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PURPOSE To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. METHODS We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. RESULTS Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p

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.

ObjectiveTo characterize muscle involvement and evaluate disease severity in patients with GNE myopathy using skeletal muscle MRI and proton magnetic resonance spectroscopy (1H-MRS).MethodsSkeletal muscle imaging of the lower extremities was performed in 31 patients with genetically confirmed GNE myopathy, including T1-weighted and short tau inversion recovery (STIR) images, T1 and T2 mapping, and 1H-MRS. Measures evaluated included longitudinal relaxation time (T1), transverse relaxation time (T2), and 1H-MRS fat fraction (FF). Thigh muscle volume was correlated with relevant measures of strength, function, and patient-reported outcomes.ResultsThe cohort was representative of a wide range of disease progression. Contractile thigh muscle volume ranged from 5.51% to 62.95% and correlated with thigh strength (r = 0.91), the 6-minute walk test (r = 0.82), the adult myopathy assessment tool (r = 0.83), the activities-specific balance confidence scale (r = 0.65), and the inclusion body myositis functional rating scale (r = 0.62). Four stages of muscle involvement were distinguished by qualitative (T1W and STIR images) and quantitative methods: stage I: unaffected muscle (T1 = 1,033 ± 74.2 ms, T2 = 40.0 ± 1.9 ms, FF = 7.4 ± 3.5%); stage II: STIR hyperintense muscle with minimal or no fat infiltration (T1 = 1,305 ± 147 ms, T2 = 50.2 ± 3.5 ms, FF = 27.6 ± 12.7%); stage III: fat infiltration and STIR hyperintensity (T1 = 1,209 ± 348 ms, T2 = 73.3 ± 12.6 ms, FF = 57.5 ± 10.6%); and stage IV: complete fat replacement (T1 = 318 ± 39.9 ms, T2 = 114 ± 21.2 ms, FF = 85.6 ± 4.2%). 1H-MRS showed a significant decrease in intramyocellular lipid and trimethylamines between stage I and II, suggesting altered muscle metabolism at early stages.ConclusionMRI biomarkers can monitor muscle involvement and determine disease severity noninvasively in patients with GNE myopathy.ClinicalTrials.gov IdentifierNCT01417533.

Introduction. Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder that leads to progressive weakness of bulbar and extremity muscles. Dynamic balance during functional tasks has not been reported in people with SBMA. Objectives. (1) To evaluate the ability to safely complete a forward lunge (FL), step quick turn (SQT), and step up and over (SUO), (2) to determine the presence and severity of dynamic balance impairments by comparing performance to normative data, and (3) to investigate the relationship between lower extremity strength and ability to complete each task. Design. Cross-sectional analysis. Participants. Fifty-three people with SBMA were included in a cross-sectional analysis. Normative datasets provided by the NeuroCom manufacturer and isometric strength literature facilitated patient comparisons. Outcome Measures. Force plate-based dynamic balance measures included FL (distance, impact index, contact time, and force impulse), SQT (turn time and turn sway), and SUO (lift up index, movement time, and impact index). Maximal isometric contractions of knee extensors, ankle dorsiflexors, ankle plantar flexors, and hip extensors were measured with fixed frame dynamometry. Results. The most difficult test, per completion rate, was SUO (52%), followed by FL (57%) and SQT (65%). t -tests revealed significant abnormalities in eight of nine balance variables ( p < 0.05 ) accompanied by large Cohe n ’ s D effect sizes ≥ 0.8 . Receiver operating characteristics analysis showed knee extensor (SUO 95% CI =0.78–1.00, SQT 95% CI =0.64-0.92) and ankle plantar flexor strength (SUO 95 % CI = 0.75 – 0.99 , SQT 95 % CI = 0.64 − 0.92 ) significantly discriminated the ability to perform SUO and SQT tests with acceptable to excellent areas under the curve. Conclusions. Considerable dynamic balance abnormalities were observed. Lower extremity strength helps explain low test completion rates. Patients modified task movement patterns, enabling safe task performance. Study results can help direct patient care and future protocol design for people with SBMA.

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.

Malignancy relapse remains a major barrier to treatment success in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) markedly reduces hematologic malignancy relapse risk, but relapses still occur in these patients. Patients (n = 275) with moderate or severe cGVHD were enrolled on the National Cancer Institute (NCI) prospective cross-sectional natural history study (NCT00092235). Subjects were median 36 months after allo-HSCT and were followed subsequently for malignancy relapse and survival. Seventeen patients experienced relapse. In a multivariable model including time-dependent influences on relapse, risk factors associated with increased risk of relapse included shorter time from transplant to cGVHD evaluation (HR 0.279, 95% CI 0.078-0.995) and lower number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.260, 95% CI 0.094-0.719). In a model excluding time-dependent influences on relapse risk, lower number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.288, 95% CI 0.103-0.804), lower C4 complement level (HR 0.346, 95% CI 0.129-0.923), and higher body mass index (HR 3.222, 95% CI 1.156-8.974), were all associated with increased relapse risk. Parameters indicating cGVHD severity and activity are associated with risk of malignancy relapse. Classical predictors of relapse after allo-HSCT do not seem to be prognostic.

Background GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions. Methods We performed targeted sequencing and copy number variant (CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation. Results We report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon–intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3-kb deletion (Chr9 [GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion. Conclusions We have identified GNE as one of the genes susceptible to Alu-mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant (CNV) analysis may be useful in arriving at the diagnosis.

The aim of this analysis was to evaluate the psychometric properties of three patient reported outcome (PRO) measures characterizing physical function in GNE myopathy: the Human Activity Profile, the Inclusion Body Myositis Functional Rating Scale, and the Activities-specific Balance Confidence scale.This analysis used data from 35 GNE myopathy subjects participating in a natural history study. For construct validity, correlational and known-group analyses were between the PROs and physical assessments. Reliability of the PROs between baseline and 6 months was evaluated using the intra-class correlation coefficient model; internal consistency was tested with Cronbach's alpha.The hypothesized moderate positive correlations for construct validity were supported; the strongest correlation was between the human activity profile adjusted activity score and the adult myopathy assessment endurance subscale score (r = 0.81; p 0.0001). The PROs were able to discriminate between known high and low functioning groups for the adult myopathy assessment tool. Internal consistency of the PROs was high (α 0.8) and there was strong reliability (ICC0.62).The PROs are valid and reliable measures of physical function in GNE myopathy and should be incorporated in investigations to better understand the impact of progressive muscle weakness on physical function in this rare disease population. Implications for Rehabilitation GNE myopathy is a rare muscle disease that results in slow progressive muscle atrophy and weakness, ultimately leading to wheelchair use and dependence on a caregiver. There is limited knowledge on the impact of this disease on the health-related quality of life, specifically physical function, of this rare disease population. Three patient reported outcomes have been shown to be valid and reliable in GNE myopathy subjects and should be incorporated in future investigations to better understand how progressive muscle weakness impacts physical functions in this rare disease population. The patient reported outcome scores of GNE myopathy patients indicate a high risk for falls and impaired physical functioning, so it is important clinicians assess and provide interventions for these subjects to maintain their functional capacity.

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.

Date Presented 03/28/20 This study used the Activity Card Sort (ACS) and the Medical Outcome Short Form 36 (SF-36) to evaluate activity participation and QoL in patients with cGVHD. The positive correlation between the ACS global score and the SF-36 physical component score (PCS) suggests that activity participation is related to physical QoL. OT consultation may improve the QoL of patients with cGVHD by facilitating meaningful activity engagement. Primary Author and Speaker: Jessica Thornton Contributing Authors: Rafael Jiménez-Silva, Pei-Shu Ho, Galen Joe, Tiara Dunigan, Leora Comis

One Sentence Summary: A Bayesian repeated measures model based on quantitative muscle strength data from a prospective Natural History Study was developed to determine disease progression and design clinical trials for GNE myopathy, a rare and slowly progressive muscle disease. GNE myopathy is a rare muscle disease characterized by slowly progressive weakness and atrophy of skeletal muscles. To address the significant challenges of defining the natural history and designing clinical trials for GNE myopathy, we developed a Bayesian latent variable repeated measures model to determine disease progression. The model is based on longitudinal quantitative muscle strength data collected as part of a prospective Natural History Study. The GNE Myopathy Progression Model provides an understanding of disease progression that would have otherwise required a natural history of unfeasible duration. "Disease age," the model-generated measure of disease progression, highly correlates with a variety of clinical, functional and patient-reported outcomes. With the incorporation of a treatment effect parameter to the GNE Disease Progression Model, we describe a novel GNE Myopathy Disease Modification Analysis that significantly increases power and reduces the number of subjects required to test the effectiveness of novel therapies when compared to more traditional analysis methods. The GNE Myopathy Disease Progression Model and Disease Modification Analysis can be applied to muscle diseases with prospectively collected muscle strength data, and a variety of rare and slowly progressive diseases.

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

Usporedba NIH kriterija za kronični GVHD 2005 i 2014 godina.

Objective The Adult Myopathy Assessment Tool (AMAT) is a 13-item performance-based battery developed to assess functional status and muscle endurance. The purpose of this study was to determine the intrarater and interrater reliability of the AMAT in adults with myositis. Methods Nineteen raters (13 physical therapists and 6 physicians) scored videotaped recordings of patients with myositis performing the AMAT for a total of 114 tests and 1,482 item observations per session. Raters rescored the AMAT test and item observations during a followup session (mean ± SD 19 ± 6 days between scoring sessions). All raters completed a single, self-directed, electronic training module prior to the initial scoring session. Results Intrarater and interrater reliability correlation coefficients were ≥0.94 for the AMAT functional subscale, endurance subscale, and total score (all P < 0.02 for Ho, ρ ≤0.75). All AMAT items had satisfactory intrarater agreement (kappa statistics with Fleiss-Cohen weights, with values κw = 0.57–1.00). Interrater agreement was acceptable for each AMAT item (κ = 0.56–0.89) except the sit up (κ = 0.16). The standard error of measurement and 95% confidence interval range for the AMAT total scores did not exceed 2 points across all observations (AMAT total score range 0–45). Conclusion The AMAT is a reliable, domain-specific assessment of functional status and muscle endurance for adult subjects with myositis. Results of this study suggest that physicians and physical therapists may reliably score the AMAT following a single training session. The AMAT functional subscale, endurance subscale, and total score exhibit interrater and intrarater reliability suitable for clinical and research use.

To investigate in a pilot study the safety and efficacy of infliximab in patients with refractory dermatomyositis (DM) and polymyositis (PM).A randomized, double-blind, placebo-controlled trial including subjects with active DM or PM. Participants had stable doses of immunosuppressive medication and prednisone (≤0.5mg/kg/day), and exhibited clinical signs of muscle weakness for at least 4 weeks prior to study entry. Participants received infusions of either placebo or infliximab 5mg/kg at 0, 2, 6, and 14 weeks in blinded manner. The primary outcome was a ≥15% manual muscle strength (MMT) improvement at week 16 compared to week 0. The secondary outcome measures were improvement defined by the International Myositis Assessment and Clinical Studies Group (IMACS) criteria. At week 16, responders in each arm had the option of either continuing the same treatment or changing to the non-responder treatment for that study arm. Non-responders in the 5mg/kg infliximab arm were increased to infliximab 7.5mg/kg for weeks 22, 30, and 38. Non-responders in the placebo arm at week 16 received infliximab 5mg/kg at weeks 16, 18, 22, 30, and 38. Outcomes were reassessed at week 40.Twelve subjects completed the study to week 16. Six of the 12 subjects received infliximab treatment at the dose of 5mg/kg with only one subject meeting the responder criteria at that dose. Of the remaining five subjects on infliximab, three crossed over to the infliximab 7.5mg/kg dose. One of those three subjects responded. All six patients in the placebo arm crossed over to the 5mg/kg dosing regimen after week 16, and two of those responded to infliximab.Infliximab therapy for patients with refractory PM and DM was well tolerated and may benefit a subset of patients.

GNE myopathy is a rare autosomal recessive muscle disease caused by mutations in GNE, the gene encoding the rate-limiting enzyme in sialic acid biosynthesis. GNE myopathy usually manifests in early adulthood with distal myopathy that progresses slowly and symmetrically, first involving distal muscles of the lower extremities, followed by proximal muscles with relative sparing of the quadriceps. Upper extremities are typically affected later in the disease. We report a patient with GNE myopathy who presented with asymmetric hand weakness. He had considerably decreased left grip strength, atrophy of the left anterior forearm and fibro-fatty tissue replacement of left forearm flexor muscles on T1-weighted magnetic resonance imaging. The patient was an endoscopist and thus the asymmetric hand involvement may be associated with left hand overuse in daily repetitive pinching and gripping movements, highlighting the possible impact of environmental factors on the progression of genetic muscle conditions.

Among patients who survive over two years post-allo-HSCT, cGVHD and subsequent cancers represent a significant source of morbidity and mortality. Long-term treatment with immunosuppressive agents and cGVHD-related immune dysregulation may promote the development of subsequent cancers. The burden of subsequent cancers has not yet been described in patients with the most severe manifestations of cGVHD, who likely represent a high-risk population. 439 patients were enrolled on the prospective NIH Chronic GVHD Natural History Study from 2004 to 2019, underwent one-week evaluation by subspecialists, and were scored in accordance with 2005 NIH criteria. Follow-up data were collected by annual survey in which patients self-reported cancer diagnoses and provided consent for confirmatory medical records. Cumulative incidence was estimated for non-melanoma skin cancer (NMSC) competing with death, relapse, or cancer other than NMSC and for cancer other than NMSC competing with death or relapse using the method of Gooley. Potential predictors of subsequent cancers including demographics, transplant characteristics, and cGVHD-related factors were assessed using Gray's test in univariable analysis and Cox proportional hazards models in multivariable analysis. Patients must have been free of post-transplant relapse, NMSC (for NMSC analyses only), and cancer other than NMSC at evaluation to be included in analysis. 22 NMSC and 19 cancers other than NMSC were observed among 205 eligible patients, with cumulative incidences at 60 months of 11.2% (95% CI: 6.9-16.7) and 7.3% (95% CI 4.1-11.8), respectively. The most common cancers other than NMSC were oral squamous cell carcinoma and melanoma (n=6 each). Factors associated with NMSC in univariable analysis were older age at transplant, older age at evaluation, having received sirolimus for cGVHD, having received extracorporeal photopheresis or psoralen-ultraviolet therapy for cGVHD as well as higher CRP, higher NK cell count, and greater BMI at evaluation. Only older age at transplant (HR=2.12; 95% CI: 1.35-3.31) and higher CRP (HR=9.61; 95% CI: 1.29-71.73) remained associated in the multivariable model. Factors associated with subsequent cancers other than NMSC in univariable analysis were T-cell depletion, lymphoid malignant indication for transplant, and increasing severity of oral cGVHD by NIH score. Only lymphoid malignant indication for transplant (HR=2.58; 95% CI: 1.31-5.07) remained significant in multivariable analysis. The association of CRP with NMSC may represent an effect of cGVHD-related inflammation, with CRP previously associated with cGVHD severity. Interestingly, sirolimus was associated with increased risk of NMSC despite its purported antineoplastic effects. One study has previously reported increased risk of NMSC in allo-HSCT recipients treated with sirolimus, however, numerous studies have reported that sirolimus reduces risk of NMSC in solid organ recipients. In this study population, sirolimus was often prescribed later in patients already with refractory cGVHD and adjustment for measures of disease severity attenuated this association in multivariable modeling. The association of lymphoid indication with cancers other than NMSC may be attributable to age as patients with lymphoid malignancies were older at transplant than those with other indications. Additionally, differences in pre-transplant therapies for lymphoid vs. other indications may also contribute to this observation. Post-transplant patients with cGVHD are at high risk of developing subsequent cancers, with higher incidence of NMSC than other cancers. This study identifies potential risk groups for subsequent cancers, highlights patients who may benefit from increased surveillance, and reiterates the need for effective cGVHD therapy to mitigate risks associated with long-term immunosuppression and immune dysfunction. Disclosures Cowen: UpToDate: Other: Royalties; Elsevier: Other: Royalties.

Chronic graft-versus-host disease (cGVHD) reduces relapse risk in patients with hematological malignancies treated with allogeneic hematopoietic stem cell transplant (allo-HSCT). Nevertheless, relapse remains a major barrier to treatment success. Better understanding of factors determining relapse risk in the cGVHD patient population may lead to development of improved strategies for malignancy control. We hypothesized that cGVHD-related factors would contribute to decreased risk of relapse in addition to other well-known transplant related factors. Patients (N=275) were enrolled on the NCI cross-sectional cGVHD natural history study (NCT00092235) and described using NIH criteria for disease severity and organ scoring. Subjects were subsequently followed for malignancy relapse and survival. Potential predictors of relapse were assessed for their association with risk of relapse using Gray's test. Cox proportional hazards modeling was performed to estimate the joint effect of factors on risk of relapse. Seventeen patients experienced relapse at a median follow-up of 85 months. 48-month cumulative incidence of relapse was 5.7% (95% CI 3.3-8.9%). Median progression-free survival was 156 months. Factors associated with increased risk of relapse in multivariable analysis included aggressive malignancy as an indication for transplant (HR 3.93, 95% CI 1.27-9.10), shorter time from transplant to cGVHD evaluation (HR 0.24, 95% CI 0.06-0.88), and higher number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.34, 95% CI 0.12-0.98). Interestingly, conditioning intensity, T-cell depletion, HLA-match, female donor to male recipient, blood vs. marrow stem cell source, or malignancy remission status at transplant were not predictive of relapse in univariate or multivariate analyses. These data suggest an important inverse relationship between cGVHD severity and likelihood of relapse post-transplant. Most classical relapse predictors seem to be abrogated by these effects.

Introduction In allogeneic hematopoietic stem cell transplant survivors, sclerotic chronic graft-versus-host disease (ScGVHD) is associated with poor quality of life (QOL) and range of motion restrictions. The latter can limit patients' ability to perform important activities of daily living (ADLs). The NIH Consensus Development Project established a standard set of measures to monitor chronic GVHD (cGVHD) progression. This includes indicators of patient-reported QOL and symptom burden, which is defined as the subjective severity and impact of physiological symptoms. Adding measures of functional performance may allow clinicians to more fully characterize the impact of ScGVHD on daily life. Objective To determine whether change in functional capacity and QOL relate to changes in symptom burden and clinician-rated cGVHD severity. Methods Between December 2008 and February 2011, patients with ScGVHD enrolled in a single-arm prospective clinical trial assessing the efficacy of imatinib mesylate. At baseline and 6 months, patients completed measures of functioning [Disabilities of the Arm, Shoulder, and Hand (DASH); Human Activity Profile (HAP); Manual Ability Measure (MAM-36)] and QOL [Short Form 36 version 2 (SF 36); Lee Symptom Scale (Lee)]. Clinicians rated patients' ADL ability [Assessment of Motor and Process Skills version 7 (AMPS)] and cGVHD symptom severity [Provider Global Score (PGS)]. Spearman's rank correlation tests evaluated the association among measures. The alpha level was set to 0.01. Results Twenty patients with ScGVHD enrolled in the trial; 13 patients were assessable for primary endpoint analysis. At study entry, patients were a median of 53 years old, a median of 53 months post-transplant, and had a median of 5 cGVHD-affected organs. Change in PGS was not correlated with change of any measures. Reduced symptom burden (Lee) correlated with improved SF 36 physical component scores (r = -0.72, p = 0.008), AMPS ADL motor skill scores (r = -0.84, p Conclusion Our results suggest the value of supplementing the Lee scale and the SF 36 with functional measures to assess clinical response to ScGVHD treatment. The association between changes in symptom burden and changes in ADL ability (AMPS and DASH scores) indicate the potential utility of these measures in this clinical population. Such scales may allow for a better understanding of patients' functional limitations, thereby promoting individualized clinical care and rehabilitative efforts. Clinician-reported cGVHD severity may not have been related to functional changes due to insufficient sensitivity of the measure or the small size of this sample. Our findings highlight the potential relevance of the AMPS and DASH in patients with cGVHD, though further exploration in larger and more diverse samples is necessary.

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.

To evaluate the safety and efficacy of once-daily intraclot injections of low doses (≤ 10 mg) of tissue plasminogen activator (tPA) for thrombolysis of venous thrombosis.In prospective studies, 33 patients with subclavian, jugular, and central venous thrombosis (SJ-CVT) (all but two cases associated with central catheters) were treated once a day with ≤ 4 mg/day of tPA, and 30 patients with acute deep vein thrombosis of the lower extremity (DVT-LE)14 days old were treated once a day with ≤ 10 mg/leg/day of tPA by intraclot "lacing" of thrombus without continuous infusions of tPA.Patency was restored in 26 (79%) of 33 patients with SJ-CVT using an average total dose of 7.1 mg of tPA/per patient and average of 2.1 treatments or days of therapy. Five patients received thrombolytic therapy for SJ-CVT as outpatients. Initial patency was restored in 29 (97%) of 30 patients with acute DVT-LE using an average total dose of 20 mg of tPA per patient over an average of 2.7 treatments/or days per patient. Follow-up imaging examinations at 6 months showed continued patency in 27 (96%)/of 28 patients. There were no major bleeding complications, and no patient required a blood transfusion.Intraclot injection of low doses of alteplase is effective for acute venous thrombosis, and pharmacokinetic data suggest potentially greater safety.

BACKGROUND Osteonecrosis is increasingly recognized as a debilitating complication of human immunodeficiency virus (HIV) infection, but the natural history has not been well described. We previously documented a high prevalence (4.4%) of magnetic resonance imaging (MRI)-documented osteonecrosis of the hip in a cohort of 339 asymptomatic HIV-infected patients. The present study was designed to determine the incidence of newly diagnosed osteonecrosis in this cohort and to describe the natural history of osteonecrosis in HIV-infected patients. METHODS Asymptomatic HIV-infected patients with a previous hip MRI negative for osteonecrosis underwent follow-up MRI. Patients with asymptomatic or symptomatic osteonecrosis were enrolled in a natural history study, which included serial MRIs and a physiotherapy follow-up. RESULTS Two hundred thirty-nine patients underwent a second MRI a median of 23 months after the initial MRI. Osteonecrosis of the femoral head was diagnosed in 3 patients (incidence, 0.65 cases per 100 person-years). During the period of January 1999 through April 2006, symptomatic hip osteonecrosis developed in 13 clinic patients (incidence, 0.26 cases per 100 person-years). Among 22 patients enrolled with symptomatic hip osteonecrosis, 18 had bilateral involvement of the femoral heads, and 7 had osteonecrosis involving other bones. Two (11%) of 18 asymptomatic patients and 13 (59%) of 22 symptomatic patients underwent total hip replacement. The percentage of involvement of the weight-bearing surface of the femoral head and the rate of progression to total hip replacement was significantly greater (P

Although fatigue is common after allogeneic hematopoietic cell transplantation, little is known about fatigue in patients with chronic GvHD (cGvHD). The aim of this study was to explore factors associated with fatigue in cGvHD. Data were drawn from a sequentially recruited, cross-sectional study of adults with moderate or severe cGvHD (n = 263). Respondents were classified as fatigued or not fatigued based on their response to a single item regarding loss of energy from the Lee cGvHD Symptom Scale. In univariate analysis, factors significantly associated with fatigue included performance status, number of prior cGvHD therapies, cGvHD symptom bother, self-assessed physical and mental health, nutritional status, walk velocity and self-reported physical activity. There were no significant associations between fatigue and disease-related cGvHD variables. Multivariable logistic regression demonstrated that being less active and having pulmonary and/or muscle/joint symptoms were independently associated with fatigue. In conclusion, clinically significant fatigue was prevalent in more than one-third of subjects with cGvHD, and was disabling. Absence of association with measures of cGvHD severity underscores the need to elucidate the pathogenesis of fatigue and its relationship with inflammatory activity. Pulmonary and muscle/joint symptoms and physical inactivity represent potential targets for intervention in clinical studies.

Objective To determine the safety and efficacy of a home-based functional exercise program in spinal and bulbar muscular atrophy (SBMA). Methods Subjects were randomly assigned to participate in 12 weeks of either functional exercises (intervention) or a stretching program (control) at the National Institutes of Health in Bethesda, MD. A total of 54 subjects enrolled, and 50 completed the study with 24 in the functional exercise group and 26 in the stretching control group. The primary outcome measure was the Adult Myopathy Assessment Tool (AMAT) total score, and secondary measures included total activity by accelerometry, muscle strength, balance, timed up and go, sit-to-stand test, health-related quality of life, creatine kinase, and insulin-like growth factor-1. Results Functional exercise was well tolerated but did not lead to significant group differences in the primary outcome measure or any of the secondary measures. The functional exercise did not produce significantly more adverse events than stretching, and was not perceived to be difficult. To determine whether a subset of the subjects may have benefited, we divided them into high and low functioning based on baseline AMAT scores and performed a post hoc subgroup analysis. Low-functioning individuals receiving the intervention increased AMAT functional subscale scores compared to the control group. Interpretation Although these trial results indicate that functional exercise had no significant effect on total AMAT scores or on mobility, strength, balance, and quality of life, post hoc findings indicate that low-functioning men with SBMA may respond better to functional exercises, and this warrants further investigation with appropriate exercise intensity.

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/m2 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/m2 daily up to 130 mg/m2 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.

Lack of standardized criteria measuring therapeutic response remains an obstacle to the development of better treatments for chronic GVHD (cGVHD). This cross-sectional prospective study examined the concurrent and predictive validity of 18 clinician-reported (‘Form A’) and 8 patient-reported (‘Form B’) response measures proposed by NIH criteria. Concurrent parameters of interest were NIH global score, cGVHD activity, Lee symptom score and SF36 PCS. Patient cohort included 193 adults with moderate-to-severe cGVHD. Measures associated with the highest number of outcomes were lung function score (LFS), 2-min walk, grip strength, 4-point health-care provider (HCP) and patient global scores, 11-point clinician- and patient-reported global symptom severity scores, and Karnofsky performance score (KPS). Measures associated with survival in univariate analyses led to a Cox model containing skin erythema, LFS, KPS, eosinophil count and interval from cGVHD diagnosis to enrollment as jointly associated with survival. In conclusion, 4-point HCP and patient global scores and 11-point clinician- and patient- reported global symptom severity scores are associated with the majority of concurrent outcomes. Skin erythema is a potentially reversible sign of cGVHD that is associated with survival. These results define a subset of measures that should be prioritized for evaluation in future studies.

Purpose. The adult myopathy assessment tool (AMAT) is a performance-based battery comprised of functional and endurance subscales that can be completed in approximately 30 minutes without the use of specialized equipment. The purpose of this study was to determine the construct validity and internal consistency of the AMAT with a sample of adults with spinal and bulbar muscular atrophy (SBMA).Methods. AMAT validity was assessed in 56-male participants with genetically confirmed SBMA (mean age, 53 ± 10 years). The participants completed the AMAT and assessments for disease status, strength, and functional status.Results. Lower AMAT scores were associated with longer disease duration (r=-0.29;P<0.03) and lower serum androgen levels (r=0.49–0.59;P<0.001). The AMAT was significantly correlated with strength and functional status (r=0.82–0.88;P<0.001). The domains of the AMAT exhibited good internal consistency (Cronbach’sα = 0.77–0.89;P<0.001).Conclusions. The AMAT is a standardized, performance-based tool that may be used to assess functional limitations and muscle endurance. The AMAT has good internal consistency, and the construct validity of the AMAT is supported by its significant associations with hormonal, strength, and functional characteristics of adults with SBMA. This trial is registered with Clinicaltrials.gov identifierNCT00303446.

Malnutrition is a known complication of chronic GVHD (cGVHD), but has not been well described in the context of organ-specific manifestations and the recent National Institutes of Health (NIH) criteria. Here, 210 cGVHD patients were analyzed, in a cross-sectional study design, for demographics, transplant-related history, clinical assessments, symptoms, function, quality-of-life, laboratory values and survival in order to determine their associations with nutritional status. Most patients had long- standing, moderate or severe cGVHD and had failed many lines of therapy. Twenty-nine percent (60/210) of subjects were malnourished, using the subjective Patient-Generated Subjective Global Assessment (PG-SGA) questionnaire and evaluation. No demographic or transplant characteristics were associated with malnutrition ; cGVHD of the lungs, gastrointestinal (GI) tract and mouth, NIH global score, cGVHD symptoms, worse functioning, low albumin, poorer survival and low BMI were associated with malnutrition. A predictive model was developed from all variables of significance: cGVHD of the lungs, GI tract, mouth and BMI accurately predicted 84.2% of malnourished patients as well as 87.2% of well-nourished patients. The PG-SGA questionnaire may be a useful tool in diagnosing nutritional deficits in cGVHD patients undergoing one-time evaluations. Longitudinal prospective studies should assess the utility of nutritional support interventions in cGVHD.

BackgroundRepeated heel raises have been proposed as a method of ankle plantar-flexor strength testing that circumvents the limitations of manual muscle testing (MMT).ObjectiveThe study objective was to examine the relationships among ankle plantar-flexion isometric maximum voluntary contraction (MVC), repeated single-limb heel raises (SLHRs), and MMT in people with myositis.DesignThis was a cross-sectional study with a between-group design. The ability to complete 1 SLHR determined group assignment (SLHR group, n=24; no-SLHR group, n=19).MethodsForty-three participants with myositis (13 women; median age=64.9 years) participated. Outcome measures included MVC, predicted MVC, Kendall MMT, and Daniels-Worthingham MMT.ResultsThe Kendall MMT was unable to detect significant ankle plantar-flexor weakness established by quantitative methods and was unable to discriminate between participants who could and those who could not perform the SLHR task. Ankle plantar-flexion MVC was not associated with the number of heel-raise repetitions in the SLHR group (pseudo R2=.13). No significant relationship was observed between MVC values and MMT grades in the SLHR and no-SLHR groups. However, a moderate relationship between MVC values and MMT grades was evident in a combined-group analysis (ρ=.50–.67).LimitationsThe lower half of both MMT grading scales was not represented in the study despite the profound weakness of the participants.ConclusionsBoth Kendall MMT and Daniels-Worthingham MMT had limited utility in the assessment of ankle plantar-flexor strength. Repeated SLHRs should not be used as a proxy measure of ankle plantar-flexion MVC in people with myositis.

Chronic GVHD is one of the most severe complications of allogeneic HSCT. The sclerotic skin manifestations of cGVHD (ScGVHD) result from inflammation and fibrosis of the dermis, subcutaneous tissue, or fascia, leading to significant functional disability. Risk factors and clinical markers associated with ScGVHD remain largely unexamined. By using a single-visit, cross-sectional design, we evaluated 206 patients with cGVHD at the National Institutes of Health. Most patients manifested severe (ie, 63% National Institutes of Health score “severe”), refractory disease (median treatments = 4). ScGVHD was detected in 109 (52.9%) patients. ScGVHD was associated with greater platelet count (P < .001) and C3 (P < .001), and decreased forced vital capacity (P = .013). Total body irradiation (TBI) was associated with development of ScGVHD (P = .002). TBI administered in reduced-intensity conditioning was most strongly associated with ScGVHD (14/15 patients, P < .0001). Patients with ScGVHD had significant impairments of joint range of motion and grip strength (P < .001). Greater body surface area involvement was associated with poorer survival (P = .015). We conclude that TBI, particularly in reduced-intensity regimens, may be an important risk factor for ScGVHD. Widespread skin involvement is associated with significant functional impairment, distressing symptoms, and diminished survival. This trial is registered at http://www.clinicaltrials.gov as NCT00331968.

The patient was a 45-year-old woman who was referred to a physical therapist and a physiatrist in a rehabilitation medicine department for evaluation and treatment of severe bilateral lower leg, ankle, and foot pain. The patient's past medical history was significant for sickle cell disease and she had undergone an allogeneic stem cell transplant 4 months prior with Sirolimus prescribed to prevent rejection. Magnetic resonance imaging of both lower legs revealed extensive bone marrow edema, as well as soft tissue swelling about the lower legs and ankles. These findings, along with the patient's presentation (constant bilateral pain and erythema of the lower legs within 6 months of transplantation) were found to be consistent with an atypical condition called posttransplant distal limb syndrome.

Abstract 4074 Background: Lack of standardized criteria for measuring therapeutic response remains a significant obstacle to the evaluation of new cGVHD treatments. In 2005 an NIH consensus conference proposed a set of organ-specific measures for quantification of change after a therapeutic intervention (BBMT 2006, 12:252). We conducted a cross-sectional prospective study to validate the NIH response criteria by analyzing the correlations between proposed clinician (Form A) or patient reported (Form B) scales and the set of established clinically important outcomes: NIH global severity, average NIH organ score, sub-specialist evaluations (SSE), disease activity by therapeutic intent, Lee symptom scale, SF-36 (PCS, MCS), HAP score (MAS, AAS) and overall survival (OS). Patients and Methods: 193 adults, age 48 years, (18–70) were enrolled from 2004–2011 on the NCI cGVHD natural history protocol at a median of 36 months (4–258) from transplant. Patients received a median of 4 (0–9) prior systemic therapies, and 83% were on systemic immunosuppression, 67% had severe, 30% had moderate and 3% had mild NIH global score. Median number of involved organs was 5 (1–8). NIH response criteria measures were obtained at the time of study entry. Univariate and multivariate logistic regression analysis were undertaken to determine correlations between response criteria items and outcomes. Results: The median values of the NIH response criteria items were: Clinician reported – Skin %BSA (erythema 0.9 [0–80], moveable sclerosis 0.54 [0–81], non-moveable sclerosis 0 [0–76]), Schirmer 1 tear test (mm) 3 [0–29.5], oral scale 1 [0–12], WBC 7.1 [1.96–31.3], AST 32 [5–256], bilirubin 0.5 [0.1–1.7], gastrointestinal (upper 0 [0–3], esophageal 0 [0–3], lower, 0 [0–3]), lung function score (LFS) 4 [0–12], health care provider global rating (HCP) 2 [0–3], clinician rated symptom severity 6 [0–10], clinician evaluation of change 0 [-3-+3], grip strength (psi) 66 [1–138], walk time (feet/min) 109 [40–145], Karnofsky score (KPS) 80 [30–100]. Patient reported - symptoms intensity (skin itching 2 [0–10], mouth dryness 2 [0–10] pain 0 [0–10] or sensitivity 1 [0–10], eyes 5 [0–10], patient global score 2 [1–3], patient rated symptom severity 5 [0–10], patient evaluation of change 0 [-3-+3]. Most of the elements had statistically significant association with clinical outcomes in univariate analyses. Multivariable analyses demonstrated associations between response criteria items and outcomes (Table 1). Schirmer tear test, oral score, WBC, AST, lower GI symptoms, grip strength, skin itching intensity and clinician or patient evaluation of cGVHD change did not show significant associations with any of the outcomes. 3-year survival for the cohort is 75%. Median follow-up of surviving patients was 33 months. Factors associated with OS included: BSA% erythema (p=0.0018), LFS (p=0.014), walk velocity (p=0.018), KPS (p3.0%, p=0.0126; HR=2.5; 95 CI: 1.2–5.1), higher LFS (>=8, p=0.0218; HR 2.3, 95 CI: 1.1–4.8) and lower KPS (30–70%, p=0.02; HR=2.3; 95 CI: 1.1–4.7) predicted lower OS. Conclusions: A number of response criteria measures proposed by the NIH cGVHD consensus project predict important clinical outcomes. These results thus identify a subset of measures that may serve as surrogate endpoints and should be prioritized for further evaluation in clinical studies. Disclosures: No relevant conflicts of interest to declare.

Background Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, adult onset, non-inflammatory neuromuscular disorder with no effective treatment. The causative gene, GNE, codes for UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, which catalyzes the first two reactions in the synthesis of sialic acid. Reduced sialylation of muscle glycoproteins, such as α-dystroglycan and neural cell adhesion molecule (NCAM), has been reported in HIBM. Methods We treated 4 HIBM patients with intravenous immune globulin (IVIG), in order to provide sialic acid, because IgG contains 8 μmol of sialic acid/g. IVIG was infused as a loading dose of 1 g/kg on two consecutive days followed by 3 doses of 400 mg/kg at weekly intervals. Results For all four patients, mean quadriceps strength improved from 19.0 kg at baseline to 23.2 kg (+22%) directly after IVIG loading to 25.6 kg (+35%) at the end of the study. Mean shoulder strength improved from 4.1 kg at baseline to 5.9 kg (+44%) directly after IVIG loading to 6.0 kg (+46%) at the end of the study. The composite improvement for 8 other muscle groups was 5% after the initial loading and 19% by the end of the study. Esophageal motility and lingual strength improved in the patients with abnormal barium swallows. Objective measures of functional improvement gave variable results, but the patients experienced improvements in daily activities that they considered clinically significant. Immunohistochemical staining and immunoblotting of muscle biopsies for α-dystroglycan and NCAM did not provide consistent evidence for increased sialylation after IVIG treatment. Side effects were limited to transient headaches and vomiting. Conclusion The mild benefits in muscle strength experienced by HIBM patients after IVIG treatment may be related to the provision of sialic acid supplied by IVIG. Other sources of sialic acid are being explored as treatment options for HIBM.

Osteonecrosis has been reported to occur occasionally among HIV-infected patients. The diagnosis of symptomatic osteonecrosis of the hip in two of the authors' patients, together with reports from community physicians, raised a concern that the prevalence of osteonecrosis is increasing.To determine the prevalence of osteonecrosis of the hip in asymptomatic HIV-infected patients and to identify potential risk factors associated with osteonecrosis.Survey and comparison study.The Clinical Center of the U.S. National Institutes of Health.339 asymptomatic HIV-infected adults (of 364 asked to participate) and 118 age- and sex-matched HIV-negative volunteers enrolled between 1 June and 15 December 1999.Osteonecrosis of the hip, as documented by magnetic resonance imaging. Data from clinic records and a patient questionnaire administered before magnetic resonance imaging were used in an analysis of risk factors. A subset of patients was evaluated for hypercoagulable state.Fifteen (4.4% [95% CI, 2.5% to 7.2%]) of 339 HIV-infected participants had osteonecrosis lesions on magnetic resonance imaging, and no HIV-negative participants had similar lesions. Among HIV-infected participants, osteonecrosis occurred more frequently in those who used systemic corticosteroids, lipid-lowering agents, or testosterone; those who exercised routinely by bodybuilding; and those who had detectable levels of anticardiolipin antibodies.Patients infected with HIV have an unexpectedly high occurrence of osteonecrosis of the hip. Although screening asymptomatic patients is not warranted, HIV-infected patients with persistent groin or hip pain should be evaluated for this debilitating complication.

Abstract 4631 A 44 year old African-American asplenic male with sickle cell disease (HbSS) underwent allogeneic HSCT in September 2009. Upon engraftment, the patient had 97% donor myeloid, and 30% donor lymphoid chimerism, and he was free of his sickle cell disease with HbA 97%, HbA2 2.9%,and HbF Twenty eight months later, he experienced onset of minor soft tissue hemorrhage associated with a long aPTT, and low FVIII activity (14% of normal), two weeks after an upper respiratory infection. vWF levels were elevated (antigen 263% & activity 246%), and the FIX level (113%), PT (13.2 seconds), and fibrinogen (395 mg/dL) were normal. He had stable FVIII levels of 10–14% for two months, but then had acute onset of pain, swelling and decreased grip strength in the right hand, consistent with a compartment syndrome. He was treated with Humate-P at a dose of 3000 U every 12 hours, which initially normalized the aPTT and corrected the FVIII to 121%, permitting fasciotomy of the palmar and volar surfaces of the forearm to treat his acute compartment syndrome. After 4 days' treatment on the same 3000 U Q 12 hour dose of Humate P, the recovered FVIII levels declined to only 18%. He was switched to Kogenate with no change in FVIII recovery, then rhFVIIa at doses of 90 μg/kg Q 4 hrs was started eleven days after surgery. Despite inhibitor bypassing therapy, the patient had recurrent pain, swelling, decreased grip strength, decreased range of motion, and numbness in the right hand, consistent with recurrent bleeding. His human FVIII inhibitor titer was 12 BIAU, but < 1 BIAU for porcine FVIII. Recombinant porcine FVIII (OBI-1) was obtained for use under an expanded access provision of IND 16395, and 200 units per kg were given 16 days after surgery, and a second dose of 100 units per kg was given 19 days after surgery. A FVIII level of 540 U/dL was obtained 20 minutes after the first treatment, and the volume of distribution was 2652 mL and the half life was 16.3 hrs. Within 8 hours the pain was diminished (4/10 vs. 7/10), and grip strength measured by dynamometer went from 8 lbs to 55 lbs (compared to unaffected left hand grip strength of 110 lbs). After the 2nd dose of OBI-1 a FVIII level of 621 U/dL was obtained 20 minutes later, and the volume of distribution was 2287 ml, and the half life was 14.7 hrs. Within two weeks the patient had improved range of motion, pain free status, and right hand grip strength of 82 lbs. The patient's grip strength was restored to 101 lbs, 76 days later with physiatry and occupational therapy hand program. Immunosuppression with rituximab and high dose corticosteroids was begun at the onset of OBI-1 porcine factor VIII treatment; cyclophosphamide was not used to minimize risk for loss of the stem cell graft that cured his sickle cell disease. The inhibitor titer to human FVIII declined from 12 BIAU to less than 0.5 BIAU within three weeks, and there was no loss of donor erythropoiesis (HbA remained >96%). Concomitantly, the patient's endogenous FVIII rose to >100% of normal by day 22, and remained normal after completion of three doses of rituximab and a complete taper of prednisone over the next two months. The patient had an H2 FVIII haplotype sequence, whereas his donor was heterozygous for the FVIII H1 and H2 haplotypes. A study of stored samples showed that at the onset of mild soft tissue hemorrhage the Bethesda inhibitor titer against a recombinant FVIII with H2 haplotype sequence (Recombinate) was higher (4.2 BIAU) than that against H1 (Kogenate) or “mixed” haplotypes derived from pooled plasma (1.9 BIAU). However, by the time of his compartment syndrome hemorrhage the differential reactivity of neutralizing titers to the H2 haplotype FVIII was not as pronounced (5.2 BIAU for H2 haplotype vs. 4–4.5 BIAU for all other haplotypes/products), suggesting that any initial specificity for the H2 FVIII haplotype had been diminished. No inhibition of OBI-1 porcine factor VIII was seen prior to treatment, or in the 90 day period after treatment. Interestingly, FVIII binding antibodies could be detected prior to the viral infection preceding the overt clinical inhibitor and soft tissue hemorrhage. In summary we demonstrate use of recombinant porcine FVIII in a patient with a compartment syndrome due to acquired hemophilia, and elimination of the inhibitor, while preserving the transplant that corrected his sickle cell disease. Disclosures: Lee: Inspiration Biopharmaceuticals Inc: Employment.

Abstract 2243 Poster Board II-220 Introduction: Although a low platelet count in chronic graft-versus-host disease (cGVHD) patients is a consistent negative survival predictor across many cGVHD studies, this association is poorly understood. Additionally, a subgroup of cGVHD patients has elevated platelets, which is also unexplained. We hypothesized that such platelet abnormalities may reflect the pathophysiology of cGVHD and therefore be associated with specific clinical manifestations. This exploratory study was conducted to investigate determinants and clinical significance of platelet counts in a large cohort of cGVHD patients. Patients and Methods: cGVHD patients were enrolled in the ongoing cross sectional National Cancer Institute protocol (clinicaltrials.gov#NCT00331968). A detailed history, physical and extensive laboratory evaluations were obtained using standardized methods. National Institutes of Health (NIH) severity scores were based on the extent of cGVHD manifestations, degree of functional impairment and the number of affected organs. Wilcoxon rank sum test, Kruskal-Wallis test, and Jonckheere -Terpstra trend test were used in statistical analyses. Results with p-values Results: The cohort included 120 adult cGVHD patients (median age 48 years, 53% male (M), 47% female (F)). Median time from transplantation to study enrollment was 2.7 years. Median time of cGVHD diagnosis was 0.5 year after transplantation, and median time from cGVHD diagnosis to enrollment was 1.6 years. 75% of subjects received related donor transplant; 84% received peripheral blood stem cells and 16% bone marrow; 63% had a history of acute GVHD (skin 88%, gastrointestinal 45%, liver 22%). Median total NIH organ severity score was 6 (range 2-14), median average total NIH organ severity score was for F 0.750 (range 0.250-1.625), and for M 0.857 (range 0.286-2.000), and median number of organs involved was 4 (range 1-8). Median platelet count was 239,000/μL (range 33,000/μL-648,000/μL). F had significantly higher platelet counts than M (median 275,500 /μL vs. 221,500/μL, p=0.004). Time from transplantation (r=0.35) and time from cGVHD diagnosis (r=0.32) correlated positively with platelet counts (p=0.001). Patients who received TBI based conditioning tended to have higher platelet counts (median 279,000/μL vs. 211,000/μL, p=0.021). Platelet counts varied among the four recipient-donor gender pairings (M recipient/M donor had median platelets 199,500/μL, M recipient/F donor had median platelets 239,500/μL, F recipient/F donor had median platelets 257,000/μL, F recipient/M donor had median platelets 301,000/μL, p=0.010). Among patients with history of acute GVHD, those with liver acute GVHD tended to have higher platelet counts (292,000/μL vs. 226,500 /μL, p=0.027). Absolute lymphocyte count (r=0.35), absolute CD3s (r=0.31), absolute CD4s (r=0.31), absolute NK cells count (r=0.32), and calcium levels (r=0.33) correlated positively with platelet counts (p Conclusions: This exploratory analysis demonstrates strong positive association of platelet counts with the lymphocyte counts and with the average total NIH cGVHD organ severity scores. These data implicate abnormalities of platelet counts in cGVHD pathophysiology and warrant further research. Disclosures: No relevant conflicts of interest to declare.

s / Biol Blood Marrow Transplant 20 (2014) S257eS285 S272 model (Miller et al., Blood, 2010). Importantly, our results show that LFA-1 expression is highly upregulated in CNS leukocyte infiltrates of animals with untreated GvHD (Figure 2). LFA-1 is an integrin that is critical for leukocyte trafficking into the CNS during demyelinating disease (Hu et al., J Leuk Bio, 2010). These results suggest that the mechanisms of T cell infiltration into the CNS during GVHD may have important similarities to autoimmune-mediated CNS diseases such as multiple sclerosis, and thus may be amenable to targeted therapies such as integrin-blockade. Our findings argue that CNS-GvHD can occur in primates undergoing HCT, and is characterized by an infiltrate of activated, integrin-expressing CD8 T cells. These results underscore the importance of including GVHD in the differential diagnosis of CNS symptoms after HCT, and suggest that targeted therapeutic strategies may be able to address this often under-recognized complication of HCT.