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Background: Post transplant lymphoproliferative disorders (PTLD) are rare pathologically and clinically heterogeneous diseases arising in the setting of immunosuppression following hematopoietic stem cell and solid organ transplants (SOT). Our understanding of PTLD is restricted by its low incidence and heterogeneous treatment approaches, resulting in paucity of data. We sought to further describe characteristics and outcomes in PTLD patients who underwent treatment at our institution. Methods and Patients: We performed a retrospective study to describe our institutional experience in a relatively large cohort of PTLD patients after SOT. Patient and disease characteristics were examined and prognostic factors for survival were determined using univariate and multivariate Cox analysis. Results: Between May 1987 to January 2014, 98 patients with a confirmed diagnosis of PTLD underwent treatment at our institution. Median time from SOT to PTLD diagnosis was 60 months with median follow of 68 months from PTLD diagnosis. Baseline characteristics include male gender 77%, ECOG performance status (PS) 0-1 in 61%, and stage III-IV 69% with a median age at diagnosis of 47 years. Most common transplanted organ included heart 30%, lung 24%, kidney 20% and liver 19% and median time from SOT to PTLD diagnosis was 60 months. Most cases had monomorphic histology (81%) and were EBV+ (82%). Graft involvement and rejection were observed in 32% and 43% respectively. Of the 84% with extranodal (EN) involvement, gastrointestinal tract (37%) and lung (27%) were the common sites, while 3.2% had bone marrow (BM) involvement. Central nervous system (CNS) was involved in 11% of the cases. Only 58% received rituximab as part of the initial therapy, as significant part of our cohort was treated prior to rituximab era. Reduction in immunosuppression (73%), chemotherapy (40%), radiation (11%) and surgery (8%) were utilized either as single modality or in combination for treatment. Of the 66 patients with response data, 59% had complete response (CR) and 14% had progressive disease (PD). Relapse occurred in 23% of cases. Median overall survival (OS) from diagnosis of PTLD was 6 years (Figure 1), but in rituximab treated patients it was 8 years. On univariate analysis, higher age at diagnosis (HR 1.19, 95% CI 1.01-1.40, p=0.033), lung transplant (HR 2.42, 95% CI 1.36-4.33, p=0.003), higher IPI (HR 1.83, 95% CI 1.40-2.39, p= Conclusions: In this large cohort of PTLD patients after SOT, lung transplants, higher IPI and poor PS were identified as poor prognostic factors for OS on both univariate and multivariate analysis. Rituximab treatment was a favorable prognostic factor for OS that resulted in prolonged survival observed in this cohort. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Hill: Millenium: Research Funding; Novartis: Research Funding.

DNA methyltransferase (DNMT1) is a validated molecular target for epigenetic therapy of non-malignant diseases (e.g., sickle cell disease, SCD) and cancer. DNMT1 can be depleted by decitabine (Dec), an FDA-approved drug, without off-target cytotoxicity, reproducibly demonstrated pre-clinically. Dec, however, has pharmacologic limitations that impede translation into clinical epigenetic therapy. For e.g., DNMT-depletion requires Dec levels to overlap with cellular S-phase entry, yet the plasma half-life of Dec is Therefore, to address limitations of Dec, this Phase 1/2 clinical trial combined oral Dec with a CDA inhibitor (oral tetrahydrouridine, THU) in patients with high risk, hydroxyurea refractory SCD (NCT01685515). The pharmacokinetic (PK) objectives were to (i) extend Dec half-life/Tmax, to hours instead of minutes to increase S-phase dependent DNMT1-depletion (ii) without high Dec Cmax that causes off-target effects and cytotoxicity (intended Cmax >5nM and Sixteen patients had received placebo or Dec at time of writing. Dec PK was measured in 8 non-placebo subjects (2 each in cohort 1 and 2, 3 in cohort 3, and the 1 subject enrolled thus far in cohort 4). Dec levels were detectable in all. Cmax was at 2 hrs, with a 50% decline from Cmax observed at 4 hrs (Fig 2, PK). There was a dose-dependent increase in Cmax and AUC (Fig 2). Previously, relative bioavailability in mice of oral THU-Dec vs oral Dec was estimated at 900% (Lavelle et al, Blood 2012). Circulating F-cells (HbF enriched red cells) were observed to increase in cohort 4 (Dec 0.08 mg/kg, approx. 3 mg/m2) when Cmax approached 20 nM: 14.4% at baseline to 22% at week 4 to 31% at week 8; with corresponding increases in HbF% from 1.8 to 3.4 to 5.4% (Fig 2, PD). This data was consistent with the minimum dose of oral THU-Dec that increases HbF% in baboons scaled by body surface area (Lavelle et al, Blood 2012). Combining mini-dose Dec with the CDA inhibitor THU Dec produced a major improvement in oral bioavailability and the wide Dec concentration-time profile (low Cmax, long Tmax) that is desirable for DNMT1-depletion without cytotoxicity. These observations also imply multi-hour, balanced distribution of Dec through solid tissues. Stated another way, this PK data confirms that CDA is responsible for the severe reduction in Dec half-life from >12 hours in vitro to Figure 1 Figure 1. Figure 2 Figure 2. Disclosures DeSimone: University of Illinois at Chicago: patents related to decitabine Patents & Royalties. Saunthararajah:University of Illinois at Chicago: patents related to decitabine Patents & Royalties.

Background: Bulky disease is considered a major driver of unfavorable prognosis in early stage Hodgkin Lymphoma (HL). Treatment guidelines for bulky early stage HL call for more aggressive initial therapy compared to non-bulky disease. There are limited data on outcomes in bulky disease, particularly in patients treated with chemotherapy alone, or on the utility of interim PET scans. We retrospectively analyzed data on patients with early stage HL to assess the impact of disease bulk, interim PET and treatment modality on outcomes. Methods: We reviewed charts of 151 consecutive patients diagnosed with previously untreated early stage (I & II) HL at the Cleveland Clinic from 1995-2011. Bulky disease was defined as a mediastinal mass >1/3 intra-thoracic diameter on PA chest x-ray or any mass ≥ 10 cm on CT scan at diagnosis. Patients were grouped by intent to treat strategy as chemotherapy alone (C) or combined modality treatment (CMT) with chemo-radiation. Baseline characteristics were compared: categorical variables by the Chi-square or Fisher's exact test; continuous variables by the Wilcoxon rank sum test. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method and compared by the log-rank test. Cox proportional hazards analysis was used to test univariable prognostic factors for OS and PFS. Results: 121 patients (mean age 40±16) with early stage HL had adequate clinical data for inclusion. At the time of review, 106 (87.6%) patients were alive with median follow-up of 47.4 (0-328) months. Characteristics at diagnosis were: 54% female; 80% Caucasian; 77% nodular sclerosis HL; 78% stage II; 31% with B-symptoms; 12% with extranodal disease; 30% (N =36) with bulky disease of whom 89% had bulky mediastinal disease. 96% patients received standard ABVD chemotherapy. The only significant differences in the baseline characteristics of patients with bulky vs. non-bulky disease were age (mean 35 vs. 42 years, P=0.03), hemoglobin (mean 12.4 vs. 13.4 g/dL, P=0.01) and absolute lymphocyte count (mean 1.29 vs. 1.71 k/µL, P=0.02). Although there was no statistically significant difference in the initial treatment strategy chosen, patients with bulky disease tended to receive CMT more often than patients with non-bulky disease (66% vs. 51%, P=0.16). More females were treated with C compared to CMT (70% vs. 43%, P=0.004). Patients with bulky disease received a greater number of chemotherapy cycles (mean 5.6 vs. 4.6, P=0.01). Five years after diagnosis, patients with non-bulky HL had Kaplan-Meier estimates of 83% OS and 69% PFS while patients with bulky HL had 88% OS and 81% PFS. There was no statistical difference in OS [Figure 1] or PFS based on disease bulk. Analysis of the available PET status (65 interim scans) revealed that both the bulky and non-bulky patients had comparable responses on interim PET (negative 82.6% vs. 95.2%, P=0.17). Interim PET scan was highly prognostic for all early stage HL patients for both OS (P < 0.01) and PFS (P < 0.001) as well as specifically for patients with bulky disease (negative vs. positive PET: 5 year OS 90% vs. 75%, P=0.012; 5 year PFS 95% vs. 25%, P Among the 23 patients with bulky disease managed with initial CMT, 4 required 2nd line treatment including 3 who underwent autologous stem cell transplant (Auto-SCT). Among the 12 patients managed initially with C, 5 required 2nd line treatment and all 5 underwent Auto-SCT. In total, among those with bulky disease, the OS and PFS were similar irrespective of initial treatment strategy chosen. In univariate analysis, extra-nodal disease was the only baseline variable that impacted PFS (HR=2.7, CI 1.01-7.20, P=0.048) but did not affect OS (HR=2.46, CI 0.66-9.19, P=0.18). Conclusions: Patients with bulky early stage HL have comparable survival to patients with non-bulky disease. Among patients with bulky disease, treatment with initial C or CMT resulted in comparable OS and PFS, although a higher proportion of patients treated with C alone required 2nd line treatment. These data support the observation that radiation therapy is not essential to achieve cure in bulky HL. Specifically, omitting radiation in female patients who achieve a negative interim PET scan is a viable treatment strategy which may mitigate the long-term risks of radiation. Figure 1: OS in Early Stage HL Based on Disease Bulk Figure 1:. OS in Early Stage HL Based on Disease Bulk Figure 2: PFS in Bulky Early Stage HL Based on Interim PET Figure 2:. PFS in Bulky Early Stage HL Based on Interim PET Disclosures No relevant conflicts of interest to declare.

Background and objectives Approximately 30% of diffuse large B-cell lymphoma (DLBCL) patients relapse following initial immuno-chemotherapy. DLBCL usually arises without a history of lymphoma (“de novo”), but can also transform from antecedent indolent lymphoma. There are limited data regarding the outcomes of the two subpopulations of transformed and de novo DLBCL patients treated with second-line chemotherapy regimens. We sought to compare the outcomes of relapsed/refractory transformed and de novoDLBCL patients after receiving frontline rituximab, cyclophosphamide, doxorubcin, vincristine and prednisone (R-CHOP) and second-line rituximab, ifosfamide, carboplatin and etoposide (R-ICE) chemotherapy prior to planned autologous stem cell transplant (ASCT). This analysis was performed on an intent-to-treat basis. Methods This retrospective review compared 100 consecutive DLBCL patients, 89 de novo and 11 transformed, at the Cleveland Clinic between 2000 and 2012. Inclusion criteria were: age ≥18 with relapsed/refractory DLBCL, prior treatment with R-CHOP and second-line R-ICE chemotherapy. Baseline characteristics were compared for categorical variables using the Chi-square test or Fisher's exact test; continuous and ordinal categorical variables were compared using the Wilcoxon rank sum test. Overall survival (OS) and progression-free survival (PFS) in transformed and de novorelapsed/refractory DLBCL patients were estimated using the Kaplan-Meier method and compared using the log-rank test. Stepwise multivariable analysis with a variable entry criterion of P Results The majority of patients had advanced stage (III or IV) disease at the time of diagnosis of DLBCL (62.5% for transformed and 68.5% de novo patients, P = 0.59).There was a male predominance in both groups, transformed (72.7%) and de novo (61.8%), P = 0.48. The median age at second-line was comparable between transformed and de novo patients (62 vs. 58 yrs, respectively, P = 0.66). The period of time between R-CHOP and R-ICE was significantly longer in transformed patients than those with de novo DLBCL (30.1 vs. 11.3 months respectively, P< 0.001). The number of cycles of R-ICE was comparable between the two groups and most commonly was 3. The percentage of patients who proceeded to a planned ASCT was comparable for transformed and de novo patients (45.5% vs. 47.2% respectively; P = 0.97). The molecular subtype for cases in which data were available was germinal center in 6 of 7 (85.7%) transformed patients and 32 of the 46 (69.6%) de novo cases as determined by the Hans immunohistochemistry algorithm (P = 0.66). Transformed patients had a statistically significant improvement in OS compared with de novo patients (77.8% vs. 27.4% 5 year OS, respectively, p=0.034). Death due to relapsed disease was comparable for both transformed and de novo patients (50% vs. 38.5% respectively). Transformed patients had marginally better PFS outcomes after 5 years (51.4%) than de novopatients (26.9%; p=0.18). In a multivariable analysis, transformed DLBCL was associated with a statistically significant odds ratio (OR) of 0.23 (95% confidence interval (C.I.) 0.05 – 0.95)1.05 -17.8) for OS (p=0.043). ASCT was associated with improved OS in multivariable analysis (OR = 0.57 (C.I. 0.33 – 1.00), p= 0.05). Conclusions Contrary to expectation, transformed DLBCL patients previously treated with R-CHOP have superior OS after second-line R-ICE than patients with de novo DLBCL. This may result from relatively longer period of time between initial treatment and the need for second-line and possibly an enrichment for cases with the more favorable germinal center molecular subtype. Improvements in second-line treatment for de novo relapsed/refractory DLBCL with novel agents are needed. Disclosures: Hill: Celgene: Honoraria, Research Funding.