HLA-mismatched placental blood from unrelated donors is an alternative source of stem cells for hematopoietic reconstitution in children.

Mesenchymal stem cells (MSCs) are found in a variety of tissues, including human bone marrow; secrete hematopoietic cytokines; support hematopoietic progenitors in vitro; and possess potent immunosuppressive properties. We hypothesized that cotransplantation of culture-expanded MSCs and hematopoietic stem cells (HSCs) from HLA-identical sibling donors after myeloablative therapy could facilitate engraftment and lessen graft-versus-host disease (GVHD); however, the safety and feasibility of this approach needed to be established. In an open-label, multicenter trial, we coadministered culture-expanded MSCs with HLA-identical sibling-matched HSCs in hematologic malignancy patients. Patients received either bone marrow or peripheral blood stem cells as the HSC source. Patients received 1 of 4 study-specified transplant conditioning regimens and methotrexate (days 1, 3, and 6) and cyclosporine as GVHD prophylaxis. On day 0, patients were given culture-expanded MSCs intravenously (1.0-5.0 x 10(6)/kg) 4 hours before infusion of either bone marrow or peripheral blood stem cells. Forty-six patients (median age, 44.5 years; range, 19-61 years) received MSCs and HLA-matched sibling allografts. MSC infusions were well tolerated, without any infusion-related adverse events. The median times to neutrophil (absolute neutrophil count > or = 0.500 x 10(9)/L) and platelet (platelet count > or = 20 x 10(9)/L) engraftment were 14.0 days (range, 11.0-26.0 days) and 20 days (range, 15.0-36.0 days), respectively. Grade II to IV acute GVHD was observed in 13 (28%) of 46 patients. Chronic GVHD was observed in 22 (61%) of 36 patients who survived at least 90 days; it was extensive in 8 patients. Eleven patients (24%) experienced relapse at a median time to progression of 213.5 days (range, 14-688 days). The probability of patients attaining disease- or progression-free survival at 2 years after MSC infusion was 53%. Cotransplantation of HLA-identical sibling culture-expanded MSCs with an HLA-identical sibling HSC transplant is feasible and seems to be safe, without immediate infusional or late MSC-associated toxicities. The optimal MSC dose and frequency of administration to prevent or treat GVHD during allogeneic HSC transplantation should be evaluated further in phase II clinical trials.

depend on a specific early diagnosis. Since 1994, we have come a long way in understanding the role of proinflammatory cytokines at the cellular level both within the fetus and in a possible relationship to fetal brain damage. Heretofore, birth markers such as Apgar scores, electronic fetal monitoring, neuroimaging, and onset of seizures in the first 48 hours are not specific and not sensitive. In the 1994 editorial, I stated that more accurate markers of hypoxia were needed and should develop as our understanding of the biochemical mechanisms unfold. Now that the biochemical mechanisms are unfolding, and once we can get specific levels of cytokines in the blood and the cerebrospinal fluid, interventions can be tried under randomized and controlled conditions with the hope of preventing some of the devastating consequences of hypoxic-ischemic brain damage.-RCC) ABSTRACTAt present, an estimated 1 in 5 leukemic patients receives a bone marrow or stem cell transplant from an unrelated donor or an HLA-mismatched related donor. Cord blood grafts from unrelated donors have been successful, most often in children. Hematopoiesis recovers more slowly than with bone marrow grafts, contributing to relatively high rates of infection and early death. This study examined outcomes in adults with leukemia, from 16 to 60 years of age, who received transplants of hematopoietic stem cells from unrelated donors. Data were acquired from the International Bone Marrow Transplant Registry and from the National Cord Blood Program of the New York Blood Center. Cord blood was mismatched for 1 HLA antigen in 34 cases and for 2 antigens in 116 others. Bone marrow had 1 HLA mismatch in 83 cases, whereas 367 patients received HLA-matched bone marrow. The patients given cord blood were younger than those given marrow transplants and likelier to have advanced leukemia.Median follow-up intervals were 4 years for marrow recipients and 40 months for those given cord blood transplants. For patients whose neutrophils and platelets recovered, recovery times were shorter after marrow transplantation and longest (27 days) after cord blood transplantation. A similar pattern was found for platelet recovery, with a median recovery interval of 60 days after cord blood transplantation. There were no major differences in recovery of either neutrophils or platelets after 12 months. Acute graft-versus-host disease (GVHD) was less likely after transplanting mismatched cord blood than mismatched bone marrow. Among patients who lived 3 months or longer, chronic GVHD was most frequent in patients given cord blood. The fewest treatment-related deaths were in patients given HLAEthics, Medicolegal Issues, and Public Policy 295

SUMMARY Background Umbilical cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPC) or bone marrow (BM), especially when a HLA-matched adult unrelated donor is not available. Methods In order to establish the appropriateness of current graft selection practices, we retrospectively compared leukemia-free survival and other outcomes for each graft source in patients aged >16 years transplanted for acute leukemia using Cox regression. Data were available on 1525 patients transplanted between 2002 and 2006 using UCB (n=165), PBPC (n=888) and BM (n=472). UCB units were matched at HLA-A and B at antigen level and DRB1 at allele level (n=10) or mismatched at one (n=40) or two antigens (n=115). PBPC and BM grafts from unrelated adult donors were matched for allele-level HLA-A, B, C and DRB1 (n=632; n=332) or mismatched at one locus (n=256; n=140). Findings Leukemia-free survival after UCB transplantation was comparable to that observed after 8/8 and 7/8 allele-matched PBPC or BM transplantation. Transplant-related mortality, however, was higher after UCB transplantation compared to 8/8 allele-matched PBPC (HR 1.62, p<0.01) or BM (HR 1.69, p<0.01). Grades 2–4 acute and chronic graft-versus-host disease were lower in UCB recipients compared to allele-matched PBPC (HR 0.57, p<0.01 and HR 0.38, p<0.01, respectively), while chronic and not acute graft-versus-host disease was lower after UCB compared to allele-matched BM transplantation (HR 0.63, p=0.01). Interpretation Together, these data support the use of UCB for adults with acute leukemia when an HLA-matched unrelated adult donor is lacking and when transplant is urgently needed.

Complement cascade (CC) becomes activated and its cleavage fragments play a crucial role in the mobilization of hematopoietic stem/progenitor cells (HSPCs). Here, we sought to determine which major chemottractant present in peripheral blood (PB) is responsible for the egress of HSPCs from the BM. We noticed that normal and mobilized plasma strongly chemoattracts HSPCs in a stromal derived factor-1 (SDF-1)-independent manner because i) plasma SDF-1 level does not correlate with mobilization efficiency, ii) the chemotactic plasma gradient is not affected in the presence of AMD3100, and iii) it is resistant to denaturation by heat. Surprisingly, the observed loss of plasma chemotactic activity after charcoal stripping suggested involvement of bioactive lipids and we focused on sphingosine-1 phosphate (S1P), a known chemoattracant of HSPCs. We found that S1P i) creates in plasma a continuously present gradient for BM-residing HSPCs, ii) is at physiologically relevant concentrations a chemoattractant several magnitudes stronger than SDF-1, and iii) its plasma level increases during mobilization due to CC activation and the interaction of membrane attack complex (MAC) with erythrocytes that are a major reservoir of S1P. We conclude and propose a new paradigm that S1P is a crucial chemoattractant for BM-residing HSPCs and that CC via MAC induces release of S1P from erythrocytes for optimal egress/mobilization of HSPCs.

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Umbilical-cord blood from unrelated donors can restore hematopoiesis in adults who receive myeloablative therapy and is associated with acceptable rates of severe acute and chronic GVHD.

HLA-mismatched cord blood should be considered an acceptable source of hematopoietic stem-cell grafts for adults in the absence of an HLA-matched adult donor.