RESUMEN
Sorafenib maintenance improves outcomes after hematopoietic cell transplant (HCT) for patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients (aged 18-65 years) 2:1 to sorafenib vs placebo (days 4-10) combined with intensive induction: idarubicin 12 mg/m2 on days 1 to 3 plus either cytarabine 1.5 g/m2 twice daily on days 1, 3, 5, and 7 (18-55 years) or 100 mg/m2 on days 1 to 7 (56-65 years), followed by consolidation and maintenance therapy for 12 months (post-HCT excluded) in newly diagnosed patients with FLT3-ITD AML. Four patients were excluded in a modified intention-to-treat final analysis (3 not commencing therapy and 1 was FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery were high in both arms (sorafenib, 78%/9%; placebo, 70%/24%). With 49.1-months median follow-up, the primary end point of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.51-1.51; P = .61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR, 0.76; 95% CI, 0.42-1.39). For patients who received HCT in first remission, the 2-year OS rates were 84% and 67% in the sorafenib and placebo arms, respectively (HR, 0.45; 95% CI, 0.18-1.12; P = .08). In exploratory analyses, FLT3-ITD measurable residual disease (MRD) negative status (<0.001%) after induction was associated with improved 2-year OS (83% vs 60%; HR, 0.4; 95% CI, 0.17-0.93; P = .028). In conclusion, routine use of pretransplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Sorafenib , Tirosina Quinasa 3 Similar a fms/genética , Estudios Retrospectivos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMEN
Based on promising results in older adults with acute myeloid leukaemia (AML), we treated patients with NPM1mut measurable residual disease (MRD) using off-label venetoclax in combination with low-dose cytarabine or azacitidine. Twelve consecutive patients were retrospectively identified, including five with molecular persistence and seven with molecular relapse/progression. All patients with molecular persistence achieved durable molecular complete remission (CRMRD- ) without transplantation. Six of seven patients with molecular relapse/progression achieved CRMRD- after 1-2 cycles of venetoclax. This paper highlights the promising efficacy of venetoclax-based therapy to reduce the relapse risk in patients with persistent or rising NPM1mut MRD.
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Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Leucemia Mieloide Aguda , Mutación , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Sulfonamidas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Neoplasia Residual , Nucleofosmina , Estudios RetrospectivosRESUMEN
Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/ß-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.
Asunto(s)
Benzodiazepinas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Animales , Azepinas/farmacología , Proteínas de Ciclo Celular , Línea Celular Tumoral , Células Cultivadas , Cromatina/metabolismo , Células Clonales/efectos de los fármacos , Células Clonales/metabolismo , Células Clonales/patología , Resistencia a Antineoplásicos/genética , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes myc/genética , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Terapia Molecular Dirigida , Células Madre Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos , Triazoles/farmacología , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismoRESUMEN
The diagnosis and monitoring of myelodysplastic syndromes (MDSs) are highly reliant on bone marrow morphology, which is associated with substantial interobserver variability. Although azacitidine is the mainstay of treatment in MDS, only half of all patients respond. Therefore, there is an urgent need for improved modalities for the diagnosis and monitoring of MDSs. The majority of MDS patients have either clonal somatic karyotypic abnormalities and/or gene mutations that aid in the diagnosis and can be used to monitor treatment response. Circulating cell-free DNA is primarily derived from hematopoietic cells, and we surmised that the malignant MDS genome would be a major contributor to cell-free DNA levels in MDS patients as a result of ineffective hematopoiesis. Through analysis of serial bone marrow and matched plasma samples (n = 75), we demonstrate that cell-free circulating tumor DNA (ctDNA) is directly comparable to bone marrow biopsy in representing the genomic heterogeneity of malignant clones in MDS. Remarkably, we demonstrate that serial monitoring of ctDNA allows concurrent tracking of both mutations and karyotypic abnormalities throughout therapy and is able to anticipate treatment failure. These data highlight the role of ctDNA as a minimally invasive molecular disease monitoring strategy in MDS.
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ADN de Neoplasias/sangre , Monitoreo de Drogas/métodos , Síndromes Mielodisplásicos/diagnóstico , Azacitidina/uso terapéutico , Examen de la Médula Ósea , Células Clonales/patología , ADN de Neoplasias/genética , Humanos , Cariotipificación , Mutación , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Reacción en Cadena de la PolimerasaRESUMEN
Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs.
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Benzotiazoles/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Naftiridinas/farmacología , Células Madre Neoplásicas/enzimología , Proteínas del Complejo de Iniciación de Transcripción Pol1/antagonistas & inhibidores , Transcripción Genética/efectos de los fármacos , Animales , División Celular/efectos de los fármacos , División Celular/genética , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Quinasa de Punto de Control 2/genética , Quinasa de Punto de Control 2/metabolismo , Fase G2/efectos de los fármacos , Fase G2/genética , Humanos , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones Mutantes , Células Madre Neoplásicas/patología , Proteínas del Complejo de Iniciación de Transcripción Pol1/genética , Proteínas del Complejo de Iniciación de Transcripción Pol1/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoAsunto(s)
Resistencia a Medicamentos/genética , Inotuzumab Ozogamicina/administración & dosificación , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Lectina 2 Similar a Ig de Unión al Ácido Siálico/genética , Adolescente , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genéticaRESUMEN
A wealth of genomic and epigenomic data has identified abnormal regulation of epigenetic processes as a prominent theme in hematologic malignancies. Recurrent somatic alterations in myeloid malignancies of key proteins involved in DNA methylation, post-translational histone modification and chromatin remodeling have highlighted the importance of epigenetic regulation of gene expression in the initiation and maintenance of various malignancies. The rational use of targeted epigenetic therapies requires a thorough understanding of the underlying mechanisms of malignant transformation driven by aberrant epigenetic regulators. In this review we provide an overview of the major protagonists in epigenetic regulation, their aberrant role in myeloid malignancies, prognostic significance and potential for therapeutic targeting.
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Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hematológicas/genética , HumanosRESUMEN
Non-intensive therapies such as the hypomethylating agent (HMA) azacitidine (AZA) have been used in patients with AML ineligible for intensive induction chemotherapy (IC) or stem cell transplant due to advanced age, comorbidities, and/or risk factors. However, response rates and survival remain dismal. Pre-clinical studies indicate the epigenetic combination of HMAs and HDAC inhibitors induce re-expression of silenced genes synergistically. The activity of pracinostat, an oral pan-HDAC inhibitor, has been shown in xenograft tumor models of AML and promising efficacy was seen in a Phase 2 study. This Phase 3 study (NCT03151408) evaluated the efficacy/safety of pracinostat administered with AZA in adult patients with newly diagnosed AML ineligible to receive IC. Patients were randomized to either pracinostat plus AZA or placebo/AZA and stratified by cytogenetic risk and ECOG status. As planned, an interim analysis was performed when 232/390 events (deaths) occurred. A total of 406 patients were randomized (203/group) at the time of the analysis. Median overall survival was 9.95 months for both treatment groups (p=0.8275). There was no significant difference between treatments in secondary efficacy endpoints, reflecting a lack of clinical response. This study did not show a benefit of adding pracinostat to AZA in elderly patients unfit for IC.
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Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Benzamidas , Quimioterapia de Inducción , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/genética , Masculino , Anciano , Femenino , Persona de Mediana Edad , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Azacitidina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Anciano de 80 o más AñosRESUMEN
Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resultado del Tratamiento , Citarabina/uso terapéutico , Gemtuzumab/uso terapéutico , Leucemia Mieloide Aguda/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Immune evasion, due to abnormal expression of programmed-death ligands 1 and 2 (PD-L1/PD-L2), predicts poor outcomes with chemoimmunotherapy in diffuse large B-cell lymphoma (DLBCL). Immune checkpoint inhibition (ICI) has limited efficacy at relapse but may sensitise relapsed lymphoma to subsequent chemotherapy. ICI delivery to immunologically intact patients may thus be the optimal use of this therapy. In the phase II AvR-CHOP study, 28 patients with treatment-naive stage II-IV DLBCL received sequential avelumab and rituximab priming ("AvRp;" avelumab 10 mg/kg and rituximab 375 mg/m2 2-weekly for 2 cycles), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone for 6 cycles) and avelumab consolidation (10 mg/kg 2-weekly for 6 cycles). Grade 3/4 immune-related adverse events occurred in 11%, meeting the primary endpoint of a grade ≥3 irAE rate of <30%. R-CHOP delivery was not compromised but one patient ceased avelumab. Overall response rates (ORR) after AvRp and R-CHOP were 57% (18% CR) and 89% (all CR). High ORR to AvRp was observed in primary mediastinal B-cell lymphoma (67%; 4/6) and molecularly-defined EBV-positive DLBCL (100%; 3/3). Progression during AvRp was associated with chemorefractory disease. Two-year failure-free and overall survival were 82% and 89%. An immune priming strategy with AvRp, R-CHOP and avelumab consolidation shows acceptable toxicity with encouraging efficacy.
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Linfoma de Células B Grandes Difuso , Recurrencia Local de Neoplasia , Humanos , Rituximab , Vincristina , Recurrencia Local de Neoplasia/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Ciclofosfamida , Prednisona , Doxorrubicina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: It is increasingly appreciated that some patients with cancer will experience financial burden due to their disease but little is known specifically about patients with haematological malignancies. Therefore, this study aimed to measure financial toxicity experienced by patients with haematological malignancies in the context of a publicly funded health care system. METHOD: All current patients diagnosed with leukaemia, lymphoma or multiple myeloma, from two major metropolitan health services in Melbourne, Australia were invited to complete a survey capturing; patient demographics, employment status, income sources, financial coping and insurances, OOP expenses and self-reported financial toxicity using a validated measure. RESULTS: Of the 240 people approached, 113 (47 %) participated and most had leukaemia (62 %). Forty-seven (42 %) participants experienced some degree of financial toxicity using the Comprehensive Score for financial toxicity (COST) instrument. On multivariate linear regression, older age (>65 years, p = 0.007), higher monthly income (>$8000, p = 0.008), not having and being forced into unemployment or early retirement (p < 0.001) remained significantly associated with less financial toxicity. CONCLUSION: Financial toxicity is present in Australian haematology patients and those at higher risk may be patients of working age, those without private health insurance and patients that have been forced to retire early or have become unemployed due to their diagnosis.
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Costo de Enfermedad , Atención a la Salud/economía , Estrés Financiero/economía , Neoplasias Hematológicas/economía , Salud Pública/economía , Adaptación Psicológica , Adolescente , Adulto , Anciano , Australia , Estudios Transversales , Atención a la Salud/métodos , Atención a la Salud/estadística & datos numéricos , Femenino , Estrés Financiero/psicología , Gastos en Salud/estadística & datos numéricos , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Humanos , Leucemia/diagnóstico , Leucemia/economía , Leucemia/terapia , Linfoma/diagnóstico , Linfoma/economía , Linfoma/terapia , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/economía , Mieloma Múltiple/terapia , Salud Pública/métodos , Salud Pública/estadística & datos numéricos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: It is increasingly appreciated that some patients with cancer will experience financial burden due to their disease but little is known specifically about patients with haematological malignancies. Therefore, this study aimed to measure financial toxicity experienced by patients with haematological malignancies in the context of a publicly funded health care system. METHOD: All current patients diagnosed with leukaemia, lymphoma or multiple myeloma, from two major metropolitan health services in Melbourne, Australia were invited to complete a survey capturing; patient demographics, employment status, income sources, financial coping and insurances, OOP expenses and self-reported financial toxicity using a validated measure. RESULTS: Of the 240 people approached, 113 (47 %) participated and most had leukaemia (62 %). Forty-seven participants (42 %) experienced some degree of financial toxicity using the Comprehensive Score for financial toxicity (COST) instrument. On multivariate linear regression, older age (>65 years, p = 0.007), higher monthly income (>$8000, p = 0.008), not having and being forced into unemployment or early retirement (p < 0.001) remained significantly associated with less financial toxicity. CONCLUSION: Financial toxicity is present in Australian haematology patients and those at higher risk may be patients of working age, those without private health insurance and patients that have been forced to retire early or have become unemployed due to their diagnosis.
RESUMEN
PURPOSE: The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. PATIENTS AND METHODS: Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days -6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m2 on days 1-5 and idarubicin 12 mg/m2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days -6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2. RESULTS: Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML. CONCLUSION: Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Factores de Edad , Anciano , Anciano de 80 o más Años , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Idarrubicina/administración & dosificación , Idarrubicina/efectos adversos , Quimioterapia de Inducción , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Nucleofosmina , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversosAsunto(s)
Trasplante de Corazón , Infecciones por Parvoviridae/diagnóstico , Aplasia Pura de Células Rojas/diagnóstico , Adulto , Femenino , Humanos , Terapia de Inmunosupresión , Infecciones por Parvoviridae/complicaciones , Infecciones por Parvoviridae/inmunología , Infecciones por Parvoviridae/virología , Parvovirus B19 Humano/fisiología , Reacción en Cadena de la Polimerasa , Aplasia Pura de Células Rojas/complicaciones , Aplasia Pura de Células Rojas/inmunología , Aplasia Pura de Células Rojas/virologíaRESUMEN
Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.
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Regulación Leucémica de la Expresión Génica , Histonas/genética , Leucemia Bifenotípica Aguda/genética , Metiltransferasas/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Acetilación , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Proteínas de Ciclo Celular , Proliferación Celular , Cromatina/química , Cromatina/metabolismo , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Femenino , N-Metiltransferasa de Histona-Lisina , Histonas/metabolismo , Humanos , Leucemia Bifenotípica Aguda/metabolismo , Leucemia Bifenotípica Aguda/patología , Masculino , Metiltransferasas/antagonistas & inhibidores , Metiltransferasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Cultivo Primario de Células , Unión Proteica , Proteómica/métodos , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Linfocitos T/metabolismo , Linfocitos T/patología , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
Improved therapeutic options for relapsing patients with acute myeloid leukemia (AML) are urgently needed. Poor outcomes following salvage therapy have been reported in those with short initial remission duration, adverse risk karyotype, prior allograft, older age, FLT3-internal tandem duplication (ITD) AML and prior high-dose cytarabine (HiDAC) induction therapy. We present a cohort of 58 patients (aged 18-70) treated with fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF) and amsacrine (FLAG-amsacrine) as salvage chemotherapy for AML at first relapse. 83% had received prior HiDAC-based therapy. The overall complete remission (CR/CR with incomplete blood count recovery [CRi]) rate was 59%, with median event-free survival (EFS) and overall survival (OS) of 6.9 and 10.6 months, respectively. FLAG-amsacrine was an effective bridge to allogeneic transplant with 38% successfully transplanted with excellent outcomes (median OS not reached). FLAG-amsacrine was also effective in elderly patients (≥ 60 years), with 61% achieving second remission. The regimen was well tolerated, with 30- and 42-day treatment-related mortality of 3.4% and 13.8%, respectively. Outcomes remained poor in those with short initial remission duration (<6 months). We conclude that FLAG-amsacrine is a useful salvage option for AML at first relapse.