RESUMEN
Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are life-threatening hematopoietic malignancies characterized by clonal expansion of leukemic blasts in the bone marrow and peripheral blood. The epigenetic reader BRD4 and its downstream effector MYC have recently been identified as potential drug targets in human AML and ALL. We compared anti-leukemic efficacies of the small-molecule BET inhibitor JQ1 and the recently developed BRD4 degraders dBET1 and dBET6 in AML and ALL cells. JQ1, dBET1, and dBET6 were found to suppress growth and viability in all AML and ALL cell lines examined as well as in primary patient-derived AML and ALL cells, including CD34+/CD38- and CD34+/CD38+ leukemic stem and progenitor cells, independent of the type (variant) of leukemia or molecular driver expressed in leukemic cells. Moreover, we found that dBET6 overcomes osteoblast-induced drug resistance in AML and ALL cells, regardless of the type of leukemia or the drug applied. Most promising cooperative or even synergistic drug combination effects were seen with dBET6 and the FLT3 ITD blocker gilteritinib in FLT3 ITD-mutated AML cells, and with dBET6 and the multi-kinase blocker ponatinib in BCR::ABL1+ ALL cells. Finally, all BRD4-targeting drugs suppressed interferon-gamma- and tumor necrosis factor-alpha-induced expression of the resistance-related checkpoint antigen PD-L1 in AML and ALL cells, including LSC. In all assays examined, the BRD4 degrader dBET6 was a superior anti-leukemic drug compared with dBET1 and JQ1. Together, BRD4 degraders may provide enhanced inhibition of multiple mechanisms of therapy resistance in AML and ALL.
Asunto(s)
Azepinas , Proteínas de Ciclo Celular , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda , Células Madre Neoplásicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Factores de Transcripción , Triazoles , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Triazoles/farmacología , Triazoles/uso terapéutico , Azepinas/farmacología , Azepinas/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de Ciclo Celular/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Línea Celular Tumoral , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pirazinas/farmacología , Pirazinas/uso terapéutico , Sinergismo Farmacológico , Piridazinas/farmacología , Piridazinas/uso terapéutico , Proteínas que Contienen Bromodominio , Compuestos de AnilinaRESUMEN
Patient-related factors are of prognostic importance in acute myeloid leukemia (AML). Likewise, cardiac disorders may limit the tolerance of intensive therapy. Little is known about the prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP). We analyzed NT-proBNP levels at diagnosis in 312 AML patients (median age: 61 years; range 17-89 years) treated with 3 + 7-based induction-chemotherapy and consolidation with up to four cycles of intermediate or high-dose ARA-C. NT-proBNP levels were elevated in 199 patients (63.8%), normal (0-125 pg/ml) in 113 (36.2%), and highly elevated (>2000 pg/ml) in 20 patients (6.4%). Median NT-proBNP levels differed significantly among patients with complete remission (153.3 pg/ml), no remission (225.9 pg/ml), or early death (735.5 pg/ml) (p = .002). In multivariate analysis, NT-proBNP, age, and the 2009 European LeukemiaNet (ELN-2009) classification were independent predictors of outcome after induction chemotherapy. Overall survival (OS) differed significantly between patients with normal, moderately elevated, and highly elevated NT-proBNP (p < .001). These differences were observed in all patients and in patients <60 years but not in those ≥60 years. In multivariate analysis, NT-proBNP, age, and ELN-2009 remained independent prognostic variables for OS (p < .01). Together, NT-proBNP is an independent prognostic factor indicating the risk of induction failure, early death, and reduced OS in patients with AML.
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Cardiopatías , Leucemia Mieloide Aguda , Humanos , Persona de Mediana Edad , Pronóstico , Biomarcadores , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Leucemia Mieloide Aguda/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
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
Leukemic stem cells (LSCs) are an emerging target of curative anti-leukemia therapy. In acute lymphoblastic leukemia (ALL), LSCs frequently express CD34 and often lack CD38. However, little is known about markers and targets expressed in ALL LSCs. We have examined marker- and target expression profiles in CD34+/CD38- LSCs in patients with Ph+ ALL (nâ¯=â¯22) and Ph- ALL (nâ¯=â¯27) by multi-color flow cytometry and qPCR. ALL LSCs expressed CD19 (B4), CD44 (Pgp-1), CD123 (IL-3RA), and CD184 (CXCR4) in all patients tested. Moreover, in various subgroups of patients, LSCs also displayed CD20 (MS4A1) (10/41â¯=â¯24%), CD22 (12/20â¯=â¯60%), CD33 (Siglec-3) (20/48â¯=â¯42%), CD52 (CAMPATH-1) (17/40â¯=â¯43%), IL-1RAP (13/29â¯=â¯45%), and/or CD135 (FLT3) (4/20â¯=â¯20%). CD25 (IL-2RA) and CD26 (DPPIV) were expressed on LSCs in Ph+ ALL exhibiting BCR/ABL1p210, whereas in Ph+ ALL with BCR/ABL1p190, LSCs variably expressed CD25 but did not express CD26. In Ph- ALL, CD34+/CD38- LSCs expressed IL-1RAP in 6/18 patients (33%), but did not express CD25 or CD26. Normal stem cells stained negative for CD25, CD26 and IL-1RAP, and expressed only low amounts of CD52. In xenotransplantation experiments, CD34+/CD38- and CD34+/CD38+ cells engrafted NSG mice after 12-20 weeks, and targeting with antibodies against CD33 and CD52 resulted in reduced engraftment. Together, LSCs in Ph+ and Ph- ALL display unique marker- and target expression profiles. In Ph+ ALL with BCR/ABL1p210, the LSC-phenotype closely resembles the marker-profile of CD34+/CD38- LSCs in chronic myeloid leukemia, confirming the close biologic relationship of these neoplasms. Targeting of LSCs with specific antibodies or related immunotherapies may facilitate LSC eradication in ALL.
Asunto(s)
ADP-Ribosil Ciclasa 1/metabolismo , Antígenos CD34/metabolismo , Leucemia Mieloide Aguda/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular , Femenino , Regulación Leucémica de la Expresión Génica/fisiología , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Ratones , Ratones Endogámicos NODRESUMEN
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
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 US Food and Drug Administration (FDA)-approved anticancer drugs or compounds currently in clinical development, we set out to identify novel effective treatments for T-PLL patients. We found that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL-specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies. Mechanistically, responses to venetoclax correlated with protein expression of BCL-2 but not with expression of the BCL-2 family members myeloid cell leukemia 1 (MCL-1) and BCL-XL in lymphoma cells. BCL-2 expression was inversely correlated with the expression of MCL-1. Based on the ex vivo responses, venetoclax treatment was commenced in 2 late-stage refractory T-PLL patients resulting in clinical responses. Our findings demonstrate first evidence of single-agent activity of venetoclax both ex vivo and in humans, offering a novel agent in T-PLL.
Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Adulto , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Resistencia a Antineoplásicos , Femenino , Ensayos Analíticos de Alto Rendimiento , Humanos , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia , Sulfonamidas/farmacología , Resultado del TratamientoRESUMEN
Some patients with diffuse large B-cell lymphoma (DLBCL) require intensive care unit (ICU) admission prior to or during chemotherapy. We analyzed all unscheduled ICU admissions in 331 consecutive patients (18-93 years) with newly diagnosed DLBCL. Thirty-seven patients (11.2%) required ICU treatment primarily due to hemodynamic (37.8%) or respiratory failure (24.3%). Bulky disease and high IPI score were predictive of ICU admission in the early course. ICU and hospital survival was 75.7% and 70.3%, respectively. Overall survival in ICU patients with newly diagnosed DLBCL was worse compared to non-ICU-patients (40.7% vs. 72.7% at two years). However, survival of high-risk patients (IPI 3-5), continuous complete remission, and disease-free survival did not differ. Post-ICU survival was poor in patients with relapsed/refractory DLBCL (0.1-10 months). Our observations favor unrestricted ICU support in DLBCL patients undergoing first-line therapy. ICU referral of patients with refractory/relapsed disease must be evaluated in the context of the hematologic prognosis.
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Cuidados Críticos/estadística & datos numéricos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/terapia , Adulto , Anciano , Antineoplásicos/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/terapia , Mortalidad Hospitalaria , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Admisión del Paciente/estadística & datos numéricos , Pronóstico , Insuficiencia Respiratoria/epidemiología , Insuficiencia Respiratoria/terapia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative rescue therapy for patients (pts) with chemotherapy-refractory acute leukaemia. Disease control prior to HSCT is essential for long-term disease-free survival after HSCT. PATIENTS AND METHODS: We have retrospectively analysed the outcome of 20 pts aged 21-64 years with refractory leukaemia (acute myeloid leukaemia, n = 16; acute lymphatic leukaemia, n = 4) who received debulking therapy with clofarabine (10 mg/m², days 1-4) and cyclophosphamide (200 mg/m², days 1-4; ClofCy) prior to HSCT. RESULTS: Clofarabine/cyclophosphamide (1-4 cycles) was well tolerated and resulted in a substantial reduction of leukaemic cells in all pts. HSCT was performed in 15 of 20 pts. After HSCT (myeloablative, n = 9; dose-reduced, n = 6), all pts showed engraftment and full donor chimerism (related donors, n = 4 or unrelated donors, n = 11) and all pts achieved complete haematologic remission (CR). The median survival after HSCT is 531 days (range: 48-1462 days), and six pts are still alive after a median of 1245 days. Seven pts died after they had relapsed between days +152 and +1496. One patient died from acute graft-versus-host disease (day +48) and one from systemic fungal infection (day +87). CONCLUSION: Clofarabine/cyclophosphamide is a novel effective treatment approach for pts with chemotherapy-refractory acute leukaemia prior to HSCT. Whether this novel debulking protocol leads to improved long-term outcome in pts with refractory leukaemias remains to be determined in forthcoming clinical studies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Nucleótidos de Adenina/administración & dosificación , Adulto , Arabinonucleósidos/administración & dosificación , Clofarabina , Ciclofosfamida/administración & dosificación , Esquema de Medicación , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Estudios Retrospectivos , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
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
There is increasing evidence for the role of chronic antigenic stimulation (CS) in the development of cancer. Clinical data, however, are rare as is the information on outcome. In this study, the occurrence of chronic infections (CI) and autoimmune diseases (AI) in patients with malignant lymphoma at diagnosis was assessed. Of 367 patients [non-Hodgkin's lymphoma (NHL) N = 297, Hodgkin's lymphoma N = 70], 9.8% (N = 36) had a history of chronic antigenic stimulation (4.4% AI, 5.4% CI) at diagnosis. After a median observation time of 74.7 months, 118 patients have died. There were more male patients in this cohort. However, sex ratio among patients with chronic antigenic stimulation was skewed in favor of women (p = 0.018), in particular among lymphoma patients with AI (p = 0.001). NHL patients with autoimmune diseases showed a tendency to develop diffuse large B cell lymphoma [8 of 12 AI + NHL patients (66.7%) vs. 100 of 266 non-CS NHL (37.6%); p = 0.066]. No significant difference in overall survival (OS) between CS and non-CS patients could be observed (median OS after 48 months was: CS 77.7% vs. non-CS 71.8%). In conclusion, chronic antigenic stimulation at diagnosis appears to be associated with a higher prevalence in women, in particular among patients with autoimmune disease. However, no difference in overall survival was observed. This suggests that the presence of chronic inflammatory conditions does not decisively influence the outcome of lymphoma patients.
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Enfermedades Autoinmunes/complicaciones , Infecciones/complicaciones , Linfoma/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Femenino , Humanos , Inflamación , Linfoma/diagnóstico , Linfoma/etiología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Factores Sexuales , Tasa de Supervivencia , Adulto JovenRESUMEN
We used nonpegylated liposomal doxorubicin (NPLD) in cytostatic drug combinations to treat 37 patients with non-Hodgkin's lymphoma and pre-existing cardiac disorder or elderly patients with reduced physical state who were ineligible for conventional anthracycline-containing therapy. High remission rates were observed in this poor-risk population: Complete remission rates were 75% for diffuse large B cell lymphoma (DLBCL) and 55% for T/NK cell neoplasm (overall response rate of 80% and 89%, respectively). Twenty-seven patients (73%) are still alive after a median observation time of 14 months. No major cardiac or gastrointestinal toxicity was observed. Extravasation of NPLD in two patients resulted in mild inflammation without tissue damage. Hematologic toxicity was comparable to that of conventional anthracycline-containing regimens. We conclude that NPLD is highly active in combination chemotherapy for lymphoma with low cardiac toxicity in patients with pre-existing cardiac disorders or higher age. Moreover, we also observed remarkable efficacy in T/NK cell lymphomas.
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Antibióticos Antineoplásicos/uso terapéutico , Doxorrubicina/uso terapéutico , Cardiopatías/complicaciones , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células T/tratamiento farmacológico , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Few data are available concerning the prevalence of autoimmune disease or chronic infections in chronic lymphocytic leukemia patients at diagnosis as well as their clinical outcome. We studied the frequency of such chronic conditions in relation to prognostic markers. A history of autoimmune disease or chronic infection was found in 21% of 186 chronic lymphocytic leukemia patients (12% in autoimmune diseases, 9% in chronic infections). Patients with a history of chronic stimulation were more likely to have unmutated IgV(H) genes (p<0.002), unfavorable or intermediate risk cytogenetics (11q, 17p deletions, trisomy 12) (p<0.001), and higher CD38 expression (p=0.004). Autoimmune conditions (n=22) were characterized by female predominance (55.0%) with a high frequency of unmutated IgV(H) (53,8%). Median time to first treatment was 83 months for the chronic stimulation group compared to 128 months for the non-chronic stimulation group (n.s.). Patients suffering from chronic conditions at chronic lymphocytic leukemia diagnosis are likely to have poor prognostic markers, particularly unmutated IgV(H) genes.
Asunto(s)
Autoinmunidad , Infecciones/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Enfermedad Crónica , Genes de Inmunoglobulinas , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Infecciones/etiología , Leucemia Linfocítica Crónica de Células B/complicaciones , Estudios RetrospectivosRESUMEN
The recognition of conformational epitopes on respiratory allergens by IgE Abs is a key event in allergic inflammation. We report a molecular strategy for the conversion of allergens into vaccines with reduced allergenic activity, which is based on the reassembly of non-IgE-reactive fragments in the form of mosaic proteins. This evolution process is exemplified for timothy grass pollen-derived Phl p 2, a major allergen for more than 200 million allergic patients. In a first step, the allergen was disrupted into peptide fragments lacking IgE reactivity. cDNAs coding for these peptides were reassembled in altered order and expressed as a recombinant mosaic molecule. The mosaic molecule had lost the three-dimensional structure, the IgE reactivity, and allergenic activity of the wild-type allergen, but it induced high levels of allergen-specific IgG Abs upon immunization. These IgG Abs crossreacted with group 2 allergens from other grass species and inhibited allergic patients' IgE binding to the wild-type allergen. The mosaic strategy is a general strategy for the reduction of allergenic activity of protein allergens and can be used to convert harmful allergens into safe vaccines.
Asunto(s)
Alérgenos/genética , Alérgenos/inmunología , Proteínas de Plantas/genética , Proteínas de Plantas/inmunología , Poaceae/genética , Polen/genética , Ingeniería de Proteínas , Vacunas de Subunidad/genética , Vacunas de Subunidad/inmunología , Alérgenos/administración & dosificación , Alérgenos/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Desensibilización Inmunológica/métodos , Femenino , Humanos , Inmunoglobulina E/metabolismo , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/fisiología , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Proteínas de Plantas/administración & dosificación , Proteínas de Plantas/metabolismo , Poaceae/inmunología , Polen/inmunología , Conejos , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/prevención & control , Vacunas de Subunidad/administración & dosificación , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/metabolismoRESUMEN
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.
Asunto(s)
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.