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

Pretransplant neutropenia is associated with poor-risk cytogenetic features and increased infection-related mortality in patients with myelodysplastic syndromes.

A retrospective cohort analysis was performed to determine the impact of neutropenia on the outcome of hematopoietic cell transplantation (HSCT) in patients with myelodysplasia (MDS). Among 291 consecutive patients, 178 (61%) had absolute neutrophil counts (ANCs) or =1500/microL within 2 weeks before HSCT. Neutropenic patients more often had poor-risk karyotypes (34% versus 12%, P < .0001) and high-risk International Prognostic Scoring System scores (37% versus 18%, P = .0006). After HSCT, the rate of infections caused by Gram-positive bacteria and invasive fungal infections was significantly increased among neutropenic patients (rate ratio [RR] 1.77, P = .02 and RR = 2.56, P = .03, respectively), whereas infections caused by Gram-negative bacteria were not affected (RR 1.33, P = .53). The hazards of nonrelapse mortality (NRM) (hazard ratio [HR] = 1.62 [1.1-2.4], P = .01), overall mortality (HR = 1.55 [1.1-2.1], P = 0.007), and infection-related mortality (HR = 2.22 [1.2-4.2], P = .01) were increased in neutropenic patients, whereas relapse, engraftment, and graft-versus-host-disease were not affected. After adjusting for cytogenetic risk and marrow myeloblast percentages, neutropenic patients remained at significant hazard for infection-related mortality (HR = 1.94 [1.0-3.8], P = .05), but not for overall mortality or NRM. We propose that intensified strategies to prevent infections should be implemented in MDS patients with preexisting neutropenia who undergo HSCT

Association of Plasma CD163 Concentration with De Novo–Onset Chronic Graft-versus-Host Disease

Chronic graft-versus-host disease (GVHD) is the leading cause of long-term morbidity and mortality after allogeneic hematopoietic cell transplantation. To identify prognostic plasma proteins associated with de novo– or quiescent-onset chronic GVHD (cGVHD), we performed a discovery and validation proteomic study. The total study cohort included 167 consecutive patients who had no clinical evidence of GVHD under minimum glucocorticoid administration and had available plasma samples obtained at 80 ± 14 days after transplantation. We first used high-throughput mass spectrometry to screen pooled plasma using 20 cases with subsequent cGVHD and 20 controls without it, and we identified 20 candidate proteins. We then measured 12 of the 20 candidate proteins by ELISA on the same individual samples and identified 4 proteins for further verification (LGALS3BP, CD5L, CD163, and TXN for de novo onset, and LGALS3BP and CD5L for quiescent onset). The verification cohort included 127 remaining patients. The cumulative incidence of de novo–onset cGVHD was higher in patients with higher plasma soluble CD163 concentrations at day 80 than those with lower concentrations (75% versus 40%, P = .018). The cumulative incidence of de novo– or quiescent-onset cGVHD did not differ statistically according to concentrations of the 3 other proteins at day 80. CD163 is a macrophage scavenger receptor and is elevated in oxidative conditions. These results suggest that monocyte or macrophage activation or increased oxidative stress may contribute to the pathogenesis of cGVHD

Nonmyeloablative Unrelated Donor Hematopoietic Cell Transplantation to Treat Patients with Poor-Risk, Relapsed, or Refractory Multiple Myeloma

AbstractThe purpose of this study was to determine long-term outcome of unrelated donor nonmyeloablative hematopoietic cell transplantation (HCT) in patients with poor-risk multiple myeloma. A total of 24 patients were enrolled; 17 patients (71%) had chemotherapy-refractory disease, and 14 (58%) experienced disease relapse or progression after previous autologous transplantation. Thirteen patients underwent planned autologous transplantation followed 43–135 days later with unrelated transplantation, whereas 11 proceeded directly to unrelated transplantation. All 24 patients were treated with fludarabine (90 mg/m2) and 2 Gy of total body irradiation before HLA-matched unrelated peripheral blood stem cell transplantation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. The median follow-up was 3 years after allografting. One patient experienced nonfatal graft rejection. The incidences of acute grades II and III and chronic graft-versus-host disease were 54%, 13%, and 75%, respectively. The 3-year nonrelapse mortality (NRM) was 21%. Complete responses were observed in 10 patients (42%); partial responses, in 4 (17%). At 3 years, overall survival (OS) and progression-free survival (PFS) rates were 61% and 33%, respectively. Patients receiving tandem autologous-unrelated transplantation had superior OS and PFS (77% and 51%) compared with patients proceeding directly to unrelated donor transplantation (44% and 11%) (PFS P value = .03). In summary, for patients with poor-risk, relapsed, or refractory multiple myeloma, cytoreductive autologous HCT followed by nonmyeloablative conditioning and unrelated HCT is an effective treatment approach, with low NRM, high complete remission rates, and prolonged disease-free survival

Marrow transplants from unrelated donors for patients with aplastic anemia: Minimum effective dose of total body irradiation

AbstractPatients with aplastic anemia who do not have suitably HLA-matched, related donors generally receive immunosuppressive treatment as first-line therapy and are considered for transplantation from an unrelated donor only if they fail to respond to immunosuppressive treatment. In this setting, rates of transplantation-related morbidity and mortality have been high. We conducted a prospective study to determine the minimal dose of total body irradiation (TBI) sufficient to achieve sustained engraftment when it is used in combination with 3 cycles of 30 mg/kg of antithymocyte globulin (ATG) and 4 cycles of 50 mg/kg of cyclophosphamide (CY). We also wanted to determine the tolerability and toxicity of the regimen. The starting dosage of TBI was 3 x 200 cGy given over 2 days following CY/ATG. The TBI dose was to be escalated in increments of 200 cGy if graft failure occurred in the absence of prohibitive toxicity, and de-escalated for toxicity in the absence of graft failure. Twenty-one female and 29 male patients aged 1.3 to 46.5 years (median age, 14.4 years) underwent transplantation at 14 medical centers. The time interval from diagnosis to transplantation was 2.8 to 264 months (median, 14.5 months). All patients had been transfused multiple times and all had received 1 to 11 courses (median, 4 courses) of immunosuppressive treatment and other modalities of treatment. In 38 cases, the donors were HLA-A, -B and -DR phenotypically matched with the patients, and, in 12 cases, the donor phenotype differed from that of the recipient by 1 HLA antigen. Recipients of mismatched transplants were considered separately for TBI dose modification, and this study is still ongoing. Seven patients did not tolerate ATG and were prepared with 6 x 200 cGy of TBI plus 120 mg/kg of CY. Of the HLA-matched recipients prepared with CY/ATG/TBI, all 20 who received 3 x 200 or 2 x 200 cGy of TBI achieved engraftment, and 10 are alive. Of the 13 patients who received 1 x 200 cGy of TBI, 1 failed to engraft, and 8 are alive. Each of 10 patients who received an HLA-nonidentical transplant achieved engraftment, and 3 of 6 who were given 3 x 200 cGy of TBI, and 4 of 4 who were given 2 x 200 cGy are alive. Pulmonary toxicity occurred in 8 of 30 patients who were given 3 x 200 or 2 x 200 cGy of TBI concurrently with ATG and CY at 200 mg/kg, and in 2 of 13 patients who received 1 x 200 cGy of TBI, a pattern that suggests a decrease in toxicity with TBI dose de-escalation. Overall, the highest probability of survival (73%) was observed among patients who underwent transplantation within 1 year of diagnosis, compared with patients who underwent transplantation after a longer period of disease. In addition, younger patients (aged < or = 20 years) were more likely to survive than older patients (aged > 20 years). Thus, for patients with an HLA-matched, unrelated donor, a TBI dose of 200 cGy (in combination with CY/ATG) was sufficient to allow for engraftment without inducing prohibitive toxicity. As in previous studies, patient age and pretransplantation disease duration remain important prognostic factors.Biol Blood Marrow Transplant 2001;7(4):208-15

Treatment change as a predictor of outcome among patients with classic chronic graft-versus-host disease

We analyzed outcomes for 668 patients who had systemic treatment for chronic graft-versus-host disease (GVHD) to assess the utility of early treatment change for exacerbation of chronic GVHD as a surrogate for survival endpoints in clinical trials. Fifty-six percent of patients had treatment change within 2 years after diagnosis of chronic GVHD. The median onset of treatment change was 4.4 months (range, 0.3 – 50 months). The cumulative incidence of non-relapse mortality (NRM) at 2 years was 16%, and overall survival at 2 years was 74%. In time-dependent Cox models, treatment change was associated with an increase in risk of NRM (hazard ratio, 2.53; 95% CI, 1.7-3.7; p < .0001). The hazard ratio was attenuated by 6% per month of delay in treatment change. Our results confirm that exacerbation of chronic GVHD is associated with an increased risk of NRM and with decreased survival, but the strength of this association is not large enough to allow the use of early exacerbation as a surrogate for survival endpoints in clinical trials. Other measures of clinical benefit, such as response, will need to be developed as endpoints in phase II trials for patients with chronic GVHD

Biomarker Panel for Chronic Graft-Versus-Host Disease

PURPOSE: To identify diagnostic and prognostic markers of chronic graft-versus-host disease (cGVHD), the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: Using a quantitative proteomics approach, we compared pooled plasma samples obtained at matched time points after HCT (median, 103 days) from 35 patients with cGVHD and 18 without cGVHD (data are available via ProteomeXchange with identifier PXD002762). Of 105 proteins showing at least a 1.25-fold difference in expression, 22 were selected on the basis of involvement in relevant pathways and enzyme-linked immunosorbent assay availability. Chemokine (C-X-C motif) ligand 9 (CXCL9) and suppression of tumorigenicity 2 (ST2) also were measured on the basis of previously determined associations with GVHD. Concentrations of the four lead biomarkers were measured at or after diagnosis in plasma from two independent verification cohorts (n = 391) to determine their association with cGVHD. Their prognostic ability when measured at approximately day +100 after HCT was evaluated in plasma of a second verification cohort (n = 172). RESULTS: Of 24 proteins measured in the first verification cohort, nine proteins were associated with cGVHD, and only four (ST2, CXCL9, matrix metalloproteinase 3, and osteopontin) were necessary to compose a four-biomarker panel with an area under the receiver operating characteristic curve (AUC) of 0.89 and significant correlation with cGVHD diagnosis, cGVHD severity, and nonrelapse mortality. In a second verification cohort, this panel distinguished patients with cGVHD (AUC, 0.75), and finally, the panel measured at day +100 could predict cGVHD occurring within the next 3 months with an AUC of 0.67 and 0.79 without and with known clinical risk factors, respectively. CONCLUSION: We conclude that the biomarker panel measured at diagnosis or day +100 after HCT may allow patient stratification according to risk of cGVHD