sirolimus and treosulfan

Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antilymphocyte Serum; Blood Platelets; Busulfan; Child; Female; Graft vs Host Disease; HLA Antigens; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Neutrophils; Peripheral Blood Stem Cell Transplantation; Prospective Studies; Rituximab; Sirolimus; T-Lymphocytes; T-Lymphocytes, Regulatory; Tissue Donors; Transplantation Conditioning; Treatment Outcome; Vidarabine; Young Adult

Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) grafts and post-transplantation cyclophosphamide (PTCy) has gained much interest for the excellent toxicity profile after both reduced-intensity and myeloablative conditioning. We investigated, in a cohort of 40 high-risk hematological patients, the feasibility of peripheral blood stem cells grafts after a treosulfan-melphalan myeloablative conditioning, followed by a PTCy and sirolimus-based graft-versus-host disease (GVHD) prophylaxis (Sir-PTCy). Donor engraftment occurred in all patients, with full donor chimerism achieved by day 30. Post-HSCT recovery of lymphocyte subsets was broad and fast, with a median time to CD4 > 200/μL of 41 days. Cumulative incidences of grade II to IV and III-IV acute GVHD were 15% and 7.5%, respectively, and were associated with a significant early increase in circulating regulatory T cells at day 15 after HSCT, with values < 5% being predictive of subsequent GVHD occurrence. The 1-year cumulative incidence of chronic GVHD was 20%. Nonrelapse mortality (NRM) at 100 days and 1 year were 12% and 17%, respectively. With a median follow-up for living patients of 15 months, the estimated 1-year overall and disease-free survival (DFS) was 56% and 48%, respectively. Outcomes were more favorable in patients who underwent transplantation in complete remission (1-year DFS 71%) versus patients who underwent transplantation with active disease (DFS, 34%; P = .01). Overall, myeloablative haploidentical HSCT with peripheral blood stem cells (PBSC) and Sir-PTCy is a feasible treatment option: the low rates of GVHD and NRM as well as the favorable immune reconstitution profile pave the way for a prospective comparative trial comparing BM and PBSC in this specific transplantation setting.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cohort Studies; Cyclophosphamide; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Sirolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Young Adult

Oral mucositis (OM) is a side effect of intensive chemotherapy and radiation and has been reported to affect 75-100% of hematopoietic stem cell transplantation (HSCT) recipients. The purpose of this study was to compare the incidence of OM in patients conditioned with myeloablative conditioning (MAC) to reduced-intensity conditioning (RIC) and to determine the effect of a new oral care protocol.. The study involved 171 HSCT recipients, with hematological malignancies transplanted between 2007 and 2011. Median age of the patients was 50 years (range 12-71). Ninety-nine (58%) received RIC and 72 received MAC. Clinical features of OM were recorded from day -3 before to day +25 after HSCT using the World Health Organization (WHO) scoring system and the oral mucositis assessment score (OMAS).. Overall, 87% of the patients developed OM of any severity, which peaked on days 10-11. The mean WHO score was 1.7. In multivariate analysis, the severity of OM was associated with MAC (relative hazard (RH) 1.57, 95% confidence interval (CI) 1.37-1.80, p < 0.001), all donor-recipient gender combinations except female-to-male (RH = 1.26, 95% CI 1.10-1.4, p = 0.001), and early year of HSCT (RH = 0.84, 95%CI 0.7-0.96, p = 0.013). There was a correlation between long hospitalization and OM (day 15, r = 0.31, p < 0.001). There was a good correlation between the WHO and OMAS scoring systems for OM (r = 0.74, p < 0.001).. Oral mucositis was reduced in patients treated with RIC and in patients treated during recent years, when oral care was intensified. Increased scores of OM prolonged hospitalization.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Cyclophosphamide; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Multivariate Analysis; Oral Hygiene; Prednisone; Sirolimus; Stomatitis; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation; Young Adult