RESUMEN
LESSONS LEARNED: The addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation. BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer. METHODS: Patients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS). RESULTS: One hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen. CONCLUSION: Addition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup.
Asunto(s)
Albúminas/administración & dosificación , Desoxicitidina/análogos & derivados , Proteínas de Choque Térmico HSP27/antagonistas & inhibidores , Proteínas de Choque Térmico HSP27/sangre , Oligonucleótidos Antisentido/administración & dosificación , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Paclitaxel/efectos adversos , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/patología , Pronóstico , Resultado del Tratamiento , GemcitabinaRESUMEN
Chronic kidney disease (CKD) in recipients of myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) has been well characterized. However, the risk of CKD after HCT using reduced-intensity conditioning (RIC) is not well known. We compared the incidence of CKD by conditioning regimen in 221 allogeneic HCT recipients (MA = 117, RIC = 104) who had survived for >or=1 year post-HCT and had no history of CKD pretransplant. CKD was defined as glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) for >or=3 months anytime after 180 days post-HCT. The median follow-up was 28 months (range: 12-75) for MA and 25 months (range: 12-67) for the RIC group. The 3-year cumulative incidence rate of CKD was 28% (95% confidence intervals [CI], 19%-36%) in MA and 29% (95% CI, 20%-38%) in the RIC group (P = .44). In multivariate analysis, conditioning regimen intensity had no impact on the risk of developing CKD (relative risk [RR] for MA 1.50 [95% CI, 0.78-2.89] versus the RIC regimen). Factors independently associated with an increased risk of CKD were older age at transplant, acute graft-versus-host disease, cyclosporine use for >6 months, and acute kidney injury in the early posttransplant period. CKD is frequent in long-term adult allogeneic HCT survivors, but RIC is associated with similar risks as MA conditioning. Continuous monitoring of renal function is necessary in allogeneic HCT survivors, and studies exploring prevention strategies are needed.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Enfermedades Renales/epidemiología , Complicaciones Posoperatorias/epidemiología , Sobrevivientes/estadística & datos numéricos , Acondicionamiento Pretrasplante/efectos adversos , Adulto , Factores de Edad , Anciano , Enfermedad Crónica , Ciclosporina/efectos adversos , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Enfermedad Injerto contra Huésped/epidemiología , Enfermedades Hematológicas/cirugía , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Incidencia , Enfermedades Renales/etiología , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/administración & dosificación , Agonistas Mieloablativos/efectos adversos , Complicaciones Posoperatorias/etiología , Modelos de Riesgos Proporcionales , Riesgo , Trasplante Homólogo , Irradiación Corporal Total/efectos adversosRESUMEN
The hematopoietic cell transplantation specific comorbidity index (HCT-CI) has been recently proposed to predict the probability of nonrelapse mortality (NRM) and overall survival (OS) in allogeneic HCT recipients while taking into account any pretransplant comorbidity. We tested the validity of the HCT-CI in a cohort of 373 adult HCT recipients (184 matched-related donor and 189 unrelated umbilical cord blood) who received a myeloablative (N = 150) or nonmyeloablative (N = 223) conditioning regimen. HCT-CI scores of 0, 1, 2, and > or =3 were present in 58 (16%), 56 (15%), 64 (17%), and 195 (52%) patients, respectively. Pulmonary conditions were the most common comorbidity. Cumulative incidence of NRM at 2 years was 10%, 20%, 24%, and 28% for HCT-CI scores of 0, 1, 2, and > or =3, respectively (P = .01). The corresponding probability of OS at 2 years was 72%, 67%, 51%, and 48%, respectively (P < .01). On multivariate analyses adjusted for recipient age, disease risk, donor source, and conditioning regimen intensity, the relative risks for NRM for HCT-CI scores of 1, 2, and > or =3 (compared to a score of 0) were 2.0 (95% confidence intervals, 0.8-5.3), 2.6 (1.0-6.7), and 3.2 (1.4-7.4), respectively. The risks for overall mortality were 1.2 (0.6-2.1), 2.0 (1.1-3.4), and 2.1 (1.3-3.3), respectively. In subgroup analyses, the HCT-CI score did not consistently predict NRM and OS among different donor sources and conditioning regimens. The HCT-CI, although a useful tool for capturing pretransplant comorbidity and risk-assessment, needs to be further validated prior to adopting it for routine clinical use.