont montré une efficacité importante dans les leucémies et les lymphomes B en rechute ou réfractaires. Dans cet article, nous décrivons les approches proposées, les résultats des essais cliniques, les effets secondaires et l'orientation future de ces thérapies dans les leucémies et d'autres cancers pédiatriques ainsi que leurs perspectives dans le contexte suisse.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antígenos CD19 , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T , Linfócitos TRESUMO
BACKGROUND: The first step in the production of chimeric antigen receptor T cells is the collection of autologous T cells using apheresis technology. The procedure is technically challenging, because patients often have low leukocyte counts and are heavily pretreated with multiple lines of chemotherapy, marrow transplantation, and/or radiotherapy. Here, we report our experience of collecting T lymphocytes for chimeric antigen receptor T-cell manufacturing in pediatric and young adult patients with leukemia, non-Hodgkin lymphoma, or neuroblastoma. STUDY DESIGN AND METHODS: Apheresis procedures were performed on a COBE Spectra machine using the mononuclear cell program, with a collection target of 1 × 109 total mononuclear cells per kilogram. Data were collected regarding preapheresis and postapheresis blood counts, apheresis parameters, products, and adverse events. RESULTS: Ninety-nine patients (ages 1.3-25.7 years) and 102 apheresis events were available for analysis. Patients underwent apheresis at a variety of absolute lymphocyte cell counts, with a median absolute lymphocyte count of 944 cells/µL (range, 142-6944 cells/µL). Twenty-two patients (21.6%) had absolute lymphocyte counts less than 500 cells/µL. The mononuclear cell target was obtained in 100% of all apheresis harvests, and chimeric antigen receptor T-cell production was possible from the majority of collections (94%). Mononuclear cell collection efficiency was 65.4%, and T-lymphocyte collection efficiency was 83.4%. Ten patients (9.8%) presented with minor adverse events during the 102 apheresis procedures, with one exception of a severe allergy. CONCLUSIONS: Mononuclear cell apheresis for chimeric antigen receptor T-cell therapy is well tolerated and safe, and it is possible to obtain an adequate quantity of CD3+ lymphocytes for chimeric antigen receptor T-cell manufacturing in heavily pretreated patients who have low lymphocyte counts.
Assuntos
Leucaférese/métodos , Leucemia/terapia , Neuroblastoma/terapia , Receptores de Antígenos de Linfócitos T/sangue , Receptores de Antígenos Quiméricos/sangue , Adolescente , Adulto , Autoenxertos , Complexo CD3/sangue , Criança , Pré-Escolar , Humanos , Imunoterapia Adotiva , Lactente , Contagem de Linfócitos , Adulto JovemRESUMO
Over the last 50 years, collaborative clinical trials have reduced the number of children dying from pediatric cancer significantly. Unfortunately, certain tumor types have remained resistant to conventional surgical, radiotherapy and chemotherapy combinations, and relapsing and/or refractory disease remains associated with dismal outcomes. Recently, renewed attention has been given to the role for immunotherapies in pediatric oncology. In fact, these combine several attractive features, including (but possibly not limited to) the specificity for cancer cells, potentially in vivo persistence and longevity, and potency against refractory disease. In this narrative review designed for the academic pediatrician, we will concisely review the biological underpinnings behind the immunological therapy of pediatric neoplasms and illustrate the current humoral, cellular approaches, and novel drugs targeting the immune checkpoint, oncolytic viruses, and tumor vaccines. We will also comment on the future directions, challenges, and open questions faced by the field. What is Known: ⢠Cancer immunotherapy drives immune cells and its humoral weaponry to eliminate tumor cells. ⢠This occurs by recognizing antigens ideally expressed only on tumoral, but not normal/healthy, cells. What is New: ⢠Clinical immunotherapy trials have shown responses in children with relapsing/refractory neoplasms. ⢠Novel humoral/cellular immunotherapies, immune checkpoint inhibitors, oncolytic viruses, and tumor vaccines are currently being investigated in pediatric oncology.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Adjuvantes Imunológicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Criança , Antígenos de Histocompatibilidade Classe II/uso terapêutico , Humanos , Imunoterapia/tendências , Terapia Viral Oncolítica , Linfócitos T/efeitos dos fármacosRESUMO
Central nervous system (CNS) involvement in patients with mature B non-Hodgkin lymphoma, post-transplantation proliferative disorder and acute lymphoblastic leukemia confers a significantly inferior prognosis as compared to patients without CNS disease. Intrathecal (IT) or intraventricular administration of rituximab is an option for this group of patients. We report 25 children with CNS involvement of CD20+ B lymphoid malignancies who received in total 163 IT/intraventricular rituximab doses. The median number of doses received by each patient was 6, with a median dose of 25 mg. The most common adverse events were Grades 1 and 2 peripheral neuropathies in five patients (20%), allergy in two patients, and headache in two patients. These events were self-limited, occurring in the 48 hours after treatment and resolving within 24 hr. Three patients presented with more severe though transient side effects, one with a Grade III neuropathy and two with seizure. Eighteen patients (72%) of those treated with IT/intraventricular rituximab, with or without other CNS directed treatment, achieved a CNS remission. This case series suggests that IT/intraventricular rituximab has therapeutic efficacy and relatively limited toxicity. Prospective trials of IT/intraventricular rituximab for patients with CNS involvement of CD20 + B lymphoid malignancies are warranted.
Assuntos
Antineoplásicos/administração & dosagem , Linfoma de Células B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Antígenos CD20/imunologia , Antineoplásicos/efeitos adversos , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Criança , Pré-Escolar , Terapia Combinada , Avaliação de Medicamentos , Hipersensibilidade a Drogas/etiologia , Feminino , Cefaleia/induzido quimicamente , Humanos , Lactente , Injeções Intraventriculares , Injeções Espinhais , Linfoma de Células B/mortalidade , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/mortalidade , Masculino , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Indução de Remissão , Estudos Retrospectivos , Rituximab/efeitos adversos , Terapia de Salvação , Convulsões/induzido quimicamente , Transplante , Resultado do Tratamento , Adulto JovemRESUMO
Primary cutaneous lymphomas are rare in children and mostly represented by mycosis fungoides and CD30(+) lymphoproliferative disorders. Most pediatric cutaneous lymphomas have similar clinical/pathological features as their adult counterparts, particularly the T-cell subtypes. With regard to outcome, adult cutaneous mature T-cell lymphomas have a tendency to progression, while this appears to be relatively infrequent in children. The outcome of cutaneous B-cell lymphomas depends on subtype, with the B-lymphoblastic entity being associated with similar outcomes to precursor B acute lymphoblastic leukemia, while there are insufficient data on other entities. The diagnosis and treatment of these patients require a close collaboration between experienced pediatric pathologists, dermatologists, and oncologists. Prospective collection of longitudinal clinical and biological data from children with these rare lymphomas is needed to better understand their biological and clinical behavior and to ultimately discover the best therapeutic strategies.
Assuntos
Linfoma Cutâneo de Células T/terapia , Micose Fungoide/terapia , Neoplasias Cutâneas/terapia , Adolescente , Criança , Humanos , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/mortalidade , Papulose Linfomatoide/terapia , Estudos Prospectivos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/mortalidadeRESUMO
BACKGROUND: Treatment of acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS) is associated with a higher incidence of life-threatening infections compared to the overall pediatric population. The objective of this study was to describe infections and identify risk factors of microbiologically documented infections at a sterile site in children with DS during chemotherapy for ALL. PROCEDURE: We conducted a single-institution retrospective review of infectious episodes encountered by patients with DS during primary treatment for ALL. Correlations between features of clinical presentation and severity of microbiologically proven infections were investigated. RESULTS: Among 237 suspected infectious episodes encountered by 35 patients with DS and ALL (DS-ALL), a total of 40 episodes (16.9%) had the clinical presentation of a severe infection (SI). Seventeen patients had 33 (13.9%) microbiologically proven infections from a sterile site. Fever was not part of the clinical presentation in 27% of microbiologically documented infectious episodes. The odds ratio of a microbiologically proven infection at a sterile site was significantly increased during a 7-day interval after treatment with glucocorticoids (2.18; 95% CI: 1.02-4.66; P = 0.04). Neither administration of anthracyclines in the preceding 14 days nor neutropenia correlated with infections. CONCLUSIONS: Serious infections in DS-ALL may present without typical signs such as fever. The immediate time period following administration of glucocorticoids is particularly associated with the risk of SIs.
Assuntos
Infecções Bacterianas/etiologia , Síndrome de Down/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Febre/etiologia , Humanos , Lactente , Recém-Nascido , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Although anaplastic large cell lymphoma (ALCL) is curable in high-income countries (HIC), data from low- and middle-income countries (LMIC) are lacking. We therefore conducted a retrospective study of the Central American Association of Pediatric Hematology Oncology (AHOPCA) experience in treating ALCL. PROCEDURE: We included all patients age <18 years newly diagnosed with ALCL treated between 2000 and 2013 in seven AHOPCA institutions. Retrospective data were extracted from the Pediatric Oncology Network Database. RESULTS: Thirty-one patients met inclusion criteria. Twenty-five (81%) had advanced disease (stages III and IV), six (19%) were treated on the APO (doxorubicin, prednisone, vincristine) regimen, 15 (49%) on multi-agent chemotherapy designed for T-cell lineage malignancies (GuatALCL protocol), and 10 (32%) on BFM-based treatment regimens. Five-year overall event-free survival and overall survival were, respectively, 67.1 ± 8.6% and 66.7 ± 8.7%. All 10 events occurred in patients treated on BFM-based treatment regimens or the GuatALCL protocol, none on APO treatment: two patients experienced relapse, six treatment related mortality (TRM), and two abandonment. CONCLUSIONS: Treatment of ALCL in countries with limited resources is feasible with similar outcomes as in HIC, though the causes of treatment failure differ. Less intensive regimens may be preferable in order to decrease TRM and improve outcomes. Prospective clinical trials determining the ideal treatment for LMIC children with ALCL are necessary.
Assuntos
Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/epidemiologia , Adolescente , América Central/epidemiologia , Criança , Feminino , Hematologia , Humanos , Linfoma Anaplásico de Células Grandes/mortalidade , Masculino , Oncologia , Estudos Retrospectivos , Sociedades MédicasRESUMO
Posttransplant lymphoproliferative disease (PTLD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. We describe here the case of a boy with history of induction failure of a T-cell acute lymphoblastic leukemia, who presented a life-threatening situation of nonengraftment and rituximab-refractory PTLD after the first hematopoietic stem cell transplantation. We decided to use an unusual strategy of combining a nonmyeloablative conditioning (fludarabine and cyclophosphamide) with a calcineurin inhibitor-free GvHD prophylaxis (sirolimus and mycophenolate mofetil). This strategy had permitted the control of an Epstein-Barr virus PLTD in umbilical cord blood transplantation without further reactivation.