Comparing Outcomes with Bone Marrow or Peripheral Blood Stem Cells as Graft Source for Matched Sibling Transplants in Severe Aplastic Anemia across Different Economic Regions.

Bone marrow (BM) is the preferred graft source for hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) compared with mobilized peripheral blood stem cells (PBSCs). We hypothesized that this recommendation may not apply to those regions where patients present later in their disease course, with heavier transfusion load and with higher graft failure rates. Patients with SAA who received HSCT from an HLA-matched sibling donor from 1995 to 2009 and reported to the Center for International Blood and Marrow Transplant Research or the Japan Society for Hematopoietic Cell Transplantation were analyzed. The study population was categorized by gross national income per capita and region/countries into 4 groups. Groups analyzed were high-income countries (HIC), which were further divided into United States-Canada (n = 486) and other HIC (n = 1264); upper middle income (UMIC) (n = 482); and combined lower-middle, low-income countries (LM-LIC) (n = 142). In multivariate analysis, overall survival (OS) was highest with BM as graft source in HIC compared with PBSCs in all countries or BM in UMIC or LM-LIC (P < .001). There was no significant difference in OS between BM and PBSCs in UMIC (P = .32) or LM-LIC (P = .23). In LM-LIC the 28-day neutrophil engraftment was higher with PBSCs compared with BM (97% versus 77%, P = .002). Chronic graft-versus-host disease was significantly higher with PBSCs in all groups. Whereas BM should definitely be the preferred graft source for HLA-matched sibling HSCT in SAA, PBSCs may be an acceptable alternative in countries with limited resources when treating patients at high risk of graft failure and infective complications.

Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy.

We studied the effect of allele-level matching at human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 in 1568 single umbilical cord blood (UCB) transplantations for hematologic malignancy. The primary end point was nonrelapse mortality (NRM). Only 7% of units were allele matched at HLA-A, -B, -C, and -DRB1; 15% were mismatched at 1, 26% at 2, 30% at 3, 16% at 4, and 5% at 5 alleles. In a subset, allele-level HLA match was assigned using imputation; concordance between HLA-match assignment and outcome correlation was confirmed between the actual and imputed HLA-match groups. Compared with HLA-matched units, neutrophil recovery was lower with mismatches at 3, 4, or 5, but not 1 or 2 alleles. NRM was higher with units mismatched at 1, 2, 3, 4, or 5 alleles compared with HLA-matched units. The observed effects are independent of cell dose and patient age. These data support allele-level HLA matching in the selection of single UCB units.

Donor killer cell Ig-like receptor B haplotypes, recipient HLA-C1, and HLA-C mismatch enhance the clinical benefit of unrelated transplantation for acute myelogenous leukemia.

Killer cell Ig-like receptors (KIRs) interact with HLA class I ligands to regulate NK cell development and function. These interactions affect the outcome of unrelated donor hematopoietic cell transplantation (HCT). We have shown previously that donors with KIR B versus KIR A haplotypes improve the clinical outcome for patients with acute myelogenous leukemia by reducing the incidence of leukemic relapse and improving leukemia-free survival (LFS). Both centromeric and telomeric KIR B genes contribute to the effect, but the centromeric genes are dominant. They include the genes encoding inhibitory KIRs that are specific for the C1 and C2 epitopes of HLA-C. We used an expanded cohort of 1532 T cell-replete transplants to examine the interaction between donor KIR B genes and recipient class I HLA KIR ligands. The relapse protection associated with donor KIR B is enhanced in recipients who have one or two C1-bearing HLA-C allotypes, compared with C2 homozygous recipients, with no effect due to donor HLA. The protective interaction between donors with two or more, versus none or one, KIR B motifs and recipient C1 was specific to transplants with class I mismatch at HLA-C (RR of leukemia-free survival, 0.57 [0.40-0.79]; p = 0.001) irrespective of the KIR ligand mismatch status of the transplant. The survival advantage and relapse protection in C1/x recipients compared with C2/C2 recipients was similar irrespective of the particular donor KIR B genes. Understanding the interactions between donor KIR and recipient HLA class I can be used to inform donor selection to improve outcome of unrelated donor hematopoietic cell transplantation for acute myelogenous leukemia.

The Impact of Graft-versus-Host Disease on the Relapse Rate in Patients with Lymphoma Depends on the Histological Subtype and the Intensity of the Conditioning Regimen.

The purpose of this study was to analyze the impact of graft-versus-host disease (GVHD) on the relapse rate of different lymphoma subtypes after allogeneic hematopoietic cell transplantation (allo-HCT). Adult patients with a diagnosis of Hodgkin lymphoma, diffuse large B cell lymphoma, follicular lymphoma (FL), peripheral T cell lymphoma, or mantle cell lymphoma (MCL) undergoing HLA-identical sibling or unrelated donor hematopoietic cell transplantation between 1997 and 2009 were included. Two thousand six hundred eleven cases were included. A reduced-intensity conditioning (RIC) regimen was used in 62.8% of the transplantations. In a multivariate analysis of myeloablative cases (n = 970), neither acute (aGVHD) nor chronic GVHD (cGVHD) were significantly associated with a lower incidence of relapse/progression in any lymphoma subtype. In contrast, the analysis of RIC cases (n = 1641) showed that cGVHD was associated with a lower incidence of relapse/progression in FL (risk ratio [RR], .51; P = .049) and in MCL (RR, .41; P = .019). Patients with FL or MCL developing both aGVHD and cGVHD had the lowest risk of relapse (RR, .14; P = .007; and RR, .15; P = .0019, respectively). Of interest, the effect of GVHD on decreasing relapse was similar in patients with sensitive disease and chemoresistant disease. Unfortunately, both aGVHD and cGVHD had a deleterious effect on treatment-related mortality and overall survival (OS) in FL cases but did not affect treatment-related mortality, OS or PFS in MCL. This study reinforces the use of RIC allo-HCT as a platform for immunotherapy in FL and MCL patients.

Center for International Blood and Marrow Transplant Research chronic graft-versus-host disease risk score predicts mortality in an independent validation cohort.

We previously reported a risk score that predicted mortality in patients with chronic graft-versus-host disease (CGVHD) after hematopoietic stem cell transplantation (HCT) between 1995 and 2004 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We sought to validate this risk score in an independent CIBMTR cohort of 1128 patients with CGVHD who underwent transplantation between 2005 and 2007 using the same inclusion criteria and risk score calculations. According to the sum of the overall risk score (range, 1 to 12), patients were assigned to 4 risk groups (RGs): RG1 (0 to 2), RG2 (3 to 6), RG3 (7 to 8), and RG4 (9 to 10). RG3 and RG4 were combined, as RG4 accounted for only 1% of the total cohort. Cumulative incidences of nonrelapse mortality (NRM) and probability of overall survival were significantly different between each RG (all P < .01). NRM and overall survival at 5 years after CGVHD for each RG were 17% and 72% in RG1, 26% and 53% in RG2, and 44% and 25% in RG3, respectively (all P < .01). Our study validates the prognostic value of the CIBMTR CGVHD RGs for overall survival and NRM in a contemporary transplantation population. The CIBMTR CGVHD RGs can be used to predict major outcomes, tailor treatment planning, and enroll patients in clinical trials.

Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation.

A single mismatch in highly expressed HLA-A, -B, -C, and -DRB1 loci (HEL) is associated with worse outcomes in hematopoietic stem cell transplantation, while less is known about the cumulative impact of mismatches in the lesser expressed HLA loci DRB3/4/5, DQ, and DP (LEL). We studied whether accumulation of LEL mismatches is associated with deleterious effects in 3853 unrelated donor transplants stratified according to number of matches in the HEL. In the 8/8 matched HEL group, LEL mismatches were not associated with any adverse outcome. Mismatches at HLA-DRB1 were associated with occurrence of multiple LEL mismatches. In the 7/8 HEL group, patients with 3 or more LEL mismatches scored in the graft-versus-host vector had a significantly higher risk of mortality (1.45 and 1.43) and transplant-related mortality (1.68 and 1.54) than the subgroups with 0 or 1 LEL mismatches. No single LEL locus had a more pronounced effect on clinical outcome. Three or more LEL mismatches are associated with lower survival after 7/8 HEL matched transplantation. Prospective evaluation of matching for HLA-DRB3/4/5, -DQ, and -DP loci is warranted to reduce posttransplant risks in donor-recipient pairs matched for 7/8 HEL.

Comparison of statistics in association tests of genetic markers for survival outcomes.

Computationally efficient statistical tests are needed in association testing of large scale genetic markers for survival outcomes. In this study, we explore several test statistics based on the Cox proportional hazards model for survival data. First, we consider the classical partial likelihood-based Wald and score tests. A revised way to compute the score statistics is explored to improve the computational efficiency. Next, we propose a Cox-Snell residual-based score test, which allows us to handle the controlling variables more conveniently. We also illustrated the incorporation of these three tests into a permutation procedure to adjust for the multiple testing. In addition, we examine a simulation-based approach proposed by Lin (2005) to adjust for multiple testing. We presented the comparison of these four statistics in terms of type I error, power, family-wise error rate, and computational efficiency under various scenarios via extensive simulation.

Risk factors associated with increased nonrelapse mortality and with poor overall survival in children with chronic graft-versus-host disease.

There is a paucity of information regarding the factors that affect nonrelapse mortality (NRM) and overall survival among children that develop chronic graft-versus-host disease (cGVHD). We performed multivariate analyses using data from the Center for International Blood and Marrow Transplant Research to identify risk factors for NRM and survival in 1117 pediatric subjects with leukemia or myelodysplastic syndrome, transplanted from related donors, unrelated donors (URD), or unrelated cord blood between 1995 and 2004. We identified 4 variables associated with higher NRM: HLA partially matched or mismatched URD, peripheral blood cell graft, Karnofsky/Lansky score < 80 at cGVHD diagnosis, and platelets < 100 × 10(9)/L at cGVHD diagnosis. Factors associated with significantly worse survival were: age > 10 years, transplantation from HLA partially matched or mismatched URD, advanced disease at transplantation, Karnofsky/Lansky < 80; and platelets < 100 × 10(9)/L. Cumulative incidence of discontinuation of systemic immune suppression at 1, 3, and 5 years after diagnosis of cGVHD were 22% (20%-25%), 34% (31%-37%), and 37% (34%-40%), respectively. This is the largest study elucidating variables affecting outcome after diagnosis of cGVHD in pediatric allograft recipients. These variables may be useful for risk stratification, development of future clinical trials, and family counseling in children with cGVHD.

Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis.

Several risk factors are associated with increased mortality in patients with chronic graft-versus-host disease (cGVHD), but there is considerable variability in the reported factors. Therefore, we evaluated patient, transplantation, and cGVHD characteristics to develop a risk score in 5343 patients with cGVHD. Ten variables were identified as being significant in multivariate analysis of overall survival and nonrelapse mortality (NRM): age, prior acute GVHD, time from transplantation to cGVHD, donor type, disease status at transplantation, GVHD prophylaxis, gender mismatch, serum bilirubin, Karnofsky score, and platelet count. These 10 variables were used to build a cGVHD risk score, and 6 risk groups (RGs) were identified. The 5-year NRM was 5% (1%-9%) in RG1, 20% (19%-23%) in RG2, 33% (29%-37%) in RG3, 43% (40%-46%) in RG4, 63% (53%-74%) in RG5, and 72% (59%-85%) in RG6. The 5-year overall survival was highest at 91% (95% confidence interval [CI]:85%-97%) in RG1, followed by 67% (65%-69%) in RG2, 51% (46%-55%) in RG3, 40% (37%-43%) in RG4, 21% (12%-30%) in RG5, and 4% (0%-9%) in RG6 (all P < .01). This analysis demonstrates the usefulness of data from a large registry to develop risk-score categories for major transplantation outcomes. Validation of this cGVHD risk score is needed in a different population to ensure its broad applicability.

Relationship of race/ethnicity and survival after single umbilical cord blood transplantation for adults and children with leukemia and myelodysplastic syndromes.

The relationship of race/ethnicity with outcomes of umbilical cord blood transplantation (UCBT) is not well known. We analyzed the association between race/ethnicity and outcomes of unrelated single UCBT for leukemia and myelodysplastic syndromes. Our retrospective cohort study consisted of 885 adults and children (612 whites, 145 blacks, and 128 Hispanics) who received unrelated single UCBT for leukemia and myelodysplastic syndromes between 1995 and 2006 and were reported to the Center for International Blood and Marrow Transplant Research. A 5-6/6 HLA-matched unit with a total nucleated cell count infused of ≥2.5 × 10(7)/kg was given to 40% white and 42% Hispanic, but only 21% black patients. Overall survival at 2 years was 44% for whites, 34% for blacks, and 46% for Hispanics (P = .008). In multivariate analysis adjusting for patient, disease, and treatment factors (including HLA match and cell dose), blacks had inferior overall survival (relative risk of death, 1.31; P = .02), whereas overall survival of Hispanics was similar (relative risk, 1.03; P = .81) to that of whites. For all patients, younger age, early-stage disease, use of units with higher cell dose, and performance status ≥80 were independent predictors of improved survival. Black patients and white patients infused with well-matched cords had comparable survival; similarly, black and white patients receiving units with adequate cell dose had similar survival. These results suggest that blacks have inferior survival to whites after single UCBT, but outcomes are improved when units with a higher cell dose are used.

Recipient survival and graft survival are not diminished by simultaneous liver-kidney transplantation: an analysis of the united network for organ sharing database.

Recipients of solitary liver and kidney transplants are living longer, and this increases their risk of long-term complications such as recurrent hepatitis C virus (HCV) and drug-induced nephrotoxicity. These complications may require retransplantation. Since the adoption of the Model for End-Stage Liver Disease, the number of simultaneous liver-kidney transplantation (SLK) procedures has increased. However, there are no standardized criteria for organ allocation to SLK candidates. The aims of this study were to retrospectively compare recipient and graft survival with liver transplantation alone (LTA), SLK, kidney after liver transplantation (KALT), and liver after kidney transplantation (LAKT) and to identify independent risk factors affecting recipient and graft survival. The United Network for Organ Sharing/Organ Procurement and Transplantation Network database (1988-2007) was queried for adult LTA (66,026), SLK (2327), KALT (1738), and LAKT procedures (242). After adjustments for potential confounding demographic and clinical variables, there was no difference in recipient mortality rates with LTA and SLK (P = 0.02). However, there was a 15% decreased risk of graft loss with SLK versus LTA (hazard ratio = 0.85, P < 0.001). The recipient and graft survival rates with SLK were higher than the rates with both KALT (P <0.001 and P <0.001) and LAKT (P = 0.003 and P < 0.001). The following were all identified as independent negative predictors of recipient mortality and graft loss: recipient age ≥ 65 years, male sex, black race, HCV/diabetes mellitus status, donor age ≥ 60 years, serum creatinine level ≥2.0 mg/dL, cold ischemia time > 12 hours, and warm ischemia time > 60 minutes. Although the recent increase in the number of SLK procedures performed each year has effectively decreased the number of potential donor kidneys available to patients with end-stage renal disease (ESRD) awaiting kidney transplantation, SLK in patients with end-stage liver disease and ESRD is justified because of the lower risk of graft loss with SLK versus LTA as well as the superior recipient and graft survival with SLK versus serial liver-kidney transplantation.

Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia.

Killer-cell immunoglobulin-like receptor (KIR) genes form a diverse, immunogenetic system. Group A and B KIR haplotypes have distinctive centromeric (Cen) and telomeric (Tel) gene-content motifs. Aiming to develop a donor selection strategy to improve transplant outcome, we compared the contribution of these motifs to the clinical benefit conferred by B haplotype donors. We KIR genotyped donors from 1409 unrelated transplants for acute myelogenous leukemia (AML; n = 1086) and acute lymphoblastic leukemia (ALL; n = 323). Donor KIR genotype influenced transplantation outcome for AML but not ALL. Compared with A haplotype motifs, centromeric and telomeric B motifs both contributed to relapse protection and improved survival, but Cen-B homozygosity had the strongest independent effect. With Cen-B/B homozygous donors the cumulative incidence of relapse was 15.4% compared with 36.5% for Cen-A/A donors (relative risk of relapse 0.34; 95% confidence interval 0.2-0.57; P < .001). Overall, significantly reduced relapse was achieved with donors having 2 or more B gene-content motifs (relative risk 0.64; 95% confidence interval 0.48-0.86; P = .003) for both HLA-matched and mismatched transplants. KIR genotyping of several best HLA-matched potential unrelated donors should substantially increase the frequency of transplants by using grafts with favorable KIR gene content. Adopting this practice could result in superior disease-free survival for patients with AML.

Analysis of non-HLA genomic risk factors in HLA-matched unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia.

BACKGROUND: Allogeneic hematopoietic cell transplantation is the main curative therapy for patients with chronic myeloid leukemia who do not respond to tyrosine kinase inhibitors. It has been proposed that non-human leukocyte antigen gene polymorphisms influence outcome after hematopoietic cell transplantation and could be used alongside traditional patient-donor and transplant characteristics to create a recipient risk profile associated with allogeneic hematopoietic cell transplantation. DESIGN AND METHODS: A previous study from the European Group for Blood and Marrow Transplantation showed that the absence of recipient tumor necrosis factor receptor II, absence of donor interleukin 10 ATA/ACC and presence of donor interleukin 1 receptor antagonist allele 2 genotypes were associated with decreased survival and increased non-relapse mortality in adult patients with chronic myeloid leukemia undergoing myeloablative human leukocyte antigen-identical sibling transplantation. To explore these associations in unrelated donor transplantation, these polymorphisms were genotyped in 383 adult patients with chronic myeloid leukemia who underwent hematopoietic cell transplantation from unrelated donors matched for 10/10 human leukocyte antigens. RESULTS: The polymorphisms were not associated with overall survival, non-relapse mortality, relapse or acute graft-versus-host disease in the unrelated donor cohort. Comparison of the unrelated donor and human leukocyte antigen-identical sibling cohorts showed differences in survival and clinical characteristics. CONCLUSIONS: We did not confirm that non-human leukocyte antigen polymorphisms were associated with outcomes in myeloablative unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia, possibly because of the strong association between clinical variables and outcome which masked more subtle genetic effects.

Effect of donor-recipient HLA matching at HLA A, B, C, and DRB1 on outcomes after umbilical-cord blood transplantation for leukaemia and myelodysplastic syndrome: a retrospective analysis.

BACKGROUND: The importance of matching at the HLA C locus has not been well defined for unrelated umbilical-cord blood transplantation. The selection algorithm for umbilical-cord blood units generally considers intermediate resolution HLA typing at A and B and allele-level typing at DRB1. We aimed to establish the relative importance of additional matching at HLA C. METHODS: We used Cox regression to assess retrospectively the effect of donor-recipient HLA matching on outcomes of single umbilical-cord blood transplantations for leukaemia and myelodysplastic syndrome. Our primary endpoint was transplant-related mortality. HLA typing was done with molecular techniques with a minimum of intermediate resolution for HLA A, B, and C, and at the allele-level for DRB1. FINDINGS: The median age of our study population was 10 years (range <1-62) and 552 (69%) of 803 patients were aged 16 years or younger at transplantation. Compared with transplantations matched at HLA A, B, C, and DRB1 (n=69), transplant-related mortality risk was higher after transplantations matched at HLA A, B, and DRB1 and mismatched at HLA C (n=23; HR 3·97, 95% CI 1·27-12·40; p=0·018). Transplant-related mortality risk was also higher after transplantations with a single mismatch at HLA A, B, or DRB1 and mismatched at HLA C (n=234; 1·70, 1·06-2·74; p=0·029) compared with transplantations matched at HLA C with a single mismatch at HLA A, B, or DRB1 (n=127). Assessing the overall effect of HLA disparity on transplant-related mortality, risks were higher with units mismatched at two (n=259; 3·27, 1·42-7·54; p=0·006), three (n=253; 3·34, 1·45-7·71; p=0·005), or four (n=75; 3·51, 1·44-8·58; p=0·006) loci compared with matched units (n=69). INTERPRETATION: Our data suggest that the present strategy for umbilical-cord blood unit selection should be reassessed; matching at HLA C for units that are matched at HLA A, B, or DRB1 or in the presence of a single locus mismatch at HLA A, B, or DRB1 should be included to minimise mortality risks. FUNDING: National Cancer Institute, National Heart Lung and Blood Institute, National Institute for Allergy and Infectious Diseases, Leukemia and Lymphoma Society, US Department of the Navy, Children's Leukemia Research Association, and INSERM.

HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation.

The association between HLA matching and outcome in unrelated-donor peripheral blood stem cell (PBSC) transplantation has not yet been established. In the present study, a total of 1933 unrelated donor-recipient pairs who underwent PBSC transplantation between 1999 and 2006 for acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia and received high-resolution HLA typing for HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 were included in the analysis. Outcomes were compared between HLA-matched and HLA-mismatched pairs, adjusting for patient and transplant characteristics. Matching for HLA-A, -B, -C, and -DRB1 alleles (8/8 match) was associated with better survival at 1 year compared with 7/8 HLA-matched pairs (56% vs 47%). Using 8/8 HLA-matched patients as the baseline (n = 1243), HLA-C antigen mismatches (n = 189) were statistically significantly associated with lower leukemia-free survival (relative risk [RR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = .0010), and increased risk for mortality (RR, 1.41; 95% CI, 1.16-1.70; P = .0005), treatment-related mortality (RR, 1.61; 95% CI, 1.25-2.08; P = .0002), and grade III-IV graft-versus-host disease (RR, 1.98; 95% CI, 1.50-2.62; P < .0001). HLA-B antigen or allele mismatching was associated with an increased risk for acute GVHD grade III-IV. No statistically significant differences in outcome were observed for HLA-C allele (n = 61), HLA-A antigen/allele (n = 136), HLA-DRB1 allele (n = 39), or HLA-DQ antigen/allele (n = 114) mismatches compared with 8/8 HLA-matched pairs. HLA mismatch was not associated with relapse or chronic GVHD. HLA-C antigen-mismatched unrelated PBSC donors were associated with worse outcomes compared with 8/8 HLA-matched donors. The study's limited power due to small sample size precludes conclusions about other mismatches.

Donor, recipient, and transplant characteristics as risk factors after unrelated donor PBSC transplantation: beneficial effects of higher CD34+ cell dose.

We report outcomes of 932 recipients of unrelated donor peripheral blood stem cell hematopoietic cell transplantation (URD-PBSC HCT) for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome enrolled on a prospective National Marrow Donor Program trial from 1999 through 2003. Preparative regimens included myeloablative (MA; N = 611), reduced-intensity (RI; N = 160), and nonmyeloablative (NMA; N = 161). For MA recipients, CD34(+) counts greater than 3.8 x 10(6)/kg improved neutrophil and platelet engraftment, whereas improved overall survival (OS) and reduced transplant-related mortality (TRM) were seen for all preparative regimens when CD34(+) cell doses exceeded 4.5 x 10(6)/kg. Higher infused doses of CD34(+) cell dose did not result in increased rates of either acute or chronic graft-versus-host disease (GVHD). Three-year OS and disease-free survival (DFS) of recipients of MA, RI, and NMA approaches were similar (33%, 35%, and 32% OS; 33%, 30%, and 29% DFS, respectively). In summary, recipients of URD-PBSC HCT receiving preparative regimens differing in intensity experienced similar survival. Higher CD34(+) cell doses resulted in more rapid engraftment, less TRM, and better 3-year OS (39% versus 25%, MA, P = .004; 38% versus 21% RI/NMA, P = .004) but did not increase the risk of GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00785525.

Adverse events among 2408 unrelated donors of peripheral blood stem cells: results of a prospective trial from the National Marrow Donor Program.

Limited data are available describing donor adverse events (AEs) associated with filgrastim mobilized peripheral blood stem cell (PBSC) collections in unrelated volunteers. We report results in 2408 unrelated PBSC donors prospectively evaluated by the National Marrow Donor Program (NMDP) between 1999 and 2004. Female donors had higher rates of AEs, requiring central line placement more often (17% vs 4%, P< .001), experiencing more apheresis-related AEs (20% vs 7%, P< .001), more bone pain (odds ratio [OR]=1.49), and higher rates of grades II-IV and III-IV CALGB AEs (OR=2.22 and 2.32). Obese donors experienced more bone pain (obese vs normal, OR=1.73) and heavy donors had higher rates of CALGB toxicities (>95 kg vs <70 kg, OR=1.49). Six percent of donors experienced grade III-IV CALGB toxicities and 0.6% experienced toxicities that were considered serious and unexpected. Complete recovery is universal, however, and no late AEs attributable to donation have been identified. In conclusion, PBSC collection in unrelated donors is generally safe, but nearly all donors will experience bone pain, 1 in 4 will have significant headache, nausea, or citrate toxicity, and a small percentage will experience serious short-term adverse events. In addition, women and larger donors are at higher risk for donation-related AEs.

Marginal models for clustered time-to-event data with competing risks using pseudovalues.

Many time-to-event studies are complicated by the presence of competing risks and by nesting of individuals within a cluster, such as patients in the same center in a multicenter study. Several methods have been proposed for modeling the cumulative incidence function with independent observations. However, when subjects are clustered, one needs to account for the presence of a cluster effect either through frailty modeling of the hazard or subdistribution hazard, or by adjusting for the within-cluster correlation in a marginal model. We propose a method for modeling the marginal cumulative incidence function directly. We compute leave-one-out pseudo-observations from the cumulative incidence function at several time points. These are used in a generalized estimating equation to model the marginal cumulative incidence curve, and obtain consistent estimates of the model parameters. A sandwich variance estimator is derived to adjust for the within-cluster correlation. The method is easy to implement using standard software once the pseudovalues are obtained, and is a generalization of several existing models. Simulation studies show that the method works well to adjust the SE for the within-cluster correlation. We illustrate the method on a dataset looking at outcomes after bone marrow transplantation.

Cutpoint selection for discretizing a continuous covariate for generalized estimating equations.

We consider the problem of dichotomizing a continuous covariate when performing a regression analysis based on a generalized estimation approach. The problem involves estimation of the cutpoint for the covariate and testing the hypothesis that the binary covariate constructed from the continuous covariate has a significant impact on the outcome. Due to the multiple testing used to find the optimal cutpoint, we need to make an adjustment to the usual significance test to preserve the type-I error rates. We illustrate the techniques on one data set of patients given unrelated hematopoietic stem cell transplantation. Here the question is whether the CD34 cell dose given to patient affects the outcome of the transplant and what is the smallest cell dose which is needed for good outcomes.

Decreased infections in recipients of unrelated donor hematopoietic cell transplantation from donors with an activating KIR genotype.

Infectious complications following allogeneic hematopoietic cell transplantation (HCT) from unrelated donors (URD) result in significant morbidity. We hypothesized that recipients of a URD with an activating natural killer cell immunoglobulin-like receptor (KIR) (B/x) genotype would have decreased infectious complications because of enhanced natural killer (NK) cell function. We compared the infectious complications in 116 recipients of a graft from a donor with an A/A KIR (n = 44) genotype and a B/x KIR (n = 72) genotype. All recipients participated in the prospective National Marrow Donor Program infection project collecting infection data from conditioning until 6 months posttransplant. The cohort with a B/x donor had fewer initial bacterial infections by day 180 (A/A: 86%; 95% confidence interval [CI], 75-95; B/x: 68%; 95% CI, 57-78; P = .02). There was no difference in the incidence of viral or fungal infections. When accounting for multiple infections, fewer bacterial infections were seen in the B/x cohort (A/A: 3.55/patient; B/x: 2.63/patient; P = .09). During the study period, only 19 patients had no infections; of these, 15 had received cells from a B/x KIR donor. The role of donor KIR genotype on infection complications is intriguing and warrants further investigation.