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.

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Umbilical cord blood is an alternative hematopoietic stem cell source for patients with hematologic diseases who can be cured by allogeneic hematopoietic cell transplantation. Initially, umbilical cord blood transplantation was limited to children, given the low cell dose infused. Both related and unrelated cord blood transplants have been performed with high rates of success for a variety of hematologic disorders and metabolic storage diseases in the pediatric setting. The results for adult umbilical cord blood transplantation have improved, with greater emphasis on cord blood units of sufficient cell dose and human leukocyte antigen match and with the use of double umbilical cord blood units and improved supportive care techniques. Cord blood expansion trials have recently shown improvement in time to engraftment. Umbilical cord blood is being compared with other graft sources in both retrospective and prospective trials. The growth of the field over the last 25 years and the plans for future exploration are discussed.

with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n ‫؍‬ 50) and 62% and 48%, respectively, after Haplomarrow transplantation (n ‫؍‬ 50). The day ؉56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1-year cumulative incidences of nonrelapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplomarrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies.

BACKGROUND Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P = 0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P = 0.02). At 72 months, Kaplan–Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P = 0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P = 0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530.)

During the 2006 Tandem BMT Meetings a workshop was convened by the Center for International Blood and Marrow Transplant Research (CIBMTR) to discuss conditioning regimen intensity and define boundaries of “reduced intensity conditioning” (RIC) prior to hematopoietic cell transplantation (HCT). The goal of the workshop was to determine acceptance within the transplant community of available RIC definitions. The participants were surveyed during the workshop to state if they strongly agreed, agreed, disagreed or strongly disagreed with specific statements on conditioning regimen intensity. The questions included the “Champlin criteria” as well as operational definitions used in registries studies exemplified in clinical vignettes. Fifty-six participants including transplant physicians, transplant center directors and transplant nurses with a median of 12 years of experience in HCT answered the survey. Sixty-seven percent agreed with statements that a RIC regimen should cause reversible myelosuppression when administered without stem cell support; result in low non-hematologic toxicity and after transplantation results in mixed donor-recipient chimerism at the time of first assessment in the majority of patients. Likewise the majority (71%) agreed or strongly agreed that regimens with less than 500 cGy of total body irradiation as a single fraction or 800 cGy in fractionated doses, busulfan less than 9 mg/kg, melphalan less than 140 mg/m2 or thiotepa less than 10 mg/kg should be considered RIC regimens. However, only 32% agreed or strongly agreed that the combination of carmustine, etoposide, cytarabine and melphalan (BEAM) be considered a RIC regimen. These results demonstrate that although a consensus of what constitutes a RIC regimen does not exist among HCT professionals, currently used criteria and operational definitions are accepted by a majority of them. These results support the continued use of current criteria for RIC regimens until a consensus statement is developed.

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• Molecular profiling was used to optimize an ex vivo modulation protocol with dmPGE 2 for UCB transplantation.• Pulse treatment of UCB with dmPGE 2 is safe and may lead to accelerated UCB engraftment and preferential cord chimerism.Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells (HSCs) for use in allogeneic transplantation. Key advantages of UCB are rapid availability and less stringent requirements for HLA matching. However, UCB contains an inherently limited HSC count, which is associated with delayed time to engraftment, high graft failure rates, and early mortality. 16,16-Dimethyl prostaglandin E 2 (dmPGE 2 ) was previously identified to be a critical regulator of HSC homeostasis, and we hypothesized that brief ex vivo modulation with dmPGE 2 could improve patient outcomes by increasing the "effective dose" of HSCs. Molecular profiling approaches were used to determine the optimal ex vivo modulation conditions (temperature, time, concentration, and media) for use in the clinical setting. A phase 1 trial was performed to evaluate the safety and therapeutic potential of ex vivo modulation of a single UCB unit using dmPGE 2 before reduced-intensity, double UCB transplantation. Results from this study demonstrated clear safety with durable, multilineage engraftment of dmPGE 2 -treated UCB units. We observed encouraging trends in efficacy, with accelerated neutrophil recovery (17.5 vs 21 days, P 5 .045), coupled with preferential, long-term engraftment of the dmPGE 2 -treated UCB unit in 10 of 12 treated participants. This study was registered at www. clinicaltrials.gov as #NCT00890500. (Blood. 2013;122(17):3074-3081)