Most adults with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR) will relapse. We examined the outcome of 609 adults with recurring ALL, all of whom were previously treated on the Medical Research Council (MRC) UKALL12/ECOG2993 study, where the overall survival (OS) of newly diagnosed patients is 38% (95% confidence interval [CI] ‫؍‬ 36%-41%) at 5 years. By contrast, OS at 5 years after relapse was 7% (95% CI ‫؍‬ 4%-9%). Factors predicting a good outcome after salvage therapy were young age (OS of 12% in patients younger than 20 years vs OS of 3% in patients older than 50 years; 2P < .001) and short duration of first remission (CR1) (OS of 11% in those with a CR1 of more than 2 years versus OS of 5% in those with a CR1 of less than 2 years; 2P < .001). Treatment received in CR1 did not influence outcome after relapse. In a very highly selected subgroup of patients who were able to receive HSCT after relapse, some were long-term survivors. We conclude from a large, unselected series with mature follow-up that most adults with recurring ALL, whatever their prior treatment, cannot be rescued using currently available therapies. Prevention of recurrence is the best strategy for long-term survival in this disease. (Blood. 2007;109:944-950)

An international collaboration was set up to prospectively evaluate the role of allogeneic transplantation for adults with acute lymphoblastic leukemia (ALL) and compare autologous transplantation with standard chemotherapy. Patients received 2 phases of induction and, if in remission, were assigned to allogeneic transplantation if they had a compatible sibling donor. Other patients were randomized to chemotherapy for 2.5 years versus an autologous transplantation. A donor versus no-donor analysis showed that Philadelphia chromosome-negative patients with a donor had a 5-year improved overall survival (OS), 53% versus 45% (P ‫؍‬ .01), and the relapse rate was significantly lower (P < .001). The survival difference was significant in standard-risk patients, but not in high-risk patients with a high nonrelapse mortality rate in the highrisk donor group. Patients randomized to chemotherapy had a higher 5-year OS (46%) than those randomized to autologous transplantation (37%; P ‫؍‬ .03). Matched related allogeneic transplantations for ALL in first complete remission provide the most potent antileukemic therapy and considerable survival benefit for standard-risk patients. However, the transplantation-related mortality for highrisk older patients was unacceptably high and abrogated the reduction in relapse risk. There is no evidence that a single autologous transplantation can replace consolidation/maintenance in any risk group. This study is registered at http:// clinicaltrials.gov as NCT00002514. (Blood.

The immunosuppressive activity of mesenchymal stromal cells (MSC) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSC are undetectable following administration. Therefore, understanding the fate of infused MSC could help to predict clinical responses. Using a murine model of graft-versus-host disease (GvHD) we demonstrate that MSC are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. When examining patients with GvHD who received MSC we found a striking parallel, whereby only those with high cytotoxic activity against MSC responded to MSC infusion whereas those with low activity did not. Importantly, the need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSC generated ex vivo. After infusion, recipient phagocytes engulf apoptotic MSC and produce indoleamine 2,3-dioxygenase (IDO) that is ultimately necessary for effecting immunosuppression. Therefore, we propose the innovative concept that patients should be stratified for MSC treatment according to their ability to kill MSC or that all patients could be treated with ex vivo apoptotic MSC.

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