RESUMEN

Cytokine release syndrome (CRS) is a potentially fatal systemic inflammatory response that can occur in patients undergoing peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT). Severe CRS has previously been associated with increased infection risk. IL-6 inhibitors, such as tocilizumab, are useful in moderate to severe CRS, but their effect on infection risk has not been established in this setting. We examined the effect of tocilizumab on blood stream infections (BSIs) in the early post-transplant period in 235 patients who underwent haplo-HCT from 2013 to 2020. Mild CRS was associated with a lower incidence of BSI than severe CRS (OR 0.31, 95% CI 0.13-0.74). In the tocilizumab group, 31% of patients had positive blood cultures versus 14% in the non-tocilizumab group (OR 1.61, 95% CI 0.30-8.60, p = 0.58). However, when controlling for CRS grade, tocilizumab was not independently associated with increased rates of BSIs, suggesting it does not further increase infection risk.

Asunto(s)

Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Sepsis , Humanos , Trasplante Haploidéntico/efectos adversos , Síndrome de Liberación de Citoquinas/epidemiología , Síndrome de Liberación de Citoquinas/etiología , Incidencia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Estudios Retrospectivos , Ciclofosfamida

RESUMEN

BACKGROUND: Posaconazole reduces the risk of invasive Aspergillus in transplant patients, but significantly inhibits tacrolimus metabolism. One study demonstrated that a three-fold dose reduction of tacrolimus was required to obtain therapeutic concentrations when used with posaconazole. However, with empiric dose reduction, there is a risk of subtherapeutic tacrolimus levels and subsequent graft failure or graft-versus-host disease. Overall, the existing data on the impact of posaconazole on tacrolimus pharmacokinetics is limited. OBJECTIVE: The purpose of this study is to determine whether tacrolimus doses should be decreased upon initiation of posaconazole in patients receiving an allogeneic stem cell transplant. METHODS: This is a retrospective chart review at an academic medical center. All allogeneic stem cell transplant adults who received concomitant posaconazole and tacrolimus from February 2016 through December 2017 were included. RESULTS: Seventy-nine patients identified using an internal electronic database were analyzed. The median time to therapeutic tacrolimus concentration was significantly longer in patients who did not receive an empiric dose reduction (0% DR, 10d; 1-30% DR, 4d; 31-65% DR, 5d; >65% DR, 4d; p = 0.0395). The rate of supratherapeutic levels was highest amongst patients who did not receive an empiric DR, and was noted to be significant compared to the group that had 31-65% DR (p < 0.001). CONCLUSION: This study validates our current practice of instituting an empiric 50% dose reduction of oral tacrolimus to 0.03 mg/kg/day when used concomitantly with posaconazole to achieve therapeutic levels in allogeneic stem cell transplant patients.

Asunto(s)

Antifúngicos/farmacocinética , Trasplante de Células Madre Hematopoyéticas/tendencias , Inmunosupresores/farmacocinética , Trasplante de Células Madre/tendencias , Tacrolimus/farmacocinética , Triazoles/farmacocinética , Adulto , Antifúngicos/administración & dosificación , Esquema de Medicación , Interacciones Farmacológicas/fisiología , Femenino , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Humanos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tacrolimus/administración & dosificación , Triazoles/administración & dosificación

RESUMEN

Introduction Due to the lack of formal guideline recommendations, available primary literature was used to develop a proposed protocol for management of hypercalcemia of malignancy at the University of Chicago Medical Center. Methods A retrospective, single center, observational study was performed including adult patients hospitalized with a diagnosis of hypercalcemia and active malignancy. Patients were retrospectively identified as treated in a manner aligned with the proposed protocol ("per protocol") or not treated according to the proposed protocol ("off protocol"), and the outcomes were compared. The primary outcome for efficacy was normalization of corrected calcium within four and seven days of treatment. Results Normalization of corrected calcium was observed in 66% of patients managed per protocol compared to 65% of patients managed off protocol ( p = 1.00) at day four, and in 73% of per protocol patients compared to 65% of off protocol patients ( p = 0.44) at day seven. Areas identified where prospective implementation of the proposed protocol can improve management include: decreasing utilization of bisphosphonates in mild hypercalcemia, optimizing bisphosphonate dosing in renal impairment, decreasing intravenous phosphate repletion, and ensuring proper fluid management and calcitonin dosing. Conclusion Although a statistical difference was not detected in terms of normalization of corrected calcium levels, areas for optimization in management were identified. Therefore, implementation of the proposed protocol is expected to promote evidence-based management of hypercalcemia of malignancy management at University of Chicago Medical Center.