RESUMO
Venetoclax is a promising agent in the treatment of acute myeloid leukemia, though its antileukemic activity is limited to combination therapies. Mcl-1 downregulation, Bim upregulation, and DNA damage have been identified as potential ways to enhance venetoclax activity. In this study, we combine venetoclax with the dual PI3K and histone deacetylase inhibitor CUDC-907, which can downregulate Mcl-1, upregulate Bim, and induce DNA damage, as well as downregulate c-Myc. We establish that CUDC-907 and venetoclax synergistically induce apoptosis in acute myeloid leukemia cell lines and primary acute myeloid leukemia patient samples ex vivo. CUDC-907 downregulates CHK1, Wee1, RRM1, and c-Myc, which were found to play a role in venetoclax-induced apoptosis. Interestingly, we found that venetoclax treatment enhances CUDC-907-induced DNA damage potentially through inhibition of DNA repair. In vivo results show that CUDC-907 enhances venetoclax efficacy in an acute myeloid leukemia cell line derived xenograft mouse model, supporting the development of CUDC-907 in combination with venetoclax for the treatment of acute myeloid leukemia.
Assuntos
Leucemia Mieloide Aguda , Fosfatidilinositol 3-Quinases , Animais , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Camundongos , Morfolinas , Pirimidinas , Sulfonamidas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Evans syndrome is defined by bilineal autoimmune cytopenia, typically coombs positive hemolytic anemia and thrombocytopenia. Corticosteroids are the mainstay of treatment, with rituximab and/or mycophenolate mofetil often used in steroid-refractory cases. However, no treatment methodology has ever evaluated by a randomized clinical trial. We present a 15-year-old boy with Evans syndrome and common variable immunodeficiency who experienced a severe, refractory flare 16 months postsplenectomy. After failing to respond to multiple other agents, he achieved a durable response to a bortezomib-based regimen. Bortezomib may be a reasonable second or third line option, especially before high-morbidity therapies such as splenectomy or stem cell transplantation.
Assuntos
Anemia Hemolítica Autoimune/cirurgia , Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Complicações Pós-Operatórias/tratamento farmacológico , Esplenectomia/efeitos adversos , Trombocitopenia/cirurgia , Adolescente , Anemia Hemolítica Autoimune/patologia , Humanos , Masculino , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Prognóstico , Recidiva , Trombocitopenia/patologiaRESUMO
Background: Clostridium difficile (CD) is often classified as a healthcare-associated infection (HAI) and a hospital-acquired condition (HAC) in the hospital setting. However, pediatric oncology patients comprise a significant portion of Clostridium difficile infections (CDI), with hematopoietic stem cell transplant (HSCT) recipients constituting a major subset of this group due to unique, non-modifiable risk factors. We evaluated patterns of clostridium difficile infections at our institution to provide an accurate evaluation of the vulnerability of pediatric oncology and HSCT patients to clostridium difficile infections in comparison to the general pediatric population and underscore the non-tenability of classifying clostridium difficile infections as a hospital-acquired condition in HSCT patients. Methods: Single-center retrospective review of all clostridium difficile stool tests performed over an 11-year period; data analyzed and statistical comparisons performed between patient groups. Results: 5271 total samples were obtained during the study time period from 3127 patients. At least one positive test result was found in 18.6% of patients. Oncology and HSCT patients (38.2%) were more likely to have a positive test result than hematology (17.5%) and other patients (16.8%) (p < 0.001). Sixty-percent of patients who underwent HSCT were tested during this time frame. Of those, 39.3% had a positive test result and 48.5% of those patients went on to have a subsequent infection that met the criteria to be defined as recurrent. Conclusions: The high incidence rate and frequency of recurrence underscores the current near-inevitable nature of clostridium difficile infections in oncology and HSCT patients. We conclude that a blanket designation of clostridium difficile infections as an hospital-acquired condition is therefore questionable in this population.
Assuntos
Clostridioides difficile , Infecções por Clostridium/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Neoplasias/epidemiologia , Neoplasias/terapia , Adolescente , Aloenxertos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
Induction therapy for patients with acute myeloid leukemia (AML) has remained largely unchanged for over 40 years, while overall survival rates remain unacceptably low, highlighting the need for new therapies. The PI3K/Akt pathway is constitutively active in the majority of patients with AML. Given that histone deacetylase inhibitors have been shown to synergize with PI3K inhibitors in preclinical AML models, we investigated the novel dual-acting PI3K and histone deacetylase inhibitor CUDC-907 in AML cells both in vitro and in vivo We demonstrated that CUDC-907 induces apoptosis in AML cell lines and primary AML samples and shows in vivo efficacy in an AML cell line-derived xenograft mouse model. CUDC-907-induced apoptosis was partially dependent on Mcl-1, Bim, and c-Myc. CUDC-907 induced DNA damage in AML cells while sparing normal hematopoietic cells. Downregulation of CHK1, Wee1, and RRM1, and induction of DNA damage also contributed to CUDC-907-induced apoptosis of AML cells. In addition, CUDC-907 treatment decreased leukemia progenitor cells in primary AML samples ex vivo, while also sparing normal hematopoietic progenitor cells. These findings support the clinical development of CUDC-907 for the treatment of AML.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Pirimidinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Genes myc , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Fever in a neutropenic oncology patient requires rapid initiation of effective empiric antibiotics to prevent mortality. We evaluated the appropriateness of our current empiric antibiotic regimen by assessing local antibiotic-susceptibility patterns in our pediatric oncology patients, and comparing them to the general pediatric patterns in our hospital. All blood culture isolates from pediatric oncology patients were reviewed over a 3-year period. Gram-negative and Gram-positive organisms were reviewed separately, with antibiotic susceptibilities for all unique isolates evaluated, and antibiograms generated and compared with general pediatric patients via the Fisher exact test. A total of 84% of Gram negatives were susceptible to meropenem; all resistant organisms were Pseudomonas aeruginosa, with 50% meropenem susceptibility. A total of 91% of Gram negatives were susceptible to cefepime, including 90% of P. aeruginosa and 80% of Escherichia coli. In total, 96% of Gram positives were vancomycin-susceptible; the only resistant organism was a single enterococcal isolate. In comparison with the general pediatric population, significantly fewer pseudomonal isolates were sensitive to meropenem among the oncology population (50% vs. 89%, P=0.0034). As such, in our population, meropenem does not provide adequate monotherapy against Pseudomonas. Ongoing surveillance of antibiotic resistance in this high-risk population is warranted, to ensure appropriate empiric antibiotic usage.
Assuntos
Antibacterianos/farmacologia , Bacteriemia/microbiologia , Bactérias/isolamento & purificação , Testes de Sensibilidade Microbiana , Neoplasias/microbiologia , Bactérias/efeitos dos fármacos , Criança , Feminino , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/isolamento & purificação , Humanos , MasculinoRESUMO
Piezo1, encoded by the gene PIEZO1, is an erythrocytic cellular membrane mechanoactivated cation channel. Mutations have been implicated in erythrocyte volume disorders (EVDs)-especially hereditary xerocytosis (HX)/dehydrated stomatocytosis (DHS). We identified three patients, all with novel PIEZO1 mutations, but only one displaying the HX/DHS phenotype. Retrospective review of three cases. Osmotic gradient red cell deformability (Osmoscan) was assessed via the Technicon Ektacytometer. Red cell band 3 content was estimated using Eosin-5'-Maleimide staining. Patient 1 was evaluated for polycythemia. Osmoscans suggested mild spherocytosis; a novel PIEZO1 mutation (p.Thr1589Ile, exon 35) was identified, causing mild erythrocytosis without hemolytic anemia. Patient 2 was evaluated for macrocytosis/reticulocytosis, normal-to-high hemoglobin, and indirect hyperbilirubinemia. Osmoscans suggested increased cellular hydration; a second novel PIEZO1 mutation (p.Arg1728Cys, exon 37) was identified, resulting in overhydrated stomatocytosis with well-compensated hemolysis. Patient 3 was evaluated for indirect hyperbilirubinemia only. Osmoscans suggested dehydrated stomatocytosis (DHS, xerocytosis); a third novel PIEZO1 mutation (p.Arg2279Cys, exon 47) was identified. All three patients' blood smears demonstrated stomatocytes and spherocytes. EVDs may be underdiagnosed due to the lack of "expected" anemia in a hemolytic disorder; two of three patients had high hemoglobin and red cell counts and one had high normal values for both parameters and the presence of stomatocytes/dehydrated cells lead to identification of causative PIEZO1 mutations. PIEZO1-associated EVDs may be more common than previously suspected and should be included in the diagnostic algorithms for mild erythrocytosis/unexplained jaundice.
Assuntos
Anemia Hemolítica Congênita/genética , Éxons , Hidropisia Fetal/genética , Canais Iônicos/genética , Mutação de Sentido Incorreto , Policitemia/genética , Esferocitose Hereditária/genética , Adolescente , Substituição de Aminoácidos , Volume de Eritrócitos , Humanos , MasculinoRESUMO
WAS is a fatal X-linked combined immunodeficiency syndrome, the only cures for which are HSCT or gene therapy. AID occur in up to 72% of patients with WAS who do not receive HSCT, likely arising secondary to impaired multilineage immune autoregulatory function; AITD is not typically seen. In this article, we describe the case of a male patient who underwent HLA-matched HSCT for WAS at the age of 5 months, with his sister (a WAS carrier) acting as his donor and subsequently developed AITD 12 months post-transplant, with marked elevation of antithyroid peroxidase antibody titer. His donor sister was subsequently found to have elevated antithyroid peroxidase antibody titer with increasing trend and normal thyroid function. Although several mechanisms exist by which our patient may have developed AITD, we suggest the transfer of autoreactive donor immune cells as the most plausible explanation.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Tireoidite Autoimune/etiologia , Síndrome de Wiskott-Aldrich/terapia , Pré-Escolar , Antígenos HLA/imunologia , Humanos , Lactente , Masculino , Irmãos , Tireoidite Autoimune/diagnóstico , Doadores de TecidosAssuntos
Acessibilidade aos Serviços de Saúde , Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Adulto , Criança , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Tirosina Quinase 3 Semelhante a fms/genéticaAssuntos
Janus Quinase 3/genética , Leucemia Linfocítica Granular Grande/diagnóstico , Imunodeficiência Combinada Severa/diagnóstico , Linfócitos T/imunologia , Proliferação de Células , Células Clonais , Análise Mutacional de DNA , Feminino , Citometria de Fluxo , Humanos , Recém-Nascido , Receptores de Antígenos de Linfócitos T/genética , Imunodeficiência Combinada Severa/genéticaAssuntos
Antineoplásicos/uso terapêutico , Astrocitoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neurofibromatose 1/tratamento farmacológico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Terapia de Salvação , Astrocitoma/complicações , Astrocitoma/patologia , Humanos , Lactente , Masculino , Neurofibromatose 1/complicações , Neurofibromatose 1/patologia , Prognóstico , Indução de RemissãoRESUMO
The first series of chimeric antigen receptor T (CAR-T) cell therapy products were approved in 2017 to 2019 and have shown remarkable efficacy in both clinical trials and the real-world setting, but at the cost of prolonged patient hospitalization. As the toxicity management protocols were refined, the concept of cellular therapy administered in the outpatient setting gained steam, and single institutions began to perform certain aspects of CAR-T monitoring in the outpatient setting for select patients. However, there are many considerations for a successful outpatient program. In anticipation of increasing use of CAR-T-cell therapy in the outpatient setting as a mechanism to overcome frequent hospital bed shortages and high cost of inpatient care, the American Society for Transplantation and Cellular Therapy convened a group of experts in hematology, oncology, and cellular therapy to provide a comprehensive review of the existing publications on outpatient CAR-T cell therapy, discuss selected ongoing clinical trials of outpatient CAR-T, and describe strategies to optimize safety without compromising efficacy for patients treated and monitored in the outpatient setting.
Assuntos
Receptores de Antígenos Quiméricos , Humanos , Estados Unidos , Receptores de Antígenos Quiméricos/uso terapêutico , Pacientes Ambulatoriais , Imunoterapia Adotiva/efeitos adversos , Sociedades , Terapia Baseada em Transplante de Células e TecidosAssuntos
Células da Medula Óssea/metabolismo , Emperipolese , Doença de Hodgkin/metabolismo , Megacariócitos/patologia , Adolescente , Células da Medula Óssea/patologia , Feminino , Doença de Hodgkin/patologia , Humanos , Megacariócitos/metabolismo , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patologiaRESUMO
Consolidation with autologous hematopoietic stem cell transplantation (HSCT) has improved survival for patients with central nervous system tumors (CNSTs). The impact of the autologous graft CD34+ dose on patient outcomes is unknown. We wanted to analyze the relationship between CD34+ dose, total nucleated cell (TNC) dose, and clinical outcomes, including overall survival (OS), progression-free survival (PFS), relapse, non-relapse mortality (NRM), endothelial-injury complications (EIC), and time to neutrophil engraftment in children undergoing autologous HSCT for CNSTs. A retrospective analysis of the CIBMTR database was performed. Children aged <10 years who underwent autologous HSCT between 2008 to 2018 for an indication of CNST were included. An optimal cut point was identified for patient age, CD34+ cell dose, and TNC, using the maximum likelihood method and PFS as an endpoint. Univariable analysis for PFS, OS, and relapse was described using the Kaplan-Meier estimator. Cox models were fitted for PFS and OS outcomes. Cause-specific hazards models were fitted for relapse and NRM. One hundred fifteen patients met the inclusion criteria. A statistically significant association was identified between autograft CD34+ content and clinical outcomes. Children receiving >3.6×106/kg CD34+ cells experienced superior PFS (p = .04) and OS (p = .04) compared to children receiving ≤3.6 × 106/kg. Relapse rates were lower in patients receiving >3.6 × 106/kg CD34+ cells (p = .05). Higher CD34+ doses were not associated with increased NRM (p = .59). Stratification of CD34+ dose by quartile did not reveal any statistically significant differences between quartiles for 3-year PFS (p = .66), OS (p = .29), risk of relapse (p = .57), or EIC (p = .87). There were no significant differences in patient outcomes based on TNC, and those receiving a TNC >4.4 × 108/kg did not experience superior PFS (p = .26), superior OS (p = .14), reduced risk of relapse (p = .37), or reduced NRM (p = .25). Children with medulloblastoma had superior PFS (p < .001), OS (p = .01), and relapse rates (p = .001) compared to those with other CNS tumor types. Median time to neutrophil engraftment was 10 days versus 12 days in the highest and lowest infused CD34+ quartiles, respectively. For children undergoing autologous HSCT for CNSTs, increasing CD34+ cell dose was associated with significantly improved OS and PFS, and lower relapse rates, without increased NRM or EICs.
Assuntos
Neoplasias do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Estudos Retrospectivos , Autoenxertos/química , Recidiva Local de Neoplasia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Antígenos CD34/análise , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias do Sistema Nervoso Central/etiologiaRESUMO
T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management. With the goal of improving patient outcomes and formulating a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy panel composed of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy. Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, explore its relationship with similar manifestations following CAR T cell infusions, and propose the term "immune effector cell-associated HLH-like syndrome (IEC-HS)" to describe this emergent toxicity. We also delineate a framework for identifying IEC-HS and put forward a grading schema that can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insight into potential treatment approaches and strategies to optimize supportive care and delineate alternate etiologies that should be considered in a patient presenting with IEC-HS. By collectively defining IEC-HS as a hyperinflammatory toxicity, we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides toward a more comprehensive assessment and treatment approach.
Assuntos
Linfo-Histiocitose Hemofagocítica , Síndromes Neurotóxicas , Adulto , Humanos , Estados Unidos , Criança , Linfo-Histiocitose Hemofagocítica/terapia , Linfo-Histiocitose Hemofagocítica/etiologia , Síndromes Neurotóxicas/etiologia , Linfócitos T , Imunoterapia Adotiva/efeitos adversos , Síndrome da Liberação de Citocina/terapia , Síndrome da Liberação de Citocina/complicaçõesRESUMO
The treatment of many types of cancers, including acute myeloid leukemia (AML), has been revolutionized by the development of therapeutics targeted at crucial molecular drivers of oncogenesis. In contrast to broad, relatively indiscriminate conventional chemotherapy, these targeted agents precisely disrupt key pathways within cancer cells. FMS-like tyrosine kinase 3 (FLT3)-encoding a critical regulator of hematopoiesis-is the most frequently mutated gene in patients with AML, and these mutations herald reduced survival and increased relapse in these patients. Approximately 30% of newly diagnosed AML carries an FLT3 mutation; of these, approximately three-quarters are internal tandem duplication (ITD) mutations, and the remainder are tyrosine kinase domain (TKD) mutations. In contrast to its usual, tightly controlled expression, FLT3-ITD mutants allow constitutive, "run-away" activation of a large number of key downstream pathways which promote cellular proliferation and survival. Targeted inhibition of FLT3 is, therefore, a promising therapeutic avenue. In April 2017, midostaurin became both the first FLT3 inhibitor and the first targeted therapy of any kind in AML to be approved by the US FDA. The use of FLT3 inhibitors has continued to grow as clinical trials continue to demonstrate the efficacy of this class of agents, with an expanding number available for use as both experimental standard-of-care usage. This review examines the biology of FLT3 and its downstream pathways, the mechanism of FLT3 inhibition, the development of the FLT3 inhibitors as a class and uses of the agents currently available clinically, and the mechanisms by which resistance to FLT3 inhibition may both develop and be overcome.
RESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas (STS) with nerve sheath differentiation and a tendency to metastasize. Although occurring at an incidence of 0.001% in the general population, they are relatively common in individuals with neurofibromatosis type 1 (NF1), for whom the lifetime risk approaches 10%. The staging of MPNSTs is complicated and requires close multi-disciplinary collaboration. Their primary management is most often surgical in nature, with non-surgical modalities playing a supportive, necessary role, particularly in metastatic, invasive, or widespread disease. We, therefore, sought to provide a comprehensive review of the relevant literature describing the characteristics of these tumors, their pathophysiology and risk factors, their diagnosis, and their multi-disciplinary treatment. A close partnership between surgical and medical oncologists is therefore necessary. Advances in the molecular characterization of these tumors have also begun to allow the integration of targeted RAS/RAF/MEK/ERK pathway inhibitors into MPNST management.
RESUMO
Rapid advances in the field of hematopoietic cell transplantation (HCT), as well as the advent of immune effector cell therapy (IEC), have resulted in an increasing number of patients undergoing these therapies and an increasing level of expertise required to manage them. Previous guidelines for the training of HCT physicians were last published in 2012. In recognition of the expanding knowledge base and increasing skill set essential to the delivery of these treatment modalities, the American Society for Transplantation and Cellular Therapy Committee on Education has updated these guidelines to reflect nearly a decade of new knowledge in the field of HCT, as well as the evolution of IEC from an experimental modality to a widely used and mainstream therapy. The resulting document reflects the Committee on Education's recommended educational structure for programs engaged in the training, evaluation, and mentorship of HCT/IEC trainees.