A B S T R A C T PurposeTransplantation-related mortality (TRM) is a major barrier to the success of allogeneic hematopoietic cell transplantation (HCT). Patients and MethodsWe assessed changes in the incidence of TRM and overall survival from 1985 through 2004 in 5,972 patients younger than age 50 years who received myeloablative conditioning and HCT for acute myeloid leukemia (AML) in first complete remission (CR1) or second complete remission (CR2). ResultsAmong HLA-matched sibling donor transplantation recipients, the relative risks (RRs) for TRM were 0.5 and 0.3 for 2000 to 2004 compared with those for 1985 to 1989 in patients in CR1 and CR2, respectively (P Ͻ .001). The RRs for all causes of mortality in the latter period were 0.73 (P ϭ .001) and 0.60 (P ϭ .005) for the CR1 and CR2 groups, respectively. Among unrelated donor transplantation recipients, the RRs for TRM were 0.73 (P ϭ .095) and 0.58 (P Ͻ .001) for 2000 to 2004 compared with those in 1990 to 1994 in the CR1 and CR2 groups, respectively. Reductions in mortality were observed in the CR2 group (RR, 0.74; P ϭ .03) but not in the CR1 group. ConclusionOur results suggest that innovations in transplantation care since the 1980s and 1990s have reduced the risk of TRM in patients undergoing allogeneic HCT for AML and that this reduction has been accompanied by improvements in overall survival. J Clin

We have reported a lower incidence of acute graft versus host disease (aGVHD) with a novel conditioning regimen using low dose rabbit anti-thymocyte globulin (TG, Thymoglobulin) with fludarabine and intravenous busulfan (FluBuTG). To assess further this single center experience, we performed a retrospective matched pair analysis comparing outcomes of adult patients transplanted using the FluBuTG conditioning regimen with matched controls from patients reported to the CIBMTR receiving a first allogeneic hematopoietic stem cell transplant (HCT) after standard oral busulfan and cyclophosphamide (BuCy). 120 cases and 215 matched controls were available for comparison. Patients receiving FluBuTG had significantly less treatment related mortality (12% vs 34%, p<0.001) and grades II–IV aGVHD (15% vs 34% p<0.001) compared to BuCy patients. The risk of relapse was higher in the FluBuTG patients (42% vs 20%, p<0.001). The risks of chronic GVHD (cGVHD) and disease free survival (DFS) were similar in the cases and controls. These results suggest that the novel regimen FluBuTG decreases the risk of aGVHD and transplant mortality after HLA-identical sibling HCT, but is associated with an increased risk of relapse, resulting in similar DFS. Whether these conditioning regimens may be more suitable for specific patient populations based on relapse risk requires testing in prospective randomized trials.

The incidence of excessive adiposity is increasing worldwide and is associated with numerous adverse health outcomes. We compared outcomes by body mass index (BMI) for adult patients with acute myeloid leukemia (AML) who underwent autologous (auto, n=373), related donor (RD, n=2041), or unrelated donor (URD, n=1801) allogeneic myeloablative hematopoietic cell transplantation (HCT) using marrow or peripheral blood stem cells reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995-2004. Four weight groups by BMI (kg/m2) were defined: underweight < 18; normal 18 – 25; overweight >25 – 30; and obese > 30. Multivariable analysis referenced to the normal weight group showed an increased risk of death for underweight patients in the RD group (RR, 1.92; 95% CI, 1.28-2.89; P = 0.002) but not in the URD group. There were no other differences in outcomes among the other weight groups within the other HCT groups. Overweight and obese patients enjoyed a modest decrease in relapse incidence, though this did not translate into a survival benefit. Small numbers of patients limit the ability to better characterize the adverse outcomes seen in the underweight RD but not the underweight URD allogeneic HCT patients. Obesity alone should not be considered a barrier to HCT.

To assess the impact of spleen status on engraftment and early morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), we analyzed 9,683 myeloablative allograft recipients from 1990 to 2006; 472 had prior splenectomy (SP), 300 splenic irradiation (SI), 1,471 with splenomegaly (SM), and 7,440 with normal spleen (NS). Median times to neutrophil and platelet engraftment were 15 vs. 18 days and 22 vs. 24 days for the SP and NS groups, respectively (p<0.001). Hematopoietic recovery at day +100 was not different across all groups, however the odds of days +14 and +21 neutrophil and day +28 platelet engraftment were 3.26, 2.25, and 1.28 for splenectomy, and 0.56, 0.55, and 0.82 for splenomegaly groups compared to normal spleen (p<0.001), respectively. Among patients with splenomegaly, use of peripheral blood grafts improved neutrophil engraftment at day +21, and CD34+ cell dose >5.7x106/kg improved platelet engraftment at day+28. After adjusting variables by Cox regression, the incidence of graft-versus-host disease (GVHD) and overall survival were not different among groups. Splenomegaly is associated with delayed engraftment while splenectomy prior to HCT facilitates early engraftment without impact on survival.

Failure to engraft donor cells is a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We describe the results of 122 patients reported to the National Marrow Donor Program between 1990 and 2005, who received a second unrelated donor HCT after failing to achieve an absolute neutrophil count of ≥ 500/ μL without recurrent disease. Patients were transplanted for leukemia (n=83), myelodysplastic disorders (n=16), severe aplastic anemia (n=20) and other diseases (n=3). The median age was 29 years. Twenty-four patients received second grafts from a different unrelated donor. Among 98 patients who received a second graft from the same donor, 28 received products that were previously collected and cryopreserved for the first transplantation. One-year overall survival after second transplant was 11% with 10 patients alive at last follow up. We observed no differences between patients who received grafts from the same or different donors, or in those who received fresh or cryopreserved product. The outcomes after a second allogeneic HCT for primary graft failure are dismal. Identifying risk factors for primary graft failure can decrease the incidence of this complication. Further studies are needed to test whether early recognition and hastened procurement of alternative grafts can improve transplant outcomes for primary graft failure.

The prevalence of obesity in the pediatric population has increased in the last two decades and represents a serious health concern with potential impact on transplantation outcomes. We studied the effect of weight, by age-adjusted body mass index (BMI) percentiles on 1,281 pediatric patients (ages 2-19) with severe aplastic anemia transplanted between 1990 and 2005. The study population was divided into five weight groups: underweight, risk of underweight, normal BMI range, risk of overweight and overweight, according to age-adjusted BMI percentiles. Cox proportional hazards regression models for survival and acute graft-versus-host disease (aGVHD), performed using weight groups as the main effect and the normal BMI range (26-75th percentile) as the baseline comparison, found higher mortality among overweight children (>95th percentile adjusted for age). Weight at transplantation did not increase the adjusted risk of grades III-IV aGVHD. One- and two-year overall survival rates were 60% and 59% for overweight children, compared to rates greater than 70% in children with lower BMI at both time points (p<0.001). Other significant factors associated with survival included race and region, donor type, conditioning regimens in related donor transplants, performance score and year of transplant. In conclusion, overweight children with aplastic anemia have worse outcomes after HCT. The impact of obesity on survival outcomes in children should be discussed during pre-transplant counseling.

Despite continual improvement, morbidity and mortality after hematopoietic stem cell transplantation (HSCT) remain high. The importance of chemokines in HSCT lies in their regulation of immune responses that determine transplantation outcomes. We investigated the role of recipient and donor chemokine system gene polymorphisms by using a candidate gene approach on the incidence of graft-versus-host disease and posttransplantation outcomes in 1370 extensively human leukocyte antigen-matched, unrelated donor-recipient pairs by using multivariate Cox regression models. Our analysis identified that recipients homozygous for a common CCR5 haplotype (H1/H1) had better disease-free survival (DFS; P ‫؍‬ .005) and overall survival (P ‫؍‬ .021). When the same genotype of both the donor and recipient were considered in the models, a highly significant association with DFS and overall survival was noted (P < .001 and P ‫؍‬ .007, respectively) with absolute differences in survival of up to 20% seen between the groups at 3 years after transplantation (50% DFS for pairs with recipient CCR5 H1/H1 vs 30% for pairs with donor CCR5 H1/H1). This finding suggests that donor and/or recipient CCR5 genotypes may be associated with HSCT outcome and suggests new diagnostic and therapeutic strategies for optimizing therapy. (Blood.

The survival of relapsed acute myeloid leukemia (AML) after autologous hematopoietic stem cell transplantation (Autologous HCT) is very poor. We studied the outcomes of 302 patients who underwent secondary allogeneic hematopoietic cell transplantation (Allo-HCT) from an unrelated donor (URD) using either myeloablative (n=242) or reduced-intensity conditioning regimens (RIC, n=60) reported to CIBMTR. After a median follow-up of 58 months (range 2–160), the probability of treatment-related mortality (TRM) was 44% (95%CI 38–50) at 1-year. The 5-year incidence of relapse and overall survival (OS) was 32% (95%CI 27–38) and 22% (95%CI 18–27), respectively. In multivariate analysis significantly better OS was observed with RIC regimens (Hazard Ratio (HR) 0.51, 95%CI 0.35–0.75, p<0.001), with Karnofsky performance status (KPS) ≥90% (HR 0.62, 95%CI 0.47–0.82, p=0.001) and in CMV-negative recipients (HR 0.64, 95%CI 0.44–0.94, p=0.022). Longer interval (>18 months) from Autologous HCT to URD Allo-HCT was associated with significantly lower Relapse risk (HR 0.19, 95%CI 0.09–0.38, p<0.001) and improved LFS (HR 0.53, 95%CI 0.34–0.84, p=0.006). URD Allo-HCT after Autologous HCT relapse results in 20% long-term leukemia-free survival, with best results with longer interval to secondary URD transplantation, KPS ≥90%, in complete remission, and using RIC regimens. Further efforts to reduce TRM and relapse are still needed.