Adjusted estimates for time-to-event endpoints.

In the analysis of retrospective data or when interpreting results from a single-arm phase II clinical trial relative to historical data, it is often of interest to show plots summarizing time-to-event outcomes comparing treatment groups. If the groups being compared are imbalanced with respect to factors known to influence outcome, these plots can be misleading and seemingly incompatible with results obtained from a regression model that accounts for these imbalances. We consider ways in which covariate information can be used to obtain adjusted curves for time-to-event outcomes. We first review a common model-based method and then suggest another model-based approach that is not as reliant on model assumptions. Finally, an approach that is partially model free is suggested. Each method is applied to an example from hematopoietic cell transplantation

Tumor Necrosis Factor Polymorphism Affects Transplantation Outcome in Patients with Myelodysplastic Syndrome but Not in Those with Chronic Myelogenous Leukemia, Independent of the Presence of HLA-DR15

Both the presence of HLA-DR15 and tumor necrosis factor (TNF)-α levels have been reported to affect outcome after hematopoietic cell transplantation (HCT). Patients with a myelodysplastic syndrome (MDS) show a high prevalence of HLA-DR15 and express high levels of TNF-α in the bone marrow. The present analysis involving 7950 patients showed an HLA-DR15 frequency of 31% in patients with MDS, compared with only 23% in patients with chronic myelogenous leukemia (CML). HLA-DR15 was more prevalent in Caucasian patients than in non-Caucasian patients (P = .01). The numbers of patients in the non-Caucasian subgroups were too small to allow further analysis. Among Caucasian patients with MDS and CML, the presence of HLA-DR15 did not significantly affect the occurrence of graft-versus-host disease, relapse, nonrelapse mortality (NRM), or survival. However, there was a significant correlation between DR15 and TNF polymorphisms at position -308 among patients with MDS, and the TNF-308 AG genotype conferred an increased risk of NRM compared with the GG genotype (hazard ratio [HR], 1.49; P = .02), even after adjusting for DR15. Conversely, the TNF-863 AA genotype was correlated with decreased overall mortality and NRM compared with the CC genotype (HR, 0.36, P = .04 vs HR, 0.13, P = .04), even after adjusting for DR15. There was no significant association between TNF-308 or -863 polymorphisms and transplantation outcome in CML patients. These results suggest that TNF polymorphisms, but not DR15, affect transplantation outcome in a disease-dependent manner

Results of a phase I-II study of fenretinide and rituximab for patients with indolent B-cell lymphoma and mantle cell lymphoma.

Fenretinide, a synthetic retinoid, induces apoptotic cell death in B-cell non-Hodgkin lymphoma (B-NHL) and acts synergistically with rituximab in preclinical models. We report results from a phase I-II study of fenretinide with rituximab for B-NHLs. Eligible diagnoses included indolent B-NHL or mantle cell lymphoma. The phase I design de-escalated from fenretinide at 900 mg/

MHC Haplotype Matching for Unrelated Hematopoietic Cell Transplantation

BACKGROUND: Current criteria for the selection of unrelated donors for hematopoietic cell transplantation (HCT) include matching for the alleles of each human leukocyte antigen (HLA) locus within the major histocompatibility complex (MHC). Graft-versus-host disease (GVHD), however, remains a significant and potentially life-threatening complication even after HLA-identical unrelated HCT. The MHC harbors more than 400 genes, but the total number of transplantation antigens is unknown. Genes that influence transplantation outcome could be identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypes of the unrelated donor and recipient could be defined. METHODS AND FINDINGS: We isolated DNA strands extending across 2 million base pairs of the MHC to determine the physical linkage of HLA-A, -B, and -DRB1 alleles in 246 HCT recipients and their HLA-A, -B, -C, -DRB1, -DQB1 allele-matched unrelated donors. MHC haplotype mismatching was associated with a statistically significantly increased risk of severe acute GVHD (odds ratio 4.51; 95% confidence interval [CI], 2.34–8.70, p < 0.0001) and with lower risk of disease recurrence (hazard ratio 0.45; 95% CI, 0.22–0.92, p = 0.03). CONCLUSIONS: The MHC harbors genes that encode unidentified transplantation antigens. The three-locus HLA-A, -B, -DRB1 haplotype serves as a proxy for GVHD risk among HLA-identical transplant recipients. The phasing method provides an approach for mapping novel MHC-linked transplantation determinants and a means to decrease GVHD-related morbidity after HCT from unrelated donors

Long-Range Haplotyping of <i>HLA-A, -B,</i> and <i>-DRB1</i> in Unrelated Individuals

<div><p>(A) Schematic illustration of two HLA phenotypically identical individuals with the same or different linkages between <i>HLA-A, -B,</i> and <i>-DRB1</i> on the MHC haplotypes.</p> <p>(B) DNA microarray images of four unrelated donor–recipient pairs from the study population demonstrating MHC haplotype-matched (upper left), and MHC haplotype-mismatched (<i>HLA-A,</i> upper right; <i>HLA-DRB1,</i> lower left; <i>HLA-A</i> and -<i>DRB1,</i> lower right) relationships. The two haplotypes in each sample were separated by hybridizing genomic DNA to an array that was spotted with oligonucleotide probes, each specific for one of the two <i>HLA-B</i> alleles in the sample. After haplotype separation, the <i>HLA-A</i> and <i>HLA-DRB1</i> alleles carried on each haplotype were identified with the use of 57 <i>HLA-A</i> and 64 <i>HLA-DRB1</i> oligonucleotide probes as described [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0040008#pmed-0040008-b032" target="_blank">32</a>]. Actual quadruplicate hybridization patterns for 16 of the probes illustrate how the two possible alleles at each locus could be distinguished from each other. Each column of panels in the figure shows the pattern of probe hybridization with one of the two MHC haplotypes from each sample. Allele assignments are indicated above each hybridization pattern. The <i>HLA-B</i> probe hybridization patterns validate the linkage of <i>HLA-B</i> alleles with <i>HLA-A</i> and -<i>DRB1</i> alleles. Sequences and specificity of probes can be found in [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0040008#pmed-0040008-b032" target="_blank">32</a>].</p></div

Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation

AbstractLipopolysaccharide (LPS) has been implicated in the pathogenesis of graft-versus-host disease (GVHD). The toll-like receptor (TLR)-4 has been recently identified as a major receptor for LPS. Mutations of TLR4 have been associated with LPS hyporesponsiveness. We hypothesized that TLR4 mutations reduce the risk of acute GVHD in allogeneic marrow transplant recipients. In a preliminary study to determine the frequency of TLR4 mutations and their possible association with GVHD, we tested 237 patients and their HLA-identical sibling donors for 2 TLR4 polymorphisms. All patients received methotrexate and cyclosporine for GVHD prophylaxis. One or more mutants were detected in 10.8% of patients and 10.6% of donors. Multivariable logistic regression models were used to analyze the association between TLR4 mutations and probability (1-sided) of GVHD. The odds ratio (adjusted for advanced disease, total body irradiation dose, and patient age) for development of grades II to IV GVHD when a mutation was present in the recipient was 0.63 (95% confidence interval [CI], 0.25-1.60; P = .16). When a mutation was present in the donor, the adjusted odds ratio was 0.88 (95% CI, 0.36-2.17; P = .40). When a mutation was present in both recipient and donor, the odds ratio was 0.72 (95% CI, 0.22-2.32; P = .29). Among 24 patients with TLR4 mutations in either donor or recipient, 4 (16.7%) developed gram-negative bacteremia. Among 213 patients without mutations, 14 (6.6%) developed gram-negative bacteremia (P = .09). The data indicate that a reduced risk of acute GVHD is associated with TLR4 mutations and that TLR4 mutations may increase the risk for gram-negative bacteremia. However, these associations are not statistically significant in recipients of HLA-matched sibling marrow transplants who are prophylactically treated for infections and GVHD. A much larger study population would be needed to confirm the role of LPS in the pathogenesis of GVHD in humans.Biol Blood Marrow Transplant 2001;7(7):384-7