Pilot Clinical Study Incorporating Hyperbaric Oxygen into Umbilical Cord Blood Transplantation

Background: Umbilical cord blood (UCB) is a rich source of hematopoietic stem cells and may be the only allogeneic transplant option for some patients with hematologic malignancies. However, UCB transplantation is associated with delayed blood count recovery and engraftment. In preclinical studies, we have demonstrated that hyperbaric oxygen (HBO) therapy, given prior to cytokine expanded and gene-transduced UCB CD34+ cell infusion, improves peripheral blood, bone marrow, and spleen engraftment in a murine model. Based on these results, we started a pilot clinical trial primarily investigating the safety of HBO in the setting of UCB transplantation. Secondarily, we are evaluating the time to neutrophil and platelet count recovery and engraftment.As a potential marker for effective HBO therapy, we also evaluated serum erythropoietin (EPO) levels in transplanted patients prior to HBO therapy and again at time of transplantation.

Materials/methods: Patients with hematological malignancies that require UCB transplantation, either reduced intensity or myeloablative, were included. On day 0, patients received HBO treatment consisting of exposure to 2.5 atmosphere absolutes for a total of 2 hours, in a single hyperbaric chamber, breathing 100% oxygen. Six hours from the start of HBO, single or double UCB units were infused and patients were followed daily for toxicity and blood count recovery. Serum EPO levels were measured by enzyme-linked immunosorbent assay (ELISA).

Results: 18 patients were screened for this study, 9 were enrolled, and 9 were treated. The treated subjects were 5 males (56%) and 4 females (44%) with median age of 44 (23-70) who had acute myeloid leukemia (n=6), non-Hodgkin’s lymphoma (n=1), and acute lymphoblastic leukemia (n=2); all patients were in first (n=8) or second (n=1) complete remission. All but two patients received one UCB unit with a median total nucleated cell dose of 3.3 (2.7-4.5) ×10⁷ /Kg recipient body weight and 6 of 9 patients received reduced intensity conditioning. All treated patients completed the planned therapy without a treatment limiting toxicity defined as the occurrence of any of the following complications within 24 hours of HBO: seizure disorder, pneumothorax, death or irreversible grade III or any grade IV toxicity that is determined by the treating physician to be, at least, likely related to HBO therapy. None of the patients experienced an unexpected toxicity. All patients engrafted except for one patient who demonstrated prompt autologous blood count recovery. Platelet count recovery was not assessable in one patient. Time to neutrophil count recovery (defined as the first of 3 consecutive days of an absolute neutrophil count (ANC) of greater than 500/μL) and time to platelet count recovery (defined as the first day of a sustained platelet count greater than 20 K/UL) were 16 (6-25) and 32 (8-87), respectively. 90% or higher donor chimerism was documented in peripheral blood/bone marrow of engrafted patients receiving reduced intensity regimen at a median of 18 (15-31) days post-transplant. Six of the 9 (67%) patients developed acute graft versus host disease at time of engraftment; 50% developed grade I, 33% had grade II and 17% had grade III. In 7 patients who had serum EPO levels assessed, median EPO levels at time of UCB infusion were lower than their median levels prior to HBO therapy (11.3 vs. 25.2 mU/mL).

Conclusions: HBO therapy prior to UCB cell infusion appears to be well-tolerated in the setting of clinical umbilical cord blood transplantation. Time to neutrophil recovery/engraftment as well as platelet count recovery appear to be encouraging. HBO therapy resulted in lower EPO serum levels at time of UCB infusion.