Jason W. Chien

Reduced mortality after allogeneic hematopoietic cell transplantation

BACKGROUND Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of transplantation. METHODS We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation. RESULTS In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs. CONCLUSIONS We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).

Toll-like Receptor 4 Polymorphisms and Aspergillosis in Stem-Cell Transplantation

BACKGROUND Toll-like receptors (TLRs) are essential components of the immune response to fungal pathogens. We examined the role of TLR polymorphisms in conferring a risk of invasive aspergillosis among recipients of allogeneic hematopoietic-cell transplants. METHODS We analyzed 20 single-nucleotide polymorphisms (SNPs) in the toll-like receptor 2 gene (TLR2), the toll-like receptor 3 gene (TLR3), the toll-like receptor 4 gene (TLR4), and the toll-like receptor 9 gene (TLR9) in a cohort of 336 recipients of hematopoietic-cell transplants and their unrelated donors. The risk of invasive aspergillosis was assessed with the use of multivariate Cox regression analysis. The analysis was replicated in a validation study involving 103 case patients and 263 matched controls who received hematopoietic-cell transplants from related and unrelated donors. RESULTS In the discovery study, two donor TLR4 haplotypes (S3 and S4) increased the risk of invasive aspergillosis (adjusted hazard ratio for S3, 2.20; 95% confidence interval [CI], 1.14 to 4.25; P=0.02; adjusted hazard ratio for S4, 6.16; 95% CI, 1.97 to 19.26; P=0.002). The haplotype S4 was present in carriers of two SNPs in strong linkage disequilibrium (1063 A/G [D299G] and 1363 C/T [T399I]) that influence TLR4 function. In the validation study, donor haplotype S4 also increased the risk of invasive aspergillosis (adjusted odds ratio, 2.49; 95% CI, 1.15 to 5.41; P=0.02); the association was present in unrelated recipients of hematopoietic-cell transplants (odds ratio, 5.00; 95% CI, 1.04 to 24.01; P=0.04) but not in related recipients (odds ratio, 2.29; 95% CI, 0.93 to 5.68; P=0.07). In the discovery study, seropositivity for cytomegalovirus (CMV) in donors or recipients, donor positivity for S4, or both, as compared with negative results for CMV and S4, were associated with an increase in the 3-year probability of invasive aspergillosis (12% vs. 1%, P=0.02) and death that was not related to relapse (35% vs. 22%, P=0.02). CONCLUSIONS This study suggests an association between the donor TLR4 haplotype S4 and the risk of invasive aspergillosis among recipients of hematopoietic-cell transplants from unrelated donors.

Treatment of idiopathic pulmonary fibrosis with Ambrisentan: A parallel, randomized trial

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.

Impact of Pretransplantation Minimal Residual Disease, As Detected by Multiparametric Flow Cytometry, on Outcome of Myeloablative Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) benefits many patients with acute myeloid leukemia (AML) in first remission. Hitherto, little attention has been given to the prognostic impact of pretransplantation minimal residual disease (MRD). PATIENTS AND METHODS We retrospectively studied 99 consecutive patients receiving myeloablative HCT for AML in first morphologic remission. Ten-color multiparametric flow cytometry (MFC) was performed on bone marrow aspirates before HCT. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow. Any level of residual disease was considered MRD positive. RESULTS Before HCT, 88 patients met morphologic criteria for complete remission (CR), whereas 11 had CR with incomplete blood count recovery (CRi). Twenty-four had MRD before HCT as determined by MFC. Two-year estimates of overall survival were 30.2% (range, 13.1% to 49.3%) and 76.6% (range, 64.4% to 85.1%) for MRD-positive and MRD-negative patients; 2-year estimates of relapse were 64.9% (range, 42.0% to 80.6%) and 17.6% (range, 9.5% to 27.9%). After adjustment for all or a subset of cytogenetic risk, secondary disease, incomplete blood count recovery, and abnormal karyotype pre-HCT, MRD-positive HCT was associated with increased overall mortality (hazard ratio [HR], 4.05; 95% CI, 1.90 to 8.62; P < .001) and relapse (HR, 8.49; 95% CI, 3.67 to 19.65; P < .001) relative to MRD-negative HCT. CONCLUSION These data suggest that pre-HCT MRD is associated with increased risk of relapse and death after myeloablative HCT for AML in first morphologic CR, even after controlling for other risk factors.

Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial.

BACKGROUND In the post-intervention period of the Womens Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period. METHODS The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611. FINDINGS After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were similar between groups. INTERPRETATION Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer. FUNDING National Heart, Lung and Blood Institute, National Institutes of Health.

Treatment of idiopathic pulmonary fibrosis with ambrisentan: a randomized trial

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.

Oral GS-5806 Activity in a Respiratory Syncytial Virus Challenge Study

BACKGROUND Respiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists. METHODS We conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of data for cohorts 1 to 4. The primary end point was the area under the curve (AUC) for the viral load, which was assessed after administration of the first dose through the 12th day after inoculation. Secondary end points were mucus weight and symptom scores. RESULTS Among the 54 participants in cohorts 1 to 4 who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log10 plaque-forming-unit equivalents [PFUe] × hours per milliliter; P<0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P=0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, -20.2 vs. 204.9 × hours; P=0.005). The results were similar in cohorts 5, 6, and 7. Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806. CONCLUSIONS Treatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01756482.).

Plasma Processing Conditions Substantially Influence Circulating microRNA Biomarker Levels

Circulating, cell-free microRNAs (miRNAs) are promising candidate biomarkers, but optimal conditions for processing blood specimens for miRNA measurement remain to be established. Our previous work showed that the majority of plasma miRNAs are likely blood cell-derived. In the course of profiling lung cancer cases versus healthy controls, we observed a broad increase in circulating miRNA levels in cases compared to controls and that higher miRNA expression correlated with higher platelet and particle counts. We therefore hypothesized that the quantity of residual platelets and microparticles remaining after plasma processing might impact miRNA measurements. To systematically investigate this, we subjected matched plasma from healthy individuals to stepwise processing with differential centrifugation and 0.22 µm filtration and performed miRNA profiling. We found a major effect on circulating miRNAs, with the majority (72%) of detectable miRNAs substantially affected by processing alone. Specifically, 10% of miRNAs showed 4–30x variation, 46% showed 30-1,000x variation, and 15% showed >1,000x variation in expression solely from processing. This was predominantly due to platelet contamination, which persisted despite using standard laboratory protocols. Importantly, we show that platelet contamination in archived samples could largely be eliminated by additional centrifugation, even in frozen samples stored for six years. To minimize confounding effects in microRNA biomarker studies, additional steps to limit platelet contamination for circulating miRNA biomarker studies are necessary. We provide specific practical recommendations to help minimize confounding variation attributable to plasma processing and platelet contamination.

A Risk Score for Mortality after Allogeneic Hematopoietic Cell Transplantation

Context Many patients who undergo allogeneic hematopoietic cell transplantation have high mortality risks. Contribution In this retrospective cohort study involving 2802 patients with a first hematopoietic cell transplant, investigators devised a 50-point pretransplantation score that predicted risk for death within 2 years. Score variables included age, donor type, disease type, conditioning regimen, FEV1, carbon monoxide diffusion capacity, serum creatinine level, and serum alanine aminotransferase concentration. Cautions We recommend validation of this prognostic score in other populations and settings before routine use. The Editors Hematopoietic cell transplantation (HCT) has become an important method of treating malignant conditions. The Center for International Blood and Marrow Transplant Research reported that approximately 16000 patients throughout the world underwent allogeneic HCT in 2002. Despite trends showing improved outcomes after HCT, death after transplantation remains a major concern for these patients and their physicians. During the past decade, the overall mortality rate after allogeneic HCT improved modestly by 3% (1). The risk for death after HCT depends on the underlying disease, the stage of the disease, and the type of donor (2, 3). However, the risk for post-transplantation death is also increased by such factors as higher exposures to total-body irradiation; certain methods of total-body irradiation delivery (4-6); and the presence of pulmonary, renal, or hepatic dysfunction before HCT (7-10). Although multivariable models have incorporated some of these conditions as risk factors for death, previous studies have not used these variables to predict this risk. The goal of this study was to develop a reliable and valid predictor of all-cause mortality during the first 2 years after allogeneic HCT. This assessment resulted in the development and validation of a 50-point integrated grading system that we have termed the Pretransplantation Assessment of Mortality (PAM) score. Methods Patient Selection This study was conducted by using clinical and laboratory data that were collected prospectively at the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, a tertiary cancer center that conducts an average of 350 to 400 allogeneic and autologous HCTs per year. Patients who underwent a first allogeneic HCT between 1 October 1990 and 31 December 2002 (n= 3055) were considered for this study. Patients who were younger than 15 years of age (n= 219) were excluded. Another 30 patients were excluded because their carbon monoxide diffusion capacity (DLCO) was not assessed before transplantation, and 4 patients were excluded because their pretransplantation serum creatinine, total bilirubin, or serum alanine aminotransferase (ALT) levels were not available. The remaining 2802 patients were randomly divided into 2 groups: a development group (n= 1401) and a validation group (n= 1401). We decided a priori to further subdivide the validation cohort into 2 subgroups to account for changes in HCT practice across time: an early validation subgroup (n= 853), which comprised patients who underwent HCT between 1 October 1990 and 31 December 1997, and a late validation subgroup (n= 548), which comprised patients who underwent HCT between 1 January 1998 and 31 December 2002. The cutoff point was set at the end of 1997 because nonmyeloablative transplant protocols were initiated at our center in 1998. Clinical Variables We defined potential 2-year mortality risk factors as demographic, clinical, and laboratory data that were known to be associated with higher mortality risk and were routinely available during a standard pretransplantation assessment. In addition to their relationship to death risk, these variables were selected because they were likely to be available to physicians outside our center and because they were likely to minimize variation in interpretation of the data, to maximize the general applicability of this scoring system, and to maximize its reproducibility in performance. Because of the large number of heterogeneous diagnoses and stages of disease, we simplified disease risk categories by ranking them according to the outcomes that we observed at our center. Low-risk diseases included chronic myelogenous leukemia in chronic phase, refractory anemia, aplastic anemia, and the BlackfanDiamond syndrome. Intermediate-risk diseases included chronic myelogenous leukemia in accelerated phase or in chronic phase after blastic phase, acute leukemia or lymphoma in remission, refractory anemia with excess blasts, chronic lymphocytic leukemia, and paroxysmal nocturnal hemoglobinuria. High-risk diseases included chronic myelogenous leukemia in blastic phase, juvenile chronic myelogenous leukemia, acute leukemia or lymphoma in relapse, refractory anemia with excess blasts in transformation, and myeloma. Solid tumors and nonhematologic diseases were also classified as high-risk diseases. Stem-cell sources were classified as bone marrow; growth factormobilized blood cells; or other, which included cord blood or a combination of bone marrow and mobilized blood cells. Matching between the donor and recipient was determined according to donorrecipient HLA-A, HLA-B, and HLA-DR compatibility. Conditioning regimens were first grouped according to myeloablative or nonmyeloablative categories. Myeloablative regimens were categorized according to the dose of total-body irradiation used (12 Gy or >12 Gy). All patients in the nonmyeloablative group received 2 Gy of total-body irradiation. All pulmonary function tests were performed at our center according to American Thoracic Society guidelines (11-13). We assessed FEV1 and DLCO, which was adjusted for the most recently documented hemoglobin level, because these studies were previously identified in multivariable models to be significantly associated with increased mortality risk after transplantation (7). All pulmonary function values were expressed as a percentage of the predicted values that were calculated according to published equations (14, 15). Serologic studies for cytomegalovirus infection were performed. We used measurements of serum creatinine, total bilirubin, and ALT levels that were obtained most recently before the conditioning regimen was initiated. By using our centers laboratory standards, we classified the following results as abnormal: serum creatinine level greater than 110 mol/L (>1.2 mg/dL), serum total bilirubin level greater than 22 mol/L (1.3 mg/dL), and serum ALT level greater than 49 U/L. The primary outcome was death (regardless of cause) within the first 2 years after transplantation. All patients were followed for at least 2 years after the procedure or until death. We contacted patients, their primary care physicians, or their oncologists by telephone at least 1 time per year as part of routine post-transplantation protocol. Statistical Analysis All statistical analyses were performed by using Stata software, version 8.0 (Stata Corp., College Station, Texas). All potential risk factors were considered to be categorical variables. The Pearson chi-square test was used for all univariate analyses. Cox proportional hazards regression models were used to conduct a survival (time-to-death) analysis. The Schoenfeld residual test was used to evaluate model fit and the tenability of the proportional hazards assumption for all Cox proportional hazards regression models. All patients were followed until death or were censored at the end of the 2-year follow-up period. Statistical significance was defined as a 2-sided P value of less than 0.1 in univariate analyses for covariate selection and as a 2-sided P value of less than 0.05 in multivariable analyses. Development of the PAM Score The development cohort was used to construct the PAM score. All clinical variables were first assessed for their association with 2-year survival in univariate analysis. Variables found to be associated with 2-year survival at a statistically significant threshold (P< 0.1) were assessed in a multivariable Cox proportional hazards model. We used a stepwise selection algorithm, retaining in the final model only those variables that contained at least 1 statistically significant category (P< 0.05). To create an easily applicable scoring system, we multiplied the coefficients from the final model by 10 and rounded the values to the nearest integer. The sum of these integer weights was used as a simplified scoring scheme. Validation of PAM Scores We divided the distribution of PAM scores into 4 categories according to the probability of death in the development cohort: category 1, less than 25%; category 2, 25% to 50%; category 3, 50% to 75%; and category 4, greater than 75%. To assess the discriminatory capability of the PAM score for 2-year survival, we computed the c-statistic. In the case of a binary outcome, such as survival, the c-statistic was interpretable as the area under a receiver-operating characteristic curve for comparing predictions in 2 outcome groups (16). We also graphically compared survival functions by using KaplanMeier survival curves to assess model fit. To make these assessments, we used both the early and the late validation cohorts and subgroups of patients with the 3 diseases observed most commonly in our entire study sample: chronic myelogenous leukemia (n= 1017), acute myelogenous leukemia (n= 667), and the myelodysplastic syndrome (n= 407). Role of the Funding Sources The funding sources, the American Lung Association and the National Marrow Donor Program, had no role in the design, conduct, or analysis of this study or in the decision to submit the manuscript for publication. Results Development of the PAM Score The overall 2-year mortality rate for the development cohort was 49%. Of the 14 clinical variables initially selected, 11 were statistically significant (P< 0.1) in univariate analysis and were considered in mu

Bronchiolitis Obliterans After Allogeneic Hematopoietic Stem Cell Transplantation

With improvements in supportive care, both long-term survival following allogeneic hematopoietic stem cell transplantations (HSCTs) and the indications for this procedure have increased. As a result, the number of patients living with long-term toxic effects due to HSCT has increased. A once rare condition of the donor immune cells attacking healthy host tissues, termed chronic graft-vs-host disease, has become a more common phenomenon. When chronic graft-vs-host disease affects the lung tissue, bronchiolitis obliterans syndrome ensues. Recent data suggest that bronchiolitis obliterans syndrome may affect up to 6% of HSCT recipients and dramatically alters survival, with overall survival of only 13% at 5 years. These statistics have not improved since the first presentation of this disease over 20 years ago. Challenges to the progress of medical management of bronchiolitis obliterans syndrome include difficulties and delays in diagnosis and a paucity of data on pathogenesis to direct new therapies. This article critically evaluates the current diagnostic criteria for bronchiolitis obliterans syndrome and reviews the epidemiology, pathogenesis, and available treatments. Improvements in survival will likely require early disease recognition, allowing for therapeutic modulation of disease prior to the development of irreversible airway obliteration.