Prophylaxis with sirolimus and tacrolimus ± antithymocyte globulin reduces the risk of acute graft-versus-host disease without an overall survival benefit following allogeneic stem cell transplantation.

Methotrexate (MTX) is a standard agent used in combination with calcineurin inhibitors for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic cell (HCT) transplantation. We retrospectively compared the incidence of acute GVHD (aGVHD), transplant-related morbidity, and mortality in patients given sirolimus/tacrolimus ± antithymocyte globulin (ATG) versus MTX/tacrolimus or cyclosporine and allogeneic transplantation for hematologic malignancies. Between January 1, 2005, and April 30, 2009, 106 consecutive patients received peripheral blood HCT or bone marrow grafts after 1 of 6 myeloablative conditioning regimens. The incidence of grade II-IV aGVHD was 18.6% in patients who received sirolimus/tacrolimus compared to 48.9% who received MTX (P = .001). The incidence of grade III-IV aGVHD was 5% and 17% (P = .045), respectively. There was no difference in overall survival (OS) between the groups (P = .160). Chronic GVHD (cGVHD) occurred in 40.4% who received sirolimus and 41.9% receiving MTX (P = .89). The incidence of thrombotic microangiopathy or interstitial pneumonitis was not significantly different between groups. The reduction in the risk of severe aGVHD was offset by an increased (20% versus 4%, P = .015) incidence of and mortality from sinusoidal obstructive syndrome (SOS). Sirolimus/tacrolimus appears to reduce the incidence of aGVHD after conventional allotransplantion compared to MTX-calcineurin inhibitor prophylaxis; however, this did not improve survival.

Peripheral blood stem cell mobilization tactics.

OBJECTIVE: To evaluate the methods and collection techniques currently used in stem cell mobilization for patients undergoing autologous transplantation. DATA SOURCES: Literature search was performed through PubMed (1948-August 2009) and MEDLINE (1977-August 2009). Reference citations from publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All literature identified was reviewed for inclusion. Original research and retrospective cohorts, along with previously published systematic reviews of stem cell mobilization and growth factors, were evaluated. Abstract data on plerixafor were also reviewed. DATA SYNTHESIS: Successful mobilization of an adequate number of progenitor cells can help ensure and improve time to neutrophil and platelet engraftment. A variety of methods have been studied to find the safest and most predictable mobilization of CD34+ progenitor cells, including use of single agents or the combinations of hematopoietic growth factors, chemotherapy, and a novel chemokine receptor 4 antagonist. Currently, granulocyte colony-stimulating factor (G-CSF) 10 microg/kg daily started 4 days prior to apheresis remains the standard of care for initial mobilization therapy. In patients who fail to mobilize or who are at high risk for mobilization failure, cyclophosphamide in conjunction with G-CSF may be used. Plerixafor, a novel chemokine receptor antagonist, in combination with G-CSF has demonstrated superiority for achieving collection goals compared to G-CSF alone in 2 Phase 3 trials. CONCLUSIONS: The optimal mobilization strategy is still unknown; however, colony-stimulating factors remain the most commonly used mobilization agents. Currently, chemotherapy or plerixafor in combination with G-CSF is a reasonable option in heavily pretreated and hard-to-mobilize patients with non-Hodgkin's lymphoma and multiple myeloma.

Possible correlation of sirolimus plasma concentration with sinusoidal obstructive syndrome of the liver in patients undergoing myeloablative allogeneic hematopoietic cell transplantation.

STUDY OBJECTIVES: To determine the frequency of sinusoidal obstructive syndrome (SOS) in patients undergoing allogeneic hematopoietic cell transplantation who received graft-versus-host disease (GVHD) prophylaxis with sirolimus and tacrolimus, and to assess whether the occurrence of SOS correlates with immunosuppressant levels. DESIGN: Retrospective cohort study. SETTING: Hematopoietic cell transplant unit at an academic medical center. PATIENTS: Fifty-nine adults who received myeloablative preparative regimens for transplantation of any hematologic malignancy and received sirolimus and tacrolimus for GVHD prophylaxis between January 1, 2007, and May 1, 2009; all donors and transplant recipients were human leukocyte antigen (HLA) matched for at least HLA-A, -B, -C, and -DRB1. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the occurrence of SOS after hematopoietic cell transplantation. Plasma concentrations of sirolimus and tacrolimus and the summative levels of sirolimus and tacrolimus were then compared in patients who developed SOS with those who did not develop SOS. Trough levels were measured from blood samples collected 30-60 minutes before the morning doses of sirolimus and tacrolimus on days 0-35, or until the development of SOS. Of the 59 patients, 12 (20%) developed SOS. The mean sirolimus level was significantly higher in patients who developed SOS relative to those who did not develop SOS (10.5 vs 8.7 ng/ml, p=0.003). The mean summative trough level of sirolimus and tacrolimus was also significantly higher in those who developed SOS compared with those who did not (19.7 vs 17.1 ng/ml, p=0.003). The mean ± SD time to the occurrence of SOS was 28 ± 8.7 days. The median time to death was 101 days for patients who developed SOS compared with 433 days for patients who did not develop SOS (p=0.002). CONCLUSION: Sirolimus plasma concentration may correlate with the development of delayed SOS; however, further research is needed to prospectively evaluate the role of sirolimus exposure in the pathogenesis of SOS.