RESUMEN
Anti-thymocyte globulin (ATG) forms an essential component of conditioning in hematopoietic stem cell transplantation (HSCT). Due to the shift of donor preference to alternate donors, reliance on rabbit-ATG (rATG) has increased. Two different forms of rATG (Thymoglobuline® and Grafalon®) are available for clinical use but data to support the use of one over the other is sparse. We retrospectively analyzed data of 144 patients who underwent allogenic-HSCT for benign hematological conditions at our center, from August 2019 to August 2023. Of these, 87 received Grafalon® and 57 received Thymoglobuline®. The majority (77.7%) underwent HSCT for hemoglobinopathies and all received pre-transplant immunosuppression. Engraftment kinetics was similar in 2 cohorts. Six patients had primary graft failure (PGF). There was no difference in the incidence of PGF stratified by serotherapy. Overall survival(OS) for the cohort was 74.9%. Kaplan-Meier estimate of OSand EFSwas significantly better in Grafalon® group than Thymoglobuline® (84.4 ± 0.04% vs 64.1% ±0.065%) (p-value= 0.04%) and (84.4 ± 0.04% and 61.2%±0.065% (p-value = 0.01)). Extensive chronic GVHD was (14%) higher in Thymoglobuline® group and (2.3%) in Grafalon®. Immune reconstitution at day + 100 was not statistically different between the two groups. On univariate analysis, Thymoglobuline® serotherapy (OR (95% CI) =4.665 (1.2-18.04))was associated with increased risk of acute grade III-IV GvHD. In our study, Grafalon® tended to have better OS, decreased incidence of acute grade III-IV GvHD, and extensive cGVHD. There was no difference in engraftment kinetics, PGF, and immune reconstitution between 2 cohorts of serotherapy.
RESUMEN
BACKGROUND: HSP90 inhibitors effectively reduce expression and activity levels of oncogenic survival proteins. However, their clinical anti-multiple myeloma (MM) activity has been found to be rather weak, spurring the exploration of combination therapies and development of compounds with improved physicochemical properties. MATERIALS AND METHODS: Preclinical effects of the novel orally bioavailable HSP90 inhibitor NVP-HSP990 on the viability, apoptosis and client protein levels of MM cells (established cell lines and clinical specimens) were tested alone and in combination with other drugs. RESULTS: NVP-HSP990 exerted profound activity against MM cells, with a molecular mode of action conforming well with its role as HSP90 inhibitor. Enhanced activity was most obvious in combination with melphalan. Combination with a phosphatidylinositol-3-kinase (PI3-kinase)/mammalian target of rapamycin (mTOR) inhibitor, rendered the HSP90 blockade-mediated stress response ineffective and considerably increased the anti-MM toxicity. CONCLUSION: Given the current interest in both HSP90 and PI3-kinase/mTOR as potential clinical targets, these observations could broaden the therapeutic utility of either class of inhibitor in MM.