ALBERT

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: Pentostatin, one of the purine nucleoside analogues, is known to decrease lymphocyte number and function. It has been successfully used to treat steroid refractory acute graft-versus-host disease (GVHD). We are currently investigating pentostatin for refractory chronic GVHD (cGVHD). Fifty-two patients were enrolled and 42 are assessable for response. All patients presented here failed at least two immunosuppressive regimens including steroids at a dose equivalent to at least 1 mg/kg/day prednisone for one month. The treatment protocol consists of giving pentostatin 4 mg/m2/dose IV every 2 weeks for 6 months. Patients with improving disease were permitted to continue pentostatin therapy at a 3 to 4 week interval. To reduce the risk of infection, steroids are tapered early in all patients and they received prophylactic antibiotics (antibiotics, fluconazole, sulfamethoxazole/trimethoprim and valcyclovir). At the end of 3 months, patients with stable or improving cGVHD are weaned off their other medications but maintained on a calcineurin inhibitor. Pentostatin is stopped at 6 months if complete response (CR) is achieved or continued if partial response (PR). Patients are followed for improvement in the skin/fascia, mouth, and liver. The severity of GVHD is scored for each system on a scale from 0 to 4. Complete response is resolution of symptoms (irreversible changes [such as long standing contractures] due to cGVHD were not required to improve to score a CR if all other changes improved); partial response is at least a 1 point improvement in this score system. Mixed response is improvement in 1 system but worsening in another. Fifty-two patients have received a median of 8.5 doses (range 1–34). Median age of the cohort is 40.5 years (range 5 to 67). Diagnoses include AML/MDS (6), ALL (7), hemoglobinopathy (2), aplastic anemia (3), CML (16), myelofibrosis (1), NHL (8), myeloma (4), paroxysmal nocturnal hemoglobinuria (3), CLL (1), and lymphohistiocytosis (1). Graft source included 20 patients: 6/6 sibling BMT; 10 patients: 6/6 sibling PBSCT; 10 patients: MUD BMT; 6 patients 5/6 MUD BMT; 2 patients: 6/6 MUD PBSCT; 1 patient 5/6 sibling BMT; 1 patient: 6/6 sibling BMT followed by DLI; 1 patient 5/6 BMT from a child; and 1 patient, unknown. Most patients were on calcineurin inhibitor, eleven on prednisone, seven on MMF, one on rapamycin, and one was receiving ECP at entry on the study. In the 42 assessable patients, 5 patients attained a CR, 16 a PR, 5 a mixed response (improvement in one organ with deterioration in another one), and 16 patients have progressed. The overall response rate is 50%. Therapy has been well-tolerated with infections being the main concern. Mucormycosis, pneumonia, disseminated fungal infection, fungal pneumonia, progressive disease were the causes of death of the 15 patients who have died and only infections could be related to the study drug. The results suggest that pentostatin has activity in the treatment of cGVHD and may be especially beneficial in children and adolescents as the 5 CR were in this group.

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 220 The classification of chronic graft-versus-host disease (cGVHD) proposed by the 2005 National Institutes of Health (NIH) Consensus Criteria established a new scoring system for individual organs (0-3) and a global severity scale (mild, moderate, and severe) according to the number and severity of organs involved. The Chronic GVHD Consortium was established to validate these criteria, since the scoring system was based on consensus opinion not yet supported by empiric data. This report includes results from the first 298 adult patients (pts) enrolled at 5 centers of this Consortium. Pts were assessed using standardized clinical data collection forms every 3–6 months (741 total visits). At the time of study enrollment, global cGVHD severity according to NIH consensus criteria was calculated from reported data as mild in 10% (n=31, no more than 2 organs with score 1), moderate in 59% (n=175, 3 or more organs with score 1, lung score 1 or any other organ score 2) and severe in 31% (n=92, lung score=2 or any organ score=3). Severity distribution was similar across incident (54%, cGVHD diagnosis within 3 months of enrollment) vs. prevalent (46%) cases (p=0.35), and between pts with overlap acute and chronic GVHD (40%) vs. classic chronic (60%) cGVHD (p=0.61). Skin, mouth, eye and liver were most commonly involved. (Figure) Score 3 skin (〉 50% BSA, or deep sclerotic features, or impaired mobility) and score 2 lung involvement (FEV1 40–59% or lung function score 6–9 or shortness of breath after walking on flat ground) accounted for most of the cases in the severe category, while scores of 3 in the mouth, eye, GI tract, joints, genital tract (females only) occurred in only 3–11% of patients in this category. Higher global severity scores (n=741) were attributable to skin (32%), lung (21%), eye (18%), mouth (9%), liver (6%), joint (6%), GI tract (4%) and genital involvement (3%). Previously reported risk factors associated with onset of cGVHD or treatment-related mortality in pts with cGVHD were analyzed for their association with severity of cGVHD using generalized estimating equations (GEE) to adjust for baseline characteristics, repeated observations per pt, variable time to study enrollment and center effect (n=296 adults, 731 assessments). Global severity of cGVHD was not associated with age, gender-match, donor type, conditioning intensity, stem cell source, prior CMV infection, underlying disease, disease status, prior acute GVHD, time intervals from transplant to onset of cGVHD and enrollment, or platelet count at onset of cGVHD (〈 or ≥ 100 × 109/L). Moderate or severe cGVHD at onset was associated with Karnofsky performance status ≤ 70 (odds ratio [OR] 2.41, 95% CI (1.5-4.0), p=0.0004). In conclusion, skin, lung and eye involvement accounted for 71% of the global severity score, although all organs contributed and should be scored. Conventional risk factors for development of cGVHD were not associated with NIH cGVHD global severity categories. Most pts fit into the moderate category, suggesting that additional refinements to the global severity scoring may be able to distinguish prognostically different subgroups within this category. Funded by NCI CA118953. Registered as NCT00637689. Disclosures: Miklos: Novartis: Honoraria, Research Funding.

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: Pentostatin, one of the purine nucleoside analogues, is known to decrease lymphocyte number and function. We are currently investigating pentostatin for refractory chronic graft-vs.-host disease (cGVHD). Within an adult/pediatric phase II study, 16 patients under age 20 are evaluable. All children presented here failed at least two immunosuppressive regimens (including steroids at a dose equivalent to at least 1 mg/kg/day prednisone for one month) before enrollment. The treatment protocol consists of adding pentostatin 4 mg/m2/dose IV every 2 weeks for 6 months. Patients with improving disease are permitted to continue pentostatin therapy at a 3 to 4 week interval. To reduce the risk of infection, steroids are tapered early in all patients. At the end of 3 months, patients with stable or improving cGVHD are weaned off their other medications but maintained on calcineurin inhibitor. Pentostatin is stopped at 6 months if complete response (CR) is achieved or continued if partial response (PR). Patients are followed for improvement in the skin, mouth, and liver. The severity of GVHD is scored for each system on a scale from 0 to 4. Major response is defined as an improvement in symptom score of 2 points or more without worsening in any system. Minor response is a 1 point improvement. Mixed response is improvement in 1 system but worsening in another. Patients have received a median of 15 doses (range 5–30). Median age of the pediatric cohort is 14.5 years (range 5 to 19). Diagnoses include AML/MDS (6), ALL (5), hemoglobinopathy (2), T-cell leukemia (1), aplastic anemia (1), and lymphohistiocytosis (1). Ten had HLA-identical sibling donors (7 BM/3 PBSC) and 6 had HLA-matched unrelated donors (4 BM/2 PBSC). Median time since transplant to start of Pentostatin is 20.5 months (range 8–72). Most patients were on calcineurin inhibitor, eleven on prednisone, seven on MMF, one on rapamycin, and one was receiving ECP at entry on the study. Five patients attained a CR, eight a major response, and three patients have progressed. The overall response rate is 81%. Since some patients had multiple organ involvement, response rate by organ (PR or CR for individual organ) is below. Therapy has been well-tolerated. There has been only one toxicity likely due to pentostatin (creatinine elevation to 4.8 in a patient with a single kidney), and this required the patient to withdraw from the study. There have been no severe infections. There have been 2 deaths, both cGVHD-related, in patients who did not respond. Of the 11 patients on prednisone, 8 were weaned completely off steroids or to

Description: To evaluate the response rate and potential toxicities, a phase II trial was conducted of fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated low-grade and select intermediate-grade lymphoid malignancies. Symptomatic patients with preserved end organ function received cyclophosphamide 600 mg/m2 intravenous (iv) day 1 and fludarabine 20 mg/m2 iv days1 through 5, followed by filgrastim 5 μg/kg subcutaneous starting approximately day 8. Treatment was repeated every 28 days until maximum response or a maximum of 6 cycles. Sixty patients, median age 53.5 years, were enrolled. Thirty-seven patients with non-Hodgkin lymphoma (NHL) were stage IV and 6 were stage III. Eleven of 17 patients with chronic lymphocytic leukemia (CLL) were Rai intermediate risk and 6 were high risk. The overall complete response (CR) rate was 51% and the partial response (PR) rate was 41%. Of patients with CLL, 47% achieved a CR and the remaining 53% achieved a PR. Of patients with follicular lymphoma, 60% achieved CR and 32% achieved a PR. Although the toxicity of this regimen was mainly hematologic, significant nonhematologic toxicities, including infections, were seen. Twenty-four patients subsequently received an autologous or allogeneic stem cell transplant. Engraftment was rapid, and there were no noticeable procedure toxicities in the immediate posttransplant period attributable to the fludarabine and cyclophosphamide regimen. Fludarabine, cyclophosphamide, and filgrastim make up a highly active and well-tolerated regimen in CLL and NHL.