The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

Background We have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reduce-graft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting. DESIGN AND METHODS: We evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease. RESULTS: The combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN γ, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft-versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. Conclusions The current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft-versus-host disease while maintaining the graft-versus-leukemia effect.     

Quality of Life in 833 outpatients with major depression treated with open-label venlafaxine extended release: An observational 24-week study

BACKGROUND Quality of Life (QoL) assessments are common in medicine and, recently, in psychiatry, mostly in patients with chronic mental illness. We evaluated QoL in depressed outpatients treated with venlafaxine-XR over a period of 24 weeks. METHOD We evaluated 833 patients with DSM-IV major depression using the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale (HAM-A), the Montgomery-Åsberg Depression Rating Scale (MÅDRS), and the QoL in Depression Scale (QLDS). The patients received venlafaxine-XR and we evaluated them after 4, 8, and 24 weeks of treatment. RESULTS HAM-D scores decreased from a baseline of 24.6 &#45 6.3 to 6.0 &#45 5.5 (mean &#45 SD; P <0.0001) after 24 weeks. HAM-A scores decreased from a baseline of 32.3 &#45 7.9 to 6.8 &#45 6.8 ( P <0.0001) after 24 weeks. QLDS scores decreased from a baseline of 25.8 &#45 5.8 to 6.6 &#45 7.5 ( P <0.0001) after 24 weeks, indicating improvement in QoL. The response after 4 weeks was also significant and continued improving during the study. Venlafaxine-XR was shown to be safe and well tolerated. DISCUSSION Open-label venlafaxine-XR was safe, effective, well tolerated, and improved not only depression and anxiety symptoms, but also QoL, in outpatients with major depression. This study has the limitations of any non-randomized, non-blinded multiple-site clinical trial.     

C.E.R.A. maintains stable hemoglobin in Latin American patients on dialysis

Background

C.E.R.A. is a continuous erythropoietin receptor activator with characteristics that permit a once-monthly schedule of administration for the maintenance treatment for chronic kidney disease (CKD) patients. The main objective of this study was to assess the maintenance of Hb concentration with once-monthly intravenous and/or subcutaneous C.E.R.A. therapy in Latin American dialysis patients with chronic renal anemia previously treated with epoetin alfa s.c or i.v 1–3 times per week.

Methods

This was a single-arm, open-label, multicenter, 32-week study of anemic patients with CKD previously treated with epoetin alfa sc or iv 1–3 times per week. After a 4-week screening period, during which mean Hb levels were maintained between 10.5 and 12.5 g/dL on their previous erythropoiesis stimulating agent, eligible patients entered a 16-week C.E.R.A. dose titration period followed by a 4-week efficacy evaluation period (EEP) and a 28-week safety follow-up. The starting dose of C.E.R.A. was based on the previous dose of epoetin alfa. Doses of C.E.R.A. were then adjusted to maintain Hb levels within ±1.0 g/dL of the reference concentration and between 10.5 and 12.5 g/dL. The Hb reference concentration was defined as the mean of all Hb levels during screening. The primary end point was the proportion of patients maintaining a mean Hb concentration (g/dL) within ±1 g/dL of their reference Hb and between 10.5 and 12.5 g/dL during the EEP.

Results

A total of 163 patients from 27 centers in Argentina, Brazil, Chile, Colombia, Ecuador, Mexico, Peru, Uruguay, and Venezuela entered the treatment period and 102 completed the prescribed course of C.E.R.A. Forty-five patients (43.7 %) maintained a mean Hb concentration within ±1 g/dL of their reference Hb value and between 10.5 and 12.5 g/dL during the EEP. The median monthly dose remained constant at 120 μg during the titration period and during the EEP. On the average, there were only 2.3 dose changes per patient in 28 weeks of treatment, covering 7 C.E.R.A. scheduled administrations. 53 % of all dose changes were dose decreases, 47 % increases. A total of 10 AEs and 4 SAEs were considered to be related to the study treatment.

Conclusions

Once-monthly C.E.R.A. treatment effectively maintains stable Hb concentrations in patients with chronic renal anemia undergoing dialysis with a good safety and tolerability profile.