RESUMEN
Aprepitant (AP) is a known inhibitor of cytochrome P450 3A4 which may affect tacrolimus metabolism. We retrospectively examined the effect of oral AP on intravenous tacrolimus concentrations in 26 patients undergoing reduced intensity transplantation from 09/2005 to 09/2006. Oral AP 125 mg daily was administered on transplant day +1 and 80 mg on days +2 and +3. Intravenous tacrolimus was administered as a 0.03 mg/kg/day continuous infusion on day -6 through day +1 (pre-AP), during-AP (days +2 to +7), and post-AP starting on day +8. Tacrolimus doses were adjusted to achieve concentrations of 5-20 ng/mL. Dose-corrected tacrolimus concentrations (ng/mL/mg per dose) in the pre-AP, during-AP, and post-AP time periods were: 8.12 (95% CI: 7.3-9.1), 11.63 (95% CI: 9.63-13.63), and 11.42 (95% CI: 8.12-14.7), respectively (P<0.01 between pre-AP and during-AP, P<0.01 between during-AP and post-AP, P = 0.01 between pre-AP and post-AP time periods). Although statistically significant, the observed rise was not clinically significant between during-AP and post-AP time periods. Previous work has shown that AP is not expected to exert an inhibitory effect within 48 h of AP discontinuation. Collectively, these data suggest that AP effect on tacrolimus metabolism is of minor clinical significance. A controlled trial is needed to confirm these findings.
Asunto(s)
Antieméticos/farmacología , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/farmacocinética , Morfolinas/farmacología , Tacrolimus/farmacocinética , Adolescente , Adulto , Antieméticos/uso terapéutico , Antifúngicos/uso terapéutico , Aprepitant , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Fluconazol/uso terapéutico , Humanos , Inmunosupresores/administración & dosificación , Inyecciones Intravenosas , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Micosis/prevención & control , Estudios Retrospectivos , Tacrolimus/administración & dosificación , Adulto JovenRESUMEN
Limited data are available for adults undergoing unrelated donor (URD) BMT for AML using chemotherapy-only preparative regimens. Previous studies incorporated irradiation, included adults and children, and excluded secondary leukemia. Herein we report long-term outcomes for adults with poor-prognostic AML receiving a novel regimen of busulfan (16 mg/kg), cytarabine (8,000 mg/m(2)), and cyclophosphamide (120 mg/kg) (BAC), followed by URD BMT. From June 1995 through October 2001, 45 adults were enrolled. Adverse features included unfavorable cytogenetics (49%), secondary AML (47%), leukemia at transplant (42%), and extramedullary disease (16%). At time of BMT, 23 were in remission (12 CR1) while 22 had leukemia. Four (9%) died early. Acute and chronic GVHD rates were 44 and 67%, respectively. Seventeen (38%) were disease-free 52 months post-BMT; 13 were leukemia-free (eight CR1) at transplant. Eleven relapsed. Three-year DFS and OS were 42 and 46%, respectively. DFS and OS were longer, and relapses less, for those in CR at time of BMT. Secondary leukemia, cytogenetics, cell dose, and GVHD did not influence outcome. In poor-risk AML, BAC provided cytoreduction comparable to reported TBI-containing regimens, when administered for URD BMT. With decreasing treatment-related mortality, it is justified to proceed early to URD BMT for patients with poor prognostic features.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Médula Ósea , Leucemia Mieloide Aguda/terapia , Donantes de Tejidos , Acondicionamiento Pretrasplante , Enfermedad Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trasplante de Médula Ósea/mortalidad , Enfermedad Crónica , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Factor XIII/administración & dosificación , Factor XIII/efectos adversos , Femenino , Fibrinógeno/administración & dosificación , Fibrinógeno/efectos adversos , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Trombina/administración & dosificación , Trombina/efectos adversos , Trasplante HomólogoRESUMEN
PURPOSE: This Phase I study was designed to evaluate the tolerability of involved-field radiotherapy (IFRT) to areas of persistent disease in patients with high-risk Hodgkin's disease and non-Hodgkin's lymphomas before autologous stem cell transplantation (ASCT). METHODS AND MATERIALS: Thirty-one patients with primary refractory or relapsed Hodgkin's disease (n = 13) and non-Hodgkin's lymphoma (n = 18) were treated with IFRT followed by high-dose chemotherapy and ASCT. All patients had bulky disease (> or =5 cm) and/or an inadequate response to salvage chemotherapy. The IFRT dose was escalated to a maximum of 36 Gy. Dose-limiting toxicity was defined as Grade 3-4 Bearman toxicity (life-threatening/fatal toxicity occurring within 28 days of ASCT). The chemotherapy regimen consisted of cyclophosphamide, etoposide, and carmustine. RESULTS: The delivered dose of IFRT was 20 Gy in 9 patients, 28-30 Gy in 20, and 32-36 Gy in 2 patients to mediastinal (n = 19) and nonmediastinal (n = 12) sites. The median interval between IFRT completion and ASCT was 19 days. One patient developed Bearman Grade 3 hepatic toxicity. No other Grade 3 or 4 Bearman toxicity was observed. An increased requirement for i.v. narcotics was observed in patients treated with mediastinal IFRT vs. nonmediastinal IFRT (p = 0.02). A trend toward increased mucositis severity was seen in patients previously treated with a larger number of chemotherapy agents (p = 0.09) and in those with a shorter interval between IFRT and ASCT (p = 0.12). Pulmonary toxicity was more common in patients treated with mediastinal IFRT than in those treated with nonmediastinal IFRT (21% vs. 0%, p = 0.13). The 2-year overall and progression-free survival rate was 70% and 49% for all patients, 84% and 50% for patients with Hodgkin's disease, and 59% and 47% for patients with non-Hodgkin's lymphoma, respectively. CONCLUSION: The maximal tolerated dose of IFRT was not reached when Grade 3-4 Bearman toxicity was dose limiting. Increased pulmonary toxicity and mucositis severity was seen after mediastinal IFRT compared with nonmediastinal IFRT. Because local control was excellent, higher doses of IFRT are not recommended. The absolute benefit of IFRT in this patient population needs investigation in future studies.