RESUMEN
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
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
The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson's r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10-14). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using azacitidine combinations.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/mortalidad , Antimetabolitos Antineoplásicos/efectos adversos , Azacitidina/efectos adversos , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Humanos , Tasa de SupervivenciaRESUMEN
PURPOSE: In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). PATIENTS AND METHODS: Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily). RESULTS: ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response. CONCLUSIONS: These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Histona Demetilasas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Transcriptoma , Tranilcipromina/administración & dosificación , Tretinoina/administración & dosificación , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Tretinoina/efectos adversosRESUMEN
PURPOSE OF REVIEW: Myelodysplastic syndrome (MDS) is a clinically and molecularly heterogeneous disease, which primarily occurs in older adults. Although hypomethylating agents have survival benefit and are the current standard of care, many MDS patients will not garner a response from therapy. For those who do respond, most responses are not durable, and the only hope for a cure is allogeneic stem cell transplant. New therapies to improve outcomes are urgently needed. RECENT FINDINGS: Clinical trials combining standard hypomethylating agents with novel experimental agents are underway in an effort to improve clinical outcomes in MDS patients. Several of these small molecules have demonstrated the ability to augment the response rates of hypomethylating agents alone, including complete remission rates, in both the front line and refractory settings. Combination approaches utilizing hypomethylating agents and novel-targeted therapies have demonstrated the ability to improve response rates in MDS patients in both the front line and salvage settings, and thus may change the standard of care.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Antimetabolitos Antineoplásicos/farmacología , Humanos , Síndromes Mielodisplásicos/patologíaRESUMEN
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
De novo and acquired drug resistance and subsequent relapse remain major challenges in acute lymphoblastic leukemia (ALL). We previously identified that pevonedistat (TAK-924, MLN4924), a first-in-class inhibitor of NEDD8 activating enzyme (NAE), elicits ER stress and has potent in vitro and in vivo efficacy against ALL. However, in pevonedistat-treated ALL cell lines, we found consistent activation of the pro-survival MEK/ERK pathway, which has been associated with relapse and poor outcome in ALL. We uncovered that inhibition of the MEK/ERK pathway in vitro and in vivo sensitized ALL cells to pevonedistat. The observed synergistic apoptotic effect appears to be mediated by inhibition of the MEK/ERK pro-survival cascade leading to de-repression of the pro-apoptotic BIM protein. Mechanistically, Ca2+ influx via the Ca2+-release-activated Ca2+ (CRAC) channel induced protein kinase C ß2 (PKC-ß2) was responsible for activation of the MEK/ERK pathway in pevonedistat-treated ALL cells. Sequestration of Ca2+ using BAPTA-AM or blockage of store-operated Ca2+ entry (SOCE) using BTP-2 both attenuated the compensatory activation of MEK/ERK signaling in pevonedistat-treated ALL cells. Pevonedistat significantly altered the expression of Orai1 and stromal interaction molecule 1 (STIM1), resulting in significantly decreased STIM1 protein levels relative to Orai1. Further, we identified eIF2α as an important post-transcriptional regulator of STIM1, suggesting that pevonedistat-induced eIF2α de-phosphorylation selectively down-regulates translation of STIM1 mRNA. Consequently, our data suggest that pevonedistat potentially activates SOCE and promotes Ca2+ influx leading to activation of the MEK/ERK pathway by altering the stoichiometric Orai1:STIM1 ratio and inducing ER stress in ALL cells.
RESUMEN
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
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
A precision medicine approach is appealing for use in AML due to ease of access to tumor samples and the significant variability in the patients' response to treatment. Attempts to establish a precision medicine platform for AML, however, have been unsuccessful, at least in part due to the use of small compound panels and having relatively slow turn over rates, which restricts the scope of treatment and delays its onset. For this pilot study, we evaluated a cohort of 12 patients with refractory AML using an ex vivo drug sensitivity testing (DST) platform. Purified AML blasts were screened with a panel of 215 FDA-approved compounds and treatment response was evaluated after 72h of exposure. Drug sensitivity scoring was reported to the treating physician, and patients were then treated with either DST- or non-DST guided therapy. We observed survival benefit of DST-guided therapy as compared to the survival of patients treated according to physician recommendation. Three out of four DST-treated patients displayed treatment response, while all of the non-DST-guided patients progressed during treatment. DST rapidly and effectively provides personalized treatment recommendations for patients with refractory AML.
Asunto(s)
Antineoplásicos/uso terapéutico , Toma de Decisiones Clínicas/métodos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Medicina de Precisión/métodos , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Adulto JovenRESUMEN
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
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
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
EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Neoplasias Hematológicas/tratamiento farmacológico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor EphA3 , Terapia Recuperativa , Resultado del TratamientoRESUMEN
Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related death in children, and cure rates for adults remain dismal. Further, effective treatment strategies for relapsed/refractory ALL remain elusive. We previously uncovered that ALL cells are prone to apoptosis via endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated mechanisms. We investigated the antineoplastic activity of pevonedistat®, a novel NEDD8-activating enzyme inhibitor that targets E3 cullin-RING ligases (CRLs) dependent proteasomal protein degradation, in ALL. Herein, we report that pevonedistat induces apoptosis in ALL cells by dysregulating the translational machinery leading to induction of proteotoxic/ER stress and UPR-mediated cell death. Mechanistically, pevonedistat led to P-eIF2a dephosphorylation causing atypical proteotoxic/ER stress from failure to halt protein translation via the UPR and upregulation of mTOR/p70S6K. Additional studies revealed that pevonedistat re-balanced the homeostasis of pro- and anti-apoptotic proteins to favor cell death through altered expression and/or activity of Mcl-1, NOXA, and BIM, suggesting that pevonedistat has a "priming" effect on ALL by altering the apoptotic threshold through modulation of Mcl-1 activity. Further, we demonstrated that pevonedistat synergizes with selected anti-leukemic agents in vitro, and prolongs survival of NSG mice engrafted with ALL cells, lending support for the use of pevonedistat as part of a multi-agent approach.
Asunto(s)
Ciclopentanos/farmacología , Factor 2 Eucariótico de Iniciación/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirimidinas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Ubiquitinas/antagonistas & inhibidores , Respuesta de Proteína Desplegada/efectos de los fármacos , Animales , Antineoplásicos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Ciclopentanos/uso terapéutico , Estrés del Retículo Endoplásmico , Inhibidores Enzimáticos , Xenoinjertos , Humanos , Ratones , Proteína NEDD8 , Pirimidinas/uso terapéuticoRESUMEN
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
The PIM genes represent a family of proto-oncogenes that encode three different serine/threonine protein kinases (PIM1, PIM2 and PIM3) with essential roles in the regulation of signal transduction cascades, which promote cell survival, proliferation and drug resistance. PIM kinases are overexpressed in several hematopoietic tumors and support in vitro and in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis. PIM kinases do not have an identified regulatory domain, which means that these proteins are constitutively active once transcribed. They appear to be critical downstream effectors of important oncoproteins and, when overexpressed, can mediate drug resistance to available agents, such as rapamycin. Recent crystallography studies reveal that, unlike other kinases, they possess a hinge region, which creates a unique binding pocket for ATP, offering a target for an increasing number of potent small-molecule PIM kinase inhibitors. Preclinical studies in models of various hematologic cancers indicate that these novel agents show promising activity and some of them are currently being evaluated in a clinical setting. In this review, we profile the PIM kinases as targets for therapeutics in hematologic malignancies.