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

Allogeneic Hematopoietic Cell Transplantation with Full-Intensity Conditioning for Adult Acute Lymphoblastic Leukemia: Results from a Single Center, 1998-2006

A retrospective analysis identified 161 consecutive adults with acute lymphoblastic leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) with full-intensity (myeloablative) conditioning between 1998 and 2006. Median patient age was 36.1 years. Seventy-six patients were in first complete remission (CR1), and 85 were in second or greater CR or in relapse. Fifty-nine patients had Philadelphia chromosome–positive acute lymphoblastic leukemia. A total of 159 patients received chemotherapy plus total body irradiation for conditioning. Graft-versus-host disease prophylaxis included a calcineurin inhibitor plus methotrexate or mycophenolate mofetil. Sixty of the donors were related, and 101 were unrelated. A total of 110 patients received granulocyte-colony stimulating factor–stimulated peripheral blood, 47 received bone marrow, and 4 received cord blood as the stem cell source. Fifty-five patients relapsed at a median of 231 days after transplantation. The estimated 5-year probabilities of relapse-free survival, relapse, and nonrelapse mortality were 47%, 30%, and 29%, respectively. By multivariate analyses, transplantation while in CR1 was the most important predictor of successful transplantation. Pretransplantation evidence of minimal residual disease, especially as detected by flow cytometric analysis, was associated with both lower overall survival and lower relapse-free survival. Compared with a similar cohort of patients undergoing transplantation between 1990 and 1997, overall survival was similar for patients undergoing transplantation in CR1, with lower nonrelapse mortality being offset by higher rates of relapse in patients who underwent transplantation more recently

Clinical Outcome after Haplotype-Matched (Solid Line) and Haplotype-Mismatched (Broken Line) Unrelated Donor HCT

<div><p>All patients in the study were <i>HLA-A, B, C, DRB1, DQB1</i> allele matched with their donors.</p> <p>(A) Probability of grades III–IV acute GVHD.</p> <p>(B) Probability of recurrent malignancy.</p> <p>(C) Probability of transplant-related mortality.</p> <p>(D) Probability of survival.</p> <p>One patient in the mismatched group had recurrent malignancy at 14.4 y, and one patient in the mismatched group died without recurrent malignancy at 13.2 y. Seven mismatched patients are alive without recurrent malignancy from 11.9–14.1 y, and nine mismatched patients are alive from 11.0–14.5 y. Twenty-three patients in the matched group are alive without recurrent malignancy from 10.2–18.5 y, and 28 matched patients are alive from 10.2–18.5 y. Each of these patients is indicated as censored at 10 y in (B), (C), and (D).</p></div

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