Journal articles on the topic 'P 25.5 UL 2008 H211'

Abstract Abstract 2638 Poster Board II-614 Background: The importance of cytogenetics in prognosis of AML is now widely recognized and accepted in clinical practice. A recent study found that autosomal chromosomal monosomy predicted for an adverse outcome. The goal of this study is to characterize patients with monosomal karyotype by mutation status and clinical features. Methods: One-hundred forty consecutive AML patients diagnosed at Stanford University Hospital between 2005 and 2008 with adequate material for mutation analysis were studied. Cases were classified using the 2008 WHO criteria. Diagnostic cytogenetic findings were reviewed and patients were stratified into risk groups using Southwest Oncology Group criteria. An abnormality was considered clonal when at least two metaphases had the same aberration, except for clonal monosomy, which required at least three metaphases. The karyotype analysis was based on 20 or more metaphases. All samples were tested for NPM, FLT3 (ITD and D835) and CEBPA mutations. Clinical parameters including hemogram data at time of diagnosis were reviewed. Clinical follow-up including overall survival (OS), progression free survival (PFS) and complete remission (CR) rates were retrospectively determined. Kaplan-Meier methods and univariate Cox proportional hazards regression analysis were used to compare the clinical data. Results: The cases included 77 males and 63 females with a median age of 58 (range 17-83). Cytogenetic risk-group stratification resulted in 14 patients with favorable, 88 with intermediate and 28 with unfavorable risk status. Loss of one or more autosomal chromosomes was present in 18 /130 patients (13.8%) with available cytogenetic studies. A single autosomal monosomy was found in 5 patients while 13 patients had two or more autosomal monosomies. The most common chromosomes lost in these 18 patients included 7 (55% of 18 cases), 5 (50%), 17 (33%), 21 (22%), 20 (22%), 22 (17%) and 18 (11%). Using the 2008 WHO criteria, there were 66 AML with myelodysplasia-related changes (AML-MRC), 55 AML not otherwise specified (AML-NOS), 14 AML with either t(8;21), inv(16) or t(15;17) and 5 therapy related AMLs. Overall, 35 patients (25% of all patients) had a NPM1 mutation (19 of which were FLT3 mutated), 33 had FLT3-ITD mutation (24%), 11 had FLT3-D835 (8%) and 11 had a CEBPA mutation (8%) (4 of which were FLT3 mutated). Patients with monosomal karyotype were significantly older (83 vs. 59 years, p=0.0125) and presented with lower WBC (34 vs. 66 K/uL, p=0.0006), lower platelets (41 vs. 64 K/uL, p=0.0111), and lower blasts (38% vs. 65%, p=0.0030) as compared to the rest of AML patients. In addition, patients with monosomal karyotype were more frequently diagnosed with AML-MRC (16/18 vs. 48/107, p=0.0034) and exhibited a decreased frequency of NPM1 mutation (0/18 vs. 28/107, p=0.0138) and FLT3-ITD mutation (0/18 vs. 29/107, p=0.0117). Clinical outcome data showed that patients with monosomal karyotype had a significantly worse OS, PFS and CR compared to the rest of AML patients (OS p=0.001, PFS p=0.002 and CR p=0.0262). Dividing patients by number of monosomies showed that patients with 2 or more monosomies had a significantly worse OS (p=0.0001) and PFS (p=0.0045) than patients without any monosomies. However, no difference in OS or PFS was seen when comparing patients with 1 monosomy to those with 2 or more monosomies. Within the AML-MRC group, monosomal karyotype correlated with lower WBC (17 vs. 37 K/uL, p=0.0005), lower platelets (21 vs. 35 K/uL, p=0.0095), lower blasts (19% vs. 36%, p=0.0015) and shorter OS (p=0.0322) and PFS (p=0.0084). Conclusion: AML patients with monosomal karyotype exhibit a significantly worse OS, PFS and lower CR as compared to other AML patients. Most of patients fall within the newly defined AML-MRC group and are characterized by significant absence of NPM1 and FLT3-ITD mutations. Disclosures: No relevant conflicts of interest to declare.

Spred1, a member of the Sprouty family of proteins and a negative regulator of RAS-MAPK signaling, is highly expressed in normal hematopoietic stem cells (HSCs) where it negatively regulates self-renewal activity. Lack of Spred1 function has been associated with aberrant hematopoiesis (Tadokoro, 2018). Spred1 knocked-out (KO) mice fed with high-fat diet develop a myeloproliferative phenotype (Tadokoro, 2018), and lower SPRED1 expression in acute myeloid leukemia associates with a poor outcome (Li, 2015; Olsson, 2014; Pasmant, 2015), suggesting a potential role of this gene as a tumor suppressor in myeloid malignancies. In CML, however, the role of Spred1 has not been fully dissected. Thus, we generated Spred1 KO CML (i.e., Spred1-/-SCLtTA/BCR-ABL) mice by crossing Spred1 KO (a gift from Dr. Yoshimura, Japan) with inducible SCLtTA/BCR-ABL CML mice. Spred1 KO mice showed increased cell cycling of BM long-term HSCs (LTHSCs; Lin-Sca-1+c-kit+Flt3-CD150+CD48-; G0: 62% vs 76%), and increased white blood cell (WBC) counts [14 vs 5.9 k/ul at 12 weeks (w) old, n=15 per group, p<0.0001], as compared to wt mice. Upon B/A induction by tetracycline withdrawal, Spred1-/-SCLtTA/BCR-ABL mice had higher WBC (102.5 vs 12 k/ul at 4 w, n=15 per group, p<0.0001), more pronounced splenomegaly (spleen weight: 0.28g vs 0.19g, n=4 per group, p=0.06) and a significantly shorter survival (median: 39 vs 83 days, n=23 per group, p<0.0001) than Spred1 wt CML mice. In Spred1-/-SCLtTA/BCR-ABL mice, we observed a more rapid expansion of circulating mature myeloid cells (CD11b+Gr-1+ cells: 63% vs 25%, n=8 per group, p<0.01) and a deeper decrease of BM LTHSCs (1,385 vs 2,164 per femur, n=5 per group, p<0.01) and increase of spleen LTHSCs (27330 vs 18546, n=5 per group, p<0.01) at 4 w after B/A induction compared with Spred1 wt CML mice. Further, we found a higher fraction of Spred-/-SCLtTA/BCR-ABL mice (33% vs 10%) developed lymph node enlargement, with infiltration with pro-B lymphoblastic cells (B220+CD43+CD19+IgM−) compared with Spred1 wt CML mice. Altogether these features suggested that Spred1 insufficiency accelerates CML development and evolution to more aggressive phases of the disease. Since upregulation of Spred1 reportedly disrupts vascular integrity (Fish, 2008; Wang 2008), a finding that we have also confirmed in the BM niche, in order to evaluate separately the leukemogenic effect of Spred1 expression on different compartments of the BM niche, we generated the following conditional Spred1 KO strains: Spred1flox(f)/fMxl-cre+ (Spred1 KO in HSCs, hereafter called Spred1HSCΔ/Δ), Spred1f/fTie2-cre+ [Spred1 KO in endothelial cells (ECs), hereafter called Spred1ECΔ/Δ], Spred1HSCΔ/ΔSCLtTA/BCR-ABL and Spred1ECΔ/ΔSCLtTA/BCR-ABL by crossing SCLtTA/BCR-ABL with the above Spred1 KO mice. LTHSCs from Spred1HSCΔ/ΔSCLtTA/BCR-ABL mice showed an increase in cell cycling, RAS/MAPK/ERK activity and Bcl-2 levels, and higher engraftment in recipient mice (blood: 9.7% vs 26.5% at 6w, 14.8% vs 42% at 8w, 14.7% vs 48% at 12w, n=10 per group, p<0.01), compared to Spred1 wt CML LTHSCs. Spred1HSCΔ/ΔSCLtTA/BCR-ABL mice (n=15) showed enhanced leukemia progression (WBC: 19 vs 12 k/ul, p=0.004; CD11b+Gr-1+ in blood: 36% vs 25%, p=0.04 at 4 w after B/A induction) and a significantly shorter survival (median: 49.5 vs 83 days, p=0.01) compared to Spred1 wt CML mice (n=20). However, the disease in these mice appeared to be overall less aggressive than global Spred1 KO CML (i.e., Spred1-/-SCLtTA/BCR-ABL) mice (WBC: 19 vs 102 k/ul; CD11b+Gr-1+ in blood: 36 vs 63%; Survival: 49.5 vs 39 days), suggesting that Spred1 depletion in other non-hematopoietic cell compartments may also be important for leukemogenesis. In fact, Spred1ECΔ/ΔSCLtTA/BCR-ABL mice (n=8) showed enhanced leukemia progression (WBC: 26 vs 9.8 k/ul at 4 w after B/A induction, p=0.02), a trend for a reduced survival (median: 56 vs 83 days, p=0.09), and increased arteriolar vascularization, compared to Spred1 wt CML mice (n=20). Mechanistic studies on how endothelial Spred1 insufficiency co-participates in leukemogenesis are ongoing. Altogether our results support a role of Spred1 insufficiency in distinct BM niche compartments to produce a more aggressive CML phenotype, likely through different, but complementary mechanisms. Spred1 may therefore emerge as a novel target for advanced CML. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 1720 Background: The myelodysplastic syndromes are commonly divided into lower- and higher-risk subtypes depending on blast percentage and International Prognostic Scoring System (IPSS) score (0–1.0, low or Int-1, median overall survival (OS) 3.5–5.7 years). Because the IPSS is limited in its ability to identify poor prognosis lower-risk patients (pts), a prognostic scoring system specifically for lower-risk MDS pts (LR-PSS) was developed (Garcia-Manero Leukemia 2008) at MD Anderson (MDA), based on unfavorable (non-del(5q), non–diploid) cytogenetics, hemoglobin (hgb) <10g/dl, platelet count (plt) <50 k/uL or 50–200k/uL, bone marrow blast %≥4, and age ≥60 years. The IPSS-R (Greenberg Leuk Res 2011) improves upon the IPSS using novel cytogenetics classifications (Schanz EHA 2010) and a neutrophil cut-off of 800 k/uL. We validated the LR-PSS and the IPSS-R in a separate cohort of lower-risk MDS patients seen at Cleveland Clinic (CC) or at MDA not included in LR-PSS development. Methods: Of 1293 MDS patients identified at CC or MDA from 1991–2010, 664 had lower-risk disease and adequate data for analyses. OS was calculated from first date seen at either institution. The Kaplan–Meier method was used to estimate median OS. Univariable analyses were performed using the log-rank test; multivariable analyses used a Cox proportional hazards model stratified by treatment center. Harrell's c index and the Akaike information criteria (AIC) were used to assess the discriminatory power of the models and relative goodness of fit, respectively. Results: Comparing CC to MDA, baseline values were similar except median age: 70 vs. 67 years (p=.02); time since diagnosis: 2.7 vs. 1.1 months (p<.0001); hgb <10: 51% vs. 43% (p=.05); plt <50k/uL: 30 vs. 24% (p=.06); ANC <1.5 k/uL: 27% vs. 36% (p=.01); blasts <4%: 75% vs. 65% (p=.003); WHO classification RA/RARS/RCMD/CMML: 11/15/26/12% vs. 16/9/45/0% (p<.0001). Cytogenetics were diploid: 61% vs. 66%; del(5q): 9% vs. 2%; del(20q): 3% vs. 5%; -Y: 4% vs. 2%, respectively (p=.5). Median OS was 36.8 months (95% C.I. 33–45) and median follow-up of patients still alive was 13.9 months (range 0.01–155). LR-PSS and IPSS-R classifications for CC and MDA Pts and OS are in Table 1 and Figure 1. In univariable analyses, The IPSS, LR-PSS, and IPSS-R were all predictive of OS (p=.002, <.0001, and <.0001, respectively). Multivariable analyses confirmed the overall predictive abilities of the prognostic tools and of Hgb, plt, age, and IPSS/IPSS-R cytogenetics (all p≤.03). Compared to the IPSS-R, the LR-PSS had the higher (better) Harrell's c value (.64 vs.63) and lower (better) AIC (2518 vs. 2525). The LR-PSS upstaged 156 pts (25%) from IPSS low or Int-1 to LR-PSS Category 3, and downstaged 47 pts (12%) from Int-1 to Category 1. The IPSS-R upstaged 164 pts (27%) from IPSS low or Int-1 to IPSS-R Categories ≥Intermediate, and downstaged 5 pts (1%) from Int-1 to Very Good. Conclusions: The LR-PSS and IPSS-R are valid tools for distinguishing among pts previously thought to have lower-risk disease by the IPSS, and identifying those who have better and worse survival. This latter group of pts may benefit from earlier interventions with disease-modifying therapies, and should be considered in trials targeting higher-risk MDS pts. The LR-PSS appears to provide slightly better prognostic information. Disclosures: Sekeres: Celgene: Consultancy, Honoraria, Speakers Bureau. Maciejewski:Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Severe acute pancreatitis (SAP) frequently progresses to pancreatitis-associated multiorgan failure (MOF) with high mortality. Decreased plasma ADAMTS13 activity (ADAMTS13:AC) results in the accumulation of unusually large von Willebrand factor multimers (UL-VWFM) and the formation of platelet thrombi, ultimately leading to MOF. We demonstrated that the imbalance between decreased ADAMTS13:AC and increased UL-VWFM could contribute to SAP pathogenesis through enhanced thrombogenesis, and serve as an early prognostic indicator for SAP patients (Scand J Gastroenterol, 2008, 26:1). Endotoxin has been considered to be the principle activator of the systemic inflammatory response syndrome, which predisposes patients for MOF and/or pancreatic necrosis, ultimately leading to SAP. We investigated the relationship of endotoxin to ADAMTS13:AC and its related parameters, and tried to explore their potential role on the development of MOF in patients with SAP. Methods: We sequentially determined plasma endotoxin concentration, ADAMTS13:AC and its related parameters in 13 SAP patients (APACHE-II score mean 6.6 ± 2.7), who were admitted into intensive care unit of our hospital between 2004 and 2006. Eleven patients were survivors and two were non-survivors whose APACHE II scores were 10 and 12 died of MOF, respectively. The degree of MOF was evaluated according to the SOFA score. Endotoxin concentration was determined by a chromogenic substrate assay (Toxicolor LS –M Set, Seikagaku Kogyo Co.) with kinetic analysis after pretreatment with detergent, Triton X-100, and heating at 70 °C for 10 min. Plasma ADAMTS13:AC was determined by a sensitive chromogenic ELISA (ADAMTS13-act-ELISA: Kainos Inc.). Plasma UL-VWFM was analyzed by a vertical SDS-1.0% agarose gel electrophoresis. Plasma VWF antigen (VWF:AG), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor -α (TNF-α) were measured by ELISA. Results: In normal healthy controls (n=20), plasma endotoxin concentration was 7.9±1.7 pg/ml (mean ± SD). The concentration in the SAP patients significantly increased at day 1 (means 65 pg/ml, p&lt;0.001) and at day 2 (88 pg/ml, p&lt;0.001) as compared to healthy controls. The values, thereafter, gradually decreased in 8 survivors (55 pg/ml at day 5, 53 pg/ml at day 7, 27 pg/ml at day 14), while in remaining 3 survivors needing necrosectomy, the concentration further increased (98 pg/ml at day 5, 178 pg/ml at day 7), and decreased to 20 pg/ml at day 14 at the recovery phase. In two non-survivors, the endotoxin levels increased from 37 pg/ml at day 1 to 462 pg/ml at day 2 in one needing necrosectomy, and showed 51 pg/ml at day 1 in another at the age of 91. Within 1 or 2 days after admission, the ADAMTS13:AC was lower in SAP patients (mean 29%, p&lt;0.001) than in healthy controls (99%), and gradually recovered in the 11 survivors but further decreased in the 2 non-survivors. On admission, VWF:Ag was higher (402%, p&lt;0.001) in SAP patients than controls (100%). VWF:Ag gradually decreased in the survivors, except in the 3 survivors needing a necrosectomy, but remained high in the non-survivors. UL-VWFM positive patients showed lower ADAMTS13:AC (25% vs. 42%, p&lt;0.05) and higher VWF:Ag ( 481% vs. 332%, p&lt;0.05), resulting in higher ratio of VWF:Ag to ADAMTS13:AC (25.2 vs. 9.1, p&lt;0.02), as compared to UL-VWFM negative ones. Patients with higher endotoxin concentration more than 50 pg/ml showed lower ADAMTS13:AC than those without (22% vs. 43%, p&lt;0.05). Plasma endotoxin concentration positively correlated with the ratio of VWF:Ag to ADAMTS13:AC (r=0.732, p&lt;0.005). The SOFA score correlated positively with plasma endotoxin concentration (r=0.604, p&lt;0.03), IL-8 (r=0.843, p&lt;0.001), and the ratio of VWF:Ag to ADAMTS13:AC (r=0.700, p&lt;0.01), and inversely with the ADAMTS13:AC (r= − 0.601, p&lt;0.03). Conclusion. The imbalance between decreased ADAMTS13:AC and increased UL-VWFM is closely related to enhanced endotoxemia, which may contribute to the development of SAP and subsequent MOF through enhanced thrombogenesis.

Abstract Background: EBV-positive diffuse large B-cell lymphoma (EBV+ DLBCL) of the elderly is a provisional entity included in the 2008 WHO Classification of Lymphomas. Diagnostic criteria include age >50 years, DLBCL morphology and EBV expression in lymphomatous cells. However, these criteria are evolving as several patients younger than 50 years of age without immunodeficiency have been diagnosed. Also, a specific cut-off for the percentage of EBV expression has not been defined. Lymphopenia, monocytosis, neutrophil-to-lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR) have been reported prognostic in patients with DLBCL and other lymphomas. The goal of this retrospective study is to evaluate these novel prognostic factors in a cohort of EBV+ DLBCL patients. Methods: Between January 2002 and January 2014, all patients meeting criteria for EBV+ DLBCL were included in the analysis. Patients with evidence of immunosuppression were excluded. All cases were positive for the presence of EBV-encoded RNA (EBER) by in situ hybridization, and CD20 and/or PAX-5 expression by immunohistochemistry. Clinical and pathological data were reviewed retrospectively. Lymphopenia was defined as an absolute lymphocyte count <1000/uL, and monocytosis as an absolute monocyte count >600/uL. NLR was defined as the division of the absolute neutrophil count over the absolute lymphocyte count. LMR was defined as the division of the absolute lymphocyte count over the absolute monocyte count. Patient's biopsies were analyzed for the expression of BCL6, CD10, CD30 and MUM-1/IRF4. Overall survival (OS) curves were calculated using the Kaplan-Meier method, and compared using the log-rank test. Results: A total of 45 EBV+ DLBCL patients are included in this study. The median age was 68.9 years (range 25-95 years). Four patients (9%) were younger than 50 years. The male:female ratio was 2.2:1. B symptoms occurred in 60%, ECOG >1 in 55%, advanced stage (III/IV) in 58%, and elevated LDH levels in 44%. The International Prognostic Index (IPI) score was 0-2 in 39% and 3-5 in 61% of the patients. Lymphopenia was seen in 35%, and monocytosis in 69% of patients. Extranodal disease occurred in 23 patients (51%): stomach (n=3), tonsil (n=3), pleura (n=2), palate (n=2), cecum (n=2), bone marrow (n=2), ileum (n=1), bone (n=1), skin (n=1), lung (n=1), meninges (n=1), soft tisue (n=1) and peritoneum (n=1). Based on the Hans classification, 76% had non-germinal center origin. Ki67 expression was >80% in 53% of the patients. Chemotherapy was not received in 25% of the cases due to poor performance status. The Oyama score was: 0 factors (13%), 1 factor (47%), and 2 factors (40%) with 2-year OS of 86%, 49% and 27%, respectively (p=0.016). Lymphopenia was an adverse prognostic factor for OS (HR 3.23, 95% CI 1.24-8.43; p=0.017) in the univariate analysis. The 2-year OS for EBV+ DLBCL patients with lymphopenia was 24%, and 55% for patients without lymphopenia. Monocytosis, NLR and LMR were not significantly associated with OS in our cohort of EBV+ DLBCL patients. Conclusions: Lymphopenia, defined as an absolute lymphocyte count <1000/uL, appears as a prognostic factor for OS in EBV+ DLBCL. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2919 Poster Board II-895 Background: Flow cytometry (FCM) assessment of cerebrospinal fluid (CSF) has recently been known to increase the rate of positivity of occult leptomeningeal disease (LD) in comparison to conventional cytologic examination (CC). However it's still unknown its prognostic value. Patients and methods: The aim of this study was to compare CC vs FCM in a large cohort of patients with newly diagnosed aggressive NHL at high risk for LD (diffuse large B-cell lymphoma (DLBCL) IPI 2-3 and elevated LDH with at least two extranodal sites or with bone marrow, testis, paranasal sinuses, orbit or paravertebral involvement; Burkitt lymphoma (BL); blastoid variant of mantle cell lymphoma (B-MCL); B-cell precursor lymphoblastic lymphoma (B-LL); HIV+ aggressive lymphoma patients). All patients were required to have no evidence or signs of neurological disease. All patients received intrathecal standard prophylactic therapy with 12 mg of methothrexate except for BL that were given prophylaxis with 50 mg of liposomial aracytin for a total of 4 doses. CFS samples were analysed both with CC and FCM. The incidence of positive test for occult LD with FCM and CC was compared using the McNemar test for paired data. Results: Between August 2004 and June 2008, a total of 159 consecutive patients were enrolled in 11 Italian centres and underwent evaluation of CSF. Out of these, 128 patients (80%) were considered at high risk of occult LD. Clinical characteristics were: median age 53 years (IQR:43-62); DLBCL 96 patients (75%); BL 21 pts (16%); B-MCL 6 pts (5%); B-LL 5 pts (4%); 26 pts (20%) were HIV positive. FCM was able to detect a clonal population in 17 out of 128 patients (13%) whereas CC detected abnormal cells only among 7 pts (5%)(p= 0.0002). Therefore, 10 patients (8%) were discordant: FCM+/CC-. Among the 128 patients, there was no association between the CFS total protein, glucose level and the presence of positive analysis of FCM, whereas the difference between the number of WBC cells in CSF was significantly higher in patients with positive versus negative FCM with a median value of 12 cells/ul (IQR: 3.5;40) versus 1.0 cells/ul (IQR: 0.0;3.0) (p=0.0120). Univariate and multivariate analyses, using logistic models, showed that abnormal LDH (OR 3.98, 95%CI: 1-15.92)(p=0.05) and number of WBC cells in CSF ≥5 (OR 4.57, 95%CI:1.37-15.33)(p=0.014) were the only predictive factors of a positive test performed by FCM. From date of diagnosis, overall median follow up of survivors was 14 months (IQR:8-22). We observed 39 (30%) systemic progressions, 6 (5%) CNS progressions (in 5 cases an isolated CNS progression whereas 1 pts experienced a CNS along with systemic progression). Thirty-two (25%) patients died and causes of deaths were as follows: 27 progressive disease, 1 infection, 1 treatment related toxicity, 1 hepatitis, 2 unknown. PFS at 1 year was 71% (95%CI:62-78) in the whole group of patients. The progression risk was significantly higher in patients both FCM+/CC+ compared with patients both FCM-/CC- (1-yr PFS 43% vs 74%) (HR 3.8 95%CI:1.6-9.0) (p=0.003). An higher but not significant risk of progression was found in pts discordant (FCM+/CC-) with respect to patients both FCM-/CC- (1-yr PFS 65% vs 74%) (HR 1.61, 95%CI:0.63-4.11) (p=0.315). In the univariate and multivariate analyses performed with Cox models, we found that the presence of ECOG PS≥2 (HR 2.14, 95%CI: 1.14-4)(p=0.018) and level of protein in CSF >40/ul (HR 1.83 95%CI: 1.01-3.29)(p=0.045) were prognostic factor of PFS. Conclusion: FCM assessment of CSF increase the rate of positivity of occult LD compare with CC but it's clinical relevance is still to be clearly defined. Our preliminary data suggest that patients both FCM+/CC+ have an higher risk of progression compared with those both negative, whereas discordant cases may have an intermediate prognosis. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1588 Background: EBV-positive diffuse large B-cell lymphoma (EBV+ DLBCL) of the elderly is a provisional entity included in the 2008 WHO Classification of Lymphomas. Diagnostic criteria include age >50 years, DLBCL morphology and EBV expression in lymphomatous cells. However, these criteria are evolving as several patients are <50 years and a specific cut-off for the percentage of EBV expression has not been defined. The goal of this retrospective study is to evaluate clinical and pathological characteristics of EBV+ DLBCL from Peruvian patients. Methods: Between January 2002 and January 2012, all patients meeting criteria for EBV+ DLBCL were included in the analysis. Patients with evidence of immunosuppression were excluded. All cases re positive for the presence of EBV-encoded RNA (EBER) by in situ hybridization, and CD20 and/or PAX-5 expression by immuno-histochemistry. Clinical data were reviewed retrospectively and patient's biopsies were analyzed for the expression of BCL6, CD10, CD30 and MUM-1/IRF4 using a tissue microarray (TMA) technique. The overall survival (OS) curves were calculated using the Kaplan-Meier method, and compared using the log-rank test. Results: A total of 43 EBV+ DLBCL patients are included in this study. The median age was 73 years (range 25–95 years). Four patients (9% ) were <50 years. The male:female ratio was 2.2:1. B symptoms occurred in 59%, ECOG >21 in 60%, advanced stage (III/IV) in 58%, elevated LDH levels in 44%, and lymphocyte count <1000/uL in 35%. The International Prognostic Index (IPI) score was 0–2 in 39% and 3–5 in 61% of the patients. Extranodal disease occurred in 20 patients (46%): stomach (n=3), tonsil (n=3), pleura (n=2), palate (n=2), cecum (n=2), bone marrow (n=2), ileum (n=1), bone (n=1), skin (n=1), lung (n=1), meninges (n=1), breast (n=1) and peritoneum (n=1). Three patients had central nervous system involvement (7%), one at presentation and two at relapse. Based on the Hans classification, 76% had non-germinal center profile. Ki67 expression was >80% in 53% of the patients. Eleven evaluated patients had a c-myc-negative status. Chemotherapy was received in 75% of the cases due to poor performance status. The overall response rate with conventional chemotherapy was 46%, with complete response in 39%, partial response in 7%, and no response in 54%. The median survival was 7.5 months. The Oyama score was: 0 factors (13%), 1 factor (47%), and 2 factors (40%) with median OS of 41, 11 and 1.5 months respectively (p=0.07). A lymphocyte count <1000/uL was a prognostic factor for OS (p=0.001). Conclusions: Based on our study, which is the largest cohort in Latin-America, EBV+ DLBCL is an aggressive entity with frequent extranodal disease and poor response to conventional chemotherapy. The overall survival remains poor. Lymphopenia, as defined as lymphocyte count <1000/uL, appears as a prognostic factor for OS. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3681 Background: Pediatric Immune Thrombocytopenia (ITP) has an incidence of 4–6/100,000 with 1/3 of cases becoming chronic. Treatment choice is arbitrary, because few studies are powered to identify predictors of therapy response. Increasingly, rituximab is becoming a treatment of choice in those refractory to other therapies (Neunert CE, et al. Pediatr Blood Cancer 2008; 51(4):513). Previous studies in ITP have not examined predictors of response to rituximab or whether response to prior treatments predicts response. Objective: To evaluate univariate and multivariable predictors of platelet count response to rituximab. Methods: After local IRB approval, 550 patients with chronic ITP enrolled in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and June 2010. Eligibility included: ages 6 months-18 years at ITP diagnosis, clinical diagnosis of ITP, and ITP duration >6 months. Primary ITP was defined as isolated thrombocytopenia without associated conditions. Secondary ITP included those patients with immune thrombocytopenia associated with other immune-mediated medical conditions, including Evans Syndrome. Treatment response was defined as a post-treatment platelet count ≥50,000/uL within 16 weeks of rituximab and within 14 days of steroids. Steroids were prescribed as 1–4 mg/kg prednisone or adult equivalent over 4–14 days with or without taper. The NACIR captured treatment responses both retrospectively prior to enrollment and then prospectively, and both periods were included in this analysis. The multivariable logistic regression modeling process utilized SAS 9.1 using binary variables which were either significant in the univariate analysis or clinically important. A backwards elimination procedure was used to select the final model. Results: Seventy-six (13.8%) patients were treated with rituximab. Demographics of the patients treated with rituximab include: 42% male; 81% Caucasian, 17% Black, and 2% Asian. The mean age at diagnosis of ITP was 8.4 ± SD 5.1 years. The median platelet count at diagnosis of acute ITP was 10,000/uL (IQR 5,000-20,000/uL). 19 (25%) patients had secondary ITP or Evans syndrome. Treatment with rituximab had an overall response rate of 63.2% (48/76). Univariate predictors of response to rituximab are shown in Table I. The strongest univariate predictor of response to rituximab was response to steroids. Gender, ethnicity, and race were not predictive of response to rituximab. Furthermore, other variables which did not predict rituximab response include: history of a bleeding score ≥3 (Buchanan and Adix, J Pediatr 2002; 141: 683), symptoms ≥1 month prior to ITP diagnosis, older age (age >5 years), platelets ≥20,000/uL at acute ITP diagnosis, and a positive ANA. In multivariable analysis, response to steroids remained a strong predictor of response to rituximab with an OR 6.2 (95% CI 1.8–21.3, p=0.004). Secondary ITP also remained a strong a predictor of a positive response to rituximab with an OR 5.9 (95% CI 1.2–33.3, p=0.03). Conclusion: In the NACIR, response to steroids and secondary ITP were strong predictors of response to rituximab, a finding not previously reported in children or adults. Although this finding requires further validation, this result may provide evidence that rituximab should be most considered in patients previously responsive to steroids. Disclosures: Off Label Use: Rituximab for chronic ITP. Lambert:Cangene: Membership on an entity's Board of Directors or advisory committees. Klaassen:Novartis: Research Funding; Cangene: Research Funding. Neufeld:Novartis, Inc: Research Funding.

Abstract Abstract 1701 Patients with features of MDS and MDS/MPN who do not fulfill diagnostic criteria for a specific subtype of MDS and MDS/MPN are categorized by the WHO 2008 diagnostic criteria as MDS-U and MDS/MPN-U. MDS includes RCUD, RCMD, RARS, RAEB-1, RAEB-2, MDS-U and 5q- syndrome while MDS/MPN includes CMML, JMML, atypical CML and MDS/MPN-U. The natural history of patients who belong to these disease subtypes are hetergeneous. Although included in currently accepted prognostic scoring schemes like the International Prognostic Scoring System (IPSS) in MDS, Revised IPSS, and MD Anderson prognostic scoring schemes, they represent a minority of patients in the cohort. Within MDS/MPN cases, the clinical heterogeneity of diseases that belong to this group has been recognized and has led to the development of the MD Anderson prognostic Scoring System for CMML. Similarly, a prognostic scoring system for JMML has also been devised to help in risk stratification and treatment decisions. However, there are no prognostic scoring systems for unclassified cases of MDS and MDS/MPN. Clinically, we observe stark differences in treatment responses and clinical outcomes between MDS/MPN-U and other MDS/MPN-subtypes, and MDS-U with other subtypes of MDS. In total, we studied 92 patients with unclassifiable cases seen at the Cleveland Clinic, including MDS/MPN-U (n=52 [57%]) and MDS-U (n=40 [43%]). Hematologic, bone marrow (BM), cytogenetic (metaphase cytogenetic [MC]/SNP-A) and survival data were collected. Survival comparisons were made by Kaplan-Meier analyses. Cox-proportional hazard ratio was used to determine factors predictive of outcomes. A p-value of ≤0.05 was considered statistically significant. In this cohort, median age at diagnosis was 69 years (20–88), 65% (60/92) were male, and 35% (32/92) were female. Median follow-up was 21 months. Median absolute neutrophil count (ANC) was 2.69k/uL (0–87), peripheral blood (PB) blasts 0% (0–70%), hemoglobin 9.6g/dL (5–15), and LDH 260 U/L (105–2113). SNP-A karyotyping was completed for 65 patients, and new cytogenetic mutations were detected in 72% (47/65): (gains [64%], losses [57%], UPDs [25%]). In 52% (49/92) of patients, we sequenced molecular mutations that typically confer poor prognosis in myeloid neoplasms, such as ASXL1, IDH1/2, EZH2, K/NRAS, CBL and TP53. This sequencing revealed a mutational frequency of 18% (9/49) in TET2, 14% (7/49) in ASXL1, 6% (3/49) in EZH2 exons 18–19, 2% (1/49) in CBL, 2% (1/49) in NRAS, and 4% (2/49) in TP53. No mutations were found in IDH1/2 and KRAS. In univariate analysis of clinciopathologic factors, the following factors were found to be associated with overall survival: ANC (≥8.5 vs <8.5k/uL) (p<.0001), presence of PB blasts (p<.0001), presence of immature myeloid cells (p<.0001), presence of BM blasts (>3% v. ≤3%) (p<.0001), age (≥65 vs <65) (p<.0003), LDH (≥550 vs <550U/L) (p<.0004), albumin (≤3.6 vs >3.6g/dL) (p<.0008), IPSS Risk Group (Int-2/high vs int-1 vs low) (p<.01), IPSS-R Risk Group (High/very high vs low vs very low) (p<.001), WBC (≥15 vs <15k/uL) (p<.001), Hgb (≤11.5 vs >11.5g/dL) (p<.003), % BM cellularity (>85 vs ≤85%) (p<.009), and number of cytopenias (3 vs 2 vs 1 vs 0) (p<.04). In multivariate analysis, age (HR=3.47 CI 1.85–6.51, p=.001), ANC (HR=2.27 CI 1.15–4.49, p=.02), Hgb (HR=2.11 CI 1.07–4.14, p.03), peripheral blasts (HR=2.27 CI 1.19–4.36,p=.01) and LDH (HR=2.40 CI 1.11–5.16, p=.03) were independent predictors of OS in unclassifiable cases of MDS and MDS/MPN. Consequently, a prognostic scoring system was developed to include these factors. A simple scoring assigned 2 points each to an ANC of ≥8.5k/uL, the presence of peripheral blood blasts, hemoglobin ≤ 11.5g/dL, LDH ≥ 550U/L; and 3 points for age ≥65. This results in three well-separated prognostic groups: (favorable [score:0–3], median OS=67.4 months; intermediate [score:4–6],median OS=28.9 months; and poor [score: ≥ 7], median OS=13.1 months, p<.0001). 34, 21, and 24 patients were placed in these three groups, respectively. In conclusion, clinic-pathologic factors like age, LDH levels, ANC count, Hgb levels and peripheral blood blasts are helpful in predicting survival outcomes in patients with unclassifiable cases of MDS and MDS/MPN disorders. This is the first scoring system devised specifically for patients with this disease subtype. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Myelodysplastic syndrome (MDS) therapeutic decisions have been traditionally based on the IPSS; however, this score system does not allow the identification of patients with low risk disease (low or intermediate-1 IPSS) but a poor prognosis, who could benefit from an early intervention. Garcia-Manero et al (Leukemia 2008) described a specific prognostic scoring system for this subgroup of patients (LR-PSS) based on age ≥60 years, hemoglobin <10g/dl, platelet count <50k/uL or 50-200k/uL, bone marrow blasts ≥4% and unfavorable cytogenetics (non-del(5q), non-diploid). This LR-PSS score system enables the stratification of low risk MDS patients into 3 different risk categories; interestingly, the third category identifies a subgroup of patients with a median overall survival (OS) similar to that of patients classified as intermediate-2 and high risk IPSS. Besides, the IPSS-R described by Greenberg et al (Blood 2012) has demonstrated a strong prognostic value for OS and LFS as compared to the IPSS when applied to different independent series of MDS patients. The prognostic impact of the LR-PSS has not been analyzed in MDS patients with very low-, low- and intermediate IPSS-R scores. Aim: To analyze the prognostic impact according to OS and leukemia free survival of the LR-PSS when applied to a population MDS patients with very low, low and intermediate IPSS-R. Methods: A total of 789 consecutive patients diagnosed with MDS (01/1992-12/2014) at the Catalan Institute of Oncology of Barcelona were included in the study. 413 (52%) had available cytogenetics and therefore, IPSS-R was calculated. Overall, 371 (89%) patients were classified as very low, low and intermediate IPSS-R and included in the study. Results: 123 (30%) patients were classified as very low, 182 (44%) low and 66 (16%) intermediated IPSS-R risk MDS; median age 72 years (range 32-101) and 258 (69%) male. 1.4 % CRDU, 7.6 % RA, 41.6 % RCMD, 16.2 % RAEB‐1, 4.1 % RAEB‐2, 25.9 % CMML and 3.2 % MDS‐U with isolated 5q deletion according to the 2008 WHO classification. At diagnosis, median hemoglobin, platelet and bone marrow blast were 11.8 g/dL (5.5-17.1), 152 x109/L (1-1492) and 3 % (0-17), respectively and fifty-three (14.3 %) patients had unfavorable LR-PSS cytogenetics. For the whole population, median follow up was 6.6 years (range 6-7.7). At the time of last follow up, 48.2 % (179) had died and only 49 (13%) had progressed to acute myeloid leukemia. When the LR-PSS was applied to the very low, low and intermediate IPSS-R subgroups three well-differentiated prognostic categories could be identified: 58 patients (15.6%) category 1, scores 0-2; 277 (74.6%) patients category 2, scores 3-4 and 36 (9.8%) patients category 3, scores 5-7 with significantly different overall survival and leukemia free survival. Median OS for categories 1 (9.4 years; 95% CI 6.7-12), 2 (6 years; 95% CI 5-7.1) and 3 (2.6 years; 95% CI 2.1-3) were significantly different (p<0.001; Figure 1). Moreover, the rate of progression to acute myeloid leukemia was 5% (3/58), 13% (37/277) and 25% (9/36) for categories 1, 2 and 3, respectively. Summary/Conclusion: When applied to a low risk (very low, low and intermediate) IPSS-R cohort of MDS population, the LR-PSS identifies a subgroup of patients with a significantly worse prognosis who could benefit from an early intervention. Further studies are warranted. Fig 1. Kaplan-Meier survival for patients with very low-, low- and intermediate IPSS-R risk assigned to categories 1 to 3 by LR-PSS. Fig 1. Kaplan-Meier survival for patients with very low-, low- and intermediate IPSS-R risk assigned to categories 1 to 3 by LR-PSS. Disclosures Sureda: Takeda: Consultancy, Speakers Bureau.

Abstract Introduction. Stem cell (SC) mobilization and collection from peripheral blood (PB) is a broadly used strategy in the setting of autologous stem cell transplantation (ASCT). An adequate correlation between CD34+ cell count in PB and CD34+ cell count in apheresis product is essential for the planning of the mobilization-apheresis process. Prediction of SC yield in the basis of peripheral blood stem cell (PBSC) number and blood volume processed (BVP) was proposed by Pierelli et al (Vox Sanguinis (2006)91:126-34). Objective. Evaluation of correlation between pre-apheresis PBSC count and CD34+ cell dose collected in the first apheresis procedure. Evaluation of correlation between predicted CD34+ yield by Pierelli's method and actual CD34+ yield collected in the first apheresis procedure. Patients and Methods. Eighty-four apheresis procedures performed to 79 patients in a single institution between 2008 and 2015 were retrospectively evaluated. Data analyzed included age, gender, body weight, diagnosis, date of first apheresis, pre-apheresis PB CD34+ counts, CD34+ cell dose collected in the first apheresis product and total BVP. Only patients in whom pre-apheresis PBSC count was available were included in this analysis. Median age was 52 years (16-66), 30 (38%) were females. Median body weight was 71 kg (47 - 120). Diagnosis was non-Hodgkin lymphoma (48%), multiple myeloma (24%), Hodgkin lymphoma (22%), acute myeloblastic leukemia (4%), amyloidosis (1%) and solid tumor (1%). Using the method described by Pierelli et al, predicted CD34+ yields were calculated (predicted CD34+ cells/kg= PB CD34+ cells/mL x 0.4 x BVP per kg (mL/kg). Correlation between variables was analyzed by Pearson's coefficient (r). An r value close to 1 indicates significant correlation between variables. An r value close to 0 indicates no statistical correlation. Predicted yields were classified in low (lower than 2 x 106 CD34+ cells / kg) (n=34), intermediate (2 to 5) (n=28) or high (higher than 5) (n=22), according with the conventional limits for SC dose in the setting of ASCT. Positive predictive value (PPV) of predicted yields was calculated as the proportion of actual yields falling into each category of predicted yields. Results. Median pre-apheresis PBSC count was 25 CD34+ cells / uL (5-310). Median BVP was 240 mL/kg (143-360). Median predicted CD34+ yield was 2.1x106 CD34+ cells/kg (0.5-29.41) and median actual CD34+ yield was 2.84 x106 CD34+ cells/kg (0.26-38.21). Pearson's correlation coefficient (r) between pre-apheresis PBSC and collected CD34+ cells was 0.842 (p=0.000). Pearson's correlation coefficient (r) between predicted and actual CD34+ was 0.836 (p=0.000). Median ratio actual CD34+ cells / predicted CD34+ cells was 1.10 (0.31-4.55). PPV of predicted yields higher than 5 x 106 CD34+ cells /kg was high (95%). Only 18% of cases with a predicted yield between 2 and 5 x 106 CD34+/kg had an actual CD34+ yield lower than 2 x 106 CD34+/kg. Conclusion. The results show a significant correlation between PBSC count and collected SC during the first apheresis procedure. A significant correlation between predicted and actual CD34+ yields reproduce what has been shown by others regarding the predictive power of this formula. The PPV of this method is higher for predicted CD34+ yields higher than 5 x 106 CD34+ cells/kg. Disclosures No relevant conflicts of interest to declare.

Abstract Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is still the only curative treatment for Chronic Myelogenous Leukemia (CML) at present. For only few patients having suitably matched donor, transplantations with stem cells from HLA mismatched related family donors have been increasingly used. But Used of HLA mismatched HCT involves crossing histocompatibility barriers, it has been limited by high risk of severe graft-versus-host disease (GVHD), graft rejection and delayed or incomplete immune reconstruction. The inducing immune tolerance and modulate allogeneic reaction may play a role in avoiding severe GVHD in HLA-mismatched HSCT. Our goal in this study was to investigate the feasibility and clinical value of this approach in the treatment of CML. From February 1999 to February 2008, 55 patients with CML, aged 8 to 52 years (median age 29 years), received HSCT from HLA two or three loci mismatched donor, 18 were in chronic phase, 19 were in accelerated phase, 18 were in blast crisis. The outcome were compared with related HLA matched hematopoietic cell transplantation performed during the same time period. As a control, 41 patients with CML, aged 13 to 52 years (median age 31 years), received HLA-matched HSCT, 21 were in chronic phase, 12 were in accelerated phase, 8 were in blast crisis. All of patients received combined transplantation of the G-CSF primed bone marrow and peripheral blood stem cell without T cell depleted, and the prophylaxis regimen for acute GVHD consisted of CSA, short-term MTX, and MMF, but ATG (Fresenius S) and CD25 monoclonal antibody were particularly used in HLA-mismatched HSCT. During the time of following-up (above 6 months), All patients achieved full engraftment.1 patient who received the HLA-mismatched transplantation failed to engraft. The rejection of patient was reversed by second HSCT from different donor. The days of ANC&gt;0.5×109 and Platelets&gt;20×109 were 15 (range, 10–25) and 17 day (range, 11–30), respectively, and the accumulative percent of Platelets&gt;50×109 until 100 days were 77%. The cumulative incidences of grades II to IV acute graft-versus-host disease (aGVHD) in the matched and mismatched cohorts were 22% versus 29%(P&gt;0.05). The cumulative incidence of cGVHD in matched and mismatched transplantation was 45% versus 51%, respectively. The recovery time to 200/ul and 400/ul of CD4 cells were 6 and 12 months, which were all no significant difference between HLA mismatched and matched groups. The median follow-up period was 47 months (range 6–112 months). The transplant related mortality was 11 cases (5 died of aGVHD, 6 died of infection), and 12 cases were relapse (11 cases died, 1 cased were controlled by donor lymphocyte infusion) in HLA mismatched patients. The DFS of 2 years were 58.2% and 71.5% in HLA mismatched and matched groups by Kaplan-Meier survival analysis, which wsa no significant difference between two groups. Actual two-year disease-free survival in HLA mismatched groups was 56.5%, the patients in chronic phase or accelerated phase and in blast crisis were 70.8% and 36.5% , respectively, with the statistical significance. In summary, HCT performed with related HLA-mismatched donors is a feasible approach with acceptable outcomes for treatment of CML .but the status of pro-transplantation affected patient’s prognosis.

Abstract Abstract 2555 High hyperdiploidy is present in 30% of children with acute lymphocytic leukemia (ALL), and is associated with a favorable prognosis. We evaluated pts with newly diagnosed ALL treated on SWOG trials S9400 (1995–2000) and S0333 (2005–2010) to determine the prevalence and prognostic impact of hyperdiploidy in adults with ALL. Additionally, we examined the prognostic impact of hypodiploidy, a feature typically associated with a poor prognosis in children. Methods: One-hundred and eighty-five pts treated on S9400 and S0333 with successful cytogenetic (CG) analysis were included. The treatment regimens were: S9400 [Induction: Daunorubicin (D), vincristine (V), prednisone (P), PEG-asparaginase (PEG); Consolidation: Cytoxan (Cy), cytarabine (AraC), 6-mercaptopurine (6MP), intrathecal methotrexate (IT Mtx). Consolidation was followed by allogeneic stem cell transplant or maintenance chemotherapy] and S0333: Double Induction Chemotherapy [Induction 1: D, V, P, PEG; Induction 2: high dose AraC, mitoxantrone, decadron. Consolidation: Cy, AraC, 6MP, Mtx; consolidation was followed by maintenance therapy]. Karyotypes were centrally reviewed and clonal abnormalities described according to ISCN (2009). Hyperdiploidy was defined as: low hyperdiploidy [47–49 chromosomes (cs)], high hyperdiploidy (51–65 cs), near triploidy (66–79 cs), and near tetraploidy (84–100 cs). Hypodiploidy was defined as: near haploidy (25–29 cs), low hypodiploidy (31–39 cs), and high hypodiploidy (42–45 cs). When more than one cell line was present, ploidy was assigned by the most complex clonal karyotype. Hypodiploidy and hyperdiploidy were analyzed as prognostic factors for complete response (CR) rate and residual disease (RD) by logistic regression and chi-square tests; and for overall survival (OS) and relapse-free survival (RFS) by proportional hazards. Multivariable analyses were stratified by study and using the baseline variables: age, WBC, lineage, and CG risk. Results: The median age was 32 yrs (range 17–64), and median WBC at diagnosis 17.2 K/uL (range 0.6–396.6). CG risk was ascribed by (Pullarket V et al. Blood 2008; 111: 2563). Forty-five pts (24%) had normal CG, and 73 (39%) had poor risk CG. Fourteen pts (8%) had hypodiploidy (2: low hypodiploidy; 12: high hypodiploidy). Fifty-three pts (29%) had hyperdiploidy [40: low hyperdiploidy, 10: high hyperdiploidy (5%), 3: near tetraploidy or tetraploidy (2%)]. The CR rate for all pts was 72%; with a median RFS of 15 mos (95% CI: 12–29 mos) and median OS of 28 mos (95% CI: 21–36 mos). There was no significant association with ploidy status and age, WBC, or lineage. However, there was an increased prevalence of the t(9;22) in the high hypodiploidy group compared to the normal/pseudo diploidy group (p=0.049). Neither hypodiploidy nor hyperdiploidy were predictive of CR or RD; although pts with hypodiploidy had a higher rate of RD (p=0.062). The 2 pts with low hypodiploidy had very poor outcomes (1 had RD and died after 11 mos; the other relapsed after 3 mos from CR and died 4 mos after study registration). There were no statistically significant differences in OS, CR rate, or RFS between the ploidy groups even after adjusting for baseline characteristics in multivariate analysis. Surprisingly, when excluding pts with poor risk CG there was still a trend towards a worse RFS (29 vs. 32 months, p=0.20) and OS (40 vs. 68 mos, p=0.29) in pts with hyperdiploidy compared to normal/pseudodiploidy. In addition, the 3 pts in the high hyperdiploidy group without poor risk CG had poor OS (median 23 mos). Conclusions: The prevalence of high hyperdiploidy is much lower in adults with ALL, compared to children. The prevalence of hypodiploidy and near tetraploidy/tetraploidy is comparable to that seen in children with ALL. Hypodiploidy and high hyperdiploidy were not prognostic factors for outcome in this group of patients. Given the low prevalence of these abnormalities, it is possible that larger numbers of pts may be needed to detect such a difference. The poor outcomes of pts with low hypodiploidy are consistent with findings by Moorman et al. (Blood 2006; 109: 3189). However, in contrast to Moorman's results, there was no evidence of an association of hyperdiploidy with age/WBC, and there was a trend towards a worse prognosis in this subset of patients. This suggests that the biology and prognosis of high hyperdiploidy may be affected more by WBC and age in the adult population. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4526 Introduction Autologous stem cell mobilization (SCM) is conventionally done using chemotherapy and G-CSF (G). Although safe and effective, patients (pts.) are exposed to risks of cytotoxic chemotherapy and myelosuppression. Plerixafor (P) and G mobilizes stem cells (SC) without any myelosuppression. Understanding the pharmacoeconomics (PE) of SCM is important so that the optimal approach can be used. Methods We studied PE of high dose cyclophosphamide (CY) and G SCM in 241 pts. (1/2004 to 3/2008) undergoing first autologous stem cell transplant and compared outcomes to projected costs using P+G. CY was dosed at 3 gm/m2 and G started the next day (10 mcg/kg) for 10 days with a planned first day of collection on day 11. Dose escalations were per institutional protocol. Pheresis was initiated if peripheral blood (PB) had >15 CD34+ cells/uL. PE analyses were done to compute total cost and included cost of CY, G, pheresis, product processing, and clinical events. Cost was based on Medicare part B physician, laboratory, and ancillary fee schedule and was calculated from review of random patient records. This approach removed the bias of inter-institutional cost variations. Ideal Outcome (IO) was defined as >2×106 CD34+ cells/kg collected on the planned day of collection in 1 or 2 apheresis without a preceding negative event that lead to additional evaluation in clinic or inpatient. Results 141 (61%) were males; 121 (50%) had myeloma (MM), 115 (48%) had lymphoma (L) and 5 had other diagnoses; 61 (25%) received radiation with prior therapy. Median WBC and neutrophil count prior to CY was 5.3 ×109 /L (range, 1.7 to 46), and 3.3 ×109/L (range, 0.95-31.37). 199 (82.6%) started pheresis on the planned first day of pheresis, 18 (7.9%) had a delay in start of pheresis (range, 1- 7 days) due to low PB CD34 count and 24 (9.9%) pts. did not proceed to pheresis due to low PB CD34+ cell count. The mean final SC dose was 10.22 ×106 CD34/kg (range, 0.45 - 60.18). Pts. with MM collected more than lymphoma (11.98 vs. 6.35, P<0.0001). 6 (2.8%) pts. collected <2 ×106 CD34/kg. Median number of pheresis was 1 (range, 0 - 4) with 41 (17%), and 10 (4.1%) requiring 2 and 3 pheresis, respectively. The target SC dose of >6×106 CD34/kg in MM pts. was collected in 1,2, or 3 pheresis in 84 (69.4%), 98 (80.9%), and 102 (84.2%), respectively. In L pts., the target SC dose of >2×106 CD34/kg was collected in 1, 2, or 3 pheresis in 68 (59%), 85 (73.9%) and 90 (74.3%), respectively. Clinical events included: febrile neutropenia (FN) clinic evaluation (7, 2.9%); FN admission (26, 10.8%); line infection (7, 2.9%); line change (8, 3.3%), gastrointestinal side effects (111, 46%), bone pain with evaluation in clinic (127, 52%) and admission for management of bone pain (9, 3.7%). Forty-three (18%) pts. were hospitalized for clinical events. IO was seen in 48 (20%) pts. 23% of MM and 15.7% of L pts. had an IO. Risk factors including prior radiation, WBC count and ANC prior to CY could not predict ability to collect SC or IO. Mean total cost of CY+G SCM was $10,732 (range, 6988-30827). IO was associated with a lower cost in overall group, (mean, $10,371 vs. $12,870, P=0.001), in MM pts. (mean, $10,511 vs. $12,152, P=0.026), and in L pts. (mean, $10,133 vs. $13,627, P=0.006). Assuming a similar distribution of IO in 100 pts. with MM and L, the projected per pt. cost of SCM would be $11,774 and $13,067 (mean, $12,421) with CY+G. Projected costs of SCM using P+G (based on published phase III data that used G dose of 10 mcg/kg without dose escalation and that the non-mobilizers had a maximum of 4 days of P) for 100 pts. with MM and L would be $12,852 and $8986 (mean, $10,919). These do not take into account costs associated with operational planning and predictability of the date of SCM with P+G, impact of the negative event on pts. quality of life with CY+G, effects of mobilization failure leading to other alternative clinical approaches including an allogeneic stem cell transplant (N=6). Conclusion Our study shows that SCM with CY+G is associated with a low incidence of IO. P+G can be justified as upfront method of SCM in pts. with MM and L from a PE perspective without any detrimental impact on SCM efficiency. As P+G is not associated with any negative clinical events related to myelosuppression, it should translate into a better quality of life for pts. SCM using P+G may allow for optimal utilization of resources which again will impact PE. These need to be validated and should be addressed in future studies of SCM. Disclosures: Jagasia: Genzyme: Research Funding.

Abstract Introduction: The 2008 World Health Organization (WHO) classification has recognized a unique overlap category that has features of proliferation found in myeloproliferative neoplasms (MPN) and also dysplasia found in myelodysplastic syndrome (MDS). The least well characterized of the 4 MDS/MPN overlap diseases is a rare entity known as MDS/MPN Unclassifiable (MDS/MPN-U), comprising <5% of myeloid disorders. Furthermore, given the rarity of this disorder, there is no validated risk stratification scoring system, although there are several commonly used prognostic models for MDS, including the International Prognostic Scoring System (IPSS), the Revised International Prognostic Scoring System (IPSS-R), and the M.D. Anderson Cancer Center model (MDAS). The objectives of this study were to evaluate the natural history of this very uncommon diagnosis and to determine which of the current scoring symptoms used for MDS best discriminates outcomes. Methods: The Moffitt Cancer Center database of over 3000 MDS patients was used to identify patients with MDS/MPN-U and to subsequently perform a comprehensive chart/pathology review. We then applied IPSS, IPSS-R, and the MDAS scores to each patient in order to compare differences in overall survival (OS) amongst different risk groups within each scoring system. Finally, we compared outcomes in the MDS/MPN-U group with a large number of matched MDS cases from within our database, using the MDAS. Descriptive statistical analyses were utilized. Chi square analysis and t- test were performed to compare categorical and continuous variables. Akaike information criteria (AIC) were used to assess the relative goodness of fit of the models. All data was analyzed using SPSS version 21.0 statistical software. Results: Forty three patients were identified with MDS/MPN-U and were pathologically confirmed to meet WHO criteria. Median age was 71 years (range 55 - 91) and the M:F = 26.17. Median baseline laboratory parameters: WBC 11.2 x 103/dL (range 0.9 - 84.8); Hb 9.7 g/dL (range 5.8-14.4); platelets 137 x 103/uL. Table 1 summarizes risk stratification per current validated MDS scoring systems. The majority of patients had lower risk disease by all the models. Forty of 42 (95%) patients evaluable for prognostic scoring were classified as low/Int-1 by IPSS. However, 11 out of the 40 pts (28%) classified as lower risk by IPSS were upgraded to Int-2 or high risk by MDAS. Twenty-two patients received hypomethylating agents (HMA) as first line treatment after supportive care. Per IWG 2006, 8 of 22, (36%) had complete response, partial remission, or hematologic improvement, 7 (32%) had stable disease, and 6 (27%) had progressive disease. The median OS for all MDS/MPN-U patients was 33 months (95% Confidence Interval 22 - 45). Within each MDS scoring system, statistically significant survival differences were detected between risk stages (table 1). The IPSS-R did not improve the IPSS prognostic value. Patients categorized as lower-risk (low/Int-1) by MDAS had superior survival compared to IPSS. Lastly, we compared outcomes between the 43 MDS/MPN-U patients and 1117 IPSS low/Int-1 matched controls within the MDS database. Median overall survival was inferior in MDS/MPN-U vs. MDS (33.4 mo vs. 57 mo, p = 0.005). In addition, using the MDAS, stage-by-stage, survival was significantly worse in the MDS/MPN-U group. Table 1. Risk Stratification Based on MDS Scoring Systems MDS/MPN-Un (%) Median Overall Survival (mo) P-value IPSS Low Int-1 Int-2 High 15 (35.7)25 (59.5)1 (2.4)1 (2.4) 33.433.312.86.0 < 0.001 IPSS-R Very Low Low Intermediate High Very High 6 (14.3)21 (50)10 (23.8)4 (9.5)1 (2.4) 18.2333.425.112.86.0 0.001 MDAS Low Int-1 Int-2 High 6 (14.3)20 (47.6)13 (31.0)3 (7.1) 52.433.425.16.0 < 0.001 Conclusions: MDS/MPN-U appears to have a variable disease course but with generally poor outcomes, even amongst lower-risk patients classified by MDS scoring systems, and despite a moderate rate of response to treatment. Matched comparisons indicate inferior outcomes compared with similarly staged MDS patients. The MDAS may offer increased discriminatory capacity for determining prognosis based on disease stage. Further work with a larger patient population and cross comparisons to other MDS/MPN diseases will assist further understanding of this rare disorder. Integration of somatic mutations data may compliment the clinical models. Disclosures Komrokji: Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Pharmacylics: Speakers Bureau; Incyte: Consultancy. Lancet:Kalo-Bios: Consultancy; Celgene: Consultancy, Research Funding; Pfizer: Research Funding; Amgen: Consultancy; Seattle Genetics: Consultancy; Boehringer-Ingelheim: Consultancy.

Background: Rabbit anti-thymocyte globulin (rATG) is used in allogeneic hematopoietic cell transplantation (alloHCT) to prevent graft versus host-disease (GVHD) and graft rejection. In the T-cell replete setting, post-HCT rATG exposure is variable with high exposures resulting in delayed CD4+immune reconstitution (CD4+IR) and higher mortality. The goal of this study was to estimate the rATG exposure in pediatric and adult recipients of ex vivo T-cell depleted CD34+ selected alloHCT and correlate it with outcomes to determine the optimal exposure. Methods: We performed a retrospective analysis of patients who underwent their first myeloablative-conditioned ex vivo CD34+ selected alloHCT between 2008 and 2018. Post-HCT rATG exposure was estimated as area under the curve (AUC) (mg*d/L) using a validated population pharmacokinetic (PK) model (Admiraal et al.,Lancet Hematology 2017). Outcomes of interest were CD4+IR, defined as CD4+&gt;50/uL at two consecutive measures within 100 days of HCT, non-relapse mortality (NRM), overall survival (OS), GVHD, and relapse. We evaluated the association between post-HCT rATG exposures and CD4+IR using a smoothed effect to define the optimal post-HCT rATG exposure. We subsequently analyzed outcomes in 3 post-HCT rATG exposure groups, &lt;30 mg*d/L, 30-55 mg*d/L, and &gt;=55 mg*d/L. Cox proportional hazard models and multi-state competing risk models were used for analyses. Results: Of 554 patients included, 239 (43%) were female, median age at HCT was 49 (range 0.2 to 73) years and 425 (76.7%) received matched donor transplant, while 129 (23.3%) patients received mismatched donor HCT. In this cohort of patients, 515 (93%) underwent alloHCT for hematologic malignancies - leukemia: 356 (64.3%), myelodysplastic syndrome: 122 (22%), and other hematological malignancies: 37 (6.7%) while 39 (7%) underwent alloHCT for non-malignant indications. Total Body Irradiation based conditioning regimen was administered in 177 (32%) patients. Among all 554 patients, 540 (97%) attained engraftment. Median post-HCT rATG exposure was 47mg*d/L (range 0 - 101 mg*d/L). A decreasing post-HCT AUC (optimum &lt;30 mg*d/L) was associated with higher probability of CD4+IR (p&lt; 0.0001, Figure 1a); lower NRM (p=0.03, Figure 1b) and improved OS (p=0.05, Figure 1c). Patients who attained CD4+IR earlier had lower rates of NRM (p&lt;0.0001, Figure 1d). On further assessing rATG exposure post allo-HCT by three cut -off levels (&lt;30mg*d/L, 30-55 mg*d/L and &gt;=55 mg*d/L), time to CD4+IR varied depending on the ATG exposure (Figure 1e). In multivariable cox models, post-HCT rATG exposure &gt;=55 mg*d/L was associated with an increased risk of NRM as compared to the lower exposure of &lt;30 mg*d/L (HR: 4.11, CI: 1.52, 11.2, Figure 1f), and inferior OS (HR: 2.03, CI: 1.03,4.00, Figure 1g). In addition, post-HCT rATG exposure &gt;=55 mg*d/L was associated with a higher risk of acute GVHD (HR: 2.28, CI: 1.01, 5.16, Figure 1h). In patients with hematologic malignancies, post-HCT rATG exposure was not associated with relapse (HR: 0.73, CI: 0.31,1.7). In the entire cohort of 554 patients, 9 (1.6%) patients had graft rejection: 1 primary rejection in the post-HCT ATG exposure &lt;30mg*d/L group, 6 secondary rejections in the post-HCT ATG exposure of 30-55 mg*d/L group and 2 secondary rejections in the post-HCT ATG exposure &gt;=55mg*d/L group. Among all patients, 204 (37%) died secondary to reasons such as relapse of disease: 73 (36%), infection: 51 (25%), GVHD: 40 (20%), toxicity/organ failure: 29 (14%) and other causes: 11 (5%). Conclusions: In a large cohort of patients who underwent ex vivo CD34+ selected alloHCT, higher post-HCT rATG exposure led to higher NRM, a paradoxical increase in GVHD, and lower OS driven by poorer CD4+ IR. The increased rates of GVHD with higher post-HCT exposure may be related to increased infections in these cohorts, though this needs to be explored further. Individualizing rATG dosing by PK targeting to a low post-HCT rATG exposure may improve outcomes. We intend to validate these results in a forthcoming prospective clinical trial. Figure 1 Disclosures Scordo: McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Curran:Celgene: Research Funding; Novartis: Consultancy, Research Funding; Mesoblast: Consultancy. Kernan:Amgen: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. O'Reilly:Atara Biotherapeutics: Consultancy, Patents & Royalties: EBV-specific T-cell bank, Research Funding. Prockop:Mesoblast, Inc,: Consultancy, Honoraria, Research Funding; Atara: Research Funding; Jasper: Research Funding. Scaradavou:Excellthera: Membership on an entity's Board of Directors or advisory committees. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Giralt:OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; KITE: Consultancy; MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; TAKEDA: Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding. Perales:Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boelens:Bluebird Bio: Consultancy; Advanced Clinical: Consultancy; Race Oncology: Consultancy; Bluerock: Consultancy; Omeros: Consultancy; Avrobio: Consultancy; Takeda: Consultancy.