RESUMO
Multiparameter flow cytometry (MPF) is an essential component of the diagnostic workup of hematologic malignancies. Recently developed tools have expanded the utility of MPF in detecting T-cell clonality and myelomonocytic dysplasia. Minimal/measurable residual disease analysis has long been established as critical in the management of B-lymphoblastic leukemia and is emerging as a useful tool in myeloid malignancies. With the continued increased complexity of MPF assays, emerging tools for data collection and analysis will allow users to take full advantage of MPF in the diagnosis of hematologic disease.
Assuntos
Citometria de Fluxo , Neoplasias Hematológicas , Humanos , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/patologia , Imunofenotipagem , Neoplasia Residual/diagnósticoAssuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Masculino , Transplante Autólogo , Pessoa de Meia-Idade , FemininoRESUMO
Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti-programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell-mediated immune responses. Importantly, ablation of AML cell-surface PD-1H by antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression, and the combination of PD-1H blockade with anti-PD therapy conferred a synergistic antileukemia effect. Our findings provide the basis for PD-1H as a potential therapeutic target for treating human AML.
Assuntos
Evasão da Resposta Imune , Leucemia Mieloide Aguda , Animais , Humanos , Camundongos , Medula Óssea , Imunidade Celular , Imunoterapia , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Effective eradication of leukemic stem cells (LSCs) remains the greatest challenge in treating acute myeloid leukemia (AML). The immune receptor LAIR-1 has been shown to regulate LSC survival; however, the therapeutic potential of this pathway remains unexplored. We developed a therapeutic LAIR-1 agonist antibody, NC525, that induced cell death of LSCs, but not healthy hematopoietic stem cells in vitro, and killed LSCs and AML blasts in both cell- and patient-derived xenograft models. We showed that LAIR-1 agonism drives a unique apoptotic signaling program in leukemic cells that was enhanced in the presence of collagen. NC525 also significantly improved the activity of azacitidine and venetoclax to establish LAIR-1 targeting as a therapeutic strategy for AML that may synergize with standard-of-care therapies.
Assuntos
Leucemia Mieloide Aguda , Animais , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Transdução de Sinais , Modelos Animais de Doenças , Células-Tronco Neoplásicas/metabolismoRESUMO
OBJECTIVES: Epstein-Barr virus-positive large B-cell lymphoma (EBV+ LBCL) is a heterogeneous group of diseases that may resemble classic Hodgkin lymphoma (CHL) both morphologically and immunophenotypically. However, these diseases are treated with different therapies and carry distinct prognoses. We examined CD200 expression by immunohistochemistry in EBV+ LBCL and evaluated its diagnostic utility in the differential diagnosis with CHL. METHODS: CD200 immunohistochemistry was performed on archival material from 20 cases of CHL (11 EBV+, 9 EBV-), 11 cases of EBV+ LBCL, and 10 cases of diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS). Staining pattern and intensity (0-3+ scale) were recorded. RESULTS: CD200 positivity was seen in Reed-Sternberg cells in 19 (95%) of 20 cases of CHL, predominantly in a strong (3+, 15/19) and diffuse (>50% of cells, 17/19) pattern. In contrast, CD200 was negative in 8 (73%) of 11 cases of EBV+ LBCL; the 3 positive cases showed 1 to 2+ staining in less than 50% of lesional cells. All cases of DLBCL NOS were negative for CD200. CONCLUSIONS: CD200 may be a useful immunophenotypic marker in differentiating EBV+ LBCL from CHL, with negative to partial/weak staining favoring a diagnosis of EBV+ LBCL and strong diffuse staining favoring a diagnosis of CHL.
Assuntos
Antígenos CD , Infecções por Vírus Epstein-Barr , Doença de Hodgkin , Linfoma Difuso de Grandes Células B , Humanos , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4 , Doença de Hodgkin/diagnóstico , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/virologia , Antígenos CD/análiseRESUMO
PURPOSE: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines. PATIENTS AND METHODS: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. RESULTS: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. CONCLUSIONS: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued.
Assuntos
Inibidores de Janus Quinases , Mielofibrose Primária , Humanos , Idoso , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Fosfatidilinositol 3-Quinases , Pirimidinas/uso terapêutico , Nitrilas/uso terapêutico , Inibidores de Janus Quinases/uso terapêuticoRESUMO
Although allogeneic hematopoietic cell transplantation (HCT) is the sole potentially curative therapy for patients with poor-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), only a minority of these patients undergo HCT. Patients with TP53-mutated (TP53MUT) MDS/AML are at particularly high risk, yet fewer TP53MUT patients undergo HCT compared with poor-risk TP53-wild type (TP53WT) patients. We hypothesized that TP53MUT MDS/AML patients have unique risk factors affecting the rate of HCT and thus investigated phenotypic changes that may prevent patients with TP53MUT MDS/AML from receiving HCT. In this single-center retrospective analysis of outcomes for adults with newly diagnosed MDS or AML (n = 352), HLA typing was used as a surrogate for physician "intent to transplant." Multivariable logistic regression models were used to estimate odds ratios (ORs) for factors associated with HLA typing, HCT, and pretransplantation infections. Multivariable Cox proportional hazards models were used to create predicted survival curves for patients with and those without TP53 mutations. Overall, significantly fewer TP53MUT patients underwent HCT compared to TP53WT patients (19% versus 31%; P = .028). Development of infection was significantly associated with decreased odds of HCT (OR, .42; 95% CI, .19 to .90) and worse overall survival (hazard ratio, 1.46; 95% CI, 1.09 to 1.96) in multivariable analyses. TP53MUT disease was independently associated with increased odds of developing an infection (OR, 2.18; 95% CI, 1.21 to 3.93), bacterial pneumonia (OR, 1.83; 95% CI, 1.00 to 3.33), and invasive fungal infection (OR, 2.64; 95% CI, 1.34 to 5.22) prior to HCT. Infections were the cause of death in significantly more patients with TP53MUT disease (38% versus 19%; P = .005). With substantially more infections and decreased HCT rates in patients with TP53 mutations, this raises the possibility that phenotypic changes occurring in TP53MUT disease may affect infection susceptibility in this population and drastically impact clinical outcomes.
Assuntos
Deficiência de GATA2 , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Adulto , Humanos , Estudos Retrospectivos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Proteína Supressora de Tumor p53/genéticaRESUMO
Myeloid sarcoma (MS) is currently considered equivalent to de novo acute myeloid leukemia (AML); however, the relationship between these entities is poorly understood. This retrospective multi-institutional cohort study compared 43 MS with NPM1 mutation to 106 AML with NPM1 mutation. Compared to AML, MS had more frequent cytogenetic abnormalities including complex karyotype (p = .009 and p = .007, respectively) and was enriched in mutations of genes involved in histone modification, including ASXL1 (p = .007 and p = .008, respectively). AML harbored a higher average number of gene mutations (p = .002) including more frequent PTPN11 mutations (p < .001) and mutations of DNA-methylating genes including DNMT3A and IDH1 (both p < .001). MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p = .037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation.
First study comparing genetic profiles of MS and AML with a common disease-defining lesion.NPM1Mut MS may be genetically distinct from NPM1Mut AML.NPM1Mut MS may have inferior overall survival compared to NPM1Mut AML.
Assuntos
Leucemia Mieloide Aguda , Sarcoma Mieloide , Humanos , Medula Óssea/patologia , Proteínas Nucleares/genética , Nucleofosmina , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/genética , Sarcoma Mieloide/patologia , Estudos Retrospectivos , Estudos de Coortes , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , PrognósticoRESUMO
Histoplasmosis, a common mycosis in the south-central United States, may be life threatening in immunocompromised patients. We describe a 4-year-old female with Down syndrome and acute lymphoblastic leukemia who developed hemolytic anemia, thrombocytopenia, and renal failure, consistent with thrombotic microangiopathy. Bone marrow biopsy revealed non-necrotizing granulomas with GMS staining demonstrating budding yeast. Serum Histoplasma antigen testing was positive, providing further evidence for the diagnosis of progressive disseminated histoplasmosis. Treatment with amphotericin B, plasma exchange, and ventilator, vasopressor, and renal replacement support led to a full recovery. Providers should have a low threshold for histoplasmosis testing in ill immunocompromised patients, who are at greater risk for infection-related morbidity.
Assuntos
Síndrome de Down , Histoplasmose , Leucemia-Linfoma Linfoblástico de Células Precursoras , Microangiopatias Trombóticas , Feminino , Humanos , Criança , Pré-Escolar , Histoplasmose/complicações , Histoplasmose/diagnóstico , Histoplasmose/terapia , Síndrome de Down/complicações , Anfotericina B/uso terapêutico , Microangiopatias Trombóticas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaçõesRESUMO
Chronic myeloid leukemia (CML), a myeloproliferative neoplasm defined by the presence of the BCR-ABL1 oncogene created by the reciprocal translocation t(9;22)(q34.1;q11.2), can often be controlled by medications that inhibit this constitutive tyrosine kinase. However, if these therapies fail, the disease may progress to a form resembling an acute leukemia. While most of these CML 'blast crises' are characterized by blasts with a myeloid (granulocytic) or lymphoid lineage, these blasts may rarely be predominantly erythroid. Cases of CML erythroid blast crises have been reported; however, secondary pure erythroid leukemia arising from a CML blast crisis has only been definitively reported once before. We report the second definitive case of pure erythroid leukemia with the t(9;22)(q34.1;q11.2) presenting as a CML blast crisis and characterize the morphologic, immunophenotypic, flow cytometric, cytogenetic, and molecular findings.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide Aguda , Crise Blástica/genética , Humanos , Imunofenotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Translocação GenéticaRESUMO
After acute leukemia and brain and central nervous system tumors, mature lymphomas represent the third most common cancer in pediatric patients. Non-Hodgkin lymphoma accounts for approximately 60% of lymphoma diagnoses in children, with the remainder representing Hodgkin lymphoma. Among non-Hodgkin lymphomas in pediatric patients, aggressive lymphomas, such as Burkitt lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma, predominate. This article summarizes the epidemiologic, histopathologic, and molecular features of selected mature systemic B-cell and T-cell lymphomas encountered in this age group.
Assuntos
Linfoma Difuso de Grandes Células B , Linfoma de Células T , Criança , Humanos , Adulto JovemAssuntos
Inibidores Enzimáticos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/terapia , Diferenciação Celular/efeitos dos fármacos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Transplante Homólogo/efeitos adversosRESUMO
Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2-4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.
Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Nutrientes/metabolismo , Microambiente Tumoral , Animais , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Feminino , Glucose/metabolismo , Glutamina/metabolismo , Humanos , Metabolismo dos Lipídeos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/imunologia , Microambiente Tumoral/imunologiaRESUMO
Hematolymphoid processes involving the gastrointestinal tract in the pediatric and adolescent young adult (AYA) populations include processes occurring primarily within the gastrointestinal tract as well as systemic diseases with predilection for gastrointestinal involvement. Here, we present a focused review of reactive and neoplastic entities occurring in the pediatric and AYA age groups.