Colin O. Wu

Horse versus Rabbit Antithymocyte Globulin in Acquired Aplastic Anemia

BACKGROUND In severe acquired aplastic anemia, hematopoietic failure is the result of immune-mediated destruction of bone marrow stem and progenitor cells. Immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporine is an effective alternative to stem-cell transplantation and improves blood counts and survival. Although horse ATG is the standard therapy, rabbit ATG is more potent in depleting peripheral-blood lymphocytes and is preferred in other clinical circumstances. METHODS From December 2005 through July 2010, we performed a randomized trial comparing these two ATG formulations in conventional regimens. Patients were treated at a single facility. The primary outcome was hematologic response at 6 months, as determined by blood counts. The study was designed to enroll 60 patients each for the rabbit-ATG and horse-ATG groups and was powered to detect a difference of 25 percentage points in the response rate. RESULTS A large, unexpected difference was observed in the rate of hematologic response at 6 months in favor of horse ATG (68%; 95% confidence interval [CI], 56 to 80) as compared with rabbit ATG (37%; 95% CI, 24 to 49; P<0.001). Overall survival at 3 years also differed, with a survival rate of 96% (95% CI, 90 to 100) in the horse-ATG group as compared with 76% (95% CI, 61 to 95) in the rabbit-ATG group (P=0.04) when data were censored at the time of stem-cell transplantation, and 94% (95% CI, 88 to 100) as compared with 70% (95% CI, 56 to 86; P=0.008) in the respective groups when stem-cell-transplantation events were not censored. CONCLUSIONS In a randomized study, rabbit ATG was inferior to horse ATG as a first treatment for severe aplastic anemia, as indicated by hematologic response and survival. (Funded by the Intramural Research Program of the National Institutes of Health; ClinicalTrials.gov number, NCT00260689.).

Reduced Ascending Aortic Strain and Distensibility Earliest Manifestations of Vascular Aging in Humans

Arterial stiffness predicts cardiovascular events beyond traditional risk factors. However, the relationship with aging of novel noninvasive measures of aortic function by MRI and their interrelationship with established markers of vascular stiffness remain unclear and currently limit their potential impact. Our aim was to compare age-related changes of central measures of aortic function with carotid distensibility, global carotid–femoral pulse wave velocity, and wave reflections. We determined aortic strain, distensibility, and aortic arch pulse wave velocity by MRI, carotid distensibility by ultrasound, and carotid–femoral pulse wave velocity by tonometry in 111 asymptomatic subjects (54 men, age range: 20 to 84 years). Central pressures were used to calculate aortic distensibility. Peripheral and central pulse pressure, augmentation index, and carotid–femoral pulse wave velocity increased with age, but aortic strain and aortic arch PWV were most closely and specifically related to aging. Ascending aortic (AA) strain and distensibility decreased, respectively, by 5.3±0.5% (R2=0.54, P<0.0001) and 13.6±1 kPa−1×10−3 (R2=0.62, P<0.0001), and aortic arch pulse wave velocity increased by 1.6±0.13 m/sec (R2=0.60, P<0.0001) for each decade of age after adjustment for gender, body size, and heart rate. We demonstrate in this study a dramatic decrease in AA distensibility before the fifth decade of life in individuals with diverse prevalence of risk factors free of overt cardiovascular disease. In particular, compared with other measures of aortic function, the best markers of subclinical large artery stiffening, were AA distensibility in younger and aortic arch pulse wave velocity in older individuals.

Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia

BACKGROUND Severe aplastic anemia, which is characterized by immune-mediated bone marrow hypoplasia and pancytopenia, can be treated effectively with immunosuppressive therapy or allogeneic transplantation. One third of patients have disease that is refractory to immunosuppression, with persistent, severe cytopenia and a profound deficit in hematopoietic stem cells and progenitor cells. Thrombopoietin may increase the number of hematopoietic stem cells and progenitor cells. METHODS We conducted a phase 2 study involving patients with aplastic anemia that was refractory to immunosuppression to determine whether the oral thrombopoietin mimetic eltrombopag (Promacta) can improve blood counts. Twenty-five patients received eltrombopag at a dose of 50 mg, which could be increased, as needed, to a maximum dose of 150 mg daily, for a total of 12 weeks. Primary end points were clinically significant changes in blood counts or transfusion independence. Patients with a response continued to receive eltrombopag. RESULTS Eleven of 25 patients (44%) had a hematologic response in at least one lineage at 12 weeks, with minimal toxic effects. Nine patients no longer needed platelet transfusions (median increase in platelet count, 44,000 per cubic millimeter). Six patients had improved hemoglobin levels (median increase, 4.4 g per deciliter); 3 of them were previously dependent on red-cell transfusions and no longer needed transfusions. Nine patients had increased neutrophil counts (median increase, 1350 per cubic millimeter). Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in patients who had a response, without increased fibrosis. Monitoring of immune function revealed no consistent changes. CONCLUSIONS Treatment with eltrombopag was associated with multilineage clinical responses in some patients with refractory severe aplastic anemia. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00922883.).

Asymptotic Confidence Regions for Kernel Smoothing of a Varying-Coefficient Model with Longitudinal Data

Abstract We consider the estimation of the k + 1-dimensional nonparametric component β(t) of the varying-coefficient model Y(t) = X T (t)β(t) + e(t) based on longitudinal observations (Yij , X i (tij ), tij ), i = 1, …, n, j = 1, …, ni , where tij is the jth observed design time point t of the ith subject and Yij and X i (tij ) are the real-valued outcome and R k+1 valued covariate vectors of the ith subject at tij. The subjects are independently selected, but the repeated measurements within subject are possibly correlated. Asymptotic distributions are established for a kernel estimate of β(t) that minimizes a local least squares criterion. These asymptotic distributions are used to construct a class of approximate pointwise and simultaneous confidence regions for β(t). Applying these methods to an epidemiological study, we show that our procedures are useful for predicting CD4 (T-helper lymphocytes) cell changes among HIV (human immunodeficiency virus)-infected persons. The finite-sample properties of o...

Factors Affecting Response and Survival in Patients With Myelodysplasia Treated With Immunosuppressive Therapy

PURPOSE Marrow failure in some patients with myelodysplastic syndrome (MDS) responds to immunosuppressive treatment (IST), but long-term outcome after IST has not been described. We evaluated patients with MDS treated with IST at our institution to determine their clinical course compared with a comparable supportive care only group. PATIENTS AND METHODS One hundred twenty-nine patients with MDS received IST with a median follow-up of 3.0 years (range, 0.03 to 11.3 years), using antithymocyte globulin (ATG) or cyclosporine (CsA) in combination or singly. Variables affecting response and survival were studied and outcomes were compared with those of 816 patients with MDS reported to the International Myelodysplasia Risk Analysis Workshop (IMRAW) who received only supportive care. RESULTS Thirty-nine (30%) of 129 patients receiving IST responded either completely or partially: 18 (24%) of 74 patients responded to ATG, 20 (48%) of 42 patients responded to ATG plus CsA, and one (8%) of 13 patients responded to CsA. Thirty-one percent (12 of 39) of the responses were complete, resulting in transfusion independence and near-normal blood counts. In multivariate analysis, younger age was the most significant factor favoring response to therapy. Other favorable factors affecting response were HLA-DR15 positivity and combination ATG plus CsA treatment (P = .001 and P = .048, respectively). In multivariate analysis of the combined IMRAW and IST cohorts, younger age, treatment with IST, and intermediate or low International Prognostic Scoring System score significantly favored survival. CONCLUSION IST produced significant improvement in the pancytopenia of a substantial proportion of patients with MDS and was associated with improved overall and progression-free survival, especially in younger individuals with lower-risk disease.

Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.

BACKGROUND In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia. METHODS We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients. RESULTS Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients. CONCLUSIONS Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.).

Smoothing Spline Estimation for Varying Coefficient Models With Repeatedly Measured Dependent Variables

Longitudinal samples, i.e., datasets with repeated measurements over time, are common in biomedical and epidemiological studies such as clinical trials and cohort observational studies. An exploratory tool for the analyses of such data is the varying coefficient model Y(t)=XT(t)β(t) + ϵ(t), where Y(t) and X(t) = (X(0)(t),…,X(k)(t))T are the response and covariates at time t, β(t) = (β0(t),…,βk(t))T are smooth coefficient curves of t and ϵ(t) is a mean zero stochastic process. A special case that is of particular interest in many situations is data with time-dependent response and time-independent covariates. We propose in this article a componentwise smoothing spline method for estimating β0(t),…,βk(t) nonparametrically based on the previous varying coefficient model and a longitudinal sample of (t,Y(t),X) with time-independent covariates X = (X(0),…,X(k))T from n independent subjects. A “leave-one-subject-out” cross-validation is suggested to choose the smoothing parameters. Asymptotic properties of our spline estimators are developed through the explicit expressions of their asymptotic normality and risk representations, which provide useful insights for inferences. Applications and finite sample properties of our procedures are demonstrated through a longitudinal sample of opioid detoxification and a simulation study.

Age-Related Changes in Aortic Arch Geometry: Relationship With Proximal Aortic Function and Left Ventricular Mass and Remodeling

OBJECTIVES We sought to define age-related geometric changes of the aortic arch and determine their relationship to central aortic stiffness and left ventricular (LV) remodeling. BACKGROUND The proximal aorta has been shown to thicken, enlarge in diameter, and lengthen with aging in humans. However, no systematic study has described age-related longitudinal and transversal remodeling of the aortic arch and their relationship with LV mass and remodeling. METHODS We studied 100 subjects (55 women, 45 men, average age 46 ± 16 years) free of overt cardiovascular disease using magnetic resonance imaging to determine aortic arch geometry (length, diameters, height, width, and curvature), aortic arch function (local aortic distensibility and arch pulse wave velocity [PWV]), and LV volumes and mass. Radial tonometry was used to calculate central blood pressure. RESULTS Aortic diameters and arch length increased significantly with age. The ascending aorta length increased most, with age leading to aortic arch widening and decreased curvature. These geometric changes of the aortic arch were significantly related to decreased ascending aortic distensibility, increased aortic arch PWV (p < 0.001), and increased central blood pressures (p < 0.001). Increased ascending aortic diameter, lengthening, and decreased curvature of the aortic arch (unfolding) were all significantly associated with increased LV mass and concentric remodeling independently of age, sex, body size, and central blood pressure (p < 0.01). CONCLUSIONS Age-related unfolding of the aortic arch is related to increased proximal aortic stiffness in individuals without cardiovascular disease and associated with increased LV mass and mass-to-volume ratio independent of age, body size, central pressure, and cardiovascular risk factors.

Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia

Horse anti‐thymocyte globulin (h‐ATG) and ciclosporin are the initial therapy for most patients with severe aplastic anaemia (SAA), but there is no practical and reliable method to predict response to this treatment. To determine whether pretreatment blood counts discriminate patients with SAA who have a higher likelihood of haematological response at 6 months to immunosuppressive therapy (IST), we conducted a single institution retrospective analysis on 316 SAA patients treated with h‐ATG‐based IST from 1989 to 2005. In multivariate analysis, younger age, higher baseline absolute reticulocyte count (ARC), and absolute lymphocyte count (ALC) were highly predictive of response at 6 months. Patients with baseline ARC ≥ 25 × 109/l and ALC ≥ 1 × 109/l had a much greater probability of response at 6 months following IST compared to those with lower ARC and ALC (83% vs. 41%, respectively; P < 0·001). This higher likelihood of response translated to greater rate of 5‐year survival in patients in the high ARC/ALC group (92%) compared to those with a low ARC/ALC (53%). In the era of IST, the baseline ARC and ALC together serve as a simple predictor of response following IST, which should guide in risk stratification among patients with SAA.

LV mass assessed by echocardiography and CMR, cardiovascular outcomes, and medical practice.

The authors investigated 3 important areas related to the clinical use of left ventricular mass (LVM): accuracy of assessments by echocardiography and cardiac magnetic resonance (CMR), the ability to predict cardiovascular outcomes, and the comparative value of different indexing methods. The recommended formula for echocardiographic estimation of LVM uses linear measurements and is based on the assumption of the left ventricle (LV) as a prolate ellipsoid of revolution. CMR permits a modeling of the LV free of cardiac geometric assumptions or acoustic window dependency, showing better accuracy and reproducibility. However, echocardiography has lower cost, easier availability, and better tolerability. From the MEDLINE database, 26 longitudinal echocardiographic studies and 5 CMR studies investigating LVM or LV hypertrophy as predictors of death or major cardiovascular outcomes were identified. LVM and LV hypertrophy were reliable cardiovascular risk predictors using both modalities. However, no study directly compared the methods for the ability to predict events, agreement in hypertrophy classification, or performance in cardiovascular risk reclassification. Indexing LVM to body surface area was the earliest normalization process used, but it seems to underestimate the prevalence of hypertrophy in obese and overweight subjects. Dividing LVM by height to the allometric power of 1.7 or 2.7 is the most promising normalization method in terms of practicality and usefulness from a clinical and scientific standpoint for scaling myocardial mass to body size. The measurement of LVM, calculation of LVM index, and classification for LV hypertrophy should be standardized by scientific societies across measurement techniques and adopted by clinicians in risk stratification and therapeutic decision making.