Wharton's Jelly-Derived Mesenchymal Stromal Cells as a Promising Cellular Therapeutic Strategy for the Management of Graft-versus-Host Disease.

Allogeneic hematopoietic cell transplantation (allo-HCT), a treatment option in hematologic malignancies and bone marrow failure syndromes, is frequently complicated by Graft-versus-host disease (GVHD). The primary treatment for GVHD involves immune suppression by glucocorticoids. However, patients are often refractory to the steroid therapy, and this results in a poor prognosis. Therefore alternative therapies are needed to treat GVHD. Here, we review data supporting the clinical investigation of a novel cellular therapy using Wharton's jelly (WJ)-derived mesenchymal stromal cells (MSCs) as a potentially safe and effective therapeutic strategy in the management of GVHD. Adult-derived sources of MSCs have demonstrated signals of efficacy in the management of GVHD. However, there are limitations, including: limited proliferation capacity; heterogeneity of cell sources; lengthy expansion time to clinical dose; expansion failure in vitro; and a painful, invasive, isolation procedure for the donor. Therefore, alternative MSC sources for cellular therapy are sought. The reviewed data suggests MSCs derived from WJ may be a safe and effective cellular therapy for GVHD. Laboratories investigated and defined the immune properties of WJ-MSCs for potential use in cellular therapy. These cells represent a more uniform cell population than bone marrow-derived MSCs, displaying robust immunosuppressive properties and lacking significant immunogenicity. They can be collected safely and painlessly from individuals at birth, rapidly expanded and stored cryogenically for later clinical use. Additionally, data we reviewed suggested licensing MSCs (activating MSCs by exposure to cytokines) to enhance effectiveness in treating GVHD. Therefore, WJCs should be tested as a second generation, relatively homogeneous allogeneic cell therapy for the treatment of GVHD.

Prophylactic use of zoledronic acid to prevent early bone loss is safe and feasible in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation.

Osteopenia and osteoporosis are well-known consequences of allogeneic stem cell transplantation (allo-SCT). The role of prophylactic zoledronic acid on bone turnover following allo-SCT has not been well characterized. We prospectively studied the role of prophylactic use of zoledronic acid on bone metabolism in 17 patients with acute myeloid leukemia (AML) undergoing allo-SCT over a period of three yr (2006-2009). We measured bone mineral density using dual energy X-ray absorptiometry (DXA) scanning and the markers of bone turnover by urinary N-terminal telopeptide (uNTX) and serum osteocalcin levels prior to and serially following transplantation. All patients received 4 mg of zoledronic acid (Zometa, Novartis Pharmaceuticals Corp., Basel, Switzerland) intravenously prior to starting conditioning regimen and at six months after SCT. DXA scores did not change significantly in any patient over time (p > 0.05). uNTX progressively decreased over time (p < 0.001) and serum osteocalcin stabilized after six months. No patient developed osteonecrosis of the jaw. In conclusion, in this prospective pilot study, prophylactic use of zoledronic acid to prevent early bone loss was found to be safe and feasible in patients with AML undergoing allo-SCT during the immediate post-transplantation period.

Is there a plateau in the survival curve after autologous transplantation in patients with intermediate and high-risk acute myeloid leukemia? A 20-year single institution experience.

In an attempt to examine whether autologous SCT provides long-term disease control in patients with intermediate and high-risk AML where a suitable donor is not available, we analyzed the outcomes of autologous SCT in patients with intermediate and high-risk AML from 1986 to 2005. No relapses occurred after 2.2 years. The overall survival curve appears to have developed a plateau after 2.2 years. In conclusion, autologous SCT in patients with AML in whom an allogeneic transplantation is not feasible appears to be a safe alternative and a plateau in the survival curve indicates cure in a small proportion of patients.

Autologous transplantation in patients with relapsed or high-grade follicular lymphoma provides long term disease-free survival and best median duration of response.

The best treatment option for patients with relapsed or high-grade follicular lymphoma (FL) is unknown. In spite of major advances in the therapy for FL, disease-free survival remains short, and median time to progression is just over a year. Autologous stem cell transplantation in patients with relapsed FL is safe and appears to improve disease-free survival. In an attempt to examine whether autologous stem cell transplantation provides long-term disease control in patients with relapsed or high-grade FL, we retrospectively evaluated our experience and analyzed the outcomes of autologous stem cell transplantation in patients with FL from 1991 to 2003. Seventeen men and seven women (n=24) of median age 47.5 years (range 28-64 years) were treated. Three patients with high-risk FL were in first remission. Twenty-one patients were salvaged after relapse with second-line chemotherapy. Of these, 14 were in CR at the time of transplantation, and seven patients were transplanted with active disease. Bone marrow was used in six patients as the source of stem cells prior to 1995 and peripheral blood stem cells were used in 18 patients. Twenty-three of 24 patients engrafted (96%). Median time for neutrophil recovery was 11.5 days (range 9-35 days) and 15 days (range 10-40 days) for platelets. Median duration of follow-up was 6 years (range 7 months-8 years). Of the 24 patients, six have died-with one patient death due to transplant-related pulmonary complications. Overall survival (OS) and disease-free survival (DFS) of all evaluable patients were 71.6 and 40%, respectively. Median duration of response was 4.3 years. OS and DFS in patients transplanted in CR were 80 and 57%, respectively. For those transplanted with disease, a complete response was achieved in 43% of patients, with the OS and DFS of 57 and 19%, respectively. Disease status at transplantation was not a significant variable for survival (p>0.3). Three patients developed moderate to severe treatment-related toxicity, two with grade III mucositis and one with life-threatening infection. When these results are compared with historical controls or patients treated with other modalities, autologous stem cell transplantation appears to be providing the longest disease-free survival and best duration of response.