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SUMMARY Defining conditioning regimen intensity has become a critical issue for the hemopoietic stem cell transplant community. In the present report we propose to define conditioning regimens in three categories: (a) myeloablative conditioning (MA) , (b) reduced intensity conditioning (RIC) and (c) non myeloablative conditioning (NMA). Assignment to these categories is based on the duration of cytopenia and on the requirement for stem cell (SC) support: MA regimens cause irreversible cytopenia and SC support is mandatory. NMA regimens cause minimal cytopenia and can be given also without SC support. RIC regimens do not fit criteria for MA or NMA regimens : they cause cytopenia of variable duration and should be given with stem cell support, although cytopenia may not be irreversible. This report also assigns commonly used regimens to one of these categories. based upon the agents, dose or combinations. Standardized classification of conditioning regimen intensities will allow comparison across studies and interpretation of study results.

BACKGROUND In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival. METHODS In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival. RESULTS In the intention-to-treat analysis, high-dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P = 0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months. CONCLUSIONS In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose.

Voriconazole is a suitable alternative to amphotericin B preparations for empirical antifungal therapy in patients with neutropenia and persistent fever.

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)

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

The international acute lymphoblastic leukemia (ALL) study was designed to prospectively define the optimal therapy for adults 60 years of age or younger with newly diagnosed ALL. All patients received identical induction therapy, and 91% achieved complete remission (CR). Patients 50 years of age or younger with a compatible sibling were assigned to undergo allogeneic transplantation; the others were randomly assigned to autologous transplantation or to consolidation/maintenance therapy for 2.5 years. Patients who did not achieve CR after induction had an overall survival rate of 5% compared with 45% for patients who achieved CR. Factors at diagnosis predictive of overall survival and diseasefree survival were age (P ‫؍‬ .001), white blood cell count less than 30 ؋ 10 9 /L for B lineage or less than 100 ؋ 10 9 /L for T lineage (P ‫؍‬ .001) and immunophenotype, T lineage versus B lineage (P ‫؍‬ .001). The data demonstrate that achieving CR with induction therapy is indispensable for long-term survival in adult patients with ALL. Furthermore, with a response rate greater than 90%, the induction regimen was highly efficacious as remissioninducing therapy. This large database has validated several previously identified independent prognostic factors in ALL, such as age, white blood cell count at presentation, cytogenetics, and immunophenotype. However, the achievement of CR within 4 weeks does not appear to be an independent prognostic factor. (Blood. 2005;106:3760-3767)