RESUMEN
Acute lymphoblastic leukemia (ALL) is a rare hematological malignancy characterized by proliferation and accumulation of premature lymphoid blasts. Depending on risk factors, the survival of acute lymphoblastic leukemia has significantly improved over the last decades. During the last years, measurable residual disease (MRD) assessment has evolved into one of the most sensitive markers for prognosis and risk of relapse. For this reason, measurable residual disease detection and monitoring count as standard evaluation in patients with acute lymphoblastic leukemia. Allogeneic stem cell transplantation is still the recommended treatment option for patients with high and highest risk profiles as well as for relapsed or refractory settings. The increased understanding of the pathomechanism and heterogeneity of acute lymphoblastic leukemia has led to the development of several novel therapeutic opportunities such as tyrosine-kinase inhibitors, antibody-based therapies and CAR-T cells with the aim of improving clinical outcomes. Furthermore, the major advances in disease understanding of ALL have led to the identification of different subgroups and better disease stratification. Even though novel therapy targets are constantly developed, acute lymphoblastic leukemia remains a challenging and life-threatening disease. To improve the historically unsatisfying result in therapy of adult acute lymphoblastic leukemia many clinical trials have recently been initiated to determine the optimum combination regimens of novel and old agents for adult acute lymphoblastic leukemia.
RESUMEN
Basophilia is a crucial prognostic variable in Ph-chromosome-positive chronic myeloid leukemia (CML). The ectoenzyme CD203c is an activation-linked surface antigen that is expressed specifically on basophil-committed progenitor cells and mature basophils. We examined the expression of CD203c on progenitors and/or basophils in 21 healthy donors and 44 patients with CML. As expected, the numbers of CD203c+ blood leukocytes were significantly higher in CML patients compared to controls (percentage of CD203c+ cells among viable cells in CML at diagnosis: 4.19 ± 3.68% vs. controls: 0.53 ± 0.23%, p < 0.05). Moreover, CML basophils expressed higher levels of CD203c compared to normal basophils (median staining-index in CML at diagnosis: 29.41 ± 19.14 versus controls: 20.44 ± 13.45). We also found that the numbers and percentage of circulating CD203c+ cells at diagnosis correlate with the disease-related risk-profile. Incubation of CML basophils with an anti-IgE-antibody resulted in further upregulation of CD203c. After successful treatment with imatinib and/or other BCR::ABL1 inhibitors leading to major or complete molecular responses, the numbers of CD203c+ basophils decreased substantially in our CML patients compared to pre-treatment values. Together, CD203c is overexpressed on CML basophils, is further upregulated by IgE receptor cross-linking, and may serve as a biomarker to quantify basophilia in patients with CML at diagnosis and during therapy.
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Basófilos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Enfermedad Crónica , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Receptores de IgE/metabolismo , Regulación hacia ArribaRESUMEN
Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. SIGNIFICANCE: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer.See related commentary by Letai, p. 290.This article is highlighted in the In This Issue feature, p. 275.
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Neoplasias Hematológicas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Austria , Estudios de Cohortes , Femenino , Neoplasias Hematológicas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Medicina de Precisión , Supervivencia sin Progresión , Adulto JovenRESUMEN
Cases of unusual thrombosis and thrombocytopenia after administration of the ChAdOx1 nCoV-19 vaccine (AstraZeneca) have been reported. The term vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) was coined to reflect this new phenomenon. In vitro experiments with VIPIT patient sera indicated that high-dose intravenous immunoglobulins (IVIG) competitively inhibit the platelet-activating properties of ChAdOx1 nCoV-19 vaccine induced antibodies. Here, we report a case of a 62-year-old woman who had received this vaccine and developed VIPIT. She visited the emergency ward because of petechiae and hematomas. In the laboratory work-up, thrombocytopenia, low fibrinogen, elevated D-dimer, and positivity in the platelet factor 4/heparin-enzyme-immunoassay were present. Signs and symptoms of thrombosis were absent. Upon immediate therapy with non-heparin anticoagulation, high-dose IVIG, and prednisolone, laboratory parameters steadily improved and the patient was discharged from hospital without thrombotic complications. We conclude that early initiation of VIPIT treatment results in a swift response without thrombotic complications.
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Púrpura Trombocitopénica Idiopática , Trombocitopenia , Vacunas , Vacunas contra la COVID-19 , ChAdOx1 nCoV-19 , Femenino , Heparina , Humanos , Persona de Mediana Edad , Factor Plaquetario 4 , Púrpura Trombocitopénica Idiopática/inducido químicamente , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Trombocitopenia/inducido químicamente , Trombocitopenia/diagnóstico , Trombocitopenia/tratamiento farmacológicoRESUMEN
Acute lymphoblastic leukemia (ALL) is characterized by leukemic expansion of lymphoid blasts in hematopoietic tissues. Despite improved therapy only a subset of patients can be cured. Therefore, current research is focusing on new drug-targets. Members of the BCL-2 family and components of the PI3-kinase/mTOR pathway are critically involved in the regulation of growth and survival of ALL cells. We examined the effects of the pan-BCL-2 blocker obatoclax and the PI3-kinase/mTOR-inhibitor BEZ235 on growth and survival of ALL cells. In 3H-thymidine uptake experiments, both drugs suppressed the in vitro proliferation of leukemic cells in all patients with Philadelphia chromosome-positive (Ph+) ALL and Ph- ALL (obatoclax IC50: 0.01-5 µM; BEZ235, IC50: 0.01-1 µM). Both drugs were also found to produce growth-inhibitory effects in all Ph+ and all Ph- cell lines tested. Moreover, obatoclax and BEZ235 induced apoptosis in ALL cells. In drug-combination experiments, obatoclax and BEZ235 exerted synergistic growth-inhibitory effects on ALL cells. Finally, we confirmed that ALL cells, including CD34+/CD38- stem cells and all cell lines express transcripts for PI3-kinase, mTOR, BCL-2, MCL-1, and BCL-xL. Taken together, this data shows that combined targeting of the PI3-kinase/mTOR-pathway and BCL-2 family-members is a potent approach to counteract growth and survival of ALL cells.
RESUMEN
Monoclonal B-cell lymphocytosis (MBL) with normal lymphocyte counts is associated with decreased numbers of normal circulating B-cell subsets.Little is known about the distribution of normal lymphoid cells and their subsets in the peripheral blood (PB) of subjects with monoclonal B-cell lymphocytosis (MBL). In our study, we compared the absolute number of PB lymphoid cells and their subpopulations in 95 MBL cases with normal lymphocyte counts vs. 617 age-/sex-matched non-MBL healthy subjects (controls), using highly sensitive flow cytometry. MBL cases showed significantly reduced numbers of normal circulating B-cells, at the expense of immature and naive B-cells; in addition, CD4+CD8+ double-positive T-cells and CD8+ T-cells were significantly lower and higher vs. controls, respectively. Moreover, most normal B-cell subsets were significantly decreased in PB at >1% MBL-counts, vs. "low-count" MBL cases, and lower amounts of immature/naive B-cells were detected in biclonal (particularly in cases with coexisting CLL-like- and non-CLL-like B-cell clones) vs. monoclonal MBL subjects. In summary, our results show imbalanced (reduced) absolute numbers of recently produced normal circulating B-cells (e.g., immature and naive B-cells) in MBL, which becomes more pronounced as the MBL cell count increases.
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Anticuerpos Monoclonales/análisis , Subgrupos de Linfocitos B/inmunología , Linfocitosis/inmunología , Paraproteinemias/inmunología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antígenos CD/sangre , Subgrupos de Linfocitos B/metabolismo , Estudios de Cohortes , Femenino , Citometría de Flujo , Humanos , Recuento de Linfocitos , Linfocitosis/sangre , Linfocitosis/metabolismo , Masculino , Persona de Mediana Edad , Paraproteinemias/sangre , Paraproteinemias/metabolismo , Células Precursoras de Linfocitos B/inmunología , Células Precursoras de Linfocitos B/metabolismoRESUMEN
The clinical benefit of the addition of granulocyte colony-stimulating factor (G-CSF) to standard immunochemotherapy of chronic lymphocytic leukemia (CLL) with fludarabine, cyclophosphamide, and rituximab (FCR) is still unclear. In this retrospective study we analyzed the outcome of 32 consecutive patients with CLL during treatment with FCR. Sixteen patients received G-CSF for treatment of CTC grade 3 or 4 neutropenia or febrile neutropenia at some point during therapy and 16 did not. Both groups were well balanced for clinical and biological risk factors. Overall response rates were not significantly different (94% vs. 75%; p=0.144). Interestingly, a significantly better progression-free survival (100% vs. 35.4% at 24 months; p<0.001) and even overall survival (100% vs. 77.8% at 24 months; p=0.022) was observed in patients receiving G-CSF. While the underlying cause remains to be elucidated, these data strongly suggest an association of the addition of G-CSF to FCR therapy with final patient outcome.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Fármacos Hematológicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/fisiopatología , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Monitoreo de Drogas , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Proyectos Piloto , Proteínas Recombinantes , Estudios Retrospectivos , Rituximab , Análisis de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
In acute lymphoblastic leukemia (ALL), the Philadelphia chromosome (Ph) is associated with a poor prognosis. For these patients, hematopoietic stem cell transplantation (HSCT) and BCR/ABL tyrosine kinase inhibitors (TKIs) are considered standard of therapy. However, it remains unclear whether BCR/ABL TKIs should be administered lifelong as maintenance post-HSCT, and whether the presence of minimal residual disease (MRD) is invariably associated with relapse. We report on two patients with Ph+ ALL who were successfully treated with polychemotherapy and consecutive autologous HSCT. Both patients are in continuous hematologic remission after an observation period of 12 years and 18 years, respectively, despite measurable MRD and although no maintenance therapy was initiated. BCR/ABL transcript-levels ranged between 0.1 and 3% in patient 1, and 0.01 and 0.1% in patient 2 during the observation time. Collectively, these data suggest that not all Ph+ subclones even those that persist after HSCT in Ph+ ALL, may have the potential to cause a hematologic relapse. We hypothesize that these small-sized clones are derived from neoplastic stem cells that have not (yet) accumulated a sufficient number of pro-oncogenic hits required for full transformation to ALL-initiating (stem) cells and thus overt leukemia.
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Neoplasia Residual/patología , Células Madre Neoplásicas/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Cromosoma Filadelfia , Inducción de Remisión , Trasplante AutólogoRESUMEN
Patients with systemic mastocytosis (SM) may acquire an associated hematologic non-mast cell (MC)-lineage disease (AHNMD). In most cases, a myeloid neoplasm is diagnosed, whereas the occurrence of a lymphoproliferative disease is an extremely rare event. We report on a patient with indolent SM associated with small lymphocytic lymphoma (SLL). The patient presented with lymphadenopathy, maculopapular exanthema, and elevated serum tryptase. The bone marrow biopsy showed focal MC aggregates together with SLL. As assessed by immunostaining, neoplastic MC were found to exhibit CD117 and CD25 but did not display CD5 or CD20, whereas SLL cells were found to coexpress CD5 and CD20 but did not express MC antigens. The KIT mutation D816V was detected in sorted CD34(+) cells and unfractionated marrow cells but not in CD5(+) SLL cells, confirming the coexistence of 2 distinct neoplasms.
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Leucemia Linfocítica Crónica de Células B/patología , Mastocitosis Sistémica/patología , Neoplasias Primarias Múltiples/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Análisis Mutacional de ADN , ADN de Neoplasias/análisis , Citometría de Flujo , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Mastocitosis Sistémica/tratamiento farmacológico , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/metabolismo , Persona de Mediana Edad , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/metabolismo , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Resultado del TratamientoRESUMEN
Autoimmune thrombocytopenia is a common immunehematologic complication in non-Hodgkin's lymphomas and may complicate the treatment. We analyzed an original series from our institute as well as published cases of non-Hodgkin's lymphomas (excluding chronic lymphocytic leukemia) associated with autoimmune thrombocytopenia with regard to demographic factors, prevalence in non-Hodgkin's lymphoma subtypes and treatment outcome. The male/female ratio is 1.75. Half of the cases occurred prior to diagnosis of lymphoma. Chemotherapy is the best treatment in many non-Hodgkin's lymphomas patients with autoimmune thrombocytopenia compared with standard treatment of autoimmune thrombocytopenia. Splenectomy is effective in splenic marginal zone lymphoma. Autoimmune thrombocytopenia in patients with non-Hodgkin's lymphomas is potentially life-threatening and difficult to treat.
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Linfoma no Hodgkin/epidemiología , Púrpura Trombocitopénica Idiopática/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Niño , Terapia Combinada , Comorbilidad , Femenino , Humanos , Leucemia de Células Pilosas/tratamiento farmacológico , Leucemia de Células Pilosas/epidemiología , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/cirugía , Masculino , Persona de Mediana Edad , Mieloma Múltiple/epidemiología , Trasplante de Células Madre de Sangre Periférica , Complicaciones Posoperatorias/epidemiología , Prevalencia , Esplenectomía , Resultado del Tratamiento , Macroglobulinemia de Waldenström/epidemiologíaAsunto(s)
Biomarcadores de Tumor/biosíntesis , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/terapia , Oncología Médica/métodos , Islas de CpG , Análisis Citogenético , Supervivencia sin Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Modelos Genéticos , Farmacogenética , Pronóstico , Resultado del TratamientoRESUMEN
We analyzed 108 cases of non-CLL non-Hodgkin lymphoma (NHL) associated with autoimmune hemolytic anemia (AIHA) (+/- pure red cell aplasia (PRCA)) or Evans' syndrome. The analysis was based on cases reported in the literature, which were retrieved by means of Pubmed and Medline searches and of an original series of 121 patients with NHL as well as reference lists of papers in the field. The number of cases in various NHL subtypes was small (n = 6-25). Nevertheless, interesting and sometimes unexpected differences in sex prevalence, temporal relationship between onset of lymphoma and AIHA, stage of lymphoma, relative frequency of warm antibody-AIHA (WA-AIHA) and cold antibody (CA-AIHA), association with PRCA and response of AIHA to treatments were noted for various lymphoma entities. WA-AIHA was more frequent in B-cell lymphomas, while CA-AIHA and PRCA predominantly occurred in T-cell lymphomas. Anti-lymphoma treatment seemed to be more effective against AIHA than conventional therapy with steroids or immunoglobulin. Although generated by a literature survey, this compilation of data indicates a complex relation of lymphoma and AIHA and warrants more attention and specific studies.
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Anemia Hemolítica Autoinmune/etiología , Linfoma no Hodgkin/complicaciones , Púrpura Trombocitopénica Idiopática/etiología , Aplasia Pura de Células Rojas/etiología , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/terapia , Humanos , Leucemia de Células Pilosas/complicaciones , Leucemia Linfocítica Crónica de Células B/complicaciones , Linfoma de Células B/complicaciones , Linfoma Folicular/complicaciones , Linfoma de Células del Manto/complicaciones , Linfoma de Células T Periférico/complicaciones , Mieloma Múltiple/complicaciones , Pronóstico , Factores de Riesgo , SíndromeRESUMEN
A number of autocrine and paracrine growth regulators are considered to be involved in the survival and proliferation of blast cells in acute myeloid leukemia (AML). We have recently shown that blast cells in a group of patients with AML produce and secrete the mitogenic enzyme tryptase. In the present study, we examined functional effects of tryptase in the context of AML. As assessed by 3H-thymidine uptake experiments, tryptase-containing serum from patients with AML as well as heparin-complexed recombinant tryptase were found to promote the proliferation of cultured bone marrow- and lung fibroblasts in a dose-dependent manner. A neutralizing antibody against human beta-tryptase was found to diminish these growth-stimulatory effects of serum-tryptase in all patients examined. Tryptase also induced the expression of mRNA for GM-CSF and SCF, two cytokines known to promote growth of AML cells, in cultured bone marrow fibroblasts. Neither recombinant tryptase nor tryptase-rich serum of AML patients, showed an effect on the growth of leukemic blast cells irrespective of the FAB category or expression of protease-activated receptor (PAR)-2, a putative molecular target of tryptase. Together, tryptase is secreted from AML blasts as a biologically active molecule that may exhibit paracrine rather than autocrine effects in AML.
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Crisis Blástica/enzimología , Leucemia Mieloide/enzimología , Serina Endopeptidasas/farmacología , Enfermedad Aguda , Adulto , Anciano , Crisis Blástica/patología , Células de la Médula Ósea/citología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/genética , Femenino , Fibroblastos/citología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Comunicación Paracrina , Serina Endopeptidasas/sangre , Serina Endopeptidasas/metabolismo , Tritio/farmacocinética , TriptasasRESUMEN
High-dose cytosine arabinoside (HiDAC) and intermediate-dose cytosine arabinoside (IDAC) have been introduced as effective and safe consolidation chemotherapy in acute myeloid leukemia, with relatively low rates of life-threatening infections despite the high total dose of the cytostatic drug. To explore the biological background of low toxicity, we examined the numbers, immunophenotype, and functional properties of granulocytes in patients with acute myeloid leukemia receiving HiDAC or IDAC. Interestingly, the absolute numbers of neutrophils remained >500/microl until day 10 in 92 of 125 (74%) HiDAC cycles and in 106 of 113 (94%) IDAC cycles. As assessed by electron microscopy, these day-10 granulocytes surviving chemotherapy were found to be mature cells containing secondary granules and phagolysosomes. They also expressed opsonization- and phagocytosis-linked surface Ags (C3biR, CR1, C1qR, C5aR, FcgammaRI, FcgammaRII, FcgammaRIII, and G-CSF and GM-CSF receptors) like neutrophils in healthy controls. Moreover, these day-10 neutrophils exhibited oxidative burst activity and took up and digested bacteria in the same way as neutrophils in healthy controls. There was a negative correlation between absolute neutrophil counts and severe infections in HiDAC- and IDAC-treated patients with a later onset of infections in IDAC patients (median: IDAC, day 18; HiDAC, day 16). Together, functionally mature neutrophils are detectable at least until day 10 in patients treated with HiDAC or IDAC, and may explain the relatively low hematologic toxicity of these consolidation protocols. IDAC is a superior protocol in this regard and may therefore be most suitable for elderly patients and those at high risk for severe infections.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infecciones Bacterianas/inmunología , Citarabina/administración & dosificación , Granulocitos/inmunología , Leucemia Mieloide/inmunología , Enfermedad Aguda , Adulto , Anciano , Esquema de Medicación , Femenino , Granulocitos/microbiología , Granulocitos/ultraestructura , Humanos , Inmunofenotipificación , Leucemia Mieloide/microbiología , Masculino , Neutrófilos/inmunología , Neutrófilos/microbiología , Neutrófilos/ultraestructura , Factores de TiempoRESUMEN
Recent data suggest that myeloid neoplasms are organized hierarchically in terms of self-renewal and maturation of early progenitor cells, similar to normal myelopoiesis. In acute myeloid leukemia (AML), the NOD/SCID mouse-repopulating leukemic stem cells usually co-express CD123 with CD34, but lack CD38. So far, however, little is known about expression of other markers and targets on these progenitors. In the present study, expression of target antigens on CD34+/CD38- cells was analysed by multi-color flow cytometry in patients with AML (n = 18), myelodysplastic syndromes (MDS, n = 6), chronic myeloid leukemia (CML, n = 8) and systemic mastocytosis (SM, n = 9). The IL-3Ralpha chain (CD123) was found to be expressed on CD34+/CD38- cells in a majority of the patients in all disease categories. Independent of the type of disease, the vast majority of these stem cells co-expressed aminopeptidase-N (CD13) and CD44 in all patients. By contrast, the CD34+/CD38- progenitor cells expressed variable amounts of the target receptor CD33, c-kit (CD117) and AC133 (CD133). In conclusion, neoplastic stem cells in various myeloid neoplasms appear to express a similar phenotype including target antigens such as CD13, CD33 and CD44. Since many of these targets are not expressed on all stem cells in all patients, the elimination of the entire clone may require combinations of targeted antibodies or use of additional drugs.
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ADP-Ribosil Ciclasa 1/análisis , Antígenos CD34/análisis , Leucemia Mieloide/diagnóstico , Mastocitosis Sistémica/diagnóstico , Síndromes Mielodisplásicos/diagnóstico , Células Madre/inmunología , ADP-Ribosil Ciclasa 1/genética , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/genética , Enfermedad Crónica , Femenino , Citometría de Flujo , Regulación Leucémica de la Expresión Génica/genética , Humanos , Inmunofenotipificación , Leucemia Mieloide/genética , Leucemia Mieloide/inmunología , Masculino , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/inmunología , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inmunologíaRESUMEN
During the past few decades, a number of functionally important cell surface antigens have been detected on human mast cells (MCs). These antigens include the stem cell factor receptor (SCFR/CD117), the high-affinity immunoglobulin E receptor, adhesion molecules, and activation-linked membrane determinants. Several of these antigens (CD2, CD25, CD35, CD88, CD203c) appear to be upregulated on MCs in patients with systemic mastocytosis and therefore are used as diagnostic markers. Quantitative measurement of these markers on MCs is thus of diagnostic value and is usually performed by multicolor-based flow cytometry techniques utilizing a PE- or APC-labeled antibody against CD117 for MCs detection. This chapter gives an overview about the methods of staining of MC in various tissues with special reference to novel diagnostic markers applied in patients with suspected systemic mastocytosis.
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Antígenos de Superficie/análisis , Inmunofenotipificación , Mastocitos/química , Mastocitos/inmunología , Anticuerpos Monoclonales/inmunología , Antígenos CD/análisis , Antígenos CD/inmunología , Biomarcadores , Células de la Médula Ósea/química , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Separación Celular , Citometría de Flujo , Humanos , Mastocitos/citología , Mastocitosis/diagnóstico , Mastocitosis/inmunologíaRESUMEN
PURPOSE: Myelomastocytic leukemia is a term used for patients with advanced myeloid neoplasms, in whom elevated numbers of immature atypical mast cells are found, but criteria for a primary mast cell disease are not met. The origin of mast cells in these patients is presently unknown. PATIENT AND METHODS: We have analyzed clonality of mast cells in an 18-year-old patient suffering from acute myeloid leukemia with a complex karyotype including a t(8;21) and mastocytic transformation with a huge increase in immature mast cells and elevated serum tryptase level, but no evidence for a primary mast cell disease/mastocytosis. RESULTS: As assessed by in situ fluorescence hybridization combined with tryptase staining, both the tryptase-negative blast cells and the tryptase-positive mast cells were found to contain the t(8;21)-specific AML1/ETO fusion gene. Myeloablative stem cell transplantation resulted in complete remission with consecutive disappearance of AML1/ETO transcripts, decrease of serum tryptase to normal range, and disappearance of neoplastic mast cells. CONCLUSION: These data suggest that mast cells directly derive from the leukemic clone in patients with myelomastocytic leukemia.
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Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mastocitos/citología , Trasplante de Células Madre/métodos , Adolescente , Antígenos CD34/biosíntesis , Biomarcadores de Tumor , Células de la Médula Ósea/metabolismo , Antígenos CD2/biosíntesis , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 8/genética , Citometría de Flujo , Células Precursoras de Granulocitos/metabolismo , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Mieloide Aguda/patología , Masculino , Mastocitos/metabolismo , Proteínas Proto-Oncogénicas c-kit/biosíntesis , Receptores de Interleucina-2/biosíntesis , Serina Endopeptidasas/sangre , Serina Endopeptidasas/metabolismo , Translocación Genética , Trasplante Homólogo , TriptasasRESUMEN
BACKGROUND: Mast cells (MC) are important effector cells of allergic and inflammatory reactions in diverse organs. These cells interact with a number of other immune cells and structural cells in the tissues as well as with proinflammatory mediators and cytokines. The various interactions are considered to be mediated through distinct cell surface membrane receptors on MC. METHODS: In the present study, we have established the cell surface membrane phenotype of human gastrointestinal MC (HGMC) using a panel of monoclonal antibodies and indirect immunofluorescence staining techniques. RESULTS: HGMC were found to react with antibodies against CD29, CD33, CD44, CD45, CD47, CD54, CD55, CD58, CD63, CD117, CD147, CD151, CD172a, and CD203c. By contrast, HGMC did not express detectable amounts of CD1, CD2, CD4, CD5, CD14, CD15, CD16, CD22, CD24, CD25, CD26, CD27, CD28, CD31, CD32, CD34, CD35, CD88, or CD116. The alpha-chain of the IL-3 receptor (CD123) was detectable neither in resting HGMC nor in HGMC exposed to stem cell factor and interleukin-4. CONCLUSIONS: HGMC express a unique profile of surface antigens including the receptor for mast cell growth factor, adhesion-related molecules, and activation-linked membrane antigens.
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Antígenos CD/análisis , Tracto Gastrointestinal/citología , Mastocitos/inmunología , Anticuerpos Monoclonales/inmunología , Antígenos de Superficie/análisis , Adhesión Celular/inmunología , Membrana Celular/inmunología , Tracto Gastrointestinal/inmunología , Humanos , Fenotipo , Receptores de Citocinas/análisisRESUMEN
CD 33 is a myeloid cell surface antigen that is expressed on blast cells in acute myeloid leukemia (AML) in a majority of all patients regardless of age or subtype of disease. The antigen is also expressed on leukemic stem cells in many cases, but is not expressed on normal hematopoietic stem cells. In an attempt to improve therapy in AML, a CD 33-targeted drug has been developed. The drug, gemtucumab ozogamicin (GO; Mylotarg), consists of a humanized CD 33 antibody (hP 67.6), a pH-dependent linker, and a highly potent chemotherapy agent, calicheamicin 1,2,-dimethyl hydrazine dichloride. Based on its clinical activity, GO has been approved for application in chemotherapy-refractory AML in various countries and is effective as a mono-substance as well as in combination with conventional chemotherapy. However, despite high efficacy and a certain specificity for leukemic (as opposed to normal) stem cells, the drug does not work in all patients, and can produce significant side-effects, including veno-occlusive disease (VOD), especially in patients who undergo stem cell transplantation. These side-effects have to be balanced against the benefit of GO therapy in patients with relapsed or refractory AML.
Asunto(s)
Aminoglicósidos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Antineoplásicos/uso terapéutico , Leucemia Mieloide/tratamiento farmacológico , Enfermedad Aguda , Aminoglicósidos/efectos adversos , Aminoglicósidos/farmacología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Antígenos CD/efectos de los fármacos , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/efectos de los fármacos , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto , Esquema de Medicación , Enediinos , Gemtuzumab , Humanos , Leucemia Mieloide/genética , Lectina 3 Similar a Ig de Unión al Ácido SiálicoRESUMEN
Signal regulatory proteins (SIRPs) and tyrosine phosphatases have recently been implicated in the control of receptor tyrosine kinase (RTK)-dependent cell growth. In systemic mastocytosis (SM), neoplastic cells are driven by the RTK KIT, which is mutated at codon 816 in most patients. We examined expression of SIRPalpha, SIRPalpha ligand CD47, and Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1), a tyrosine phosphatase-type, negative regulator of KIT-dependent signaling, in normal human lung mast cells (HLMC) and neoplastic MC obtained from nine patients with SM. As assessed by multicolor flow cytometry, normal LMC expressed SIRPalpha, CD47, and SHP-1. In patients with SM, MC also reacted with antibodies against SIRPalpha and CD47. By contrast, the levels of SHP-1 were low or undetectable in MC in most cases. Corresponding data were obtained from mRNA analysis. In fact, whereas SIRPalpha mRNA and CD47 mRNA were detected in all samples, the levels of SHP-1 mRNA varied among donors. To demonstrate adhesive functions for SIRPalpha and CD47 on neoplastic MC, an adhesion assay was applied using the MC leukemia cell line HMC-1, which was found to bind to immobilized extracellular domains of SIRPalpha1 (SIRPalpha1ex) and CD47 (CD47ex), and binding of these cells to CD47ex was inhibited by the CD172 antibody SE5A5. In summary, our data show that MC express functional SIRPalpha and CD47 in SM, whereas expression of SHP-1 varies among donors and is low compared with LMC. It is hypothesized that CD172 and CD47 contribute to MC clustering and that the "lack" of SHP-1 in MC may facilitate KIT-dependent signaling in a subgroup of patients.