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Introduction Allogeneic hematopoietic stem cell transplant (HCT) patients are at risk for having a low Vitamin D (VD) level. VD level has been correlated with cancer incidence, pulmonary disease and infection. VD also has immunomodulatory properties and reports suggest that a low VD level increases the incidence of chronic GVHD and may impact mortality in HCT. HCT morbidity and mortality is attributed to infection, organ system toxicity, GVHD and recurrent disease. Identifying a correctable factor that would reduce the occurrence or severity of these complications would be beneficial. It is possible that VD may have significant effect on outcome after HCT due to its described properties. Normal VD level may infer better outcome for HCT patients by improving response in or preventing infection, protecting organ function, decreasing risk of relapse and/or decrease incidence or severity of GVHD. We hypothesize that there is a relationship between VD level and morbidity and mortality after HCT. We therefore studied VD levels pre- and post-HCT to determine if there was an impact of VD level on these outcomes. Patients and Methods Two hundred and fifty patients underwent myeloblative or non-myeloablative HCT between 3/12/2009 and 10/29/2012 at our institution. Baseline demographic data, disease characteristics, transplant variables and outcomes data were obtained from the transplant database. These data were supplemented by retrospective chart review for VD levels prior to transplant, at day 100 and 1 year post-HCT. Data were collected through day 100 for occurrence of infection and admissions to the ICU. Categories for VD level included normal (≥30 ng/ml) or abnormal (<30 ng/ml). Patient characteristics were compared using the Chi-square test or Wilcoxon rank sum test. The logrank test was used to compare the survival curves between groups, and the Cox proportional hazard model was used to measure the association between outcomes (mortality, relapse, acute or chronic GVHD) and VD level. Results Of the 250 patients undergoing HCT VD level was performed on 180 (72%) patients pre-HCT, 149 (60%) patients at day 100 post-HCT and 81 (32%) patients at 1 year post-HCT. The rate of acute or chronic GVHD was not significantly associated with VD level pre or post-HCT. Overall infection risk was not significant pre or post-HCT but when sorted by type of infection bacterial infection (p=0.01), radiologic evidence of pulmonary nodules/consolidation (p=0.03), and ICU admissions (p=0.0313) within the first 100 days post-transplant were significantly increased in patients who had a low VD level at day 100 post -HCT. Pre-HCT and 1 year post-HCT VD level did not impact mortality or relapse but there was a significant increase in one year mortality (p=0.02, HR = 5.99) and relapse (p = 0.03, HR=9.47) in patients who had a low VD level at day 100 post-HCT. Discussion This study shows that VD may play a significant role in bacterial infection, pulmonary infection, ICU admission, mortality and relapse after HCT. Those patients with a low VD level at day 100 post-HCT had significantly worse outcomes for relapse and mortality. Those patients with a low VD level at day 100 post-HCT had a higher incidence of lung infection, bacterial infection and admission to the ICU. In contrast to previous studies, we found no correlation between VD level and incidence of acute or chronic GVHD. This study is one of the largest reported and the first to our knowledge that reports decreased risk of certain types of infection (bacterial and lung), mortality and relapse in those with an adequate VD level receiving HCT. It is possible that supplementation of VD to keep levels ≥30 would reduce these complications of HCT. Future prospective study of VD is warranted. Finding a low cost and easy to administer therapy (such as VD replacement) that would reduce morbidity, mortality and relapse in the HCT population is needed. Disclosures: Reeder: Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.

Abstract Abstract 2778 Introduction: Lenalidomide is approved for the treatment of del(5q) MDS in US and Japan. In Low to Intermediate-1 (Int-1) risk non-del(5q) MDS, lenalidomide treatment is less effective with a lower response rate (25%) and shorter response duration [Raza A. et al, Blood, 2008.111,1]. Ezatiostat, a glutathione S-transferase P1-1 (GST P1-1) inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in malignant cells. Based on the novel mechanism of action, response rates, non-overlapping toxicities, and tolerability observed in a single agent ezatiostat Phase 2 study in MDS, a study of the combination of ezatiostat and lenalidomide was conducted to determine the safety and efficacy of ezatiostat with lenalidomide in non-del(5q) Low to Int-1 risk MDS. Methods: In this multicenter Phase 1 dose-ranging study, ezatiostat was given at a starting dose of 2000 mg in combination with lenalidomide at 10 mg, days 1–21 of a 28-day cycle. In stage 1, 3–6 patients in a standard 3+3 design were treated before escalation to the ezatiostat/lenalidomide 2500/10 mg dose level. Treatment was given until lack of MDS response or unacceptable toxicity. Hematologic improvement-erythroid (HI-E) rates were determined by the MDS International Working Group (IWG; 2006) criteria. Results: Eighteen pts (median age 73 yrs; range 57–82; 72% male), with World Health Organization classifications: 4 refractory anemia (RA), 2 RA with excess blasts-1, 4 refractory cytopenia with multilineage dysplasia (RCMD), 5 RCMD with ring sideroblasts, 2 MDS-unclassified, 1 MDS/myeloproliferative disorder-U were enrolled. Thirteen pts (72%) were Int-1 risk, 5 (28%) Low risk; 4 pts (22%) had abnormal cytogenetics. Twelve RBC transfusion-dependent pts (67%) required a median of 6 units (range 4–10)/8-weeks. Two pts (11%) were platelet transfusion dependent. A total of 67 treatment cycles were given (median 3.5 cycles/pt [range 1–11]) and only 6 cycles (9%) required dose reductions and 8 (12%) dose delays. Two of 6 pts reported DLTs (Grade 3 diarrhea and Grade 3 rash) at 2500/10 mg, with 9 additional pts receiving the recommended combination dose of 2000/10 mg. Eleven of 18 pts were evaluable (4 at 2500/10 mg and 7 at 2000/10 mg), and 3 pts are still on therapy with insufficient treatment duration to be evaluable. The HI-E rate was 43% (3/7; 95% CI, 10%–82%) for pts at the recommended 2000/10 mg dose and 6 pts are continuing therapy at the time of analysis. Three of 8 (38%; 95% CI, 9%–76%) RBC transfusion-dependent evaluable pts achieved transfusion independence including 1 responder who did not respond to prior lenalidomide. In responders, the median increase in hemoglobin level was 3.4 g/dL (from 7.9 g/dL). In 2 of 4 thrombocytopenic pts, a HI-platelet (HI-P) response was observed. A bilineage (HI-E and HI-P) response in 2 of 4 pts with anemia and thrombocytopenia was reported. One RBC and platelet transfusion-dependent pt who had a poor response to prior anti-thymocyte globulin treatment achieved complete RBC and platelet transfusion independence. The combination was generally well tolerated with no unexpected toxicities. Most common treatment-related non-hematologic adverse events (AEs) were Grades 1 and 2 including: fatigue (6%, 28%), swelling (0%, 11%), anorexia (11%, 6%), rash (0%, 6%), skin odor (11%, 6%), nausea (39%, 11%), diarrhea (22%,17%), vomiting (28%,17%), upper abdominal pain (5.6%, 5.6%), and constipation (11%, 0%). Grade 3 events were rash (11%), nausea (6%), diarrhea (17%), and vomiting (6%). Most common hematologic-related AEs were Grades 1 and 2 thrombocytopenia (11%, 6%) and neutropenia (0%, 11%). Grade 3–4 AEs were thrombocytopenia (11%, 17%), neutropenia (17%, 11%), anemia (6%, 6%), and febrile neutropenia (11%, 0%). Conclusions: Ezatiostat is the first GST P1-1 inhibitor to cause clinically significant reductions in RBC and platelet transfusions, including RBC and platelet transfusion independence. Since ezatiostat is non-myelosuppressive, it is a good candidate for combination with lenalidomide and in this study, the combination was well tolerated. Interestingly, ezatiostat may also have the potential to enhance lenalidomide's efficacy. The recommended doses of this combination regimen for future studies is the ezatiostat/lenalidomide 2000/10 mg. Disclosures: Off Label Use: Lenalidomide was used off-label in patients with non-del5q MDS. Mulford:Celgene: Speakers Bureau. Brown:Telik, Inc.: Employment, Equity Ownership. Meng:Telik, Inc.: Employment, Equity Ownership. Lyons:Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Mesa:NS Pharma: Research Funding; Astra Zeneca: Research Funding; SBio: Research Funding; Lilly: Research Funding; Incyte: Research Funding; Celgene: Research Funding.

Background Steroid-refractory (SR) acute graft-versus host disease (aGVHD) is a serious complication of allogeneic HCT, for which there is no established standard treatment. Both ECP and cytokine inhibitors such as Infliximab have apparent single agent activity in the therapy of SR aGVHD, but there are no published data that address the efficacy of combination anticytokine therapy and ECP in this setting. We report here results in 18 adult patients (pts) with grade III or IV SR aGVHD who were treated with concurrent Infliximab and ECP. Patients All pts underwent allogeneic HCT (first transplant, n=15, second transplant, n=3) for a hematologic malignancy at Mayo Clinic Arizona between March 2012 and May 2013. The median age was 61 (range 22-70), and the median follow-up of 6 surviving pts is 263 days (range 79-433). Donors were related in 3, matched unrelated in 8, and mismatched unrelated in 7. GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil in 13 pts and tacrolimus/methotrexate in 5; in addition, 17 pts received in vivo T-cell depletion with Thymoglobulin 2.5 – 7.5 mg/kg. All pts developed grades III-IV aGVHD at a median day 27 post-transplant (range 10-107) and failed to respond to a course of high-dose corticosteroids (methylprednisolone or equivalent 2 mg/kg daily) for at least 5 days. Treatment Regimen At diagnosis of SR aGVHD, pts were scheduled to receive weekly Infliximab 10 mg/kg (maximum 4 doses), concurrent with ECP performed twice or thrice weekly for one month, followed by a pre-specified taper schedule (anticipated total treatment duration of 6-9 months). To minimize infectious risk and morbidity, corticosteroids were tapered rapidly after the start of Infliximab/ECP therapy. Results Thirteen pts (72%) responded to the Infliximab/ECP combination; complete response (CR; resolution of all GVHD symptoms for at least 30 days and able to discontinue corticosteroids) was observed in 6 pts (33%), and partial response (PR; improvement in GVHD symptoms, partial taper of corticosteroids, and no additional agent for at least 30 days) in 7 pts (39%). At the time of this report, 6 pts are alive, and the Kaplan-Meier estimate of one-year survival is 22.5 % (95% CI, 8.8%-47%). Only pts who achieved CR had good outcomes (5/6 surviving and clinically well); among 13 pts with PR (7) or no response/progression (6) to Infliximab/ECP, 12 have died and one is day 79 post transplant and remains on ECP and low-dose prednisone. Eleven of the 12 deaths were related to GVHD or complications of its treatment (infection, multi-organ failure). Conclusions In this retrospective study of adult pts with severe (grade III/IV) SR aGVHD, treatment with 4 doses of weekly Infliximab and concurrent ECP resulted in an overall response rate of 72%, with one-third of pts achieving CR; the regimen was well-tolerated and facilitated early taper and rapid discontinuance of corticosteroids. Unfortunately, the overall survival of 22.5% at one year does not appear superior to other single agent or combination therapies reported in the literature, or to historical data from our program. Although a small percentage of pts appear to be long-term survivors, the majority of pts succumb to complications of progressive GVHD or infection. Given poor results with available therapies, and the dismal prognosis of pts with SR aGVHD, future research should focus on better preventative strategies for this devastating complication of allogeneic HCT. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 87 Background: The International Prognostic Index (IPI) remains the most powerful predictor of clinical outcome in DLBCL in the R-CHOP era, serving as a useful surrogate for the biology we are just beginning to understand. With a follow-up of more than 9 years, its uniformly staged and treated patients and its prospectively collected unstained slides for correlative studies, the clinical data set from E4494, the US Intergroup trial comparing CHOP and RCHOP in patients >60 years with DLBCL, stands as a valuable resource for investigating prognosis in DLBCL. Based on immunohistochemistry, we previously showed that rituximab modulates the prognostic significance of some biomarkers in DLBCL. With these same specimens, the quantitative nuclease protection assay (qNPA), a methodology for measuring mRNA levels in FFPET, was used to develop separate prognostic signatures for the CHOP and RCHOP arms that can be simply applied using stored unstained slides. Methods: Five micron unstained FFPET sections from 183 eligible and evaluable cases enrolled on E4494 and submitted for prospective immunohistochemical correlative studies more than ten years ago were used for this analysis. Tissue was scraped from slides and a multiplexed qNPA was performed in triplicate using a customized Array Plate assay (HTG, Inc) for 43 genes of interest. TBP served as a housekeeping gene. Association between standardized log gene expression and patient failure-free survival (FFS) and overall survival (OS) was obtained using the Cox proportional hazards model. A weighted analysis was used to eliminate the confounding effect of maintenance rituximab. Genes that showed at least marginal significance in the univariate analysis were used to perform LASSO (penalized method to select best subset) to select a final list of genes in the multivariate analysis. Using the predictive model for either CHOP or R-CHOP induction, individual risk scores were calculated based on the multivariable model, and cases were dichotomized into low and high risk groups based on the median risk score. The model was then validated using the Lenz dataset (NEJM, 2008). Results: In six cases, tissue from slides prepared >10 years ago was compared to freshly cut sections from corresponding blocks, and showed excellent concordance (corr=0.86). On-study characteristics for the 176 cases with analyzable data were representative of the greater E4494 patient population. Six gene predictors were developed for each arm of the trial: RCHOP: FN1, LMO2, AKT1, HIF1a, AKT3, BCL2; and CHOP: PDCD4, HLADRB1, COL3A1, LMO2, ROBO4, TP53. Both signatures proved powerful predictors of FFS and OS among CHOP (FFS: p=0.0031; OS: p=0.0013) and RCHOP (FFS: p=0.001; OS=p=0.0015) treated patients. When adjusted for the clinically-based IPI, the gene-risk score retained its significance (CHOP: FFS p=0.0007; OS p=0.0011; RCHOP: FFS p=0.003; OS, p=0.001) while the IPI became only marginally significant (CHOP: FFS: p=0.06, OS p=0.06; R-CHOP: FFS p=0.09, OS p=0.02), suggesting that the gene predictor accounted for much of the predictive power of the IPI. The predictive model was then validated using the Lenz dataset for OS. The predictor models for CHOP and R-CHOP-treated patients effectively dichotomized patients into prognostic subgroups (CHOP: p<0.0001; RCHOP: p=0.0014; see figure below) and this difference was maintained when the subset over age 60 was analyzed (CHOP: p=0.0008; RCHOP: p=0.017). When adjusted for the IPI, the molecular predictor developed for CHOP treated patients remained robust (OS: P=.0001; HR 2.39), while the molecular predictor for RCHOP predicted OS marginally (p=.06; HR 1.82), with shorter followup than the CHOP cohort. Conclusions: Unstained slides from FFPET stored for many years may be used to investigate gene expression in lymphoma biopsy specimens for which there is mature followup. Gene risk scores based on the expression of a limited number of genes are powerful predictors of clinical outcome. Disclosures: Pollock: HTG, Inc.: Employment, Equity Ownership. Botros:HTG, Inc.: Employment, Equity Ownership. Horning:Genentech: Employment, Equity Ownership.

Abstract Abstract 1024 Background: The MMRC is a non-profit, disease-focused consortium founded in 2004. Sixteen North American member institutions with expertise in multiple myeloma (MM) work collaboratively with the MMRC Inc. (Norwalk, CT) and numerous pharmaceutical partners to speed development of new treatment options to MM patients. In December 2007, MMRC Inc. implemented business solutions to address barriers to rapid activation of phase I-II trials and established benchmarks for initiating and conducting these studies. In December 2010, we reported significantly faster trial start up and accrual data from previous years1,2. Today, we update and expand on MMRC performance data and analysis of progress. Methods: Twenty-five (25) trials conducted within the Consortium from May 2006 to July 2011 had sufficient start up trial data for review. FPFD was defined as the time from the member institutions' receipt of the final protocol (FP) from the trial sponsor, to the time the first patient was dosed on the trial at any participating MMRC member institution. With respect to enrollment, pre-study enrollment commitment (EC) established between MMRC and the study sponsor was defined as the total number of subjects committed to receive at least one dose of study drug across all participating MMRC centers on a trial; baseline enrollment timeline (BET) was prospectively defined as the target time period to attain EC. Results: Mean time to FPFD in the recent group of trials (RG; n=18; Sept 08-Jul 11) held steady at 131 calendar days from receipt of FP as compared to 181 days for the early group of trials (EG; n=7; Jun06-Sept08) representing a 28% reduction in time to FPFD. More importantly, there was a 20% decrease in time to FPFD by all participating MMRC centers on any MMRC trial from 189 days in the RG compared to 236 days in the EG representing an important achievement especially in the Phase I/II arena. MMRC trial accrual data was available for 17/25 trials (2 EG trials were missing data and 6 RG trials continue enrolling). The pre-study mean MMRC EC was 44 subjects per trial (n=19 trials; 849 patients); the mean actual MMRC enrollment was 49 subjects per trial (n=19; 935 patients through July 11) representing a 10% over enrollment versus committed enrollment. A total of 17/19 evaluable trials (89%) met their EC; 12/19 trials met EC within BET (71%) of which 8/12 trials (67%) reached EC 34% faster than their BET (representing a mean reduction of 4.5 months). The overall pre-study mean BET for 19 trials was 13.6 months. MMRC's actual mean enrollment timeline was 12.8 months for the group of 17 evaluable trials representing improvement over the original BET by a mean of 10%. Discussion: MMRC's acceleration of clinical trials provides physicians and patients with rapid access to novel compounds; industry with data for important drug development decisions; and academic institutions with more trials of high scientific interest. Even so, our data uncovered opportunities for improvement. The submission time from receipt of the final protocol from the trial sponsor to Scientific Review Committee (SRC) took an average 30 calendar days across all trials. A reduction to half this time could make a difference to patients and therefore warrants further exploration. Conclusion: Today, drug development in multiple myeloma is fast-paced and highly competitive. MMRC's frequent review of trial metrics provides valuable insight to continually speed answers to physicians, patients and industry. Disclosures: Richardson: Multiple Myeloma Research Consortium: Annual grant in support Clinical Trial Project Management. Vij:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Lonial:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Siegel:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jakubowiak:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Reece:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jagannath:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Hofmeister:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Stewart:Multiple Myeloma Research Consortium: Annual Grant in support of clinical trial Project Management. Wolf:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Krishnan:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Zimmerman:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Kumar:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Roy:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Fay:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Anderson:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management.

Abstract Abstract 4876 Background Recent studies have found obesity to be associated with a 1.5- to 2-fold elevated risk of developing multiple myeloma. This is of particular interest given that elevated levels of the pro-inflammatory cytokine interleukin (IL)-6 have been found in obese persons, and, at the same time, IL-6 has well-known proliferative and anti-apoptotic effects on monoclonal plasma-cells. Also insulin-like growth factors (IGFs) have been proposed to play a role since obesity often causes insulin resistance, which in turn modulates the bioavailability of IGF-1 Similar to IL-6, prior studies have found IGF-1 to have both growth and survival effects on monoclonal plasma-cells. Based on these facts, we have speculated that obesity might increase the risk of the multiple myeloma precursor monoclonal gammopathy of undetermined significance (MGUS), or, alternatively, that obesity may increase the risk for transformation from MGUS to multiple myeloma. We conducted the first large screening study designed to assess the association between obesity and MGUS among almost 2,000 African-American and Caucasian women. Methods We included 1000 African-American and 996 Caucasian women (age 40-79, median 48 years) from the Southern Community Cohort Study to assess MGUS risk in relation to obesity. Per our sampling strategy, about 50% of the participants were obese. Medical record-abstracted weight and height (measured on the day of study enrollment) and self-reported values had very high concordance (Pearson correlation >0.95). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Using logistic regression models, we estimated odds ratios (ORs) as measures of risk. Results Among all study participants, 39 (3.9%) African-Americans and 21 (2.1%) Caucasians were found to have MGUS, yielding a 1.9-fold (95%CI 1.1-2.3; p=0.021) higher risk of MGUS among African-Americans (vs. Caucasians). On multivariate analysis, we found obesity (OR=1.8, 95%CI 1.03-3.1; p=0.039), African-American race (OR=1.8, 95%CI 1.04-3.1; p=0.037), and increasing age (quartiles: ≥55 vs. <43 years) (OR=2.5, 95%CI 1.1-5.7; p=0.028) to be independently associated with an excess risk of MGUS. Another interesting finding was that the distribution of the monoclonal immunoglobulin isotype usage among African-American and Caucasian women was significantly different (p=0.007). Their respective rates were: IgG in 79.5% and 71.3 %; IgA in 7.7% and 0%; IgM in 7.7% and 19%; biclonal in 5.1% and 4.7%; and triclonal in 0% and 4.7%. The distribution of serum light-chain types between the two races was also significantly different (P=0.003, chi-square test): kappa in 53.8% and 47.6%; lambda in 43.6% and 42.8%; biclonal 2.6% and 4.7%; and triclonal in 0% and 4.7%. Conclusions Our finding that MGUS is twice as common among obese (vs. non-obese) women, and independent of race, supports the hypothesis that obesity is etiologically linked to myelomagenesis and may have public health impact. The observed 2-fold excess of MGUS among African-Americans (vs. Caucasians) of similar socio-economic status, coupled with other recent studies supports a role for susceptibility genes as the cause for racial disparity in the prevalence of MGUS. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 4000 Poster Board III-936 Background There is insufficient information regarding the epidemiology and outcomes of DVT in children. The CDC began a consented registry in August 2003 at eight pilot Centers for Thrombosis and Thrombophilia including six pediatric sites in order to assess the scope and severity of DVT morbidity in children. Methods Data for this analytic project were extracted from the CDC thrombosis registry. We performed a nested case-control study within the registry cohort. Children and adults are eligible to enroll onto this consented registry if they have a history of thrombosis, thrombophilia or a positive family history or either. DVT site, extent, recurrence and BMI were determined clinically. In addition, thrombophilia testing batteries, imaging protocols and determinations of PTS outcomes of DVT were made locally and criteria were not standardized among participating centers. Results As of March 2009 the CDC registry included 316 cases of DVT in infants and children (ages 0-21), and 2414 cases in adults (> 21). There were 16 cases reported to have lower extremity (LE) PTS in children and 184 in adults. Table 1 displays effects of thrombus site, recurrence and BMI on PTS prevalence. The proportion of LE DVT involving the inferior vena cava (IVC) was 5.5-fold higher in children compared to adults (11% vs 2%). Furthermore, among cases of IVC involvement, the prevalence of PTS following IVC thrombosis was remarkably higher in children compared with adults (38.9 vs 6.3%, P < 0.001). The prevalence of PTS following LE DVT overall in children did not differ from adults. Results for upper extremity DVT and resultant PTS were similar. Fifteen percent of children had recurrence. Increasing number of DVT events was associated with an increased risk of PTS. BMI was higher in children who developed PTS (p = 0.06; BMI > 28, OR 3.3 [1.08, 9.59]). In addition, thrombophilia was a risk factor for developing PTS in children (p = 0.02; OR = 2.9 [CI 1.03, 8.05]), with the highest risk determined with antiphospholipid syndrome (p = 0.02; OR = 3.4 [1.09, 9.93]) and protein C deficiency (p = 0.02, OR = 10.9 [0.84, 99.3]). Discussion Children with LE DVT demonstrate a high rate of IVC thrombosis, and a higher relative risk of PTS in cases of IVC involvement. Elevated BMI and thrombophilia augment the risk of PTS in children. The limitations of this study include the lack of standardization in DVT diagnostic and PTS evaluations. The study findings support application of standardized approaches to the diagnosis and follow-up evaluation of children with DVT in order to more meaningfully determine outcomes for future interventive trials. Disclosures: Moll: Ovation: Consultancy; GTC Biotherapeutics: Consultancy; Talecris: Consultancy.

Abstract Abstract 4048 Poster Board III-983 Introduction Iron deficiency is the most common nutritional disorder in the world with an estimated two billion affected persons. Although commonly considered environmental in origin, the existence of multiple genetic disorders of iron metabolism in man, rodents and other vertebrates suggest a genetic contribution to iron deficiency. Methods: The Hemochromatosis and Iron Overload Screening (HEIRS) Study is a multi-center, multi-ethnic study in which transferrin saturation (TS), serum ferritin (SF), and HFE mutations were determined in 101,168 adults. To identify genomic locations associated with iron deficiency, we performed a genome-wide association study (GWAS) using DNA collected from white HEIRS Study participants who had SF ≤ 12 μg/L (cases) and an equal number of white controls (SF > 100 μg/L in men, SF > 50 μg/L in women) frequency-matched to cases by sex and geographic location. Men aged ≥ 25 y and women ≥ 50 y were included in both groups. Tissue body iron, an index of iron deficiency, was estimated from serum transferrin receptor (sTfR) and SF. Genotyping was performed with the Illumina HumanCNV370K Beadchip platform. Quality control filters excluded single nucleotide polymorphisms (SNPs) or samples with > 5% missing genotypes, SNPs showing heterozygosity or Hardy-Weinberg deviations (P<10−7), and SNPs with minor allele frequency < 0.02. Population admixture/structure was assessed using principal component analysis. Regression analysis was used to examine the association between outcomes (case-control status, tissue body iron, serum ferritin, transferrin receptor, serum iron, total iron-binding capacity [TIBC], and unsaturated iron-binding capacity [UIBC]) and each SNP genotype variable; covariates included age, sex, and geographic location. Replication for 56 SNPs was conducted in a population attending primary care clinics at a Veterans Affairs (VA) medical center using the iPlex platform. Eligibility within the VA replication population was restricted to age and self-reported white ethnicity as for the HEIRS subset from a total of 2559 people (138 women). VA participants with SF ≤ 20 μg/L were classified as iron-deficient cases and frequency matched 1:2 with controls (men with SF > 100 μg/L and women with SF > 50 μg/L). Results The GWAS genomic control parameter was not significantly different from 1.0. There were 392 cases (96 men) and 390 controls (96 men) in the HEIRS subset GWAS with average age (SD) of 59 (10) y and 61 (11) y, respectively. Geometric mean SF (minimum, maximum), and mean (SD) for sTfR and tissue body iron in the HEIRS subset were 7.5 (1.2, 12) μg/L, 6.4 (3.77) mg/kg and -2.0 (2.50) for cases and 141 (51, 881) μg/L, 3.0 (0.98) mg/kg and 10.8 (2.5) for controls. After quality control tests, GWAS analysis included genotype data for 331,060 SNPs in 734 individuals (364 cases, 370 controls). For the VA replication population there were 67 male and 11 female cases, and 136 male and 27 female controls for whom DNA was successfully prepared; the average age (SD) was 68 (12) y for cases and 65 (11) y for controls. Regression analysis identified seven SNPs within four independent regions that replicated associations found in the GWAS (GWAS P<1×10-4 and VA P<0.05).The SNP rs6735681 on chromosome 2p24 was associated with serum iron (GWAS P<3.9×10-5, VA P=0.038). Three SNPs on chromosome 2p14 (rs6750096, rs2698541 and rs2698530) significantly influenced both TIBC and UIBC (GWAS P<2.9×10-5, VA P< 0.04 for all). Two SNPs in the TF gene region on chromosome 3q22 also showed significant effects on TIBC and UIBC (GWAS P<4.7×10-6, VA P<0.03 for all). The SNP rs10512064 on chromosome 9q21 was associated with serum ferritin concentration and tissue body iron (GWAS P<2.5×10-5, VA P<0.05 for both). Conclusion: From these GWAS and replication studies, we have identified three new genetic loci and one known iron gene, TF, associated with iron phenotype variability. These results point to specific loci as targets for gene identification and TF polymorphisms as determinants of iron metabolism, which in turn may play a role in regulation of body iron status. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Myeloablative hematopoietic cell transplantation (HCT) provides a cure for children with hemoglobinopathies, but transplant related early and late morbidity remains a challenge. Toxicities associated with myeloablative chemotherapy include early complications such as mucositis, hemorrhagic cystitis, seizures, and hepatic injury. Late effects such as infertility and compromised linear growth impair long-term quality of life, often decreasing enthusiasm for the procedure. Reduced intensity preparative regimens are especially attractive in children with non-malignant disorders to mitigate these toxicities but have been associated with increased risk of graft rejection. The primary objective of this study was to determine the toxicity and efficacy of a non-myeloablative preparative regimen using alemtuzumab, fludarabine, and melphalan followed by HCT from HLA matched related donors (MRD) in children with hemoglobinopathies. Methods: Following institutional review board approval, and parent and/or patient consent, participants were enrolled at 18 centers. Children < 21 years of age with severe sickle cell disease (SCD) manifestations, or transfusion dependent (> 8 red blood cell transfusions per year) thalassemia with a MRD and a performance status > 40 were eligible for inclusion. The preparative regimen included alemtuzumab (total dose 48 mg) IV (between days –22 and –19), fludarabine (30 mg/m2/day) (days –8 to –4) and melphalan (140 mg/m2) on day -3. Graft versus host disease (GVHD) prophylaxis included a calcineurin inhibitor (tapered after day 100, and methotrexate (7.5 mg/m2 on days 1, 3 and 6) or mycophenolate mofetil. Five patients also received methylprednisone (1 mg/kg/day) between days 1 and 28; this practice was discontinued in 2007. Results: A total of 52 children (43 with SCD and 9 with thalassemia), median age 11 years (range, 10m - 20y) underwent HCT between March 2003 and July 2014. Of these, 46 received bone marrow, 5 received marrow and cord blood (CB), and 1 received CB alone. Median follow up was 35.5 months (range, 3 – 136). Forty-nine children were alive at last follow up (Figure 1); 48 were symptom-free; one CB recipient had disease recurrence following graft rejection and successfully underwent a 2nd HCT. No hepatic veno-occlusive disease was noted. Three deaths 6, 11 and 21 months post HCT were from GVHD related causes [bronchiolitis obliterans (n=1); infection with GVHD (n=2)]. The cumulative incidence of graft failure and transplant related mortality was 1.9% and 5.7% respectively. The mean time to engraftment of neutrophils (ANC >500/cu mm) and platelets (>50,000/cu mm) was 13.0 (range 5-21) and 25.9 (range 8-120) days respectively. Three patients had neurologic toxicity (seizures/PRES) post HCT. At the time of last follow up, 35 patients (67%) were complete donor chimera (>90% donor) and 16 (31%) were mixed chimera (28-89% donor). Acute GVHD (grade 1-3) was noted in 30.8%. Four had grade I, 6 had grade II, and 6 had grade III GVHD. No patient developed grade IV aGVHD. Chronic GVHD was noted in 13%. Of 43 patients that were alive without disease and >6 months post HSCT, 38 had successfully discontinued all immune suppression and maintained donor chimerism post withdrawal. Immune reconstitution was robust by the end of the first year post transplant; infectious complications (23 of 30 CMV+ recipients had reactivation) were noted primarily in the first 3 months post HSCT. Conclusions: Children with hemoglobinopathies undergoing MRD HCT tolerated this non-myeloablative preparative regimen well, with minimal early toxicities. The event-free survival rate was comparable to those achieved with myeloablative regimens. Withdrawing immunosuppression was not associated with graft loss or recurrent GVHD. GVHD complications resulted in a low mortality rate. Alternative GVHD prophylaxis may further improve event-free survival. No gonadal toxicity (determined by hormone levels) has been identified to date in 15 HCT recipients of pubertal age (>13 years). Follow up however is early and in progress to determine long-term toxicities. These results support consideration of reduced intensity conditioning regimens for HCT in children with hemoglobinopathies as an alternative to standard myeloablative regimens. Figure 1: Overall/Event-free survival following non-myeloablative conditioning andMRD transplants for hemoglobinopathy Figure 1:. Overall/Event-free survival following non-myeloablative conditioning andMRD transplants for hemoglobinopathy Disclosures No relevant conflicts of interest to declare.

Abstract Background: Relapse after ATRA-based induction therapy is relatively uncommon in patients with acute promyelocytic leukemia (APL). Long term follow up studies have estimated a 15-25% relapse rate. Autologous and allogeneic hematopoietic stem cell transplantation (HCT) has been used as an effective salvage strategy. We present a single institution study of the outcomes of patients with relapsed APL that underwent HCT. Methods: After due IRB approval, the Mayo Clinic Transplant Database was retrospectively reviewed to identify all patients across three Mayo Clinic sites with relapsed APL that underwent HCT from 1995-2013. Data was abstracted at diagnosis and at relapse. The aims of this study were to report the descriptive characteristics of patients, with a focus on HCT outcomes. Results: Baseline Patient Characteristics A total of 15 patients (9 (60%) males) with relapsed APL that underwent HCT were identified. Median age was 36 years (range: 19-63) and median follow up from diagnosis was 8.8 years (range: 1.7-17). 2 (13%) deaths (1 from relapse) were recorded. 14 (93%) received ATRA and anthracycline-based induction therapy and 1 received anthracycline-based induction without ATRA. All relapsed patients achieved a complete remission (CR) after induction. Median time to relapse was 1.6 years (range: 0.6-3.9). 10 (67%) patients had a medullary relapse (hematologic-7(70%), cytogenetic -2 (20%) and molecular-1(10%)), 3 (20%) had additional extramedullary (EM) disease (CNS-2, myeloid sarcoma-1), while 2 (13%) presented with EM disease only (CNS-2). Salvage regimens included ATRA in 5 (33%) patients and arsenic trioxide (ATO) in 8 (53%) patients. 12 (80%) patients were transplanted in CR2 and 1 in CR3 (7%), while 2 (13%) had persistent disease (PD) at time of HCT. Allogeneic HCT 4 (27%) patients with a median age of 37 years (range: 33-49) underwent allogeneic HCT. 2 (50%) patients received myeloablative (MA) conditioning and 2 received reduced-intensity conditioning (RIC). 2 patients who underwent MA HCT had PD at time of transplant, while 1 patient in CR3 received a RIC. 2 (50%) patients developed acute GVHD while 2 (50%) had extensive stage chronic GVHD. At a median follow up of 2.6 years (range: 0.3-10.9), 3 (75%) patients remain alive and disease-free. 1 patient died of infectious complications within 100 days of transplant. Autologous Transplantation 11 (73%) patients with a median age of 40 years (range: 23-68) underwent autologous HCT with MA conditioning. 7 (64%) patients were in molecular remission at time of HCT, 3 (27%) patients transplanted before 2004 were in cytogenetic remission and information about type of remission was unavailable in 1 patient. At a median follow up of 6.8 years (range: 0.5-16) since HCT, 1 (9%) patient had a documented relapse at 175 days after HCT and died of disease-related complications. 10 (91%) are alive and in remission. Conclusions: Our single-institution study reaffirms the efficacy of HCT for APL patients with medullary and EM relapse. Autologous HCT has excellent long-term results in selected patients in CR2. Allogeneic HCT was mainly reserved for patients with high risk disease (CR3) and persistent disease at time of HCT. Table 1: Baseline Patient Characteristics N (%) Number of patients 15 Follow up (years) (median, range) 8.8 (1.7-17) Age at diagnosis (years) (median, range) 36 (19-53) Gender Male 9 (60%) Female 6 (40%) Sanz risk score High 4 (29%) Intermediate 8 (57%) Low 2 (14%) Induction Regimen ATRA + anthracycline 14 (93%) Anthracycline-based 1 (7%) Response to induction therapy CR 15 (100%) Time from diagnosis to relapse (years) (median, range) 1.6 (0.6 - 3.9) Type of relapse Hematologic 7 (47%) Cytogenetic 2 (13%) Molecular 1 (7%) Hematologic and EM 3 (20%) CNS only 2 (13%) Salvage regimen ATRA-based 5 (33%) ATO-based 8 (53%) Chemotherapy only 2 (13%) Table 2: Outcomes at HCT N (%) Age at HCT (years) (median, range) 38 (23-68) Disease status at HCT CR2 12 (80%) CR3 1 (7%) PD 2 (13%) Type of HCT Allogeneic 4 (27%) Autologous 11 (73%) Conditioning regimen Myeloablative 13 (87%) Non-myeloablative 2 (13%) Follow up since HCT (years) (median, range) 4.5 (0.3 - 16.3) Disease status at last follow up CR 13 (86%) Relapsed disease 1 (7%) Unable to assess 1 (7%) Alive at last follow up 13 (87%) Disclosures No relevant conflicts of interest to declare.