Citations

Abstract Introduction: Primary central nervous system lymphoma (PCNSL) is a rare intracranial lymphoma that accounts for less than 1% of all non-Hodgkins lymphomas and 3% of all brain tumors. Histopathologically, approximately 90% of PCNSL cases are categorized as a diffuse large B-Cell lymphoma (DLBCL). DLBCL malignancies are subdivided by Cell of Origin (COO), with the vast majority of PCNSL categorized as non-germinal center B cell (non-GCB) by immunohistochemistry. Gene expression profiling (GEP), however, has shown that immunohistochemically defined non-GCB resolves into two distinct subtypes, namely activated B-cell (ABC) and unclassified (UNC) subtypes. Using the Lymph2Cx molecular COO subtyping assay, we have found that 91% of PCNSL are ABC (unpublished data). Unlike systemic-DLBCL, PCNSL is largely confined to and rarely metastasizes outside of the immune privileged central nervous system. Despite this, PCNSL is one of the most aggressive forms of DLBCL. Given the immune privileged milieu in which PCNSL arises, we hypothesized that this milieu elicits a transcriptional profile that contributes to the enhanced aggressive nature of PCNSL compared to systemic-DLBCL. To investigate this hypothesis, this study assessed the gene expression differences between ABC-PCNSL and ABC-systemic-DLBCL, in order to identify novel players in the pathogenesis of ABC-PCNSL. Methods: A total of 35 HIV negative samples, with proven ABC-subtype COO as per the GEP Lymph2Cx assay, were employed; including 10 ABC systemic-DLBCL and 25 primary ABC PCNSL cases with no concurrent or prior history of systemic DLBCL. Samples were reviewed by a hematopathologist to confirm diagnoses and determine tumor content. Samples with <60% tumor content were macro-dissected before nucleic acid extraction, which was performed using the Qiagen AllPrep DNA/RNA FFPE Kit. Extracted DNA and RNA were quantified using the Qubit HS-kit and NanoDrop respectively. Digital gene expression technology was used to perform the PanCancer Pathways panel (NanoString, Seattle, WA). Differential gene expression analysis was performed using the NanoString specific statistical method NanoStringDiff. Identified gene sets were analyzed using the online Gene Set Enrichment Analysis (GSEA) Molecular Signatures Database (MSigDB). Results: Of the 739 cancer related genes targeted by the PanCancer panel, 256 were found to be significantly differentially expressed in the ABC-PCNSL cohort compared to the ABC-DLBCL cohort (p<0.05). Fifty six genes were upregulated and 200 were downregulated. With a 4.9 fold change, the most significantly overexpressed gene was FGF1 (p=4.7E-11). FGF1 encodes a primary ligand for the fibroblast growth factor receptors (FGFR) -1, -2, -3 and -4; of which, FGFR2 (p=1.0E-7) and FGFR3 (p=0.003) were also significantly overexpressed. Moreover, MSigDB identified the FGF signaling pathway as enriched in the upregulated gene set (5 genes, p=7.4E-9, FDR=6.6E-7). FGFRs are a family of receptors that activate known mitogenic signaling pathways including MAPK signaling, which MSigDB identified as the most enriched pathway in the upregulated gene set (14 genes, p=1.65E-19, FDR=2.2E-16). MSigDB analysis of the 200 down regulated genes revealed that 5 of the top 20 enriched signaling pathways were immune related and included Signaling by interleukins (26 genes, p=2.9E-38, FDR=3.2E-36), Immune cytokine signaling (31 genes, p=1.1 E-34, FDR=1.1E-32), chemokine signaling (28 genes, p=1.5E-34, FDR=1.4E-32), T-cell receptor signaling (24 genes, p=2.4E-34, FDR=1.9E-32) and Toll-like receptor signaling (23 genes, p=4.1E-33, FDR=3.0E-31). Conclusions: We show, for the first time, that ABC-PCNSL and ABC-systemic-DLBCL possess significantly different transcriptional profiles despite identical, molecularly determined, COO status. A principle difference between these DLBCL malignancies is their anatomical location related immune privilege status which is reflected as reduced immune related signaling in the CNS-DLBCL cohort and may have important mitogenic signaling implications. Indeed, the results suggest that the enhanced aggressive nature of PCNSL compared to systemic-DLBCL is mediated, at least in part, by enhanced FGF signaling; a pathway with known roles in cell survival and proliferation. Disclosures Rimsza: NanoString: Other: Inventor on the patent for the Lymph2Cx assay.

Abstract Objectives: Primary central nervous system lymphoma (PCNSL) is a rare aggressive B-cell lymphoma, particularly in HIV-negative individuals, that represents a clinical challenge due to its location and lack of comprehensive molecular and biologic description. Histopathologic features are that of diffuse large B-cell lymphoma with expression of pan-B-cell markers as well as cell of origin (COO) germinal center B cell (GCB) and post-germinal center B cell (non-GCB) markers. Previous studies using immunohistochemistry (IHC) suggest that the majority of PCNSL cases are non-GCB. However, gene expression profiling has revealed non-GCB to be comprised of two distinct subtypes, namely activated B-cell (ABC) and unclassified (UNC) subtypes that are indistinguishable by IHC. To date COO testing using the highly accurate Lymph2Cx gene expression profiling assay has not been reported in PCNSL. Methods: IRB approval was obtained and HIV negative patients diagnosed with PCNSL, who had given informed consent and for whom archived tumor tissue was available for testing were identified. COO testing was performed using the Lymph2Cx NanoString assay on RNA extracted from formalin-fixed, paraffin embed tissues using our established laboratory protocols. Clinical data including patient demographics, lines of treatment and survival outcomes were collected and correlated with each other and Lymph2Cx COO results. Results: Thirty-two HIV-negative patients diagnosed between January 2005 and June 2015 were included. Median age was 61 years (30-82) and 53% were male. Radiographic information was available for 18/32 patients. Eleven (61%) had a single brain lesion at diagnosis, while 7 (39%) had >1 brain lesion. Lines of systemic therapy were 1 (91%) and 2 (9%). All patients received methotrexate-based induction therapy (44% received methotrexate, rituximab and temozolomide, 16% received single-agent methotrexate, 31% received methotrexate and rituximab, and 9% received the modified Bonn regimen; methotrexate and cytarabine-based induction). A total of 10 patients (31%) received high-dose chemotherapy and autologous stem cell transplant (ASCT) for consolidation. Of the 10 patients that underwent consolidation therapy, 9 underwent ASCT after first line induction, and 1 underwent ASCT after second line therapy. None of the patients received whole-brain radiation therapy. At a median follow-up of 29 months (range of 2-107) median event-free survival (EFS) was 16.3 months (95% CI, 8.8-45.7), and median overall survival (OS) was 41.2 months (95% CI, 28.5-NE). COO testing using the Lymph2Cx assay revealed that 91% (29/32) were ABC, 9% (3/32) were GCB, and none were UNC. Histopathology reports described COO using the Hans algorithm in 11 of the 32 cases. Of the 3 determined to be GCB on Lymph2Cx, 1 was denoted GCB by the Hans algorithm and 2 were not stained to determine COO. Of the 29 determined to be ABC by Lymph2Cx, 9 were denoted non-GCB and 1 was denoted GCB by the Hans algorithm, and 19 were not stained to determine COO. Conclusions: This series of HIV-negative patients with PCNSL showed median survival consistent with previous studies. In this first series using the Lymph2Cx assay, we confirmed that over 90% of PCNSLs are of ABC subtype, which concurs with previous reports that PCNSL tumors are predominately non-GCB by the Hans algorithm. These findings provide biological rationale forthat pharmacologic interventions targeting B-cell receptor signaling to be explored in clinical trials in the majority of patients with PCNSL. Figure. Figure. Disclosures Rimsza: NanoString: Other: Inventor on the patent for the Lymph2Cx assay.

Abstract Introduction Myelofibrosis (MF), both primary myelofibrosis (PMF) and post essential thrombocytosis/polycythemia vera myelofibrosis (post ET/PV-MF), are chronic myeloproliferative neoplasms that are incurable with standard medical therapy. The only potential curative therapeutic modality remains allogeneic stem cell transplant (ASCT), but the optimum conditioning regimen has yet to be defined and may vary due to pre-ASCT factors such as age, donor source, and comorbidities. In the past, traditional myeloablative (MA) regimens have proven toxic. Reduced intensity conditioning (RIC) regimens have generally become the accepted standard of care for patients with PMF or Post PV/ET MF in need of ASCT, but with the potential for increase in relapse especially for high risk disease. The optimal conditioning regimen has yet to be defined. The regimen of Fludarabine, BCNU, and melphalan (FBM) is considered a reduced toxicity regimen that may afford the benefit of reduction in relapse without increase in toxicity and may “bridge the gap” between MA and RIC especially in older patients. Patients with MF have high inflammatory cytokine levels which may act as mediators of MF symptom burden and may further aggravate mediators of acute GVHD, which is one of the most frequent and severe complications of ASCT. Selection of conditioning regimen and GVHD prophylaxis are keys to MF transplant outcomes. We report here the results of 16 patients who received conditioning with FBM with rATG (FBM-A) with PMF and post PV/ET MF. Methods We conducted a retrospective review of all patients from October 2009 to November 2012 with PMF or post ET/PV-MF who underwent an ASCT with FBM-A. Patient demographic and transplant data were analyzed from a comprehensive database. The use of such data for reporting purpose was approved by the Mayo Clinic Arizona Institutional Review Board. Overall survival was estimated using Kaplan-Meier. Results There were 16 patients analyzed who had PMF or post PV/ET MF or overlap syndromes. The median follow-up of surviving patients is 20.4 months (range 8 months – 46 months). The median age was 60 (range 47-68 yrs) with 56% of patients being ≥ 60yrs. There were 8 males and 8 females. The JAK2 V617F mutation was present in 64% of patients. 86% were high risk according to the DIPSS system with 14% being intermediate-2 risk. None of the patients underwent splenectomy prior to transplant. The median HCT-CI score was 1.5 with 6 (38%) of the patients having an HCT-CMI ≥3. Donors were related in 10 patients (8 matched, 2 mismatched at 1 antigen) and unrelated in 6 (matched, n=3, 1-antigen mismatch, n=3). GVHD prophylaxis consisted of tacrolimus, MMF, and ATG 2.5 – 5.0 mg/kg. The cumulative incidence of acute GVHD grades III-IV was 15.3% at 6 months, and the cumulative incidence of NIH-defined moderate-to-severe chronic GVHD was 25% at 2 years. No patient has relapsed, and no patient has developed graft failure. There have been 4 deaths, 3 from GVHD, and 1 from infection. Among the 3 patients who died from GVHD, all were unrelated donor transplants, and 2 were mismatched unrelated transplants. The 2-year Kaplan-Meier estimate of overall survival (OS) is 72% (95% CI, 45 – 91%). The cumulative incidence of TRM was 12.6% (95% CI 3.9%-34%) at 1 year. Conclusion The reduced-toxicity regimen of FBM-A in PMF, Post ET/PV MF and overlap syndromes appear to provide the benefit of an ablative regimen with the tolerance of a RIC. The 2-year overall survival of 72% in our series is encouraging in an older population of predominantly high-risk patients. Treatment failure was related predominately to GVHD, which continues to be a significant obstacle to better long-term outcomes, especially in unrelated and mismatched patients. Reduced toxicity ASCT conditioning regimens in the setting of MF warrant further investigation. Disclosures: Reeder: Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.

Abstract Abstract 4479 Background: In vivo T-cell depletion with antithymocyte globulin (ATG) is known to decrease the incidence of acute and chronic graft vs. host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). However, the detailed patterns of GVHD (incidence, severity, timing, and quality) after ATG-based conditioning have not been examined in large patient cohorts, and it is unknown whether they differ from those seen in patients who do not receive ATG during conditioning therapy. Patients and Methods: We analyzed the incidence and characteristics of acute and chronic GVHD, requirements for immunosuppressive therapy (IST) and survival in a cohort of 174 patients who underwent a first HCT for hematologic malignancy with ATG as a part of their conditioning regimen. The median age was 54 years (range 19–76); all but 5 pts received PBSC, and median follow-up of survivors was 16.9 months (range 3–70 months). Donors were matched related in 18% (n=32), matched unrelated in 44% (n=77), and mismatched unrelated in 37% (n=65). Conditioning regimens were myeloablative in 33% (n=57) and reduced intensity in 67% (n=117). Additional GVHD prophylaxis included tacrolimus in all patients combined with either methotrexate (42%) or MMF (58%). Results: The cumulative incidence of grade II-IV and III-IV acute GVHD at 100 days was 34% and 7%, respectively, with the median time of onset at 43 days (range 11–98 days) after transplant. Eleven patients (6.3%) required additional immunosuppressive treatment due to steroid refractory GVHD. Late/persistent acute GVHD without any evidence of chronic occurred in 25% of patients. NIH chronic GVHD developed in 25 patients, with a cumulative incidence of 24.4% at 2 years. Forty four percent of these patients were classified as classic chronic, and 56% as overlap. The onset of chronic GVHD was quiescent in 20 (80%), progressive in 3 (12%), and de-novo in 2 (8%) patients. The global severity was mild in 9 (36%), moderate in 11 (44%) and severe in 5 (20%) cases. The median time of onset for chronic GVHD was 185 days (range 99–763). In a multivariate analysis of factors predictive for development of chronic GVHD, the only factor associated with development of chronic GVHD was prior grade II-IV acute GVHD (HR 2.5, p =.03). The most common diagnostic organ was mouth (n=16), followed by skin (n=8) and eye (n=1). The median number of sites involved during the course of chronic GVHD was 4 (range 1–7), and the median number of systemic immunosuppressive agents for treatment was 2 (range 0–4). Among the 25 chronic GVHD patients, 5 have discontinued immunosuppression at a median time of 13.1 months (range 6–26) since the diagnosis of chronic GVHD. The cumulative incidence of discontinuation of IST was 23% at one year and 50% at two years. Three deaths in the overall cohort were attributed to complications related to acute (n=2) or chronic GVHD (n=1). At 2 years, the overall survival among all 174 pts was 62.4%, cumulative incidence of relapse was 23.1%, and non-relapse mortality was 22.7%. Conclusion: These data from a large, uniformly treated and graded, predominantly peripheral blood stem cell transplant recipient population, confirm that ATG decreases both the incidence and severity of acute and chronic GVHD. In particular, the rate of moderate to severe chronic GVHD is extremely low, resulting in minimal need for tertiary treatment and decreased duration of immunosupression. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: As our healthcare system faces increasing complexity, it is important for all healthcare providers to practice at the full scope of their training. However, there are limited current options for subspecialty training in hematology for advanced practice providers (APPs), a group of health care providers including both nurse practitioners and physician assistants. We are unaware of any existing postgraduate fellowship for APPs focused on education in both malignant and nonmalignant hematologic disorders. We hope that by creation of the first such fellowship, we can better prepare APP graduates with the subspecialty-specific knowledge required to become highly skilled and competent clinicians in hematology. Methods: Using surveyhero.com, we conducted a web-based needs assessment survey which was distributed to 68 APPs currently working in the hematology and blood & marrow transplant (BMT) teams at three Mayo Clinic sites (Rochester, Scottsdale, and Jacksonville). This survey included questions regarding hematology-specific education the respondents had received in their APP schools, as a way to assess participant's perceptions about the readiness to practice in hematology after completion of APP education, and to identify the learning/training needs that are most important for APPs to practice in hematology. Results: Of 68 APPs, 49 (72%; 34 NPs,15 PAs) completed the survey. 57% of respondents were new APP graduates when hired and 35% had no prior work experience in hematology/BMT. All APPs held a Master's or higher degree (doctorate 31%). Thirty-nine (80%) reported <5% of their APP school curriculum was hematology-focused. The majority (92%) felt that the level of subspecialty training they received in APP schools did not adequately prepare them with the full confidence to practice in hematology. Forty-four (90%) APPs believed subspecialty training could help them to become more competent providers for patients with hematologic disorders. Forty-seven (96%) APPs agreed that being confident and knowledgeable in their practice positively impacted their job satisfaction, and most APPs (84%) felt structured hematology training would attract them to stay within the specialty. The educational subjects that APPs identified as most important included variety of malignant and benign hematologic disorders as well as hematopathology, bone marrow transplant, palliative care, transfusion medicine, infectious disease and pharmacology related to hematology practice. The top three effective learning strategies reported by the APP respondents were active learning from direct patient care, cased based teaching, and educational experience during hospital rounds. Conclusions and Discussions: This needs-based assessment educational project revealed to us the significant gaps in subspecialty training of APP education in hematology and confirmed the necessity of this fellowship. The findings of the survey helped us to optimize the fellowship curriculum in order to meet the learning needs of future APP trainees. Development of the subspecialty fellowship program is a step forward in the future training of APPs. We believe our fellowship has the potential to serve as the postgraduate training model for other institutions nationwide. Disclosures Lacy: Celgene: Research Funding.

Abstract Background: New targeted therapies continue to show improved efficacy in various stages of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), sparing patients from chemoimmunotherapy. However, cure remains elusive. Here, we present a front-line alternative based on a combination of high-dose methylprednisolone (HDMP) and ofatumumab, followed by consolidative therapy with lenalidomide plus ofatumumab. Methods: This is a phase II, single-center study in patients with treatment-naive (TN) CLL/SLL. During the first treatment phase (cycles 1-3) patients received HDMP 1000 mg/m2 IV and ofatumumab 2000 mg (300 mg given week 1 then 2000 mg for a total of 12 doses) IV infusions weekly x 4 doses in cycle 1 of a 28 day cycle, then every 2 weeks for cycles 2 and 3. During the second treatment phase (cycles 4-12), patients received renally adjusted lenalidomide 5-10 mg daily and ofatumumab 2000mg IV once every 8 weeks. Growth factor support was permitted at the discretion of treating physician. Prophylactic medications included allopurinol for tumor lysis syndrome (TLS) 3 days before C1D1 through C1; and trimethoprim/sulfamethoxazole and fluconazole through cycle 4, and acyclovir through C12. Patients received aspirin 81 mg/day as thrombosis prophylaxis while on lenalidomide. Patients were assessed for response by iwCLL 2008 criteria (including imaging assessment) after completion of cycles 3 and 12. The study allowed continuation of lenalidomide if patients achieved complete (CR), partial (PR) response or stable disease (SD). Primary endpoints were efficacy, adverse events (AEs) profile, and time-to-treatment failure (TTF). Results: Between January 2012 and September 2015, the study enrolled a total of 45 patients. Median follow-up was 50.4 (5.6-72.8) months. The median age was 62.6 (48.2-86.1) years. Chromosomal analysis by FISH demonstrated Del17p in 8 (17.8%), Del11q (+/- others, except Del17p) in 10 (22.2%), Trisomy 12 (+/- others, except Del17p and Del11q) in 8 (17.8%), Del13q in 10 (22.2%), no mutations in 9 (20%) patients. The IGHV status was unmutated in 34 (75.6%) cases. Indications to start treatment were: symptomatic lymphadenopathy, symptomatic splenomegaly, anemia, and thrombocytopenia in 5 (11.1%), 10 (22.2%), 12 (26.7%), and 18 (40%), respectively. The median duration of treatment was 35.6 (2.7-66.9) months. Reasons for treatment discontinuation were: progressive disease (PD) in 9 (20%), AEs in 15 (33.3%), transplantation in 3 (6.7%), consent withdrawal in 1 (2.2%), and secondary malignancies in 2 (4.4%) cases. The overall response rates (PR+CR) at 3, 12, 24, 36, and 48 months were 75.6%, 77.8%, 66.7%, 44.4%, and 37.8%, respectively. The CR rates at 3, 12, 24, 36, and 48 months were 2.2%, 11.1%, 20%, 17.8%, and 13.3% respectively. Fifteen patients remain in PR/CR and on treatment at the time of this analysis. The intention-to-treat median TTF was 45.2 (2.9-69.7) months, and was not different among high risk groups such as Del17p, Del11q and/or unmutated IgHV. In patients who discontinued for reasons other than PD the median duration of response without treatment was 30.7 (9.8-69.7) months. Three (6.7%) patients underwent allogeneic hematopoietic cell transplantation after a median of 3 (3 - 4) treatment cycles. Treatment was well tolerated with grade 3/4 infusion reaction in 1 (2.2%) patient. Grade 3/4 treatment-related hematological AEs were neutropenia, thrombocytopenia, and anemia in 33 (73.3%), 5 (11.1%), and 1 (2.2%), respectively. Grade 3/4 infections occurred in 6 (13.3%) patients. No grade 3/4 tumor flares were observed, and there were no cases of TLS or thrombosis. Conclusion: The combination of ofatumumab, HDMP and lenalidomide is effective and well tolerated in treatment-naive CLL/SLL, even when poor prognostic features are present. Disclosures Komrokji: Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Locke:Novartis Pharmaceuticals: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite Pharma: Other: Scientific Advisor. Kharfan-Dabaja:Seattle Genetics: Speakers Bureau; Incyte Corp: Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau. Sokol:Spectrum Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy.

Abstract Background:The role of radiation therapy (XRT) for advanced stage Hodgkin lymphoma (HL) is controversial. In the HD15 trial, the German Hodgkin Study Group (GHSG) administered XRT for PET-positive residual disease ≥2.5 cm at least 2 weeks after completion of chemotherapy and showed 91.5 % in-field control rate with a median follow-up of 102 months (Engert, A; personal communication). However, there is no comparison arm where patients with PET-positive residual disease ≥2.5 cm did not receive XRT. SWOG S0816 was a US intergroup trial utilizing ABVD-based therapy with response adaptation based on interim PET imaging; XRT was not allowed per protocol, and counted as an event. In this analysis, we identified patients in S0816 who would have met HD15 criteria for XRT, but did not receive XRT per design. We then modeled the potential impact of XRT on disease control. Patients and Methods:Of 336 eligible and evaluable HIV-negative patients enrolled in S0816, 49 had an end-of-treatment PET (termed "PET3," to be done 6-8 weeks after completion of chemotherapy) that was positive (i.e. Deauville 4-5) upon central review. We simulated the progression free survival (PFS) if XRT had been delivered per HD15 criteria (PET positive disease and ≥2.5 cm), evaluating by assumptions of 50, 80 and 90% control of the disease within the XRT fields. Receiver operating characteristics (ROC) analyses were performed with additional size cut-off points of 2.0 and 1.5 cm. Results:The median follow-up for the 49 PET3 positive patients was 71 months (range 9.7-92.6). For these 49 patients, the observed landmark PFS at 2 years after the date of PET3 was 30.6%. Twenty-four (49%), 33(67%), and 40 (82%) of the 49 patients had at least one site of disease that met the HD15 criteria for XRT with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm size cut-offs respectively. Sixteen, 19, and 25 patients had disease progression respectively from each group at median of 1.4-1.5 months. Twelve, 12, and 15 patients had relapses limited to the sites that would have been radiated following HD15 criteria with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm respectively. Estimated landmark PFS at 2 years for the 49 PET3 positive patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are summarized in columns A, B, and C of the table respectively. For the entire group of 336 patients, the observed PFS at 2 years was 79%. Estimated 2-year PFS for the entire group of 336 patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are in columns D, E, and F of the table respectively. Conclusion: Among the PET3 positive patients, consolidation XRT per HD15 criteria with cut-off points of 2.5, 2.0, and 1.5 cm could have raised the 2-year PFS by 12-28 % assuming 50-90% local control within radiated sites. However, the improvement in PFS is more moderate at 1.6-3.9 % if we consider the entire cohort of 336 patients. Although there may be some gain in PFS as the cut-off point is lowered by our ROC analysis, one needs to consider the trade-off against potentially increasing normal tissue toxicity as more sites are irradiated. Table. Table. Disclosures Brem: Pharamcyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees. Bartlett:Merck & Co: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Immune Design: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImaginAB: Research Funding; Janssen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Millennium: Research Funding; Genentech: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Janssen: Consultancy; Tesaro: Research Funding; Bayer: Consultancy; Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Leonard:Novartis: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy; BMS: Consultancy; Biotest: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy; Juno: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Bayer: Consultancy. Kahl:Seattle Genetics: Consultancy; Genentech: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy; Juno: Consultancy; Celgene: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

Abstract Introduction - Allogenic hematopoietic cell transplantation (HCT) remains potential curative treatment for hematologic malignancies. Anti-thymocyte globulin (ATG) is an immunoglobulin directed to human T lymphocytes, and may decrease the risk of chronic graft versus host disease (cGVHD). Use of ATG has been associated with higher incidence of disease relapse and infection. While the optimal dosing of ATG has not been well established, higher doses (≥ 7.5 mg/kg) have a stronger association with infection and disease relapse. Our institution utilizes low dose rabbit ATG at 2.5 mg/kg for in-vivo T-cell depletion. In this retrospective study we evaluated outcomes in patients receiving low dose ATG to those not undergoing in-vivo T-cell depletion with the hypothesis that low dose ATG protects against cGVHD without impacting infectious complications or relapse. Patients and Methods - We evaluated all patients with 8/8 HLA Matched unrelated Donors (MUD) undergoing HCT between 2007 and 2016. Patients were divided in to two cohorts, those receiving low dose ATG to those that did not. Both cohorts received standard GVHD prophylaxis with calcineurin inhibition plus methotrexate or mycophenolate. The primary outcome was overall survival (OS). Secondary outcomes included relapse free survival (RFS), EBV reactivation, CMV reactivation, CMV disease, invasive fungal infection, incidence of acute GVHD (aGVHD) grades III-IV, and moderate to severe cGVHD. A subset analysis was performed to assess relapse free survival (RFS) in patients with myeloid malignancies. Descriptive statistics were utilized for baseline characteristics; and a series of univariate and multivariant Cox proportional hazard regression models were conducted for outcomes of interest. A Kaplan-Meier (K-M) survival curve was used to depict probability of survival by ATG cohort. Results - We identified 209 patients, with 129 (62%) in ATG group and 80 (38%) in non-ATG group. At baseline, there were no differences in the age at transplant, sex, ABO incompatibility, or performance status. The ATG cohort had fewer low disease risk index (DRI) patients and more patients with intermediate or high DRI (2.4%, 64.6%, 28.3% vs 18.4%, 51.3%, 23.7% respectively), and Fisher's Exact test showed that this difference between ATG groups was statistically significant, p = <0.001. The ATG cohort also had significantly different rates of myeloablative (MA) conditioning regimens from the non-ATG cohort with fewer receiving MA (31% vs 53% p < 0.01). No statistically significant differences in OS were observed between the two ATG cohorts at up to 5 years post-transplant (p=0.35; Fig. 1). The primary predictor of OS was DRI very high vs low [HR 6.0 (2-18) p < 0.01]. The ATG exposed cohort had significantly lower risk of cGVHD [HR 0.17 (0.08-0.37) p = <0.001]. There was no difference in risk of death from relapse, incidence of EBV or CMV reactivation, CMV disease, invasive fungal infection, or grade III-IV acute GVHD. Low dose ATG was not associated with inferior RFS, including in subset analysis of patients with myeloid malignancies [HR 0.85 (0.5-1.4) p = 0.549]. Conclusions - Our study shows no significant difference in survival or death from relapse for patients who receive ATG. Importantly, patients receiving ATG had a lower rate of cGVHD with no increased rates of infectious complications. Low dose ATG did not appear to increase the risk of relapse, even when considering only myeloid malignancies. These findings suggest that low dose ATG can improve cGVHD with no impact on survival, relapse, or infectious complications. Additional prospective trials using low dose ATG compared to no ATG are warranted. Disclosures Palmer: Novartis: Research Funding.

Abstract Background The prognosis for AML or MDS patients (pts) with monosomal karyotype (MK) is dismal. Although a benefit for allogeneic hematopoietic cell transplantation (allo-HCT) compared to chemotherapy or autologous HCT has been demonstrated in young (≤ 60) pts (Cornelissen, 2012), the curative potential of allo-HCT in older (≥ 60) pts with monosomal karyotype AML/MDS is not known. Patients and methods In this retrospective review, we analyzed outcomes for 69 AML (n = 49) or MDS (n = 20) pts ≥ 60 who underwent allo-HCT at Mayo Clinic Arizona between 2005 and 2013, based on cytogenetic grouping as follows: cytogenetically normal (CN, n = 23), cytogenetically abnormal but not MK (CA, n = 32), and MK (n = 14). Monosomal karyotype was defined (Breems, 2008) as a karyotype with at least two autosomal monosomies or a single autosomal monosomy in combination with at least one structural abnormality. Univariate and multivariate statistical analyses were performed to evaluate the impact of these 3 cytogenetic groupings on outcome (primary endpoint progression-free survival). The median age for all pts was 66 (60-76), and median follow-up for surviving pts was 22 months (range 70 days – 7.1 years). Thirty-seven pts had high-risk disease (MDS > 5% blasts or AML not in CR), while 32 were considered standard risk (MDS <5% blasts or AML in CR). The majority of pts had good performance status (KPS ≥ 90% in 66), but 34 pts (49%) had an HCT-CI score of ≥ 3. Conditioning was myeloablative (Bu-Cy) in 4, reduced toxicity FBM (Fludarabine, BCNU, Melphalan) in 36, and RIC/NMA in 29. Donors were matched related in 18, matched unrelated in 36, and mismatched unrelated in 15. GVHD prophylaxis included tacrolimus in all pts combined with mycophenolate mofetil (37) or methotrexate (32); 49 pts received in-vivo T-cell depletion with rabbit anti-thymocyte globulin (rATG, Thymoglobulin, Genzyme, Cambridge, MA). Results The Kaplan-Meier estimate of progression-free survival (PFS) at 2 yrs was 59% (CN), 39% (CA), and 1.5% (MK); P = 0.004 (Fig. 1). The cumulative incidence of relapse at 2 yrs (with death without relapse as a competing risk) was 34% (CN), 25% (CA), and 94% (MK); P= 0.009). In a Cox proportional hazards analysis adjusted for age (≤ 66 vs. > 66), risk status (standard vs. high), conditioning (myeloablative [Bu-Cy + FBM] vs. RIC/NMA), use of ATG (yes/no), donor type (unrelated vs. related), and HCT-CI (0-2 vs. ≥ 3), the only factor predictive for inferior PFS was cytogenetic status (MK vs. CN, HR 4.64 [95% CI, 1.7 – 13]; P = 0.003); (MK vs. CA, HR 2.4 [95% CI 0.97 – 5.9]; P = .057). Conclusions Standard allo-HCT in AML or MDS pts ≥ 60 with a monosomal karyotype appears to have limited curative potential. Although larger studies will be required to confirm our results, novel transplant approaches or post-transplant strategies to prevent relapse should be a focus of future studies in this incurable pt population. Disclosures: Reeder: Novartis: Research Funding; Celgene: Research Funding; Millennium: Research Funding.

Abstract Abstract 277 Background: Current information on the natural history of polycythemia vera (PV) is mostly derived from early studies based on the PV Study Group diagnostic criteria. The World Health Organization (WHO) diagnostic approach to PV is currently the gold standard. The main objective of the current study was to describe survival, disease complication rates and risk factors in WHO-defined PV. Methods: Under the auspices of an International Working Group, seven international centers of excellence for myeloproliferative neoplasms submitted a total of 1,430 patients, locally diagnosed with “WHO-defined PV”. The two principle investigators (AT and TB) reviewed all the cases and selected 1,263 patients who were age 18 years or older, diagnosed after 1970, and whose submitted data included diagnostically essential information. Results I: Presenting Features: Median age was 60 years (range, 18–95; 51% females). The number of patients diagnosed between 1970–1990, 1991–2000, and 2001–2011 were 136 (11%), 337 (27%) and 790 (62%), respectively. Arterial/venous thrombosis history before or at diagnosis was documented in 142/73 and 80/42 patients, respectively. Other features at diagnosis included pruritus (37%), microvascular disturbances (29%), palpable splenomegaly (37%), abnormal karyotype (13%), and leukoerythroblastosis (6%). History of hypertension (45%), hyperlipidemia (17%), diabetes (9%), and tobacco use (15%) was also obtained. Results II: Clinical Course: To date, 228 (18%) deaths, 42 (3%) leukemic progressions, and 101 (8%) fibrotic transformations have been recorded. Post-diagnosis arterial or venous thrombosis occurred in 139 (11%) and 85 (7%) patients, respectively. Cytoreductive therapy had not been used in 342 (27%) patients whereas 154 (12%) patients were exposed to two or more cytoreductive drugs. Results III: Risk Factors: Multivariable analysis identified advanced age, leukocytosis, venous thrombosis history and abnormal karyotype as significant (p<0.01) risk factors for overall survival (OS). Receiver operating characteristic (ROC) plots delineated ages 69 (AUC 0.83) and 59 (AUC 0.61) years and leukocyte count 13 × 109/L (AUC=0.61) as the best discriminant levels in this regard; HR (95% CI) were 11.4 (7.7–16.9) for age ≥70 years, 3.8 (2.6–5.7) for age 60–69 years, and 2.0 (1.5–2.6) for leukocyte count ≥15 × 109/L. Results IV: Risk Stratification: HR-based risk scores were assigned to age ≥70 years (3 points), age 60–69 years (2 points) and leukocyte count ≥15 × 109/L (one point), in order to create four risk groups: low (zero points; n=492; median survival 322 months), intermediate-1 (one or 2 points; n=353; median survival 208 months; HR 3.8, 95% CI 2.5–5.8), intermediate-2 (3 points; n=286; median survival 132 months; HR 10.7, 95% CI 6.9–16.5), and high (4 points; n=56; median survival 90 months; HR 22.7, 95% CI 13.9–37.1) (Figure 1). Similar results were obtained when analysis was restricted to the 1,011 JAK2 mutation-positive patients (Figure 2). The particular risk model was equally robust in predicting leukemia-free survival (p=0.001). Conclusions: Age and leukocyte count matter the most in predicting survival in PV. The current study suggests additional prognostic value from karyotype and venous thrombosis history. Disclosures: Vannucchi: Novartis: Honoraria. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Speakers Bureau; AOP-Orphan: Speakers Bureau.