RESUMEN
BACKGROUND: CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity. METHODS: ABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression. RESULTS: Fifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population. CONCLUSIONS: ABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02955251.
Asunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antígenos CD40/agonistas , Mesotelina/agonistas , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/farmacocinética , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacocinética , Femenino , Francia , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/inmunología , Neoplasias/mortalidad , Neoplasias/patología , Supervivencia sin Progresión , Factores de Tiempo , Microambiente Tumoral , Estados UnidosRESUMEN
In a phase-2 study, the telomerase inhibitor imetelstat induced rapid hematologic responses in all patients with essential thrombocythemia who were refractory or intolerant to prior therapies. Significant molecular responses were achieved within 3-6 months in 81% of patients with phenotypic driver mutations in JAK2, CALR and MPL. Here, we investigated the dynamics of additional somatic mutations in response to imetelstat. At study entry, 50% of patients carried 1-5 additional mutations in the genes ASXL1, CBL, DNMT3A, EZH2, IDH1, SF3B1, TET2, TP53 and U2AF1. Three patients with baseline mutations also had late-emerging mutations in TP53, IDH1 and TET2. Most clones with additional mutations were responsive to imetelstat and decreased with the driver mutation, including the poor prognostic ASXL1, EZH2 and U2AF1 mutations while SF3B1 and TP53 mutations were associated with poorer molecular response. Overall, phenotypic driver mutation response was significantly deeper in patients without additional mutations (P = 0.04) and correlated with longer duration of response. In conclusion, this detailed molecular analysis of highly pretreated and partly resistant patients with essential thrombocythemia reveals a high individual patient complexity. Moreover, imetelstat demonstrates potential to inhibit efficiently co-incident mutations occurring in neoplastic clones in patients with essential thrombocythemia. (ClinicalTrials.gov number, NCT01243073. N Engl J Med 2015; 373:920-928, DOI: 10.1056/NEJMoa1503479.).
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Trombocitemia Esencial , Células Clonales , Humanos , Janus Quinasa 2/genética , Mutación , Oligonucleótidos , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/genéticaRESUMEN
PURPOSE: Defective homologous recombination (HR) has been reported in multiple myeloid disorders, suggesting a shared dysregulated pathway in these diverse malignancies. Because targeting HR-defective cancers with PARP inhibition (PARPi) has yielded clinical benefit, improved understanding of HR defects is needed to implement this treatment modality. EXPERIMENTAL DESIGN: We used an ex vivo irradiation-based assay to evaluate HR repair, HR gene promoter methylation, and mRNA expression in primary myeloid neoplastic cells. In vitro BRCA1 gene silencing was achieved to determine the consequences on HR repair, sensitivity to PARPi, and expression of miR-155, an oncogenic miRNA. RESULTS: Impaired HR repair was frequently detected in myeloid neoplasm samples (9/21, 43%) and was linked to promoter methylation-mediated transcriptional repression of BRCA1, which was not observed for other members of the HR pathway (BRCA2, ATM, ATR, FANC-A). In vitro BRCA1 knockdown increased sensitivity to PARP inhibition, and BRCA1 expression is inversely correlated with miR-155 expression, a finding reproduced in vitro with BRCA1 knockdown. Increased miR-155 was associated with PU.1 and SHIP1 repression, known myeloid differentiation factors that are frequently downregulated during leukemic transformation. CONCLUSIONS: This study demonstrates frequent defective HR, associated with BRCA1 epigenetic silencing, in a broad range of myeloid neoplasms. The increased prevalence of BRCA1 promoter methylation, resulting in repressed BRCA1, may have an additional role in leukemogenesis by increasing miR-155 expression, which then inhibits transcription factors associated with normal myeloid differentiation. Further study of HR defects may facilitate the identification of HR-defective myeloid neoplasms sensitive to PARPi.
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Proteína BRCA1/genética , Metilación de ADN , Leucemia Mieloide/genética , Leucemia Mieloide/patología , MicroARNs/genética , Regiones Promotoras Genéticas , Reparación del ADN por Recombinación , Adulto , Anciano , Diferenciación Celular/genética , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Silenciador del Gen , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacologíaRESUMEN
Timed sequential therapy (TST) aims to improve outcomes in acute myelogenous leukemia (AML) by harnessing drug-induced cell cycle kinetics of AML, where a second drug is timed to coincide with peak leukemia proliferation induced by the first drugs. We analyzed outcomes in 301 newly diagnosed AML patients treated from 2004-2013 with cytarabine, anthracycline, and etoposide TST induction. Median age was 52 (range 20-74) and complete remission rate 68%. With median follow-up 5.8 years, 5-year DFS and overall survival (OS) were 37% (95% CI 31-45%) and 32% (95% CI 27-38%), respectively. In multivariate analysis, older age, unfavorable cytogenetics, and WBC≥50×109/L resulted in worse OS. Among patients not undergoing blood and marrow transplant, a propensity score analysis, which reduces imbalance in baseline characteristics, showed consolidation with TST compared with 1 or more cycles high-dose cytarabine trended toward lower DFS and post-remission survival with hazard ratio (HR) 1.9 (95% CI 0.9-4.0), and 1.6 (95% CI 0.7-3.6), respectively. Our results demonstrate the efficacy and feasibility of TST induction for newly diagnosed patients with AML, with results comparable to that seen in clinical trials with other TST therapies and 7+3.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Quimioterapia de Inducción , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE: In preclinical studies, the PARP inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies. EXPERIMENTAL DESIGN: Patients received veliparib [20-200 mg once a day on day 1 and twice daily on days 4-12 in cycle 1 (days 1-8 in cycle ≥2)] and temozolomide [150-200 mg/m2 daily on days 3-9 in cycle 1 (days 1-5 in cycle ≥2)] every 28 to 56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP-ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter, and integrity of the Fanconi anemia pathway were also examined. RESULTS: Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting >7 days. The MTD was veliparib 150 mg twice daily with temozolomide 200 mg/m2 daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34+ cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR. CONCLUSIONS: Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted. Clin Cancer Res; 23(3); 697-706. ©2016 AACR.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Metilación de ADN/efectos de los fármacos , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Sinergismo Farmacológico , Esofagitis/inducido químicamente , Femenino , Histonas/metabolismo , Humanos , Estimación de Kaplan-Meier , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mucositis/inducido químicamente , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/antagonistas & inhibidores , Fosforilación/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasa-1/análisis , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Regiones Promotoras Genéticas/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Inducción de Remisión , Terapia Recuperativa , Temozolomida , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone.Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML).Results: A total of 99 patients received veliparib 10-100 mg orally twice daily on days 1-8, 1-14, or 1-21 along with continuous infusion topotecan 1.0-1.2 mg/m2/d + carboplatin 120-150 mg/m2/d on days 3-7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage-induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27-0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders.Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. Clin Cancer Res; 23(4); 899-907. ©2016 AACR.
Asunto(s)
Leucemia Bifenotípica Aguda/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Trastornos Mieloproliferativos/tratamiento farmacológico , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Adulto , Anciano , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carboplatino/farmacocinética , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Femenino , Humanos , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Masculino , Persona de Mediana Edad , Poli(ADP-Ribosa) Polimerasa-1/genética , Topotecan/administración & dosificación , Topotecan/efectos adversos , Topotecan/farmacocinéticaRESUMEN
BACKGROUND: Deletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms. MATERIALS AND METHODS: To define the pathogenic molecular features associated with del(5q), next-generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with del(5q) as a sole abnormally or a part of complex karyotype and results were compared to molecular features of patients diploid for chr5. FINDINGS: A number of 5q genes with haploinsufficient expression and/or recurrent somatic mutations were identified; for these genes, CSNK1A1 and G3BP1 within the commonly deleted 5q region and DDX41 within a commonly retained region were most commonly affected by somatic mutations. These genes showed consistent haploinsufficiency in deleted cases; low expression/mutations of G3BP1 or DDX41 were associated with poor survival, likely due to decreased cellular function. The most common mutations on other chromosomes in patients with del(5q) included TP53, and mutations of FLT3 (ITD or TKD), NPM1 or TET2 and were mutually exclusive. Serial sequencing allowed for definition of clonal architecture and dynamics, in patients with exome sequencing allelic imbalance for informative SNPs facilitated simultaneous approximation of clonal size of del(5q) and clonal burden for somatic mutations. INTERPRETATION: Our results illuminate the spectrum of molecular defects characteristic of del(5q), their clinical impact and succession of stepwise evolution.
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Anemia Macrocítica/genética , Biomarcadores de Tumor/genética , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética , Anemia Macrocítica/mortalidad , Anemia Macrocítica/patología , Estudios de Casos y Controles , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Diploidia , Predisposición Genética a la Enfermedad , Haploinsuficiencia , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Mutación , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Trastornos Mieloproliferativos/mortalidad , Trastornos Mieloproliferativos/patología , Nucleofosmina , Fenotipo , Polimorfismo de Nucleótido Simple , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Secuencia de ADN/métodos , Factores de TiempoRESUMEN
PURPOSE: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo EXPERIMENTAL DESIGN: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays. RESULTS: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage-induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes. CONCLUSIONS: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894-902. ©2016 AACR.
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Antineoplásicos/efectos adversos , Hipersensibilidad a las Drogas/etiología , Trastornos Mieloproliferativos/complicaciones , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Antineoplásicos/uso terapéutico , Proteína BRCA1/genética , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Daño del ADN , Metilación de ADN , Reparación del ADN , Tolerancia a Medicamentos/genética , Genómica/métodos , Humanos , Janus Quinasa 2/genética , Mutación , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismoRESUMEN
BACKGROUND: Imetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity. It has been shown to inhibit megakaryocytic proliferation in vitro in cells obtained from patients with essential thrombocythemia. In this phase 2 study, we investigated whether imetelstat could elicit hematologic and molecular responses in patients with essential thrombocythemia who had not had a response to or who had had unacceptable side effects from prior therapies. METHODS: A total of 18 patients in two sequential cohorts received an initial dose of 7.5 or 9.4 mg of imetelstat per kilogram of body weight intravenously once a week until attainment of a platelet count of approximately 250,000 to 300,000 per cubic millimeter. The primary end point was the best hematologic response. RESULTS: Imetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response. At the time of the primary analysis, 10 patients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15 to 66%. The most common adverse events during treatment were mild to moderate in severity; neutropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity. CONCLUSIONS: Rapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron; ClinicalTrials.gov number, NCT01243073.).
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Indoles/administración & dosificación , Niacinamida/análogos & derivados , Telomerasa/antagonistas & inhibidores , Trombocitemia Esencial/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Esquema de Medicación , Femenino , Humanos , Indoles/efectos adversos , Infusiones Intravenosas , Janus Quinasa 2/genética , Hígado/enzimología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Mutación , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Oligonucleótidos , Proyectos Piloto , Trombocitemia Esencial/genéticaRESUMEN
PURPOSE: Recent advances in nonmyeloablative (NMA), related HLA-haploidentical blood or marrow transplantation (haplo-BMT) have expanded the donor pool. This study evaluated the effect of age on NMA haplo-BMT outcomes in patients age 50 to 75 years. PATIENTS AND METHODS: A retrospective analysis was performed of 271 consecutive patients with hematologic malignancies, age 50 to 75 years, who received NMA, T-cell-replete haplo-BMT with high-dose post-transplantation cyclophosphamide. RESULTS: The median age was 61 years, with 115 patients (42%) age 50 to 59, 129 (48%) age 60 to 69, and 27 (10%) age 70 to 75 years. Overall, 84% of patients had intermediate- or high-/very high-risk disease. The 6-month probabilities of grade 3 or 4 acute graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) were 3% and 8%, respectively. Patients in their 50s, 60s, and 70s had 6-month NRM probabilities of 8%, 9%, and 7%, respectively (P=.20). With a median follow-up of 4 years, corresponding 3-year progression-free survival probabilities were 39%, 35%, and 33% (P=.65), and corresponding 3-year overall survival probabilities were 48%, 45%, and 44% (P=.66). Three-year progression-free survival probabilities were 40% in acute myeloid leukemia (n=65), 39% in aggressive non-Hodgkin lymphoma (n=83), and 37% in indolent or mantle-cell lymphoma (n=65). Older patient age was associated with a significantly higher risk of grade 2 to 4 acute GVHD but not grade 3 to 4 acute or chronic GVHD. No statistically significant associations were found between older age (relative to age 50 to 59 years or as a continuous variable) and NRM, relapse, or survival. CONCLUSION: NMA haplo-BMT with post-transplantation cyclophosphamide has encouraging safety and survival outcomes in patients age 50 to 75 years. In patients otherwise fit for BMT, the results support consideration of this approach despite advanced age.
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Antineoplásicos Alquilantes/administración & dosificación , Trasplante de Médula Ósea , Ciclofosfamida/administración & dosificación , Antígenos HLA/genética , Haplotipos , Neoplasias Hematológicas/terapia , Donantes de Tejidos , Acondicionamiento Pretrasplante , Factores de Edad , Anciano , Antineoplásicos Alquilantes/efectos adversos , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/mortalidad , Quimioterapia Adyuvante , Ciclofosfamida/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Antígenos HLA/inmunología , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Selección de Paciente , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Related HLA-haploidentical blood or marrow transplantation (BMT) with high-dose posttransplantation cyclophosphamide (PTCy) is being increasingly used because of its acceptable safety profile. To better define outcomes of nonmyeloablative (NMA) HLA-haploidentical BMT with PTCy, 372 consecutive adult hematologic malignancy patients who underwent this procedure were retrospectively studied. Risk-stratified outcomes were evaluated using the refined Disease Risk Index (DRI), developed to stratify disease risk across histologies and allogeneic BMT regimens. Patients received uniform conditioning, T-cell-replete allografting, then PTCy, mycophenolate mofetil, and tacrolimus. Six-month probabilities of nonrelapse mortality and severe acute graft-versus-host disease were 8% and 4%. With 4.1-year median follow-up, 3-year probabilities of relapse, progression-free survival (PFS), and overall survival (OS) were 46%, 40%, and 50%, respectively. By refined DRI group, low (n = 71), intermediate (n = 241), and high/very high (n = 60) risk groups had 3-year PFS estimates of 65%, 37%, and 22% (P < .0001), with corresponding 3-year OS estimates of 71%, 48%, and 35% (P = .0001). On multivariable analyses, the DRI was statistically significantly associated with relapse, PFS, and OS (each P < .001). This analysis demonstrates that the DRI effectively risk stratifies recipients of NMA HLA-haploidentical BMT with PTCy and also suggests that this transplantation platform yields similar survivals to those seen with HLA-matched BMT.
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Antineoplásicos Alquilantes/uso terapéutico , Trasplante de Médula Ósea , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas/terapia , Histocompatibilidad , Complicaciones Posoperatorias , Adolescente , Adulto , Anciano , Terapia Combinada , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Tasa de Supervivencia , Acondicionamiento Pretrasplante , Trasplante Homólogo , Adulto JovenRESUMEN
High-dose, posttransplantation cyclophosphamide (PTCy) reduces severe graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT), but the impact of PTCy on long-term, disease-specific outcomes is unclear. We conducted a retrospective study of 209 consecutive adult patients transplanted for acute myeloid leukemia (AML, n = 138), myelodysplastic syndrome (n = 28), or acute lymphoblastic leukemia (ALL, n = 43) using PTCy as sole GVHD prophylaxis after myeloablative conditioning and HLA-matched-related or -unrelated T-cell-replete allografting. At alloBMT, 30% of patients were not in morphologic complete remission. The cumulative incidences of grades II to IV and III to IV acute GVHD at 100 days and chronic GVHD at 2 years were 45%, 11%, and 13%, respectively. Forty-three percent of patients did not require immunosuppression for any reason beyond PTCy. At 3 years, relapse cumulative incidence was 36%, disease-free survival was 46%, survival free of disease and chronic GVHD was 39%, and overall survival was 58%. Lack of remission at alloBMT, adverse cytogenetics, and low allograft nucleated cell dose were associated with inferior survival for AML patients. Minimal residual disease but not t(9;22) was associated with inferior outcomes for ALL patients. The ability to limit posttransplantation immunosuppression makes PTCy a promising transplantation platform for the integration of postgrafting strategies to prevent relapse.
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Trasplante de Médula Ósea/métodos , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Leucemia Mieloide/terapia , Síndromes Mielodisplásicos/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Enfermedad Aguda , Adolescente , Adulto , Anciano , Trasplante de Médula Ósea/efectos adversos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Prueba de Histocompatibilidad , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasia Residual , Inducción de Remisión , Estudios Retrospectivos , Factores de Tiempo , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
DNA repair aberrations and associated chromosomal instability is a feature of chronic lymphocytic leukemia (CLL). To evaluate if DNA repair insufficiencies are related to methylation changes, we examined the methylation of nine promoter regions of DNA repair proteins by bisulfide sequencing in 26 CLL primary samples and performed quantitative PCR on a subset of samples to examine BRCA1 expression. We also investigated if changes in cytogenetic or expression level of DNA repair proteins led to changes in sensitivity to a novel PARP inhibitor, CEP-8983, alone and in combination with bendamustine. No changes in promoter methylation were identified in BRCA1, BRCA2, FANC-C, FANC-F, FANC-L, ATM, MGMT, hMLH1 and H2AX except for two cases of minor BRCA1 hypermethylation. CLL samples appeared to have reduced BRCA1 mRNA expression uniformly in comparison to non-malignant lymphocytes irrespective of promoter hypermethylation. CEP-8983 displayed single agent cytotoxicity and the combination with bendamustine demonstrated synergistic cytotoxicity in the majority of CLL samples. These results were consistent across cytogenetic subgroups, including 17p deleted and previously treated patients. Our results provide rationale for further exploration of the combination of a PARP inhibitor and DNA damaging agents as a novel therapeutic strategy in CLL.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Linfocitos B/efectos de los fármacos , Carbazoles/farmacología , Inhibidores Enzimáticos/farmacología , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Compuestos de Mostaza Nitrogenada/farmacología , Ftalimidas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Linfocitos B/metabolismo , Linfocitos B/patología , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Clorhidrato de Bendamustina , Daño del ADN , Metilación de ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , ADN de Neoplasias/antagonistas & inhibidores , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Sinergismo Farmacológico , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Regiones Promotoras Genéticas/efectos de los fármacos , Análisis de Secuencia de ADN , Transducción de SeñalRESUMEN
Myeloproliferative neoplasms are a varied group of disorders that can have prolonged chronic phases, but eventually accelerate and can transform into a secondary acute myeloid leukemia that is ultimately fatal. Triapine is a novel inhibitor of the M2 subunit of ribonucleotide reductase. Sequential inhibition of ribonucleotide reductase with triapine and an M1 ribonucleotide reductase inhibitor (fludarabine) was noted to be safe, and led to a 29% complete plus partial response rate in myeloproliferative neoplasms. This article reports the findings of a phase II trial of triapine (105 mg/m(2)/day) followed by fludarabine (30 mg/m(2)/day) daily for 5 consecutive days in 37 patients with accelerated myeloproliferative neoplasms and secondary acute myeloid leukemia. The overall response rate was 49% (18/37), with a complete remission rate of 24% (9/37). Overall response rates and complete remissions were seen in all disease subsets, including secondary acute myeloid leukemia, in which the overall response rate and complete remission rate were 48% and 33%, respectively. All patients with known JAK2 V617F mutations (6/6) responded. The median overall survival of the entire cohort was 6.9 months, with a median overall survival of both overall responders and complete responders of 10.6 months. These data further demonstrate the promise of sequential inhibition of ribonucleotide reductase in patients with accelerated myeloproliferative neoplasms and secondary acute myeloid leukemia. This study was registered with clinicaltrials.gov (NCT00381550).
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Trastornos Mieloproliferativos/tratamiento farmacológico , Piridinas/uso terapéutico , Ribonucleótido Reductasas/antagonistas & inhibidores , Tiosemicarbazonas/uso terapéutico , Vidarabina/análogos & derivados , Adulto , Anciano , Antineoplásicos/administración & dosificación , Esquema de Medicación , Inhibidores Enzimáticos/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/mortalidad , Piridinas/administración & dosificación , Tiosemicarbazonas/administración & dosificación , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/uso terapéuticoRESUMEN
Here we report whole-exome sequencing of individuals with various myeloid malignancies and identify recurrent somatic mutations in SETBP1, consistent with a recent report on atypical chronic myeloid leukemia (aCML). Closely positioned somatic SETBP1 mutations encoding changes in Asp868, Ser869, Gly870, Ile871 and Asp880, which match germline mutations in Schinzel-Giedion syndrome (SGS), were detected in 17% of secondary acute myeloid leukemias (sAML) and 15% of chronic myelomonocytic leukemia (CMML) cases. These results from deep sequencing demonstrate a higher mutational detection rate than reported with conventional sequencing methodology. Mutant cases were associated with advanced age and monosomy 7/deletion 7q (-7/del(7q)) constituting poor prognostic factors. Analysis of serially collected samples indicated that SETBP1 mutations were acquired during leukemic evolution. Transduction with mutant Setbp1 led to the immortalization of mouse myeloid progenitors that showed enhanced proliferative capacity compared to cells transduced with wild-type Setbp1. Somatic mutations of SETBP1 seem to cause gain of function, are associated with myeloid leukemic transformation and convey poor prognosis in myelodysplastic syndromes (MDS) and CMML.
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Proteínas Portadoras/genética , Leucemia Mieloide/genética , Mutación , Trastornos Mieloproliferativos/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Células de la Médula Ósea/metabolismo , Transformación Celular Neoplásica/genética , Análisis por Conglomerados , Exoma , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide/mortalidad , Masculino , Ratones , Persona de Mediana Edad , Datos de Secuencia Molecular , Células Progenitoras Mieloides/metabolismo , Células Progenitoras Mieloides/patología , Trastornos Mieloproliferativos/mortalidad , Linfocitos T/metabolismo , Adulto JovenRESUMEN
Patients with cytopenias and a cellular bone marrow can be a diagnostic and therapeutic challenge. Previous reports suggested a role for progenitor assays for diagnosis and predicting response to therapy. We report the results of Burst-forming unit-erythroid (BFU-E) assays in 48 consultative cases of single or multilineage cytopenias with cellular marrows. The final diagnoses included 17 patients with myelodysplastic syndrome, 9 patients with pure red cell aplasia (non-large granular lymphocytosis [LGL] in etiology], 15 patients with LGL (eight of whom had a single-lineage cytopenia only, whereas the other seven had multilineage cytopenias), and 7 patients with cytopenias associated with systemic inflammation from autoimmune conditions. In this cohort, nonmalignant diseases were well-distinguished from myelodysplastic syndrome by BFU-E growth. Our data suggest that low BFU-E growth (less than 10 BFU-E per 10(5) marrow mononuclear cells) helps to exclude LGL, pure red cell aplasia, or cytopenias associated with systemic inflammation as a cause of pancytopenia with a sensitivity of 96.8%, specificity of 76.5%, and a predictive value of 88.2% (p = 0.0001). BFU-E growth also was examined to predict treatment response. Of the 29 patients in this cohort treated with immunosuppressive therapy, there was an 86% response rate with 25 responders (11 partial responses and 14 complete responses) and 4 nonresponders. This result correlated with higher BFU-E growth. Our results suggest that BFU-E assays are a useful adjunct in the diagnosis and management of cytopenias in the setting of a normocellular or hypercellular marrows.
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Ensayo de Unidades Formadoras de Colonias/métodos , Células Precursoras Eritroides/metabolismo , Linfocitosis/diagnóstico , Síndromes Mielodisplásicos/diagnóstico , Aplasia Pura de Células Rojas/diagnóstico , Anciano , Células Precursoras Eritroides/patología , Femenino , Humanos , Linfocitosis/metabolismo , Linfocitosis/patología , Linfocitosis/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/terapia , Aplasia Pura de Células Rojas/metabolismo , Aplasia Pura de Células Rojas/patología , Aplasia Pura de Células Rojas/terapiaRESUMEN
Chronic myelomonocytic leukemia is a heterogeneous disease with multifactorial molecular pathogenesis. Various recurrent somatic mutations have been detected alone or in combination in chronic myelomonocytic leukemia. Recently, recurrent mutations in spliceosomal genes have been discovered. We investigated the contribution of U2AF1, SRSF2 and SF3B1 mutations in the pathogenesis of chronic myelomonocytic leukemia and closely related diseases. We genotyped a cohort of patients with chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia for somatic mutations in U2AF1, SRSF2, SF3B1 and in the other 12 most frequently affected genes in these conditions. Chromosomal abnormalities were assessed by nucleotide polymorphism array-based karyotyping. The presence of molecular lesions was correlated with clinical endpoints. Mutations in SRSF2, U2AF1 and SF3B1 were found in 32%, 13% and 6% of cases of chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, respectively. Spliceosomal genes were affected in various combinations with other mutations, including TET2, ASXL1, CBL, EZH2, RAS, IDH1/2, DNMT3A, TP53, UTX and RUNX1. Worse overall survival was associated with mutations in U2AF1 (P=0.047) and DNMT3A (P=0.015). RAS mutations had an impact on overall survival in secondary acute myeloid leukemia (P=0.0456). By comparison, our screening of juvenile myelomonocytic leukemia cases showed mutations in ASXL1 (4%), CBL (10%), and RAS (6%) but not in IDH1/2, TET2, EZH2, DNMT3A or the three spliceosomal genes. SRSF2 and U2AF1 along with TET2 (48%) and ASXL1 (38%) are frequently affected by somatic mutations in chronic myelomonocytic leukemia, quite distinctly from the profile seen in juvenile myelomonocytic leukemia. Our data also suggest that spliceosomal mutations are of ancestral origin.
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Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Juvenil/genética , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Empalmosomas/genética , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Juvenil/diagnóstico , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: Incorporation of cytarabine into DNA activates checkpoint kinase 1 (Chk1), which stabilizes stalled replication forks, induces S-phase slowing, and diminishes cytarabine cytotoxicity. The selective Chk1 inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest and enhances cytarabine cytotoxicity in acute leukemia cell lines and leukemic blasts in vitro. To extend these findings to the clinical setting, we have conducted a phase I study of cytarabine and SCH 900776. EXPERIMENTAL DESIGN: Twenty-four adults with relapsed and refractory acute leukemias received timed sequential, continuous infusion cytarabine 2 g/m(2) over 72 hours (667 mg/m(2)/24 hours) beginning on day 1 and again on day 10. SCH 900776 was administered as a 15- to 30-minute infusion on days 2, 3, 11, and 12. The starting dose of SCH 900776 was 10 mg/m(2)/dose. RESULTS: Dose-limiting toxicities consisting of corrected QT interval prolongation and grade 3 palmar-plantar erythrodysesthesia occurred at 140 mg flat dosing (dose level 5, equivalent to 80 mg/m(2)). Complete remissions occurred in 8 of 24 (33%) patients, with 7 of 8 at 40 mg/m(2) or higher. SCH 900776 did not accumulate at any dose level. Marrow blasts obtained pretreatment and during therapy showed increased phosphorylation of H2Ax after SCH 900776 beginning at 40 mg/m(2), consistent with unrepaired DNA damage. CONCLUSIONS: These data support a randomized phase II trial of cytarabine +/- SCH 900776 at a recommended flat dose of 100 mg (equivalent to 56 mg/m(2)) for adults with poor-risk leukemias. The trial (SP P05247) was registered at www.clinicaltrials.gov as NCT00907517.