ALBERT

Description: Insulin receptor substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many pathways activated in lung cancer. It has been assumed that IRS-1 promotes tumor growth through its ability to activate PI3K signaling downstream of the insulin-like growth factor receptor. Surprisingly, tumors with reduced IRS-1 staining in a human lung adenocarcinoma tissue microarray displayed a significant survival disadvantage, especially within the Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant subgroup. Accordingly, adenoviral Cre recombinase (AdCre)-treated LSL-Kras/Irs-1fl/fl (Kras/Irs-1−/−) mice displayed increased tumor burden and mortality compared with controls. Mechanistically, IRS-1 deficiency promotes Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling via the IL-22 receptor, resulting in enhanced tumor-promoting inflammation. Treatment of Kras/Irs-1+/+ and Kras/Irs-1−/− mice with JAK inhibitors significantly reduced tumor burden, most notably in the IRS-1-deficient group.

Description: Abstract 151 In 2005, the NIH Consensus Conference proposed measures to improve the documentation of clinically meaningful changes in chronic GVHD (cGVHD) for clinical trials. We evaluated the NIH recommended measures and the Vienna Skin Scale (VSS) for their correlation with provider and patient perceptions of skin changes and with survival. Methods: Patients ≥ age 2 with cGVHD ≤ 3 years after allogeneic hematopoietic cell transplantation requiring systemic treatment were eligible. The NIH response tool scores 8 body regions according percentage of body surface area (BSA) involved with erythematous rash, moveable sclerosis, and non-moveable sclerosis. The VSS scores 10 body regions with percentage involvement of pigmentary changes, rash, and sclerosis. Regional scores are summed for a Vienna Skin Total (VST) score of 0–50. The categorical NIH skin score grades subjects from 0–3 based on extent of skin involvement, sclerotic features, and symptoms. Also collected were the Hopkins skin sclerosis score (0–4), Hopkins fascia score (0–3), and two patient-reported measures: skin itching (0–10) and the Lee Symptom Score skin subscale (0–100). At follow-up visits every six months, patients and providers rated separately their perception of change in skin involvement on an 8-point scale, which was analyzed as improved, stable, or worse. Multivariable linear models were used to test the strength of association between changes in measures of skin severity and clinician and patient assessments of change in skin involvement, adjusting for other significant clinical variables. Overall survival (OS) and non-relapse mortality (NRM) were analyzed using Cox regression models, adjusting for other significant variables. Results: Nine sites in the Chronic GVHD Consortium had enrolled 458 participants as of December, 2010. At enrollment, 200 (44%) patients had no skin involvement and one was missing skin assessments. The remaining 257 patients had erythema (n=196, 43%), moveable sclerosis (n=85, 19%), and non-moveable sclerosis (n= 43, 9%). Per NIH overall scoring criteria, 148 (32%) subjects had severe and 262 (57%) had moderate chronic GVHD at study entry. At a total of 538 follow-up visits with skin involvement or following a visit with skin involvement, change in cGVHD skin symptom was rated by the providers as improved in 45%, stable in 46%, or worse in 9%, and by patients as 58%, 35%, 7% respectively. Change in the categorical NIH skin score assessed by clinicians and the skin subscale of the Lee Symptom Score assessed by patient were best correlated with clinician and patient perception of change (Table and Figure). With a median survivor follow-up of 18.3 months, baseline NIH skin score of 3 was associated with worse OS (HR 2.6, 95% CI 1.3–5.0, p =.004) and NRM (HR 3.7, 1.8–7.7, p 〈 0.001) compared to no skin involvement. In addition, worsening in NIH skin score at 6 months was associated with lower OS (HR 5.3, 1.2–25.5, p =.03) and higher NRM (HR 7.0, 1.4–40.4, p =.02) compared to stable skin among patients with cutaneous involvement at baseline. Change of NIH skin score at 12 months was not associated with OS or NRM. Conclusions: The strong correlation between change in NIH skin score 0–3 with provider- and patient-reported cutaneous changes in both directions and its predictive value for OS at 6 months supports use of this single item scale as a composite measure to evaluate skin involvement in clinical trials.Figure.Correlation between change in the categorical NIH skin score and the Lee Symptom Skin Score with clinician and patient perception of change.Figure. Correlation between change in the categorical NIH skin score and the Lee Symptom Skin Score with clinician and patient perception of change.Table.Multivariable linear mixed models to predict clinician or patient reported change in skin involvementMeasure of skin severityContrast in clinician or patient perception of changeClinicianPatientp-valuep-valueNIH erythemaImproved vs Stable

Description: Abstract 2256 Poster Board II-233 Correlation of the NIH and Vienna Skin scores with provider and patient-reported skin changes in chronic graft-versus-host disease (GVHD) In 2007 we began a multi-center, prospective, observational study of patients diagnosed with chronic GVHD (cGVHD) by National Institute of Health (NIH) Consensus Conference criteria. A major objective is to develop sensitive and valid organ-specific criteria for cGVHD activity to document clinically meaningful changes in clinical trials. This preliminary analysis evaluated the NIH skin tool and the Vienna Skin scale (VS) for their ability to quantify the type and extent of skin involvement, and for their correlation with provider and patient perceptions of change in the skin. Methods: Patients ≥ age 2 diagnosed with cGVHD within 3 years after allogeneic hematopoietic cell transplantation requiring systemic treatment were eligible. Providers and patients complete multiple cGVHD assessment tools at study entry and every 3-6 months. The NIH scale grades 8 body regions according to the percent of body surface area (BSA) involvement by 3 manifestations: 1) erythematous rash, 2) moveable sclerosis, and 3) non-moveable sclerosis, with possible values of 0-100% total BSA for each manifestation. The VS scores each of 10 body regions with percentage involvement of 4 types of skin manifestations: 1 = hypo/hyperpigmentation, erythematous rash, 2 = lichenoid plaque, thickening, able to move, 3 = thickened, limited motion, pinchable, 4 = hidebound, unable to move or pinch. For areas scored as 3 or 4, concurrent fraction involved with erythema is also recorded. Regional scores are summed for a Vienna Skin Total (VST) score of 0-50. At follow-up visits patients and providers rated change in skin involvement as improved, stable, or worse. Proportional odds regression was used to predict improved, stable and worse rates using the difference in NIH subscales or VST since the last visit (change scores). Predictive ability for each scale was summarized using the c index of concordance. Results: Of the 229 participants as of 4/30/09, 61% were males, the median age was 52 years (2-79) and median time from transplant to study entry was 393 days (91-1233). Table 1 shows the scores on the two scales for patients with any skin involvement at baseline (n=161, 70%). At 168 follow-up visits with NIH and VS data, skin GVHD was rated by the providers as improved, stable, or worse in 43%, 48%, and 9%, respectively. Both tools appeared to predict subjective change with the c index of concordance of 0.76 for NIH and 0.71 for VS. Compared to providers, patients were more likely to rate the skin as improved (56%), and less likely to report stable (38%) or worse (6%). The same differences (VST, and NIH erythema and non-moveable sclerosis) were still significant predictors of patients' subjective change. Concordance (c index) and parameter estimates (odds ratios) were attenuated compared to models of provider ratings.Results of the 4 models are summarized in Table 2. Conclusions: Skin involvement is frequent in cGVHD. Both NIH and VS scores are associated with provider- and patient-reported changes in skin severity. These results suggest that the NIH and VS tools are quantitative measures that are sensitive to provider and patient-perceived skin changes over time. Data from additional patients with a broader range of skin severity and longer follow up are needed to better define the roles of these scales as endpoints in clinical trials. Disclosures: Jagasia: Genzyme: Research Funding.

Description: There are no validated criteria to measure skin response in chronic GVHD. In a prospectively assembled, multicenter cohort of patients with chronic GVHD (N = 458), we looked for correlation of change in several different scales recommended by the National Institutes of Health (NIH) Consensus with clinician and patient perception of change and overall survival. Of the clinician scales, the NIH composite 0-3 skin score was the only one that correlated with both clinician and patient perception of improvement or worsening. Of the patient-reported scales, the skin subscale of the Lee Symptom Scale was the only one that correlated with both clinician and patient perception of improvement or worsening. At study entry, NIH skin score 3 and Lee skin symptom score 〉 15 were both associated with worse overall survival. Worsening of NIH skin score at 6 months was associated with worse overall survival. Improvement in the Lee skin symptom score at 6 months was associated with improved overall survival. Our findings support the use of the NIH composite 0-3 skin score and the Lee skin symptom score as simple and sensitive measures to evaluate skin involvement in clinical trials as well as in the clinical monitoring of patients with cutaneous chronic GVHD.

Description: Abstract 393 Chronic graft-versus-host disease (cGVHD) can negatively impact quality of life (QOL) following allogeneic hematopoietic cell transplantation (HCT). Whether the new NIH cGVHD global severity grading correlates with patient reported QOL is not known. In a prospectively assembled multi-center observational cohort study of adult HCT recipients with cGVHD, we examined the relationship between cGVHD severity according to NIH criteria and patient-reported QOL. Major objectives of this analysis were: (1) Describe the relationship between cGVHD severity and patient reported QOL; (2) compare QOL in HCT recipients with cGVHD to US population normative data; (3) compare QOL in HCT recipients with cGVHD to patients with other chronic health conditions; and (4) investigate the ability of SF-36 and FACT-BMT QOL instruments to discriminate cGVHD severity. This analysis included 298 patients with cGVHD who were enrolled at a median of 12.3 months from HCT. Overall, 54% patients were diagnosed 〈 3 months before enrollment. 56% had classic and 44% had overlap cGVHD. Organs most commonly involved included skin (63%), mouth (61%), eye (50%), and liver (50%). 31 (10%) had mild, 175 (59%) had moderate and 92 (31%) had severe cGVHD. Univariable modeling confirmed the relationship between cGVHD severity and QOL outcomes (SF-36 and FACT-BMT composite scores and subscales). Among other considered disease-, transplantation-, and socio-demographic variables, only age was significantly correlated with QOL (physical functioning and the physical component score (PCS) of the SF-36 instrument). Multivariable linear regression analysis adjusting for age at enrollment showed QOL measures, especially involving physical functioning, to differ according to cGVHD severity. For example, controlling for age, the average physical component score (PCS) of the SF-36 was 5.6 points higher for mild cGVHD compared to severe cGVHD (p 〈 0.01) and 3.2 points higher for moderate cGVHD compared to severe cGVHD (p = 0.02). In comparison to age- and gender-matched US population normative data for SF-36, mean scores for cGVHD cohort members were significantly lower for physical functioning, role-physical, bodily pain, general health, vitality, social functioning, and PCS. There were no significant differences observed in the domains of role-emotional, mental health, or MCS. We also compared the mean SF-36 scores (PCS and MCS) of cGVHD patients with those reported for other chronic health conditions: Patients with moderate and severe cGVHD had PCS scores comparable to scores reported for systemic sclerosis, systemic lupus erythematosis, and multiple sclerosis, and greater impairment compared to common conditions such as diabetes, hypertension, and chronic lung disease (see figure). MCS scores of those with severe cGVHD rivaled MCS scores reported with clinical depression, while mild and moderate cGVHD MCS scores were comparable to that of the general population. Discriminative accuracy of the QOL instruments (SF-36 and FACT-BMT) was assessed utilizing an extension of the concordance index to an ordinal gold standard (cGVHD severity). The concordance index was modest (∼0.60) for all QOL scales examined, with no significant differences between the QOL instruments' discriminative ability. We conclude that, while physical components of self-reported quality of life are lower on average for patients with more severe cGVHD, the extent of impairment and symptom burden represented by cGVHD severity are not solely captured by differences in quality of life. Future analyses will evaluate sensitivity to change and may help identify the better instrument to use in this population. In summary, NIH consensus criteria global cGVHD severity is independently associated with patient reported QOL, with worsening QOL for increasing severity of cGVHD. Patients with moderate to severe cGVHD have poor QOL, comparable to patients with other with immune mediated disorders, and much worse than general population norms. We hypothesize that better prevention and control of cGVHD has the potential to not only decrease morbidity and mortality but also to significantly improve QOL. Figure: Comparison of SF-36 PCS and MCS mean scores (with 95% confidence interval) from chronic GVHD cohort members according to NIH severity and chronic health conditions Figure:. Comparison of SF-36 PCS and MCS mean scores (with 95% confidence interval) from chronic GVHD cohort members according to NIH severity and chronic health conditions Disclosures: No relevant conflicts of interest to declare.

Description: Quality of life (QOL) after hematopoietic cell transplantation (HCT) is compromised by chronic GVHD. In a prospectively assembled multicenter cohort of adults with chronic GVHD (n = 298), we examined the relationship between chronic GVHD severity defined by National Institutes of Health (NIH) criteria and QOL as measured by the SF-36 and FACT-BMT instruments at time of enrollment. Chronic GVHD severity was independently associated with QOL, adjusting for age. Compared with population normative data, SF-36 scores were more than a SD (10 points) lower on average for the summary physical component score (PCS) and role-physical subscale, and significantly lower (with magnitude 4-10 points) for several other subscales. Patients with moderate and severe cGVHD had PCS scores comparable with scores reported for systemic sclerosis, systemic lupus erythematosus, and multiple sclerosis, and greater impairment compared with common chronic conditions including diabetes, hypertension, and chronic lung disease. Moderate to severe cGVHD as defined by NIH criteria is associated with significant compromise in multiple QOL domains, with PCS scores in the range of other systemic autoimmune diseases. Compromised QOL provides a functional assessment of the effects of chronic GVHD, and may be measured in cGVHD clinical studies using either the SF-36 or the FACT-BMT.

Description: This prospective study evaluated sexual function through 5 years after myeloablative allogeneic hematopoietic cell transplantation (HCT) for cancer to determine sexual function recovery and residual problems. Adults completed measures before HCT (N = 161), with survivors followed at 6 months and at 1, 2, 3, and 5 years. At 5 years case-matched controls also completed assessments. Analyses indicated that men and women differed in rates of being sexually active across time (P 〈 .001) and in overall sexual function (P 〈 .001). Both sexes declined in sexual activity rates and sexual function from before HCT to 6 months afterward (P ≤ .05). Activity rates recovered for men by 1 year (74%) and for women by 2 years (55%). Men improved from their 6-month nadir in sexual function by 2 years (P = .02), whereas women did not improve by 5 years (P = .17). Both male and female survivors were below controls in rates of sexual activity and sexual function at 5 years. Most women reported sexual problems (80% of survivors vs 61% of controls, P = .11); in contrast for men 46% of survivors versus 21% of controls (P = .05) reported problems. Thus, despite some recovery, sexual dysfunction remained a major problem for men and women after HCT. Aggressive efforts are needed to treat these deficits.

Description: Abstract 464 Background: Assessing joint chronic GVHD needs to be accomplished reliably, simply and in a clinically meaningful way. To determine the optimal tool for assessing joint GVHD, we evaluated 2 NIH recommended joint tools (Table), a photographic range of motion (P-ROM) scale, and 7 other NIH recommended tools (Lee symptom scale, 10-point overall symptoms, FACT-G, SF36, Human Activities Profile, walk test and grip test). Methods: Patients ≥ age 2 with systemically treated chronic GVHD ≤ 3 years after hematopoietic cell transplantation were eligible for a prospective multicenter observational study. Incident and prevalent cases were included. At follow-up visits every 3–6 months, the clinician (MD) and patient (PT) rated separately their perception of change in joint GVHD on an 8-pt scale, which was collapsed into improved, stable or worse categories. Linear mixed models were used to correlate change in each tool with MD or PT-perceived change (improved vs. stable or worse vs. stable) in joint GVHD status. Results: Nine sites in the Consortium enrolled 567 participants through December 2011. Joint involvement, as defined by NIH joint/fascia score ≥1, was present at enrollment in 164 (29%) patients and included wrists (64%), ankles (47%), shoulders (35%) and elbows (30%). Joint involvement at enrollment was associated with longer duration of chronic GVHD, high-dose total body irradiation, higher symptom burden, lower quality of life (QOL), similar activity profile and similar physical function, compared to those without joint involvement. Change in joint GVHD status was examined for 652 paired visits when joint involvement was documented in the previous or current visit. In the later visits, both MDs and PTs more often reported improvement (44% and 45%) than worsening (5% and 11%). Tools that correlated with both MD and PT-perceived joint improvement were NIH joint/fascia score, Hopkins fascia score and SF36-PCS. Tools that correlated with both MD and PT-perceived joint worsening were P-ROM total score, NIH joint/fascia score, Hopkins fascia score, Lee muscle/joint subscale, Lee symptom overall score, 10-point overall symptoms and FACT-G. Among the 3 joint/fascia tools (Figure), for MD-perceived improvement, estimated change in the NIH score and P-ROM score was slightly larger than in the Hopkins score. For PT-perceived improvement, estimated change was similar for NIH and Hopkins scores. In contrast, for both MD and PT-perceived worsening, estimated change for the P-ROM score was significantly larger than in the other tools. Conclusion: Joint involvement with chronic GVHD is frequent and associated with increased symptom burden and decreased QOL. Our results support the combined use of NIH joint/fascia score and P-ROM scale to assess joint GVHD. The NIH score better reflects joint improvement and the P-ROM scale better reflects joint worsening. The more objective P-ROM scale is insensitive to PT-perceived joint improvement possibly because unlike the other two joint assessment tools, it does not incorporate tightness with or without activities of daily living. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1940 Background: Chronic graft-versus-host disease (GVHD) is a significant source of morbidity, mortality, impaired patient-reported quality of life (QOL), greater symptom burden, and prolonged duration of immune suppressive therapy following allogeneic hematopoietic cell transplantation (HCT). While available data support the adverse prognosis of overlap subtype of chronic GVHD, the relative importance of site of gastrointestinal (GI) and type of hepatic involvement is not known. Methods: We analyzed prospectively acquired observational cohort data to examine whether the site of GI involvement (esophageal, upper GI, lower GI) and type of hepatic laboratory test abnormality (bilirubin, alkaline phosphatase (AP), alanine aminotransferase (ALT) elevation over the upper limit of normal based on study site-specific laboratory reference ranges) among chronic GVHD-affected patients are associated with overall survival (OS) and non-relapse mortality (NRM), symptoms (Lee Symptom Scale), and quality of life (QOL) per SF-36 and FACT-BMT instruments. Results: This analysis included 567 individual subjects with baseline and 1548 follow up visits. The majority were incident cases (59%), adults (98%), and predominantly White/Non-Hispanic. Median time from HCT to cohort enrollment was 11.9 months (range 3–294 months). Overall NIH chronic GVHD severity was mild in 10%, moderate in 52%, and severe in 38% at enrollment. Prior acute GVHD was noted in 66%, KPS 〈 80% in 17%, and platelet count at chronic GVHD onset of 〈 100 K/uL in 23%. At enrollment, GI involvement was seen in 40% (upper GI 20%, esophagus 16%, lower GI 13%), and liver involvement was seen in 52% (AP 38%, ALT 38%, bilirubin 10%). Time from transplant to cGVHD onset was not different for patients with or without GI involvement or hepatic involvement. In multivariate analysis utilizing data from enrollment visits only and adjusting for patient and transplant variables, lower GI involvement (HR 1.7, p=0.03) and elevated bilirubin (HR 2.36, p=0.001) were associated with OS; both were also associated with NRM. In multivariable analysis using all visits (time-dependent covariates), GI score greater than zero (HR 1.7, p=0.01) and elevated bilirubin (HR 3.7, p