A randomized phase 2 trial of pomalidomide in subjects failing prior therapy for chronic graft-versus-host disease.

Steroid-refractory chronic graft-versus-host disease (cGVHD) is a therapeutic challenge. Sclerotic skin manifestations are especially difficult to treat. We conducted a randomized phase 2 clinical trial (#NCT01688466) to determine the safety, efficacy, and preferred dose of pomalidomide in persons with moderate to severe cGVHD unresponsive to corticosteroids and/or subsequent lines of therapy. Thirty-four subjects were randomized to receive pomalidomide 0.5 mg per day orally (n = 17; low-dose cohort) or 2 mg per day at a starting dose of 0.5 mg per day increasing to 2 mg per day over 6 weeks (n = 17; high-dose cohort). The primary endpoint was overall response rate (ORR) at 6 months according to the 2005 National Institutes of Health cGVHD Response Criteria. Thirty-two patients had severe sclerotic skin and received a median of 5 (range, 2-10) previous systemic therapies. ORR was 47% (95% confidence interval, 30-65) in the intention-to-treat analyses. All were partial responses, with no difference in ORR between the cohorts. ORR was 67% (45%-84%) in the 24 evaluable subjects at 6 months. Nine had improvement in National Institutes of Health joint/fascia scores (P = .018). Median change from the baseline in body surface area involvement of skin cGVHD was -7.5% (-10% to 35%; P = .002). The most frequent adverse events were lymphopenia, infection, and fatigue. Eight subjects in the high-dose cohort had dose decreases because of adverse events. There was 1 death in the low-dose cohort from bacterial pneumonia. Our data indicate antifibrotic effects of pomalidomide and possible association with increases in concentrations of blood regulatory T-cell and interleukin-2. Pomalidomide 0.5 mg per day is a safe and effective therapy for advanced corticosteroid-refractory cGVHD.

Survivorship Issues in Adult Patients With Histiocytic Neoplasms.

Adult-onset histiocytoses (AOH), primarily Rosai-Dorfman disease (RDD), Erdheim-Chester Disease (ECD), and adult Langerhans cell histiocytosis (ALCH), are a group of related histiocytic neoplastic disorders featuring multisystemic manifestations. The disorders are largely incurable, and are essentially chronic neoplastic diseases with a variable prognosis. Prompt diagnosis and treatment is important to prevent debilitating and even life-threatening complications. Survivorship issues abound in AOH, due to their multisystemic manifestations and the sometimes recalcitrant chronic inflammation, which can lead to other debilitating complications such as fatigue, weakness, and pain. Because these disorders are rare, few healthcare professionals are proficient in their management; therefore the aim of these guidelines is to offer guidance on how to manage patients, and how to create survivorship care plans through the efforts of an interdisciplinary team.

Rehabilitation Interventions in the Multidisciplinary Management of Patients With Sclerotic Graft-Versus-Host Disease of the Skin and Fascia.

Graft-versus-host disease (GVHD) is a multisystemic disorder that affects 30%-80% of patients who undergo allogeneic hematopoietic stem cell transplantation 10%-15% of GVHD patients develop sclerotic features affecting the skin or deeper tissues, leading to functional limitations and poor quality of life. There is limited literature regarding the indications and efficacy of specific rehabilitative interventions in sclerotic GVHD (sclGVHD). In this article, we summarize the current evidence supporting rehabilitation intervention in sclGVHD and offer our approach to the multidisciplinary management of this disease. In addition, we review techniques that have been employed in other sclerotic skin diseases (eg, iontophoresis, extracorporeal shock waves, botulinum toxin A, adipose derived stromal vascular fraction), but that require further validation in the sclGVHD setting. Ultimately, optimal care for this complex disease requires a multidisciplinary approach that includes a rehabilitation and adaptive program tailored to each patient's needs.

Motor ability, function, and health-related quality of life as correlates of symptom burden in patients with sclerotic chronic graft-versus-host disease receiving imatinib mesylate.

PURPOSE: To explore improvement in motor ability, function, health-related quality of life (HRQOL), and symptom severity in patients with sclerotic chronic graft-versus-host disease (ScGVHD) in response to treatment as well as the relationship among changes on such measures. METHODS: This study was a secondary analysis of data from 13 individuals with severe ScGVHD enrolled in a clinical trial evaluating the efficacy of imatinib mesylate (clinicaltrials.gov identifier: NCT00702689). Self-reported, clinician-reported, and performance-based indicators of motor ability, function, HRQOL, and symptom severity were assessed at baseline and 6 months following the administration of imatinib mesylate. RESULTS: Participants did not show statistically significant improvement on any measures over time. Approximately one-third of patients displayed clinically significant improvement on measures of motor ability (palmar pinch strength, dominant hand, 30.8%), functioning (Manual Ability Measure-36, 41.7%), HRQOL (Short Form 36 [SF-36] Mental Component Summary, 33.3%), and symptom severity (Lee Symptom Scale, 38.5%). Improvement in cGVHD symptom burden was correlated with improvement in function (Assessment of Motor and Process Skills [AMPS] and Disabilities of the Arm, Shoulder, and Hand [DASH] scores) and HRQOL (SF-36 Physical Component Summary scores). CONCLUSIONS: Findings suggest the potential utility of administering patient-reported and performance-based functional measures, such as the DASH and the AMPS, to patients with cGVHD. By understanding the functional consequences of ScGVHD, interdisciplinary teams of health care providers, including rehabilitation professionals, can work to improve long-term outcomes.

Psychosocial Characteristics of Women with a Delayed Diagnosis of Turner Syndrome.

OBJECTIVES: To characterize the psychosocial profiles of adult women diagnosed with Turner syndrome before (early diagnosis) and at or after (late diagnosis) 13 years of age. STUDY DESIGN: Women with Turner syndrome ages 22 and older at evaluation (n = 110) participated in a cross-sectional study at the National Institutes of Health. Researchers performed nonparametric and logistic regression analyses to assess early and late diagnosis cohorts on measures of depression, substance use, and perceptions of competence and identity. RESULTS: Of study participants, 47% received a Turner syndrome diagnosis at or after age 13 years. Median age at diagnosis was 12.0 years (range, 0-43). Covariate-adjusted models revealed that women with late diagnoses had an increased likelihood of developing mild to severe depressive symptoms (OR, 7.36) and a decreased likelihood of being perceived as competent (OR, 0.26). Women with a late diagnosis also exhibited more frequent substance use compared with women with early diagnoses. CONCLUSIONS: These data suggest that Turner syndrome diagnoses received at or after age 13 years may contribute to adverse outcomes related to depression, substance use, and perceptions of competence. Delayed Turner syndrome diagnoses may place women and girls at risk for negative psychosocial development extending into adulthood. These findings indicate it is important for pediatricians to evaluate psychosocial domains in girls with Turner syndrome regularly, particularly among those diagnosed at age 13 years or older. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00006334.

Imatinib mesylate for the treatment of steroid-refractory sclerotic-type cutaneous chronic graft-versus-host disease.

Sclerotic skin manifestations of chronic graft-versus-host disease (ScGVHD) lead to significant morbidity, including functional disability from joint range of motion (ROM) restriction. No superior second-line therapy has been established for steroid-refractory disease. Imatinib mesylate is a multikinase inhibitor of several signaling pathways implicated in skin fibrosis with in vitro antifibrotic activity. We performed an open-label pilot phase II trial of imatinib in children and adults with corticosteroid-refractory ScGVHD. Twenty patients were enrolled in a 6-month trial. Eight received a standard dose (adult, 400 mg daily; children, 260 mg/m(2) daily). Because of poor tolerability, 12 additional patients underwent a dose escalation regimen (adult, 100 mg daily initial dose up to 200 mg daily maximum; children, initial dose 65 mg/m(2) daily up to 130 mg/m(2) daily). Fourteen patients were assessable for primary response, improvement in joint ROM deficit, at 6 months. Primary outcome criteria for partial response was met in 5 of 14 (36%), stable disease in 7 of 14 (50%), and progressive disease in 2 of 14 (14%) patients. Eleven patients (79%), including 5 with partial response and 6 with stable disease, demonstrated a positive gain in ROM (range of 3% to 94% improvement in deficit). Of 13 patients with measurable changes at 6 months, the average improvement in ROM deficit was 24.2% (interquartile range, 15.5% to 30.5%; P = .011). This trial is registered at http://clinicaltrials.gov as NCT007020689.

National Institutes of Health chronic graft-versus-host disease staging in severely affected patients: organ and global scoring correlate with established indicators of disease severity and prognosis.

Between 2004 and 2010, 189 adult patients were enrolled on the National Cancer Institute's cross-sectional chronic graft-versus-host disease (cGVHD) natural history study. Patients were evaluated by multiple disease scales and outcome measures, including the 2005 National Institutes of Health (NIH) Consensus Project cGVHD severity scores. The purpose of this study was to assess the validity of the NIH scoring variables as determinants of disease severity in severely affected patients in efforts to standardize clinician evaluation and staging of cGVHD. Out of 189 patients enrolled, 125 met the criteria for severe cGVHD on the NIH global score, 62 of whom had moderate disease, with a median of 4 (range, 1-8) involved organs. Clinician-assigned average NIH organ score and the corresponding organ scores assigned by subspecialists were highly correlated (r = 0.64). NIH global severity scores showed significant associations with nearly all functional and quality of life outcome measures, including the Lee Symptom Scale, Short Form-36 Physical Component Scale, 2-minute walk, grip strength, range of motion, and Human Activity Profile. Joint/fascia, skin, and lung involvement affected function and quality of life most significantly and showed the greatest correlation with outcome measures. The final Cox model with factors jointly predictive for survival included the time from cGVHD diagnosis (>49 versus ≤49 months, hazard ratio [HR] = 0.23; P = .0011), absolute eosinophil count at the time of NIH evaluation (0-0.5 versus >0.5 cells/µL, HR = 3.95; P = .0006), and NIH lung score (3 versus 0-2, HR = 11.02; P < .0001). These results demonstrate that NIH organs and global severity scores are reliable measures of cGVHD disease burden. The strong association with subspecialist evaluation suggests that NIH organ and global severity scores are appropriate for clinical and research assessments, and may serve as a surrogate for more complex subspecialist examinations. In this population of severely affected patients, NIH lung score is the strongest predictor of poor overall survival, both alone and after adjustment for other important factors.

Occupational engagement, fatigue, and upper and lower extremity abilities in persons with melorheostosis.

INTRODUCTION: Melorheostosis is a rare bone disorder with limited literature that describes the effect of this disease on functional and motor abilities. As part of a natural history study, four outcome measures were administered to better understand the burden this disease has on a person's ability to engage in basic and instrumental activities of daily living. OBJECTIVE: To investigate the relationship between functional engagement, fatigue, and motor ability in patients with melorheostosis. DESIGN: Cross-sectional data gathered from a longitudinal natural history observational study. SETTING: Rehabilitation department within a single institution. PARTICIPANTS: Forty-seven adult volunteers with melorheostosis were enrolled. Two participants were removed for failure to meet diagnosis eligibility. Thirty patients had lower extremity (LE) osteosclerotic bone lesions, 14 had upper extremity (UE) lesions, and one had lesions in both UEs and LEs. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Activity Card Sort, Second Edition (ACS); Multi-Dimensional Fatigue Inventory; Lower Extremity Functional Scale; Upper Extremity Functional Index. RESULTS: On the ACS, high-demand leisure (HDL) activities were the least retained (p < .001). Of the activities rated most important, HDL activities were the most likely to have been given up (27%). General fatigue (µ = 11.8) and physical fatigue (µ = 11.0) were the two most limiting fatigue constructs. There were moderate negative correlations with HDL activities compared to physical fatigue (r = -0.524, p < .001) and reduced activity fatigue (r = -0.58, p = .001). LE lesions had a large effect on completing LE tasks (d = 0.95) and UE lesions had a medium effect on completing tasks involving the UE (d = 0.69). CONCLUSIONS: Patients with melorheostosis experience fatigue and low engagement in HDL activities. The results of this study underscore the importance of acknowledging activity domain, fatigue constructs, and lesion location to support and provide targeted evidence-based rehabilitative therapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT02504879.

Predictors and significance of kidney dysfunction in patients with chronic graft-versus-host disease.

Kidney complications have been studied in allogeneic hematopoietic stem cell transplant patients but not specifically among chronic graft-versus-host disease (cGVHD) patients. Participants (n = 365) enrolled in the cross-sectional cGVHD natural history study (NCT00092235) were assessed for kidney dysfunction and overall survival. Kidney dysfunction was analyzed for associations in univariate and multivariable analyses. Kidney dysfunction (eGFR < 60) was found in 64 patients, and 29 patients had moderate-severe kidney dysfunction (eGFR < 45). Patients with kidney dysfunction were more likely treated with cyclosporine at evaluation or to have received it for GVHD prophylaxis, or prior treatment of GVHD. Patients with kidney dysfunction were less severely affected by cGVHD of skin, mouth, and joints/fascia. In multivariable modeling, history of cyclosporine use (OR = 2.19, 95% CI 1.13-4.25), angiotensin receptor blocker use (OR = 5.57, 95% CI 1.49-20.84), proteinuria (OR = 2.39, 95% CI 1.19-4.79), lower CRP (OR = 0.95, 95% CI 0.91-0.99), lower C3 (OR = 0.98, 95% CI 0.97-0.99), and lower hemoglobin (OR = 0.70, 95% CI 0.58-0.84) were jointly associated with kidney dysfunction. Overall survival was lower in those with moderate-severe kidney dysfunction (p = 0.015), demonstrating the importance of addressing kidney dysfunction in this population. The association of kidney dysfunction with less severe cGVHD suggests an etiology unrelated to cGVHD but potentially a consequence of drug-related toxicities.

Metabolic syndrome prevalence and impact on outcomes in patients with chronic graft-versus-host disease.

Patients with chronic graft-versus-host disease (cGVHD) are at heightened risk for components of metabolic syndrome (MetS), yet the prevalence and impact of MetS in the cGVHD patient population remain unknown. Adult patients (n = 229) with cGVHD enrolled in the cross-sectional NIH cGVHD Natural History Study (NCT00092235) were evaluated for MetS at enrollment and for variables associated with MetS. A majority (54.1%, 124/229) of the cohort met the diagnostic criteria for MetS. Patients with higher body mass index and lower performance status scores were more likely to have MetS (P < 0.0001; P = 0.026; respectively). Higher circulating erythrocyte sedimentation rate, C-reactive protein, and creatinine concentrations, along with lower estimated glomerular filtration rate, were associated with MetS (P < 0.001; P < 0.004; P = 0.02; P = 0.002; respectively). Patients with MetS compared to patients without MetS had no statistical differences in survival or NRM (5-year OS: 64% [95% CI: 54.8-71.8%] vs. 75.1% [95% CI: 65.6-82.3%]; respectively; overall P = 0.20; 5-year NRM: 21.7% [95% CI: 13.6-30.9%] vs. 10.1% [95% CI: 4.4-18.7%]; respectively; overall P = 0.12). Additionally, there was no difference in cGVHD severity between the two groups. Given the high prevalence of MetS in this cohort, clinicians should screen for its presence before it develops into comorbidities that complicate the course of cGVHD treatment.

Simple and economical HandClench Relaxometer device for reliable and sensitive measurement of grip myotonia in myotonic dystrophy.

Grip myotonia and weakness are attractive treatment response biomarkers in clinical trials of myotonic dystrophy type 1 (DM1). There is a need to develop simple, patient-friendly and reproducible methods of quantifying grip myotonia in multisite trial settings. We designed a HandClench Relaxometer (HCR) that measures grip myotonia and strength. In contrast with the existing quantitative myometry (QMA) setup, the HCR is portable, economical, can be used with any laptop and generates automated command prompts. We demonstrate the feasibility and reliability of HCR device in twenty DM1 individuals and ten age-matched controls; patients returned for follow up within two months. The device showed excellent day to day reproducibility (ICC >0.80) in patients. The HCR device detected myotonia in milder muscle disease and measured longer myotonia duration than QMA indicating enhanced sensitivity for quantifying myotonia in DM1. The reaction time to the relax but not squeeze command was delayed and showed warm up similar to myotonia in DM1. HCR outcomes were correlated with key pinch strength, hand dexterity test, and fat replacement in the MRI of the long finger flexor muscles. Use of the HCR is warranted for grip myotonia and strength measurements in longitudinal observational and interventional studies of DM1.

Prospective Phase II Trial of Montelukast to Treat Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation and Investigation into Bronchiolitis Obliterans Syndrome Pathogenesis.

Bronchiolitis obliterans syndrome (BOS) is a severe manifestation of chronic graft-versus-host disease (cGVHD) following hematopoietic cell transplantation (HCT). Montelukast interrupts cysteinyl leukotriene (CysLT) activity and may diminish the activation and homing of cells to bronchioles and subsequent fibrosis. We performed a prospective phase II trial to test whether montelukast altered lung decline for patients with BOS after HCT. In this single-arm, open-label, multi-institutional study, the primary endpoints were stability or improvement (<15% decline) in forced expiratory volume in 1 second (FEV1) and a <1-point decline in the slope of FEV1 after 6 months of treatment. Secondary endpoints included symptom and functional responses and immune correlates investigating the role of leukotrienes in BOS progression. The study enrolled 25 patients with moderate to severe lung disease after 3 months of stable cGVHD therapy. Montelukast was well tolerated, and no patient required escalation of BOS-directed therapy. At the primary endpoint, all 23 evaluable patients met the criteria for treatment success using FEV1% predicted, and all but 1 patient had stable or improved FEV1 slope. In those with a >5% improvement in FEV1, clinically meaningful improvements were seen in the Lee scores of breathing, energy, and mood. Improvements in the Human Activity Profile and 6-minute-walk test were observed in those with a <5% decline in FEV1. Overall survival was 87% at 2 years. Immune correlates showed elevated leukotriene receptor levels on blood eosinophils and monocytes versus healthy controls, elevated urine leukotrienes in 45% of the cohort, and CysLT receptors in bronchoalveolar lavage subsets and a predominance of Th2 cells, all pretreatment. These data suggest that montelukast may safely halt the progression of BOS after HCT, and that leukotrienes may play a role in the biology of BOS.

Subsequent Cancers in Patients Affected with Moderate or Severe Chronic Graft-versus-Host Disease.

Subsequent cancer (SC) is a significant cause of morbidity and mortality in long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) and treatment-related immunosuppression have been recognized as risk factors for SC. This study sought to investigate the incidence and risk factors for SC in patients with established cGVHD, assessed separately for onset of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)-categorized into nonmelanoma skin cancer (NMSC)-and all cancers other than NMSC. Two hundred and four patients were enrolled in the prospective cross-sectional cGVHD Natural History Study and underwent comprehensive clinical evaluation. Patients were followed-up with an annual survey. The cumulative incidences of NMSC and cancers other than NMSC with competing risks were estimated separately, and transplantation- and cGVHD-related factors were assessed for association with outcomes using Gray's test and multivariable Cox models. The time period for all analyses began at 2 years postevaluation to restrict analyses to patients presumed to not have had SC present at evaluation. Nineteen patients were diagnosed with NMSC and 19 were diagnosed with cancers other than NMSC, with 10-year cumulative incidences of 15.5% (95% confidence interval, 9.0% to 27.6%) and 13.8% (95% CI, 8.2% to 20.8%), respectively. Age at transplantation (hazard ratio [HR], 1.94; 95% CI, 1.23 to 3.06) and higher C-reactive protein level at evaluation (HR, 9.49; 95% CI, 1.26 to 71.58) were jointly associated with NMSC, and gastrointestinal cGVHD at evaluation (HR, 0.26; 95% CI, 0.09 to 0.78) was associated with reduced risk of NMSC. T cell depletion at transplantation (HR, 3.09; 95% CI, 1.17 to 8.20), lymphoma as an indication for transplantation (HR, 3.96; 95% CI, 1.56 to 10.05), and oral cGVHD severity at evaluation (HR, 4.36; 95% CI, 1.52 to 12.46) were jointly associated with cancers other than NMSC. This study estimates the incidence of SC in a population of allo-HSCT recipients with severe cGVHD and identifies correlations with the subsequent development of SC. These factors seem to differ between NMSC and cancers other than NMSC. Further longitudinal investigations accounting for dynamic and cumulative processes are needed to improve our understanding and management of SC.

Cognitive Functioning in Turner Syndrome: Addressing Deficits Through Academic Accommodation.

Background: The cognitive profile of Turner syndrome, a genetic disorder resulting from partial or complete X-chromosome deletion, presents characteristic deficits. Despite this, studies have yet to evaluate how deficits translate into and are compensated for in academic settings. This study seeks to explore cognitive functioning, as well as the accessibility and development of academic accommodations in females with Turner syndrome from adolescence to adulthood. Materials and Methods: This cross-sectional study took place at the National Institutes of Health. Females with Turner syndrome (age range: 10-68; n = 142) were evaluated on need for and procurement of academic accommodations. Cognitive functioning was evaluated in participants aged 20 years and older (n = 101), as per the age validation of the Repeatable Battery for the Assessment of Neuropsychological Status. Data were analyzed using descriptive statistics, one-sample comparisons, and analyses of variance. Results: Females with Turner syndrome scored significantly lower than the normative population on visuospatial (p < 0.001), delayed memory (p < 0.001), and overall (p < 0.001) functioning. About 25.9% of participants reported that accommodations were not needed, despite displaying one or more cognitive deficits. Approximately 12.7% reported needing but not receiving accommodations, however, this is only reported by females 30 years and older; no females aged 10-29 years indicated this discrepancy. Conclusions: Findings suggest that procurement of academic accommodations has increased within recent decades. Still, there is a discrepancy between those displaying cognitive deficits and those receiving academic accommodations. We highlight frequently received accommodations so that students and professionals can target deficits with appropriate accommodations.

Impact of the 2014 NIH chronic graft-versus-host disease scoring criteria modifications assessed in a large cohort of severely affected patients.

In 2005, the National Institutes of Health (NIH) chronic graft-versus-host disease (cGVHD) consensus project provided diagnosis and staging criteria, based mostly on clinical experience and expert opinion. These criteria were revised in 2014, aiming to provide enhanced specificity and clarity. However, the impact of 2014 changes to the original NIH cGVHD severity scoring criteria has not been reported. In this study, 284 patients, prospectively enrolled on the National Cancer Institute's cross-sectional cGVHD natural history study, were scored using the 2005 NIH cGVHD criteria and then rescored according to the 2014 modifications. In comparing the two criteria, 2014 cGVHD global severity scoring resulted in a tendency toward being categorized as milder scores (75 vs. 72% of severe score per 2014, p = 0.0009), with a statistically significant shift in NIH liver and lung scores toward milder categories (p < 0.0001). 2005 and 2014 NIH global severity scores showed a significant association with reduced grip strength (p < 0.0001), reduced joint range of motion (p = 0.0003), and the subspecialist evaluation score (p < 0.0001). Poor survival prediction of the severe NIH lung score is also retained in the new criteria (p = 0.0012). These findings support the use of 2014 cGVHD scoring criteria in continuous efforts to develop better classification systems.