RESUMEN
BACKGROUND: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population. METHODS: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy. RESULTS: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts. CONCLUSIONS: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.
Asunto(s)
Leucemia Mieloide Aguda , Proteína p53 Supresora de Tumor , Humanos , Decitabina , Proteína p53 Supresora de Tumor/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Cariotipo , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).
Asunto(s)
Inhibidores Enzimáticos/administración & dosificación , Glicina/análogos & derivados , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Piridinas/administración & dosificación , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Estudios de Seguimiento , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/farmacocinética , Hemoglobinas/análisis , Humanos , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Piridinas/efectos adversos , Piridinas/farmacocinética , Recurrencia , Inducción de Remisión , Tasa de Supervivencia , Adulto JovenRESUMEN
Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.
Asunto(s)
Azacitidina/administración & dosificación , Ciclopentanos/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Pirimidinas/administración & dosificación , Enzimas Ubiquitina-Conjugadoras/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Azacitidina/efectos adversos , Ciclopentanos/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Femenino , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Pirimidinas/efectos adversos , Factores de Riesgo , Enzimas Ubiquitina-Conjugadoras/metabolismoRESUMEN
Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Combinación de Medicamentos , Neoplasias Hematológicas/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Mieloide Aguda/metabolismo , Mutación/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismoRESUMEN
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in â¼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.
Asunto(s)
Aminopiridinas/uso terapéutico , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Triazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Aminopiridinas/efectos adversos , Aminopiridinas/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Médula Ósea/patología , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Triazinas/efectos adversos , Triazinas/farmacocinética , Adulto JovenRESUMEN
Growth hormone-releasing hormone (GHRH) is secreted by the hypothalamus and acts on the pituitary gland to stimulate the release of growth hormone (GH). GHRH can also be produced by human cancers, in which it functions as an autocrine/paracrine growth factor. We have previously shown that synthetic antagonistic analogues of GHRH are able to successfully suppress the growth of 60 different human cancer cell lines representing over 20 cancers. Nevertheless, the expression of GHRH and its receptors in leukaemias has never been examined. Our study demonstrates the presence of GHRH receptor (GHRH-R) on 3 of 4 human acute myeloid leukaemia (AML) cell lines-K-562, THP-1, and KG-1a-and significant inhibition of proliferation of these three cell lines in vitro following incubation with the GHRH antagonist MIA-602. We further show that this inhibition of proliferation is associated with the upregulation of pro-apoptotic genes and inhibition of Akt signalling in leukaemic cells. Treatment with MIA-602 of mice bearing xenografts of these human AML cell lines drastically reduced tumour growth. The expression of GHRH-R was further confirmed in 9 of 9 samples from patients with AML. These findings offer a new therapeutic approach to this malignancy and suggest a possible role of GHRH-R signalling in the pathology of AML.
Asunto(s)
Apoptosis/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Receptores de Neuropéptido/antagonistas & inhibidores , Receptores de Hormona Reguladora de Hormona Hipofisaria/antagonistas & inhibidores , Sermorelina/análogos & derivados , Transducción de Señal/efectos de los fármacos , Animales , Femenino , Humanos , Células K562 , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ratones Desnudos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sermorelina/farmacología , Células THP-1 , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Monocytosis can develop during disease course in primary myelofibrosis simulating that seen in chronic myelomonocytic leukemia, and should not lead to disease reclassification. In contrast, at presentation, rare cases have clinical, morphologic, and molecular genetic features truly intermediate between primary myelofibrosis and chronic myelomonocytic leukemia. The taxonomy and natural history of these diseases are unclear. We identified cases which either: (1) fulfilled the 2008 World Health Organization criteria for primary myelofibrosis but had absolute monocytosis and, when available, chronic myelomonocytic leukemia-related mutations (ASXL1, SRSF2, TET2) or (2) fulfilled criteria of chronic myelomonocytic leukemia but had megakaryocytic proliferation and atypia, marrow fibrosis, and myeloproliferative-type driver mutations (JAK2, MPL, CALR). Patients with established primary myelofibrosis who developed monocytosis and those with chronic myelomonocytic leukemia with marrow fibrosis were excluded. By combining the pathology databases of two large institutions, six eligible cases were identified. Patients were predominantly male and elderly with monocytosis at diagnosis (average 17.5%/2.3 × 103/µl), organomegaly, primary myelofibrosis-like atypical megakaryocytes admixed with a variable number of chronic myelomonocytic leukemia-like hypolobated forms, variable myelodysplasia, marrow fibrosis and osteosclerosis. All had a normal karyotype and no myelodysplasia-associated cytogenetic abnormalities. Five of the patients in whom a more extensive molecular characterization was performed showed co-mutations involving JAK2 or MPL and ASXL1, SRSF2, TET2, NRAS, and/or KRAS. Disease progression has occurred in all and two have died. Rare patients present with features that overlap between primary myelofibrosis and chronic myelomonocytic leukemia and are thus difficult to classify based on current World Health Organization criteria. Biologically, these cases likely represent primary myelofibrosis with monocytosis, dysplasia, and secondary (non-driver) mutations at presentation. Alternatively, they may represent a true gray zone of neoplasms. Their clinical behavior appears aggressive and innovative therapeutic approaches may be beneficial in this particular subset.
Asunto(s)
Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/patología , Anciano , Proteínas de Unión al ADN/genética , Diagnóstico Diferencial , Dioxigenasas , Progresión de la Enfermedad , Femenino , GTP Fosfohidrolasas/genética , Humanos , Janus Quinasa 2/genética , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptores de Trombopoyetina/genética , Proteínas Represoras/genética , Factores de Empalme Serina-Arginina/genéticaRESUMEN
Here we report the case of a 30-year-old woman with relapsed acute myeloid leukemia (AML) who was treated with all-trans retinoic acid (ATRA) as part of investigational therapy (NCT02273102). The patient died from rapid disease progression following eight days of continuous treatment with ATRA. Karyotype analysis and RNA-Seq revealed the presence of a novel t(4;15)(q31;q22) reciprocal translocation involving the TMEM154 and RASGRF1 genes. Analysis of primary cells from the patient revealed the expression of TMEM154-RASGRF1 mRNA and the resulting fusion protein, but no expression of the reciprocal RASGRF1-TMEM154 fusion. Consistent with the response of the patient to ATRA therapy, we observed a rapid proliferation of t(4;15) primary cells following ATRA treatment ex vivo. Preliminary characterization of the retinoid response of t(4;15) AML revealed that in stark contrast to non-t(4;15) AML, these cells proliferate in response to specific agonists of RARα and RARγ. Furthermore, we observed an increase in the levels of nuclear RARγ upon ATRA treatment. In summary, the identification of the novel t(4;15)(q31;q22) reciprocal translocation opens new avenues in the study of retinoid resistance and provides potential for a new biomarker for therapy of AML.
Asunto(s)
Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Retinoides/uso terapéutico , Factores de Transcripción/metabolismo , Translocación Genética/genética , Células Cultivadas , Femenino , Humanos , Cariotipificación , Leucemia Mieloide Aguda/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Factores de Transcripción/genética , Translocación Genética/efectos de los fármacos , Tretinoina/uso terapéutico , ras-GRF1/genética , ras-GRF1/metabolismoRESUMEN
The presence of >5% blasts at "day 14" (D14), in patients undergoing induction chemotherapy for acute myeloid leukemia (AML) is problematic. It is unclear if a second course of chemotherapy for early persistent disease will alter outcome in these patients. We conducted a retrospective study of AML patients undergoing induction chemotherapy where diagnostic, interim (around day 14), and recovery (days 21-42) bone marrow (BM) evaluations were available for review. Of the 113 patients included in the final analysis, 99 (87.6%) achieved CR at hematologic recovery. At D14, 90 patients (79.6%) had <5% blasts and of these, 87 (96.7%) ultimately achieved CR. At D14, Twenty-three (20.4%) patients had residual leukemia (>5% blasts). Of these, 11 (47.8%) received a second course of chemotherapy (double induction [DI]) and 12 (52.2%) were observed until count recovery (single induction [SI]). No significant difference in CR rates was observed between these two groups (58.3% DI group vs. 45.5% SI group, P value = 0.684). In our analysis, D14 BM evaluation did not uniformly identify patients with primary induction failure. To unequivocally determine the value of a D14 marrow assessment in AML, prospective studies in the context of large cooperative group trials are required. Considering our findings and similar reports from others, we propose that D14 marrow assessment should be individualized, and that other factors, such as cytogenetics and early peripheral blood blast clearance should be considered, to identify patients most likely to benefit from interim disease assessment during AML induction therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Inducción/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Adulto , Anciano , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Médula Ósea/patología , Femenino , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenRESUMEN
This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.
Asunto(s)
Ciclopentanos , Inhibidores Enzimáticos , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Pirimidinas , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Ciclopentanos/administración & dosificación , Ciclopentanos/efectos adversos , Ciclopentanos/farmacocinética , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Insuficiencia Multiorgánica/sangre , Insuficiencia Multiorgánica/inducido químicamente , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/farmacocinéticaRESUMEN
Acute leukaemias are a group of malignancies characterised by the invasion of the bone marrow by immature haematopoietic precursors and differentiation arrest at various maturation steps. Multiplicity of intrinsic and extrinsic factors influences the transformation and progression of leukaemia. The intrinsic factors encompass genetic alterations of cellular pathways leading to the activation of, among others, inflammatory pathways (such as nuclear factor kappa B). The extrinsic components include, among others, the inflammatory pathways activated by the bone marrow microenvironment and include chemokines, cytokines and adhesion molecules. In this chapter, we review the role of inflammatory processes in the transformation, survival and proliferation of leukaemias, particularly the role of nuclear factor kappa B and its downstream signalling in leukaemias and the novel therapeutic strategies that exploit potentially unique properties of inflammatory signalling that offer interesting options for future therapeutic interventions.
Asunto(s)
Inflamación/complicaciones , Leucemia/etiología , Animales , Antiinflamatorios/uso terapéutico , Citocinas/fisiología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Mediadores de Inflamación/fisiología , Leucemia/patología , Leucemia/terapia , Macrófagos/patología , Macrófagos/fisiología , Transducción de Señal/fisiologíaRESUMEN
Mutation of thetumor suppressor gene, TP53 (tumor protein 53), occurs in up to 15% of all patients with acute myeloid leukemia (AML) and is enriched within specific clinical subsets, most notably in older adults, and including secondary AML cases arising from preceding myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), patients exposed to prior DNA-damaging, cytotoxic therapies. In all cases, these tumors have remained difficult to effectively treat with conventional therapeutic regimens. Newer approaches fortreatmentofTP53-mutated AML have shifted to interventions that maymodulateTP53 function, target downstream molecular vulnerabilities, target non-p53 dependent molecular pathways, and/or elicit immunogenic responses. This review will describe the basic biology of TP53, the clinical and biological patterns of TP53 within myeloid neoplasms with a focus on elderly AML patients and will summarize newer therapeutic strategies and current clinical trials.
Asunto(s)
Leucemia Mieloide Aguda , Terapia Molecular Dirigida , Mutación , Proteína p53 Supresora de Tumor , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/diagnóstico , Proteína p53 Supresora de Tumor/genética , Terapia Molecular Dirigida/métodos , Anciano , Ensayos Clínicos como Asunto , Factores de Edad , Antineoplásicos/uso terapéuticoRESUMEN
While the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥ 60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML ≥ 60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-risk, 11% had intermediate-risk, and 78% had adverse-risk AML as defined by ELN. ELN risk was prognostic for overall survival (OS) (P<0.001) but did not stratify favorable-risk from intermediate-risk (P=0.71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (N=316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P<0.05). A "mutation-score" was calculated for each combination of these mutations, assigning adverse-risk patients into two risk groups: -1 to 0 points ("Beat-AML-intermediate") vs 1+ points ("Beat-AML-adverse"). In the final refined risk classification, the ELN favorable- and intermediate-risk groups were combined into a newly defined "Beat-AML-favorable-risk", in addition to mutation scoring within the ELN adverse-risk. This approach redefines risk for older ND AML and proposes refined Beat-AML-favorable- (22%), Beat-AML-intermediate- (41%), and Beat-AML-adverse-risk (37%) groups with improved discrimination for OS (2-year OS: 48% vs 33% vs 11%, respectively, P<0.001; C-index: 0.60 vs 0.55 for ELN), providing patients and providers additional information for treatment decision-making.
RESUMEN
The hedgehog (Hh) pathway is a critical regulator of vertebrate embryonic development and is involved in the function of processes such as stem cell maintenance and differentiation, tissue polarity and cell proliferation. Given how critical these functions are, it is not surprising that mutations in Hh pathway components are often implicated in the tumorigenesis of a variety of human cancers. Promotion of tumor growth has recently been shown by activated Hh signaling in the tumor itself, as well as by pathway activation within surrounding cells comprising the tumor microenvironment. Targeted disruption of various Hh pathway proteins has been successfully employed as an anticancer strategy with several synthetic Hh antagonists now available. Here, the molecular basis of Hh signaling, the therapeutic rationales for targeting this pathway and the current status of Hh pathway inhibitors in the clinic are reviewed.
Asunto(s)
Transformación Celular Neoplásica/genética , Proteínas Hedgehog/genética , Neoplasias Hematológicas/tratamiento farmacológico , Terapia Molecular Dirigida , Diferenciación Celular/genética , Proliferación Celular , Proteínas Hedgehog/metabolismo , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Humanos , Mutación , Transducción de Señal/genéticaRESUMEN
A molecular scoring system (IPSS-M) was recently proposed for myelodysplastic syndrome (MDS). We conducted a retrospective study of adults with MDS referred 2019-2021. The primary outcomes were leukemia-free survival (LFS) and overall survival (OS). One hundred and forty-four patients diagnosed between 2011 and 2021 were analyzed. After IPSS-M re-stratification, 33% of patients were up-staged and 11% down-staged. Median follow-up was 2.8 years and 53 patients died (37%). Cumulative incidence of acute myeloid leukemia (AML) transformation was 20% at 3 years post-diagnosis. International Prognostic Scoring System (IPSS), revised version (IPSS-R) was significantly associated with LFS (log-rank p = 9.2e-05; 'very high' vs. 'low' risk HR = 3.85, p = 5.8e-04) and OS (log-rank p = 7.2e-06; 'very high' vs. 'low' HR = 5.09, p = 1.7e-04). IPSS-M was also a significant predictor of LFS (log-rank p = 1.1e-06; 'very high' vs. 'low' HR = 4.97, p = 2.2e-05) and OS (log-rank p = 4.8e-07; 'very high' vs. 'low' HR = 6.42, p = 2.5e-05) while providing better discrimination than IPSS-R for both outcomes. This mutation-incorporating prognostic index has greater discriminative potential than IPSS-R to predict AML transformation and any-cause mortality.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Adulto , Humanos , Estudios Retrospectivos , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/genética , Pronóstico , Riesgo , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/genéticaRESUMEN
Secondary AML (sAML), defined by either history of antecedent hematologic disease (AHD) or prior genotoxic therapy (tAML), is classically regarded as having worse prognosis than de novo disease (dnAML). Clinicians may infer a new AML diagnosis is secondary based on a history of antecedent blood count (ABC) abnormalities in the absence of known prior AHD, but whether abnormal ABCs are associated with worse outcomes is unclear. Secondary-type mutations have recently been incorporated into the European LeukemiaNet (ELN) 2022 guidelines as adverse-risk features, raising the question of whether clinical descriptors of ontogeny (i.e., de novo or secondary) are prognostically significant when accounting for genetic risk by ELN 2022. In a large multicenter cohort of patients (n = 734), we found that abnormal ABCs are not independently prognostic after adjusting for genetic characteristics in dnAML patients. Furthermore, history of AHD and tAML do not confer increased risk of death compared to dnAML on multivariate analysis, suggesting the prognostic impact of ontogeny is accounted for by disease genetics as stratified by ELN 2022 risk and TP53 mutation status. These findings emphasize the importance that disease genetics should play in risk stratification and clinical trial eligibility in AML.
Asunto(s)
Enfermedades Hematológicas , Leucemia Mieloide Aguda , Neoplasias Primarias Secundarias , Humanos , Pronóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Factores de Riesgo , Neoplasias Primarias Secundarias/complicaciones , Enfermedades Hematológicas/complicaciones , MutaciónRESUMEN
Risk stratification in acute myeloid leukemia (AML) remains principle in survival prognostication and treatment selection. The 2022 European LeukemiaNet (ELN) recommendations were recently published, with notable updates to risk group assignment. The complexity of risk stratification and comparative outcomes between the 2022 and 2017 ELN guidelines remains unknown. This comparative analysis evaluated outcomes between the 2017 and 2022 ELN criteria in patients enrolled within the multicenter Beat AML cohort. Five hundred thirteen patients were included. Most patients had 1 or 2 ELN risk-defining abnormalities. In patients with ≥2 ELN risk-defining mutations, 44% (n = 132) had mutations spanning multiple ELN risk categories. Compared with ELN 2017 criteria, the updated ELN 2022 guidelines changed the assigned risk group in 15% of patients, including 10%, 26%, and 6% of patients categorized as being at ELN 2017 favorable-, intermediate-, and adverse-risk, respectively. The median overall survival across ELN 2022 favorable-, intermediate-, and adverse-risk groups was not reached, 16.8, and 9.7 months, respectively. The ELN 2022 guidelines more accurately stratified survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy compared with ELN 2017 guidelines. The updated ELN 2022 guidelines better stratify survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy. The increased complexity of risk stratification with inclusion of additional cytogenetic and molecular aberrations necessitates clinical workflows simplifying risk stratification.
Asunto(s)
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Factores de Riesgo , Mutación , Citogenética , Quimioterapia de InducciónRESUMEN
The BCL2 inhibitor venetoclax combined with the hypomethylating agent azacytidine shows significant clinical benefit in a subset of patients with acute myeloid leukemia (AML); however, resistance limits response and durability. We prospectively profiled the ex vivo activity of 25 venetoclax-inclusive combinations on primary AML patient samples to identify those with improved potency and synergy compared with venetoclax + azacytidine (Ven + azacytidine). Combination sensitivities correlated with tumor cell state to discern three patterns: primitive selectivity resembling Ven + azacytidine, monocytic selectivity, and broad efficacy independent of cell state. Incorporation of immunophenotype, mutation, and cytogenetic features further stratified combination sensitivity for distinct patient subtypes. We dissect the biology underlying the broad, cell state-independent efficacy for the combination of venetoclax plus the JAK1/2 inhibitor ruxolitinib. Together, these findings support opportunities for expanding the impact of venetoclax-based drug combinations in AML by leveraging clinical and molecular biomarkers associated with ex vivo responses. SIGNIFICANCE: By mapping drug sensitivity data to clinical features and tumor cell state, we identify novel venetoclax combinations targeting patient subtypes who lack sensitivity to Ven + azacytidine. This provides a framework for a taxonomy of AML informed by readily available sets of clinical and genetic features obtained as part of standard care. See related commentary by Becker, p. 437 . This article is featured in Selected Articles from This Issue, p. 419.
Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Azacitidina/farmacología , Azacitidina/uso terapéuticoRESUMEN
NEDD8 activating enzyme (NAE) has been identified as an essential regulator of the NEDD8 conjugation pathway, which controls the degradation of many proteins with important roles in cell-cycle progression, DNA damage, and stress responses. Here we report that MLN4924, a novel inhibitor of NAE, has potent activity in acute myeloid leukemia (AML) models. MLN4924 induced cell death in AML cell lines and primary patient specimens independent of Fms-like tyrosine kinase 3 expression and stromal-mediated survival signaling and led to the stabilization of key NAE targets, inhibition of nuclear factor-kappaB activity, DNA damage, and reactive oxygen species generation. Disruption of cellular redox status was shown to be a key event in MLN4924-induced apoptosis. Administration of MLN4924 to mice bearing AML xenografts led to stable disease regression and inhibition of NEDDylated cullins. Our findings indicate that MLN4924 is a highly promising novel agent that has advanced into clinical trials for the treatment of AML.
Asunto(s)
Ciclopentanos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteasoma , Pirimidinas/farmacología , Ubiquitinas/metabolismo , Animales , Western Blotting , Línea Celular Tumoral , Proteínas Cullin , Daño del ADN/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Humanos , Ratones , Proteína NEDD8 , FN-kappa B/genética , FN-kappa B/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
The aberrant overexpression of Wilms tumor 1 (WT1) in myeloid leukemia plays an important role in blast cell survival and resistance to chemotherapy. High expression of WT1 is also associated with relapse and shortened disease-free survival in patients. However, the mechanisms by which WT1 expression is regulated in leukemia remain unclear. Here, we report that heat shock protein 90 (Hsp90), which plays a critical role in the folding and maturation of several oncogenic proteins, associates with WT1 protein and stabilizes its expression. Pharmacologic inhibition of Hsp90 resulted in ubiquitination and subsequent proteasome-dependant degradation of WT1. RNAi-mediated silencing of WT1 reduced the survival of leukemia cells and increased the sensitivity of these cells to chemotherapy and Hsp90 inhibition. Furthermore, Hsp90 inhibitors 17-AAG [17-(allylamino)-17-demethoxygeldanamycin] and STA-9090 significantly reduced the growth of myeloid leukemia xenografts in vivo and effectively down-regulated the expression of WT1 and its downstream target proteins, c-Myc and Bcl-2. Collectively, our studies identify WT1 as a novel Hsp90 client and support the crucial role for the WT1-Hsp90 interaction in maintaining leukemia cell survival. These findings have significant implications for developing effective therapies for myeloid leukemias and offer a strategy to inhibit the oncogenic functions of WT1 by clinically available Hsp90 inhibitors.