Academic literature on the topic 'P 25.5 UL 2012 L445'

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 Background: The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is the first approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). Discontinuation of ibrutinib has been associated with an adverse prognosis in patients with chronic lymphocytic leukemia and mantle cell lymphoma. However, reasons for discontinuing ibrutinib therapy and the outcomes following discontinuation in patients with WM has not been previously evaluated. Methods: We identified patients seen at our institution between May 2012 and April 2017 who met clinicopathological criteria for WM and received ibrutinib therapy. An IgM rebound was defined as a 25% increase in the serum IgM level (with an absolute increase of 500 mg/dl) following the discontinuation of ibrutinib. Time to events was estimated using the Kaplan-Meier method. Univariate and multivariate logistic regression models were fitted to evaluate the association between clinical variables and the occurrence of ibrutinib discontinuation and an IgM rebound. The Cox-proportional hazard regression model was used to fit univariate and multivariate models for overall survival (OS). P-values &lt;0.05 were considered statistically significant. Results: A total of 189 patients with WM who received treatment with ibrutinib were identified, of whom 51 (27%) have discontinued ibrutinib therapy. The overall cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months was 22%, 25%, 35%, and 43%, respectively. Ibrutinib was discontinued due to progressive disease (PD) in 27 patients (53%). The median time to PD discontinuation was 12 months (95% CI 7-25), and the 12-, 24-, 36-, and 48-month cumulative incidence was 2%, 4%, 7%, and 11%, respectively. Non-PD events caused ibrutinib discontinuation in 24 patients (47%) attributable to toxicity (n=15; 63%), non-response (n=5; 21%), and miscellaneous (n=4; 17%). The median time to non-PD discontinuation was 5 months (95% CI 3-7), and the 12-, 24-, 36-, and 48-month cumulative incidence was 6%, 7%, 10%, and 12%, respectively. A baseline platelet count &lt;100 K/uL (OR 3.85, 95% CI 1.20-12.3; p=0.02) and CXCR4 mutation (OR 3.89, 95% CI 1.74-8.69; p=0.001) were associated with higher odds of ibrutinib discontinuation, whereas a serum IgM level &gt;4,000 mg/dl was associated with lower odds (OR 0.38, 95% CI 0.17-0.86; p=0.02). An IgM rebound was observed in 37 patients (73%) following ibrutinib discontinuation. The cumulative incidence of an IgM rebound at 4 and 8 weeks following discontinuation was 48% and 79%, respectively. An increased risk of an IgM rebound at 4 weeks (72% versus 29%) and 8 weeks (95% versus 66%) was observed for patients with PD versus non-PD discontinuation. Six patients (16%) developed symptomatic hyperviscosity requiring emergent plasmapheresis. Male sex was associated with lower odds of an IgM rebound following ibrutinib discontinuation (OR 0.18, 95% CI 0.03-0.90; p=0.04). Thirty-eight patients (76%) received salvage therapy following ibrutinib discontinuation. The median time to salvage therapy was 5 weeks (95% CI 3.6-8.1). Twenty-seven patients (73%) responded to salvage therapy with the following regimens: combination therapy with an anti-CD20 monoclonal antibody and alkylator (16/22; 73%), proteasome inhibitor (4/5; 80%), or nucleoside analogue (2/2; 100%), BCL2 inhibitor (3/5; 60%), and other (2/5; 40%). Patients without an IgM rebound were more likely to respond to salvage therapy versus those with an IgM rebound (100% versus 62%; p=0.04). Thirteen patients (24%) have not received salvage therapy. Reasons for not receiving salvage therapy include: treatment not required (n=6; 46%), patient choice (n=4; 31%), death (n=2; 15%), and acute myeloid leukemia (n=1; 8%). The median OS was 32 months (95% CI 19-NR) following discontinuation with an estimated 1-, 2-, and 3-year OS of 72%, 56%, and 45%, respectively. Response to salvage therapy was associated with a decreased risk of death following ibrutinib discontinuation (HR 0.18, 95% CI 0.04-0.72; p=0.02) Conclusion: Ibrutinib discontinuation is associated with CXCR4 mutations in WM patients. Rapid increases in serum IgM level often occur following discontinuation, which can result in hyperviscosity syndrome. Patients who must discontinue ibrutinib require close monitoring, and continuation of ibrutinib until initiation of the next therapy should be considered. Disclosures Treon: Pharmacyclics: Consultancy, Research Funding. Castillo: Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding; Millennium: Research Funding; Janssen: Consultancy, Research Funding.

Abstract Background Hematologic toxicity is a common treatment complication of chronic hepatitis C virus (HCV) infection, especially when interferon (IFN) and ribavirin are used. The side effects of treatment are often augmented in cancer patients due to baseline cytopenias. These adverse events often lead to dose reduction or discontinuation of antivirals. Hematopoietic growth factors (GF) and blood transfusions are used to counteract toxicities allowing patients to complete treatment. We aimed to evaluate the incidence and management of hematological toxicity associated with different types of HCV treatment in cancer patients. Methods Medical records of cancer patients treated for HCV infection at MD Anderson Cancer Center between 2009 and 2014 were reviewed. Those seen from 8/2009 to 10/2012 were analyzed retrospectively, whereas those seen from 11/2012 to 7/2014 were prospectively studied. Patients who received combination treatment with peg-IFN and ribavirin (PR), telaprevir or boceprevir plus PR (TBPR), sofosbuvir plus PR (SPR), sofosbuvir with simeprevir (SS) and sofosbuvir with ribavirin (SR) were included in the study. Data regarding treatment interventions (dose reductions and/or discontinuation of antivirals), use of GFs or blood transfusions in the management hematological side effects were analyzed. Categorical variables were analyzed using the χ2 or Fischer's exact test. Results Sixty-five patients were identified (Table). The need for treatment interventions, GFs or blood transfusions was comparable between patients with hematologic malignancies and solid tumors. Seventeen (81%) of the PR group, 13 (93%) of the TBPR group, 6 (67%) of the SPR group, 9 (64%) of the SR group and 0 of the SS group required treatment interventions (p <0.001) (Figure). Twelve (57%) of the PR group, 9 (64%) of the TBPR group, 3 (33%) of the SPR group, 2 (14%) of the SR group and 0 of SS group required the use of GFs (p <0.01). Six (29%) patients of the PR group, 9 (64%) from the TBPR group, 1 (11%) from the SPR group, 1 (7%) from the SR group and 0 from the SS group received blood transfusions (p <0.01). From patients who received GFs (N=26), 2 received epoetin alfa, 11 darbepoetin alfa, 2 filgrastim, 17 pegfilgrastim, 4 eltrombopag and 1 romiplostim. Ten of them (39%) required multiple GFs, with darbepoetin alfa and pegfilgrastim being the most common combination. Combined use of GFs was only needed in those receiving TBPR (56%), PR (33%) or SPR (33%). Overall, 82% of the patients who received treatment interventions, 77% of those who received GFs and 47% of those who received blood transfusions were able to complete HCV treatment. Thirteen patients (62%) from the PR group, 12 (86%) from the TBPR group, 3 (33%) from the SPR group, 2 (14%) from the SR group and 0 from the SS group developed grade 3 or 4 hematologic toxicities (p <0.001). One (25%) of 4 patients receiving eltrombopag developed portal vein thrombosis. No other patients developed side effects attributed to GF support. Conclusions Hematologic toxicity during HCV treatment in cancer patients is common. The use of GFs helps manage such toxicity, allowing completion of antiviral therapy. The newer HCV direct-acting antiviral agents are associated with less hematological toxicity, requiring fewer interventions, GFs and blood transfusions. No hematologic side effects were seen with the IFN-free, ribavirin-free combination of SS. Abstract 4126. Table Characteristics of HCV-infected cancer patients treated with different antiviral regimens PR (N=21)% TBPR (N=14)% SPR (N=9)% SR (N=14)% SS (N=7)% Age, median (range) 54.3 (45-68) 59.7 (49-69) 54.7 (35-75) 62.7 (33-82) 60.9 (46-64) Male gender 13 (62) 6 (43) 4 (44) 8 (57) 4 (57) Type of cancer Solid Hematologic 16 (76)5 (24) 10 (71)4 (29) 4 (44)5 (56) 6 (43)8 (57) 4 (57)3 (43) Cirrhosis 5 (24) 7 (50) 2 (22) 3 (21) 6 (86) Baseline labs, median (range) Hemoglobin (g/dL) Platelets (x1,000 K/uL) Absolute Neutrophil count (K/uL) 12.8 (10-15.9)165 (83-408)1385 (940-6120) 13.5 (9.6-16.3)112 (52-397)2360 (800-4900) 13.8 (8.8-14.2)183 (121-268)2680 (1650-5810) 13.1 (9.8-15.5)179 (57-390)2490 (1040-4040) 13.8 (12.3-16.1)141 (59-239)3000 (1390-5030) FDA-recommended duration of antiviral treatment, weeks 24-48 24-48 12 12-24 12 Duration of antiviral treatment, median (range) 24 (2-48) 19 (3-52) 12 (1-12)* 12 (3-24)* 6 (3-12)* *Patients may still be on treatment. Figure Management of hematologic toxicity during HCV treatment of cancer patients Figure. Management of hematologic toxicity during HCV treatment of cancer patients Disclosures Torres: Genentech,: Consultancy; Vertex Pharmaceuticals: Consultancy, Research Funding; Merck & Co., Inc. : Consultancy, Research Funding; Gilead Sciences: Consultancy.

Introduction: The Bruton tyrosine kinase inhibitor ibrutinib is the only FDA approved therapy for the treatment of symptomatic Waldenstrom macroglobulinemia (WM), and has been associated with high response rates and durable progression-free survival (PFS). Factors associated with depth of response and PFS duration are not well established. We performed a retrospective study aimed at identifying predictive and prognostic factors in WM patients treated with ibrutinib. Methods: We included consecutive patients with a diagnosis of WM treated with ibrutinib monotherapy evaluated at the Dana-Farber Cancer Institute since January 2012 through March 2019. Patients with Bing-Neel syndrome (WM involving the central nervous system) were excluded. Baseline clinical and laboratory characteristics were gathered. MYD88 and CXCR4 mutations were assessed using polymerase chain reaction assays and Sanger sequencing. Responses at 6 months were assessed using criteria from IWWM3. PFS was defined as the time from ibrutinib initiation until last follow-up, death or progression. Univariate and multivariate logistic regression models were fitted for partial response (PR) and very good partial response (VGPR) at 6 months, and Cox proportional-hazard regression models were fitted for PFS. Results: A total of 252 patients were included in our analysis. Selected baseline characteristics include: age ≥65 years (60%), hemoglobin <11.5 g/dl (68%), platelet count <100 K/uL (12%), albumin <3.5 g/dl (39%), b2-microglobulin ≥3 mg/l (70%), serum IgM level ≥7,000 mg/dl (6%), bone marrow involvement ≥60% (54%), previously untreated for WM (33%), time to ibrutinib <3 years (46%). MYD88 L265P and CXCR4 mutations were detected in 98% and 38% of patients, respectively. At 6 months, 71% of patients obtained PR, and 17% VGPR. Multivariate logistic regression analyses showed higher odds of PR at 6 months for hemoglobin <11.5 g/dl (78% vs. 56%; OR 2.8, 95% CI 1.1-6.9; p=0.03) and serum albumin <3.5 g/dl (90% vs. 66%; OR 3.2, 95% CI 1.0-10; p=0.045), while CXCR4 mutations associated with lower odds (44% vs. 82%; OR 0.15, 95% CI 0.06-0.37; p<0.001). Multivariate logistic regression analyses showed higher odds of VGPR at 6 months for b2-microglobulin ≥3 mg/l (21% vs. 3%; OR 3.3, 95% CI 1.1-10; p=0.04) and lower odds for serum IgM level ≥4,000 mg/dl (9% vs. 23%; OR 0.3, 95% CI 0.1-0.8; p=0.02). The median follow-up was 30 months, and the median PFS has not yet been reached. The 5-year PFS rate was 60% (95% CI 48-69%). In the multivariate Cox regression analysis, worse outcomes were seen with CXCR4 mutations (5-year PFS: 45% vs. 71%; HR 2.8, 95% CI 1.4-5.8; p=0.004) and serum albumin <3.5 g/dl (5-year PFS: 36% vs. 68%; HR 2.7, 95% CI 1.3-5.5; p=0.007). A novel PFS risk score was designed using CXCR4 mutational status and serum albumin (Figure), which divided patients into 3 distinct groups: low risk (no risk factors: 43%; 5-year PFS 81%), intermediate risk (1 risk factor: 46%; 5-year PFS 51%) and high risk (2 risk factors: 11%; median PFS 25 months). The PFS difference between groups was statistically significant (p<0.001). The PFS risk score showed consistent results when evaluating previously treated and untreated patients, as well as patients on and off clinical trials. Conclusion: Serum albumin and CXCR4 mutations emerge as important factors predictive of PR at 6 months and also prognostic of PFS in WM patients treated with ibrutinib. A novel PFS stratification tool that separates patients into 3 risk groups was established and would need further validation. Figure Disclosures Castillo: Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; TG Therapeutics: Research Funding. Hunter:Janssen: Consultancy. Treon:Pharmacyclics: Research Funding; BMS: Research Funding; Janssen: Consultancy.

Abstract Introduction: Interleukin 2 receptor-α (CD25) expression on myeloid leukemic blasts may be a marker for chemotherapy-resistant leukemia stem cells (Saito et al., 2010) and has been associated with poor overall survival (OS) in AML patients (pts) <60 years treated with cytotoxic chemotherapy (Terwijn et al., 2009; Gonen et al., 2012; Cerny et al., 2013). The prognostic impact of CD25 expression in older pts remains unclear. We therefore retrospectively analyzed CD25 expression in baseline bone marrow (BM) of newly diagnosed AML pts >60 years enrolled in a Phase I clinical trial combining the CXCR4 antagonist, plerixafor and the DNA methyltransferase inhibitor, decitabine (Roboz et al., 2013). Methods: BM aspirates were available for 69 newly diagnosed older AML pts treated with 1-4 cycles of 5 days of plerixafor combined with 10 days of decitabine. Pts with favorable risk cytogenetic or mutational profiles were excluded from the clinical trial. Multi-parameter flow cytometry was used to evaluate the expression of CD25 in blast and progenitor (CD34+) populations. Cells were gated on CD45dim/SSClo characteristics. Pts were considered positive (CD25+) when greater than 10% of the gated population expressed CD25. Results: Of 69 pts, 58 were evaluable for survival and 57 for response; one pt died prior to scheduled response assessment. Of 58 pts evaluated at baseline (pre-treatment BM), 20 (34.5%) were CD25+ vs. 38 (65.5%) CD25-negative (CD25-). CD25+ pts had significantly inferior median OS (152 days vs. 419 days, p=0.003) and were at higher risk of dying within 1 year of diagnosis, relative risk (RR) 1.58 (95% 1.04-2.41). Similarly, pts surviving less than 1 year had significantly higher percentages of CD34+ cells expressing CD25 than those who lived greater than 1 year (7.82% vs. 4.77%, p=0.028). CD25+ pts were less likely to respond to therapy, RR 1.90 (95% CI 1.23-2.93) and, in turn, pts who were resistant to therapy had higher baseline CD25 expression level than those who responded (7.82% vs. 4.87%, p=0.033). Five CD25+ pts (25%) and 12 CD25- pts (32%) received an allogeneic transplant. Transplanted CD25+ pts had improved OS vs. CD25+ pts without transplant, (median OS not reached (NR) vs. 107 days), p=0.005. In contrast, there was no significant difference in survival between CD25- pts with and without allogeneic transplant, p=0.96. Also, there was no difference in median OS between CD25+ pts receiving transplant vs. CD25- pts (median OS NR vs. 419 days), p<0.40. There was no difference in survival between CD25+ pts with intermediate risk cytogenetics vs. CD25+ pts with unfavorable cytogenetics (OS 153 vs. 172, p=0.77). Lastly, CD25+ pts had significantly worse OS compared to CD25- pts with unfavorable cytogenetics, (median OS 152 vs. 333 days) respectively, p=0.05. Compared to CD25- pts, CD25+ pts were older (median age 74.5 vs. 71.5, p=0.096), more likely to be male (75% vs. 47.3%, p=0.055) and had higher baseline WBC (19x1000/uL vs. 5x1000/uL, p=0.089) and pretreatment lactate dehydrogenase (LDH) (median 365 vs. 271, p=0.04). Analysis of diagnosis BM blast percentage yielded no difference between CD25+ and CD25- pts (62% and 46%, p=0.44). Sixteen (80%) and 4 (20%) of CD25+ patients had intermediate and unfavorable cytogenetics vs. 21 (55%) and 17 (44%) CD25- pts respectively, p=0.09. No significant difference between groups was noted when evaluating the mutational status of TET2, TP53, RUNX1, DNMT3A, NPM1, or FLT3. Conclusions: Interleukin 2 Receptor-α expression on leukemic blasts is known to correlate with poor prognosis and OS in young pts with AML who have been treated with cytotoxic chemotherapy. We have demonstrated that >10% CD25 expression on CD34+ blasts is associated with poor OS and resistance to therapy in AML pts > 60years of age treated with the combination of plerixafor and decitabine. Pts with >10% CD25 expression on CD34+ cells were at increased risk of death within one year and increased risk of resistance to induction therapy. Thirty-four percent of the pts in this study were CD25+, consistent with previous reports (Terwijn et al., 2009). This study highlights the importance of CD25 expression on CD34+ leukemic cells in determining prognosis, OS, response to hypomethylating agent therapy and benefit of transplant in older pts with newly diagnosed AML. Further investigations into the aggressive nature of CD25+ AML, mechanisms of resistance and novel therapeutics are ongoing. Disclosures Roboz: Teva Oncology: Consultancy; Novartis: Consultancy; Sunesis: Consultancy; Astra Zeneca: Consultancy; Glaxo SmithKline: Consultancy; Celgene: Consultancy; Agios: Consultancy; Novartis: Consultancy; Astex: Consultancy. Ritchie:Celgene, Incyte: Speakers Bureau.

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: Presence of advanced OL was recently reported as a risk for poor mobilization in patients with multiple myeloma who had poor HPC collections (Jung et al. J Clin Apheresis 2014; Apr 25. doi: 10.1002). We sought to confirm this finding and also whether poor collection correlated with low peripheral blood CD34+ cell numbers as evaluated by flow cytometry. Patients and Methods: Patients: We performed a retrospective study of patients who underwent autologous HPC collection at our institution between 2005 and 2012 to identify poor mobilizers and mega-mobilizers in a 2:1 ratio for data analysis. We defined poor mobilizers as those who required maximal plerixafor support (4 days) for collection, and mega-mobilizers as those who collected >30 x 106 CD34+ cells/kg in 2 days. We found 79 poor mobilizers, but removed 9 from data analysis because the collection variables of plerixafor timing and G-CSF dose differed from the others, leaving 64 myeloma (MM) and 6 non-myeloma plasma cell dyscrasias (NMPCD) patients for analysis: 41 male, 29 female, age range 43–86 (median 67.5). There were 37 mega-mobilizers: 36 MM, 1 NMPCD: 21 male, 16 female, age range 40–73 (median 61). Cumulative CD34+ cells/kg during leukapheresis and peak peripheral CD34+ cell counts were recorded. Apheresis: Apheresis was initiated using a central venous catheter when the predicted CD34+ cell collection for 30 L of blood processed was at least 1 x 106/kg using a predictive formula (Rosenbaum et al. Cytotherapy 2012; 14(4): 461-6). The volume of blood processed each day was based on the same predictive formula, and ranged from 5 to 30L. Cells were collected on a COBE ® Spectra apheresis machine, software version 7.0, using 1000 mL anticoagulant citrate dextrose (ACD) and 5000 units heparin for anticoagulation at an inlet:anti-coagulant ratio of 31:1, and an inlet flow rate of 150 mL/min with anti-coagulant infused at 5 mL/min. The collection flow rate was set at 1.5 mL/min and 10 mL ACD was added to the component at processed volumes of 10 L, 20 L and 30 L. An infusion of 2 g calcium chloride in 250 mL normal saline (0.9% sodium chloride) ran at 85 mL/h. Flow cytometry: CD34+ cells in peripheral blood and HPC products were quantified by flow cytometry using the ISHAGE protocol. Statistics: Mean peripheral blood CD34+ cells/µL and mean CD34+ cells/kg collected were calculated separately for the mega-mobilizer + poor mobilizer combined group, mega-mobilizer and poor mobilizer groups. All patients were subcategorized into those with ≤10 and >10 OL, and means for CD34+ cells/kg collected and peripheral blood CD34+ cells/uL were compared separately between the ≤10 and >10 OL groups using two-tailed Student’s t-tests and p-values evaluated for significance. Results: For all patients combined (mega + poor mobilizers) there were no significant differences in either peripheral CD34+ cells/µL or mean total CD34+ cells/kg collected between the ≤10 and >10 OL subgroups. Mean CD34+ cells/µL peripheral blood was 276 and 250 for the ≤10 and >10 OL groups, respectively (p=0.73), with means of 27.7 and 23.6 CD34+ × 106 CD34+ cells/kg collected (p=0.41). For the mega-mobilizers there was no significant difference in mean peripheral blood CD34+ cells/µL between the OL (</=10 and >10) groups (722 vs. 709, respectively; p=0.92) or in total CD34+/kg collected (55.8 and 53.8, respectively; p=0.78). For the poor mobilizers there was no significant difference in mean peripheral CD34 cells/µL between the ≤10 and >10 OL groups (27 and 20, respectively; p=0.10); however, there was a statistically significant difference in total number of CD34+ cells/kg collected, 11.9 and 8.4 ×106 CD34+ cells/kg, respectively (p=0.02). Conclusion: No significant difference was seen in mobilization as judged by peripheral blood CD34+ cells/ µL in mega-mobilizers or poor separately or combined, but a difference in the total number of CD34+ cells collected was seen in poor mobilizers. We suggest this difference results from variables in collection protocols, as we have previously shown that both mobilization and collection variables impact total CD34+ cells collected by apheresis (Abuabdou et al 2013; J Clin Aph Dec 18. doi: 10.1002). Disclosures Barlogie: Celgene: Consultancy, Patents & Royalties, Research Funding; Millenium: Consultancy, Patents & Royalties, Research Funding.

Abstract Introduction: Cytomegalovirus (CMV) reactivation remains one of the most serious complications after allogeneic hematopoietic stem cell transplantation (HSCT) occurring in up to 30-50% of HSCT recipients. CMV reactivation can lead to adverse outcomes including end-organ damage and graft failure. Prevention of CMV infection may improve outcomes of HSCT recipients; however, CMV reactivation can still occur in HSCT recipients despite receiving prophylactic acyclovir. In this study, we used prophylactic ganciclovir pre-transplant to reduce the incidence of CMV reactivation and CMV disease. Methods: To reduce the incidence of CMV reactivation and disease, ganciclovir was administered before transplantation (5 mg/kg twice daily intravenously from day −8 to day −2) for all donor and recipient seropositive allogeneic HSCT. This was followed by high dose valacyclovir or acyclovir starting day 0 until one year post-transplant. Patients were monitored weekly with serum CMV PCR through Day 100 post transplantation. Preemptive therapy was started for an elevated CMV viral load. CMV reactivation was defined as a CMV viral load of more than 135 IU/ml. Over the course of the analysis period, two different PCR methods were used for CMV viral load; since 2015 Roche Cobas AmpliPrep/Cobas TaqMan CMV test was implicated. CMV disease was defined as detection of CMV by one of the following diagnostic tests including: culture, immunohistochemistry staining, or histopathology examination accompanied by documentation of disease signs and symptoms of the affected organ. Statistical analysis was performed using SAS version 9.4. Logistic regression models were explored to assess the association of age, graft source, and disease type on CMV reactivation. We performed a retrospective analysis of all recipient or donor CMV seropositive patients who received their first allogeneic HSCT at the University of Virginia between 2012 and 2017. Results: Seventy-nine consecutive patients were treated. The median age was 58 years (range 20 to 72). The most common diagnoses were acute myeloid leukemia (n=39, 49%) and acute lymphocytic leukemia (n=11, 14% ). Graft sources were matched related donor, (n=24, 30%), matched unrelated donor, (n=28, 35%), haploidentical (n=4, 5%) and cord blood (n=23, 29%). 43 patients (55%) received myeloablative (CyTBI, BuCy and FluBu) conditioning. 36 patients (45%) received reduced intensity/nonmyeloablative conditioning (Flu/Cy/TBI+/- ATG, Flu/Cy/ATG ,Flu Mel, Flu Bu and Cy ATG). All patients received calcineurin inhibitor based prophylactic immunosuppressive therapy for GVHD prevention. 24 patients (30%) had CMV reactivation with median time of reactivation of 47 days post-transplant (range 27 to 229). 22 out of the 24 (88%) patients required treatment for CMV reactivation with a median treatment duration of 37 days (range 14 to 315). Patients were treated with either ganciclovir or foscarnet, as clinically indicated. The cumulative incidence of CMV reactivation at day 100 post-transplant was 27% with a 95% CI (18%-37%). The median highest viral load was 2130 copies/ml (range 151 to 3,250,000 copies/ml). There were no patients with biopsy proven CMV disease. There were no deaths attributed to CMV reactivation or disease. The median time-to neutrophil recovery (ANC > 500 k/uL) was 18 days and the median time to platelet count greater than 20,000 k/ul unsupported was 19 days. The incidence of acute GVHD (Grades II-IV) was 25 %. The incidence of significant acute kidney injury defined by serum creatinine of more than 2.5 mg/dL was 2.4 %. 1 year overall survival estimate was 54% with 95% CI (42-65%). In multivariate analysis, patients who received cord blood transplants, were approximately 4 times more likely to have a CMV reactivation (Odds Ratio 3.9 with a 95% CI(1.4-10.9)), p= 0.01, than those who did not. Conclusions:The incidence of CMV reactivation by day 100 of 27% with pre-transplant ganciclovir may be improved compared to historical controls of 30-50%.The use of pre-transplant ganciclovir was associated with no CMV disease, in this single center study.The use of pre-transplant ganciclovir is safe, with low incidence of kidney damage. These data suggest that pre-transplant ganciclovir with Preemptive therapy for viral reactivation should be considered regardless of graft source. Future prospective randomized trials are needed to evaluate strategies for CMV prophylactic regimens. Disclosures No relevant conflicts of interest to declare.

The objective: to establish the frequency, structure and interconnection with accompanying gynecological pathology incidence of patients with uterine leiomyoma by retrospective analysis.Materials and methods. A retrospective analysis of 12241 case histories of patients treated during 2012–2016 in the Department of Gynecology with minimally invasive technologies, beds of fetal medicine and pathology of early pregnancy Khmelnytsky Regional Perinatal Center, as a department of general gynecology, as well as a specialized department assistance to women interested in the preservation and restoration of reproductive function, namely the Department of Family Planning and Operational Rehabilitation of the Reproductive Function of Women SI «Institute of Pediatrics, Obstetrics and Gynecology named Academician OM Lukyanova National Academy of Medical Sciences of Ukraine «.The results of the examination in a specially developed formalized medical history for further input and processing of information were recorded.Results. As a result of the retrospective analysis, it was found that, according to the Khmelnytsky Regional Perinatal Center, the frequency of LM ranged from 17.3% with a gradual increase to 21.6%. Radical interventions were performed in 55.5% of women without a tendency to decrease by age. Only in 5% of cases organ-preserving intervention was performed, and in 8.4% hysteroscopy (HS) was used. However, there is a positive trend to increase the frequency of both conservative myomectomy (CM) and HS over the years. .As a result of the retrospective analysis, it was found that uterine leiomyoma occurred in 824 patients, which amounted at 18.3% of patients. There is a steady increase in the incidence of uterine leiomyoma among patients treated in the family planning and surgical rehabilitation department. Among these patients, to 305 (37%) patients were held underwent surgery (surgical group – SG), such as conservative myomectomy or radical surgery with different approaches. The remaining 519 (63%) women received conservative therapy (conservative group – CG). The mean age of the examined patients was 38,3±0,4 years at women of the surgical group and 39,2±0,3 years at the conservative group. The LM up to 25 years was rare, less than 1% of cases, but in the surgical group four times more often. From the age of 26, the frequency of LM begins to increase in both groups to 8.5% with a sharp increase after 30 years, in 3 times. It peaks at the age of 36-40 years in the surgical group and at 41-45 in the conservative group, with a gradual decrease after 45 years. It peaks at the age of 36-40 years in the surgical group and at 41-45 in the conservative group, with a gradual decrease after 45 years. At women, CG significantly more often LM occurred on the background of chronic inflammatory diseases of the pelvic organs (HZZOMT), at 207 patients (39.9%) against 92 women (30.2%) in HG, p<0.05. Whereas pelvic adhesions were diagnosed in both groups with the same frequency (54 women (17.7%) in CG and 82 patients (15.8%) in CG). With regard to endometriosis, external genital endometriosis was significantly more common in women with CG, namely in 40 patients (13.1%) against 31 women (6.0%) in CG, p <0.05. Whereas internal endometriosis (adenomyosis) in both groups was detected with the same frequency (49 patients (16.1%) in CG and 90 patients (17.3%) in CG). Surgical interventions were dominated by organ-sparing operations (262 patients or 85.9%) against 72 women (23.6%) who underwent radical intervention. Laparoscopy (LS) was used twice as rarely, mostly in infertile women, to remove small leiomatous nodules with a predominantly subserous location (60 patients or 19.7%). At 41 women (13.4%) the submucosal nodes were removed by hysteroresectoscopy. Anemia was significantly more common at women with LM who required surgery (47 patients (15.4%) in HCG versus 48 patients (9.2%) in CG, p <0.05). The infertility among UL occurred in every fourth patient, slightly more often in HG (83 women (27.2%) against 124 patients (23.9%) in CG).Conclusions. The UL occurred in one in five women with a tendency to increase in frequency in this department. One in three women with LM (37%) required surgery, organ-sparing interventions predominated (85.9%), and laparotomy access was preferred (42.6%). For women of the conservative group is characterized by a more frequent combination with chronic inflammatory diseases of the pelvic organs (39.9%), pathology of the endometrium (43.9%) and cervix (20.0%). Infertility occurred in every fourth woman with LM without differences both between groups and between primary and secondary infertility.

Abstract Background: In Chuvash polycythemia (CP) (Problemi Gematologii I Perelivaniya Krovi 1974, 10:30), impaired degradation of hypoxia inducible factor (HIF)-1α and HIF-2α from a homozygous germline VHLR200W mutation leads to augmented hypoxic responses during normoxia (Nat Genet 2002, 32:614). In addition to elevated hematocrit, CP is marked by leg varices, benign vertebral hemangiomas, decreased systemic blood pressure, increased systolic pulmonary artery pressure, and by the defining phenotypes of thrombosis and early mortality (Blood 2004, 103:3924; Haematologica 2012, 97:193). There is no effective therapy. While phlebotomy has been recommended for idiopathic polycythemia by the British Committee for Standards in Haematology (Br J Haematol 2005, 130:174) and is administered to some CP patients, its benefits are unknown. Phlebotomy-induced iron deficiency inhibits PHD2 enzyme, the principal negative regulator of HIFs, which further augments hypoxic responses. This affects the transcription of many genes (BCMD 2014, 52:35). Hypoxia-regulated IRAK1 is augmented in inflammation and may promote thrombosis (Circ Res. 2013, 112:103). Methods: 165 patients with CP were enrolled in a registry between 2001 and 2009 after providing written informed consent. Survival analysis was used to examine the predictors of new thrombosis and death during the follow-up period. mRNA from peripheral blood mononuclear cells (PBMCs) was profiled by Affymetrix Human Exon 1.0 ST Array in 42 of the subjects. Results: The median age at enrollment was 35 years and 90 participants were females, 25 had a history of one thrombosis, 5 of two thromboses and 3 of three thromboses. In the year prior to study entry, 72 had received phlebotomy therapy (Table 1). In July 2015 the median follow-up was 9.0 years (range 1-14.5). During this follow-up period, 30 (18.2%) participants had one new thrombosis, 6 (3.6%) had two new thromboses and 17 (10.3%) died. The median age of death was 55 years (range 16-76) and deaths were related to thrombotic cerebrovascular accident (n = 4), myocardial infarction (n = 4), mesenteric or portal vein thrombosis (n = 3), other major thromboembolic events (n = 2) and trauma or unknown cause (n = 2). Baseline characteristics of older age, prior thrombosis, pentoxifylline treatment, smoking and splenomegaly were independently associated with greater thrombosis risk during follow-up (P < 0.003). After adjustment for these variables, the estimated probability of new thrombosis at 10 years was 26% in those receiving phlebotomies compared to 12% in those not phlebotomized (log rank P = 0.014) (Figure 1). There was also a trend for increased risk of death with phlebotomy: estimated probability 8.7% versus 3.7% (P = 0.15). Examination of gene transcripts affecting thrombosis by logistic regression identified 12 protective and 16 risk genes at 5% false discovery rate. Upregulation of two mRNAs was of singular significance: 1) IL1RAP, a proximal signaling adaptor of IRAK1 (Immunity 1997, 7: 837) and 2) THBS1, encoding thrombospondin1 (Blood 2015, 125: 399). Both genes have known roles in thrombosis promotion and we previously reported that THBS1 is upregulated in CP (BCMD 2014, 52:35). Further analysis revealed a further upregulation of THBS1 in patients with baseline history of phlebotomy (β=0.41, P=0.046). Conclusion: These findings underscore a high rate of thrombosis and death in patients with CP and reveal a potential role of increased IRAK1/IL1RAP signaling in these complications. They raise the possibility that phlebotomy therapy has a detrimental rather than beneficial effect, possibly contributed to by increased THBS1 expression. Table 1. Baseline characteristics by phlebotomy in the year prior to enrollment. Results in median (interquartile range) or n (%); four without phlebotomy data. No phlebotomy N=89 Received phlebotomy N=72 Age (years) 32 (18-48) 37 (26-49) 0.08 Female gender, n (%) 52 (58%) 34 (47%) 0.16 Smoking, n (%) 18 (20%) 24 (33%) 0.060 History of thrombosis, n (%) 20 (23%) 12 (17%) 0.4 Splenomegaly, n (%) 2 (2.3%) 2 (2.8%) 0.8 ASA treatment, n (%) 27 (30%) 36 (50%) 0.011 Pentoxifylline, n (%) 7 (7.9%) 17 (23.6%) 0.005 BMI (kg/m2) 20.4 (18.3-22.9) 21.6 (19.9-24.6) 0.010 Systolic BP (mm Hg) 109 (100-123) 118 (105-124) 0.6 Diastolic BP (mm Hg) 76 (68-84) 78 (71-83) 0.8 Hemoglobin (g/dL) 18.1 (16.4-21.0) 17.9 (16.0-19.8) 0.5 WBC (per uL) 5.7 (4.6-7.0) 5.5 (4.6-6.7) 0.9 Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.