Academic literature on the topic 'P 25.5 UL 2009 R674'

نظرية الأهلية: دراسة تحليلية مقارنة بين الفقه وعلم النفس، هدى محمد حسن هلال، هيرندن: المعهد العالمي للفكر الإسلامي، 2011م، 340 صفحة. علم النفس والعولمة؛ رؤى مستقبلية في التربية والتنمية، مصطفى حجازي، القاهرة: المركز الثقافي العربي، 2010م، 335 صفحة. أزمة علماء النفس المسلمين، مالك بدري، عمان: مركز ديبونو لتعليم التفكير، 2010م، 84 صفحة. إسلامنا والتراث "نحو تقويم الخطاب الديني"، أحمد عبده ماهر، وأحمد عبد الرحيم السايح،خاص: أحمد عبده ماهر، 2010م، 280 صفحة. المعرفة والسلطة في التجربة الإسلامية "قراءة في نشأة علم الأصول ومقاصد الشريعة"، عبد المجيد الصغير، القاهرة: رؤية للنشر والتوزيع، 2010م، 616 صفحة. التبادل الاقتصادي وضبطه بمقاصد الشريعة: دراسة مقارنة، ثناء محمد إحسان الحافظ، بيروت: دار الفكر المعاصر، 2010م، 480 صفحة. الدليل المبسط في مقاصد الشريعة، محمد هاشم كمالي، هيرندن: المعهد العالمي للفكر الإسلامي، 2011م، 48 صفحة. مقاصد الشريعة: دليل للمبتدئ، جاسر عودة، هيرندن: المعهد العالمي للفكر الإسلامي، 2011م، 76 صفحة. Religion and Spirituality in Psychotherapy: An Individual Psychology Perspective, Thor Johansen, New York: Springer Publishing Company; 5 edition (December 7, 2009), 240 pages. Conceptions of Islamic Education: Pedagogical Framings (Global Studies in Education), Yusef Waghid, Switzerland: Peter Lang Publishing, First printing edition (May 25, 2011), 160 pages. Nature and Technology in the World Religions (A Discourse of the World Religions), P. Koslowski, Dordrecht, Netherlands: Kluwer Academic Publishers, (July 29, 2011), 166 pages. Imam Bukhari and the Love of the Prophet- pbuh, (Al-Hidayah Series), Muhammad Tahir-ul-Qadri, London: Minhaj-ul-Quran International (MQI), July 30, 2009, 148 pages. Hadith: Muhammad's Legacy in the Medieval and Modern World. Jonathan Brown, London: Oneworld (June 1, 2009), 304 pages. Light From the East: How the Science of Medieval Islam Helped to Shape the Western World, John Freely, London: B. Tauris (April 12, 2011), 256 pages. للحصول على كامل المقالة مجانا يرجى النّقر على ملف ال PDF في اعلى يمين الصفحة.

Abstract Background The inflammatory and immune response in tumor microenvironment plays a critical role in cancer progression. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic factor in solid and lymphoid malignancies. We explored the association of NLR with response to chemotherapy and overall survival (OS) in patients with relapsed/refractory acute myeloid leukemia (RR-AML). Methods A single-center retrospective study was conducted, including 63 adult RR-AML patients who underwent salvage therapy at the University of Wisconsin from 2009 to 2018. Demographic, clinical and pathologic factors were ascertained at the time of RR-AML diagnosis. Refractory AML was defined as failure to achieve remission and <50% reduction in myeloblasts after one or more courses of induction chemotherapy according to the Center for International Blood and Marrow Transplant Research (CIBMTR) reporting criteria. Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and Kaplan-Meier analyses, using log-rank test, were performed. Cox regression analyses were conducted to correlate factors with OS. Hazard ratios (HR) and adjusted HR (aHR) with 95% confidence intervals (CI) were obtained. Statistical significance was considered at P<0.05. Results The study included 63 patients with relapsed (57%) or refractory (43%) AML. Median age was 58 years and 59% of patients were male. AML was classified according to WHO 2016 guidelines as AML with recurrent genetic abnormalities (25%), myelodysplasia (MDS)-related AML (25%), therapy-related AML (6%) and AML not otherwise specified (43%). Cytogenetics were good (5%), intermediate (68%) and poor (27%) with normal (46%), complex (17.5%) and trisomy (14%) being common karyotypes. Frequent molecular abnormalities were NPM1 (21%), FLT3-ITD (17.5%), FLT3-TKD (8%), DNMT3A (6%) and CEBPA (5%). AML risk status was good (19%), intermediate (36.5%) and poor (44.5%), based on cytogenetic and molecular abnormalities as defined by the ELN 2017 and NCCN 2018 guidelines. Extramedullary disease was present in 11% of patients. Prior hematopoietic stem cell transplant (HSCT) was performed in 13% of patients. Median values for clinical factors were: hemoglobin 9.2 g/dL, platelets 43 K/uL, leukocytes 1.7 K/uL, neutrophils 262 /uL, lymphocytes 820 /uL and LDH 211 U/L. Median bone marrow cellularity was 50% with 35% myeloblasts. Median NLR was 0.22 (mean 1.54) and 11% patients had NLR of 3 or more. Salvage chemotherapy included MEC (71%), CLAG-M (24%) and CLAG (5%). Complete remission (CR) was noted in 36.5% patients, 8% of patients had CR with incomplete hematologic recovery (CRi) and 55.5% patients were refractory. Thirty patients (48%) received HSCT, of which 40% (n=12/30) were refractory or relapsed. After index salvage regimen, about half of patients received one (33%) or two (16%) lines of further chemotherapy. At last follow-up, 32% of patients were in CR and 62% had relapsed or refractory disease. Nineteen (30%) patients were alive at last follow-up with a median OS of 8.1 months (95% CI 5.0-11.1). Significant correlates of poor OS included MDS-related AML (HR 2.19, 95% CI 1.13-4.27, P=0.021) and therapy-related AML (HR 4.02, 95% CI 1.16-13.90, P=0.028) compared to de-novo AML, poor-risk AML (HR 3.09, 95% CI 1.18-8.10, P=0.022) compared to good-risk AML, refractory to salvage chemotherapy (HR 7.04, 95% CI 3.51-14.14, P<0.001) and high NLR (HR 1.13, 95% CI 1.04-1.23, P=0.003) while HSCT (HR 0.25, 95% CI 0.13-0.48, P<0.001) predicted better OS. Relapsed vs refractory AML was not associated with OS. In age- and gender-adjusted multivariate model, MDS-related AML (aHR 3.85, 95% CI 1.68-8.87, P=0.002), therapy-related AML (aHR 4.72, 95% CI 1.10-20.31, P=0.037), refractory to salvage chemotherapy (aHR 12.93, 95% CI 4.95-33.78, P<0.001), HSCT (aHR 0.12, 95% CI 0.05-0.27, P<0.001) and high NLR (aHR 1.14, 95% CI 1.05-1.25, P=0.004) independently predicted OS. Median OS in patients with NLR of 3 or more was 3.4 months (95% CI 3.2-3.7) versus 9.2 months (95% CI 7.1-11.3) in those with NLR <3 (P=0.040). Conclusion High NLR independently predicts poor OS in RR-AML patients. Our findings warrant further studies with a large prospective cohort to explore the prognostic significance of NLR and incorporate it in AML risk assessment. Disclosures Atallah: BMS: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Pfizer: Consultancy.

Abstract Abstract 4366 Previous studies suggested that cytarabine was not required in the treatment of newly diagnosed acute promyelocytic leukaemia (APL). They suggested that omitting cytarabine in the treatment of APL could reduce treatment toxicity without increasing relapses and affecting survival. No previous study assessed the effect of cytarabine in the treatment of Chinese APL patients. We compared the outcome of APL patients with or without cytarabine in induction and consolidation therapy in Hong Kong Chinese in a local hospital. Method It was a retrospective study of newly diagnosed APL patients from Jan 1996 to Dec 2009. They were divided into two groups. One group was given ATRA (All-trans-retinoic acid) 45mg/m2/day combined with daunorubicin 60mg/m2/day for 3 days plus cytarabine 200mg/m2/day for 7 days as induction therapy. It was followed by two courses of consolidation with daunorubicin and cytarabine and then 2-year maintenance with low dose chemotherapy and intermittent ATRA. Another group was given the same treatment without cytarabine. The remission rate, relapse rate, overall survival and event-free survival were compared in the two groups of patients. Results Eighteen patients with median age of 41 (range 24–62) received cytarabine. 22% of them had initial WBC count >10,000/uL. Eight patients with median age of 42 (range 16–57) received no cytarabine. 25% of them had WBC count >10,000/uL. The complete remission rates were 100% in both groups. The two-year relapse rate was 5.5% (1/18) for cytarabine group and 62% (5/8) for no cytarabine group (p=0.004, Fisher's exact test). The two-year event-free survival was 82% for cytarabine group and 37% for no cytarabine group (p=0.0017). The two-year overall survival was 89% for cytarabine group and 75% for no cytarabine group (p=0.18). The adverse effects profile was similar in both groups. Conclusion The results support a role of cytarabine in addition to ATRA and daunorubicin in the treatment of newly diagnosed APL. The relapse rate was much lower in patients receiving cytarabine. The two-year event-free survival and two-year overall survival were also significantly better in the cytarabine group. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Induction therapy for acute myeloid leukemia (AML) with a cytarabine-anthracycline regimen (7+3) is well-established; however, there is no standard salvage therapy for patients with relapsed/refractory AML (RR-AML). There is a paucity of data regarding outcomes with salvage regimens in RR-AML that include cladribine, cytarabine, and filgrastim with mitoxantrone (CLAG-M) or without mitoxantrone (CLAG), and mitoxantrone, etoposide, and cytarabine (MEC). We compared outcomes of patients receiving CLAG-M, CLAG or MEC as salvage therapy for RR-AML. Methods A multi-center retrospective study was conducted, including 146 adult RR-AML patients who underwent salvage therapy at the University of Wisconsin and Medical College of Wisconsin from 2009 to 2018. Demographic, clinical and pathologic factors were ascertained at the time of RR-AML diagnosis. The Center for International Blood and Marrow Transplant Research (CIBMTR) response criteria were used. Refractory AML was defined as failure to achieve remission after one or more courses of induction chemotherapy. Minimal residual disease (MRD)-negative was defined by the absence of leukemic cells by morphology and flow cytometry (<0.01%). Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and logistic regression analyses were performed for baseline characteristics and response to salvage chemotherapy. Kaplan-Meier analyses, using the log-rank test, were conducted. Cox regression analyses were used to correlate factors with OS. Hazard ratios (HR) with 95% CI were obtained. Statistical significance was considered at P<0.05. Results The study included 146 patients with relapsed (57.5%, n=84) or refractory (42.5%, n=62) AML who received CLAG-M (51%, n=74), MEC (39%, n=57) or CLAG (10%, n=15) salvage chemotherapy. Baseline characteristics were similar between the three groups (all P>0.1). Median age was 60 years (range 22-77 years) and 59% patients were male. AML was classified according to WHO 2016 guidelines as AML with recurrent genetic abnormalities (23%), myelodysplasia (MDS)-related AML (25%), therapy-related AML (8%) and AML not otherwise specified (44%). Cytogenetics were good (5%), intermediate (60%) and poor (36%) with normal (41%), complex (25%), trisomy (8%) and monosomy 5 or 7 (5.5%) being common karyotypes. Among those who had molecular testing (n=119), NPM1 and FLT3-ITD were reported in 21% and 20% patients respectively. AML risk status was good (16%), intermediate (32%) and poor (52%), based on cytogenetic and molecular abnormalities as per ELN 2017 and NCCN 2018 guidelines. Extramedullary disease was present in 13% patients. Prior hematopoietic stem cell transplant (HSCT) was performed in 13% patients. Median lab values prior to salvage regimen were: hemoglobin 9.1 g/dL, platelets 49 K/uL, leukocytes 2.5 K/uL, LDH 231 U/L and bone marrow myeloblasts 28%. Overall response rate was 49% (CLAG-M 55%, n=41/74; MEC 44%, n=25/57, CLAG 40%, n=6/15) with complete remission (CR) rate of 46% (CLAG-M 54%, MEC 37%, CLAG 40%) [P=0.140]. Three percent patients (n=5; CLAG-M=1, MEC=4) had CR with incomplete hematologic recovery (CRi). MRD analysis was available for 83 patients and a trend was seen in MRD-negative CR rates favoring CLAG-M (44%) over MEC (25%) or CLAG (17%) [P=0.128]. Sixty-six patients (45%) received subsequent HSCT (CLAG-M 50%, n=37/74; MEC 44%, 25/57; CLAG 27%, n=4/15) [P=0.245]. At last follow-up, 34% patients were in CR (CLAG-M 42%, MEC 28%, CLAG 20%) [P=0.120]. Fifty (34%) patients were alive at last follow-up (CLAG-M 46%, MEC 23%, CLAG 20%) [P=0.010]. Median OS was 9.7 months (95% CI 6.8-12.6) that was significantly better with CLAG-M (13.3 months, 95% CI 2.4-24.3) compared to MEC (6.9 months, 95% CI 2.9-10.9) or CLAG (6.2 months, 95% CI 2.4-12.6) [P=0.025] Figure 1. In multivariate model adjusted for age, gender and refractory vs relapsed AML, MEC (HR 1.75, 95% CI 1.13-2.71, P=0.013) and CLAG (HR 1.97, 95% CI 1.02-3.79, P=0.043) regimens had worse OS compared to CLAG-M. After adjusting for age, gender, refractory vs relapsed AML and HSCT, CLAG-M remained independent predictor of better OS (HR 0.64, 95% CI 0.42-0.97, P=0.037). Conclusion CLAG-M compared to MEC or CLAG is associated with significantly better OS in RR-AML regardless of age, refractory vs relapsed AML and HSCT. Our findings support the use of CLAG-M as a preferred salvage regimen for RR-AML. Figure 1. Figure 1. Disclosures Atallah: Novartis: Consultancy; BMS: Consultancy; Jazz: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy.

Abstract Abstract 942 Background: Early death in APL, most often due to bleeding, has emerged as the major cause of treatment failure now that curative strategies exist. Despite the routine use of ATRA, EDR remains high (Lehmann et al Leukemia 2011, Park et al Blood 2011). Although the optimal strategy to prevent early death is not clear, the recommendation is to initiate ATRA immediately at first suspicion of the disease without waiting for genetic confirmation. Therefore, we examined the timing of ATRA administration. Methods: To determine time interval from initial presentation to ATRA administration, we retrospectively collected data on all newly diagnosed APL pts presenting between 1992–2009 to 4 institutions: Northwestern University, Chicago, IL (university medical center); Memorial Sloan-Kettering Cancer Center, New York, NY (free standing cancer center); John J. Stroger Hospital of Cook County, Chicago, IL (public hospital); and Rambam Medical Center, Haifa, Israel, (Northern Israel's largest hospital; a tertiary referral center). We also examined 3 other time intervals: presentation to suspicion of APL, suspicion of APL to ordering ATRA, and ordering ATRA to its administration. Results: We identified 205 newly diagnosed APL pts: 46% men, median 48 years (range 1.5–85). Median white blood cell (WBC) count at presentation was 2,100/uL (range 300/uL-222,500/uL); 25% had high risk (HR) disease (WBC >10,000/uL). Median time interval from initial presentation to suspicion of APL was 1 day and median time from suspicion of APL to ordering ATRA was an additional day (table 1). ATRA was ordered on the day APL was suspected in 32% pts, the next day in 31%; 2 days after suspicion in 17%; and after 3 or more days in 16%. 89% received ATRA on the day ordered. At least 1 bleeding episode was identified in 34% of 185 pts with bleeding data available. Bleeding was associated with higher WBC count (p=0.0003) and lower hemoglobin (p=0.027) at presentation. 46 of 186 pts with complete information on time from presentation to administration of ATRA died. 23 (12%) died within 30 days of presentation; comprising half of all fatalities. Causes of death were: hemorrhage −15, sepsis −4, suspected MI −2, pneumonia −1, and sepsis plus differentiation syndrome -1. Among deaths within 30 days, 48%, 22%, 26% and 7% were in 1st through 4th weeks, respectively. 4 (18%) of these 23 pts died before ATRA was administered, all day 1 or 2 after presentation and all from bleeding. Only 15/182 pts received ATRA on day of presentation. Two of these 15 (13%) died within 30 days (none from bleeding). In comparison, 7/40 (18%) who received ATRA on day after presentation died within 30 days (71% from bleeding). 10/127 (8%) who received ATRA on day 2 or after died within 30 days (6 from bleeding). 20% in each group who received ATRA on either day of presentation or day 1 after presentation had HR disease. For this subgroup, if ATRA was administered on the day APL was suspected or one of the following 2 days, EDR was 19% (7/37). However, if ATRA was initiated on day 3 or 4, EDR was 80% (4/5); (p=0.013). 59% received ATRA prior to confirmation and 41% received ATRA on the day APL was confirmed or later. Conclusions: (1) APL was suspected rapidly upon presentation, usually within 1 day and ATRA was almost always administered on the day ordered. (2) However, ATRA was not given to most pts the day APL was suspected and for some 2 or more days elapsed. This time interval contributed to the delay in ATRA administration, suggesting physicians waited for marrow morphology or genetic confirmation before ordering ATRA. (3) Although at these centers a lower EDR (12%) than reported from the SEER database (17.3%) was observed, the current recommendation to give ATRA at first suspicion of APL was often not practiced. (4) There appears to be an association between EDR and timing of ATRA administration; other factors contribute to the EDR including variability in blood product support. (5) Our study argues that educating health care professionals who are the first to encounter APL pts as to the urgency of ATRA administration will reduce early deaths that occur even in the ATRA era. Disclosures: No relevant conflicts of interest to declare.

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 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: JAK2 is located on chromosome 9p24 and includes 25 exons encoding a protein of about 1132 amino acids. JAK2 is one of the four Janus family non-receptor protein tyrosine kinases. JAK2V617F is by far the most prevalent mutation in BCR-ABL1-negative Myeloproliferative neoplasms (occurs in ∼95% of patients with polycythemia vera, in ∼55% with essential thrombocythemia and in ∼65% with primary myelofibrosis) 1, 2. More than 80% of hemochromatosis patients are homozygous for a C282Y mutation in HFE gene, and a smaller proportion are compound heterozygous for both the C282Y mutation and an H63D mutation3. Here we present the first case of an elderly female with concomitant diagnosis of Polycythemia Vera (PV) and hemochromatosis. To our knowledge, there is no literature about the co-existence or associations of these diseases. Case Reports: 75 year old female, former smoker with PMH of hemochromatosis and COPD with recent exacerbation, presented to the oncology clinic after hospital discharge for continuing care of her hemochromatosis requiring phlebotomy. She reports to have had multiple phlebotomies in the past fifteen years. Patient denied any history of liver disease, diabetes, arthralgia, skin pigmentation or sleep problems. Vital signs and examination were within normal limits. Her initial work up reported significantly elevated hemoglobin of 17.4gm/dl, hematocrit of 56.1%, RBC count of 6.98M/UL with MCV 80.4 fl, MCH 24.9 pg and platelet count of 673 K/UL. Peripheral smear showed normal red cell morphology and few giant platelets. Subsequently, further lab testing revealed ferritin of 25.7ng/ml. Her elevated hematocrit was further evaluated and erythropoietin was surprisingly <1mIU/ml. Genetic testing for HFE gene mutation screen was positive for homozygous C282Y mutation. Due to high suspicion for Polycythemia Vera, JAK2 mutation was also tested, which to our surprise, came back positive for JAK2 V617F point mutation. Patient is diagnosed with Polycythemia Vera and Hereditary Hemochromatosis and is recommended to start Aspirin, continue phlebotomy to maintain Hematocrit below 45% and take hydroxyurea for thrombocytosis. Discussion: It is interesting to note the co-existence of two un-related diseases. Franchini M et al analyzed 52 patients with PV for 12 HH gene mutations and found no significant association between the two conditions4. Hannuksela J et al studied C282Y and H63D mutations in 232 patients with hematological malignancies and reported no significant association5. Beaton and Adams in their review article about the myths and realities of hemochromatosis reports an elevated hemoglobin, in hemochromatosis's patient as a myth, based on their review of 634 C282Y homozygous patients at London health Science center, with mean hemoglobin of 145±13 g/L6. Our case re-iterates the importance of clinical suspicion of polycythemia Vera in a hemochromatosis patient with elevated hematocrit and undetectable erythropoietin. The coincidence is, phlebotomy is the treatment for both conditions as long as patient is fairly asymptomatic. References: 1. Ayalew Tefferi; Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1; J Cell Mol Med. 2009 Feb; 13(2): 215-237. 2. Cross NC (2011); Genetic and epigenetic complexity in myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program 2011:208-214. 3. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet1996; 13:399-408. 4. Analysis of hemochromatosis gene mutations in 52 consecutive patients with polycythemia vera. Franchini M1, de Matteis G, Federici F, Solero P, Veneri D. Hematology. 2004 Oct-Dec;9(5-6):413-4. 5. Prevalence of HFE genotypes, C282Y and H63D, in patients with hematologic disorders. Hannuksela J, Savolainen ER, Koistinen P, Parkkila S. Haematologica. 2002 Feb;87(2):131-5. 6. The myths and realities of hemochromatosis Melanie D Beaton, Paul C Adams Can J Gastroenterol. 2007 February; 21(2): 101-104. PMCID: PMC2657669 Disclosures No relevant conflicts of interest to declare.

Introduction: The only cure for sickle cell disease (SCD) is allogeneic hematopoietic stem cell transplant (HSCT) although autologous HSCT of genetically engineered hematopoietic stem cells is promising. Lack of suitable matched related donors (MRD) is a major limitation driving interest in improving outcomes using unrelated donors. While excellent outcomes are achieved with non-myeloablative MRD HSCT in adults (Hsieh et al, 2009 and 2014), results from matched unrelated donor (MUD) HSCT have been limited by excessive graft versus host disease (GVHD) and treatment-related mortality (Shenoy et al, 2016). Here we present updated follow up of our institutional experience using MUD and mismatched unrelated donors (MMUD) in comparison to patients with MRD. Methods: Eligibility for HSCT included frequent pain crises requiring hospitalization and evidence of end-organ damage. Non-myeloablative conditioning with alemtuzumab and 3 Gy total body irradiation (TBI) was used for MRD HSCT (n=7), whereas patients without an MRD were transplanted using MUD, MMUD or haploidentical grafts (n=6) on a previously reported institutional protocol after conditioning with alemtuzumab (54 mg/m2), fludarabine (180 mg/m2), and melphalan (140 mg/m2), using a CD34+ selected graft with CD3+ cell add back. MRD recipients received sirolimus as GVHD prophylaxis. Non-MRD recipients initially received tacrolimus as GVHD prophylaxis (n=1) but subsequently received sirolimus (n=5) due to the first patient developing posterior reversible encephalopathy syndrome (PRES). All grafts were G-CSF mobilized peripheral blood grafts and all patients underwent RBC exchange to achieve Hgb S <30%. Data is reported using n (%) or median (range) and Wilcoxon rank-sum test was used for continuous variables. Results: Median follow up is 21.7 months (range 4.7 - 63.4). Median age for MRD recipients was 28.7 (21.4 - 35.5) years and 22.8 (18.5 - 34.6) for non-MRD recipients. Of note, the MRD group included one patient with a renal allograft from the same donor and another with stage V renal disease awaiting a kidney transplant. All patients where homozygous for hemoglobin S except one who had hemoglobin Sβo -thalassemia in the MRD group, and another heterozygous for hemoglobin S and C in the non-MRD group. Patients in the MRD group received unmanipulated grafts with a median of 14 (6.2 - 16.9) x 10E6 CD34+ cells/kg. Non-MRD recipients received CD34 - selected grafts with a median of 7.8 (4.1 - 15.1) x 10E6 CD34+ cells/kg with 2.2 x 10E5 (0.1 - 2.5) CD3+ cells add back. No growth factors were used post-transplant. All patient engrafted with no cases of graft failure. Median time to engraftment was significantly longer for the MRD group at 25 (22 - 30) vs 19 (13 - 21) days, p=0.003. Two patients in the MRD group developed acute/late acute GVHD (2 grade II), and 3 patients in the non-MRD group (1 grade II, 2 grade III), 2 of which developed in while switching immune suppression due to PRES. All GVHD cases were steroid responsive and resolved. Three patients in the non-MRD group developed PRES and none in the MRD group. There were no cases of treatment related mortality and all patients are alive and free of SCD. As both groups received alemtuzumab, and the non-MRD group received a CD34-selected graft, we examined lymphocyte subset reconstitution at day 100 and 1 year post-HSCT. The most striking difference was in median CD8+ T cell counts at day +100 which were lower in the non-MRD group approaching significance [101 (43 - 2995) vs 6.5 (3 - 2233) cells/uL, p=0.055, for the MRD and non-MRD respectively]. CD8+ T-cell counts were not significantly different at 1 year [402 (184 - 1066) vs 774 (143 - 1002) cells/uL, p<0.99]. Results from other lymphocyte subsets including CD4+ T-cells, NK cells and B cells are shown in table 1 and were not significantly different between the 2 groups. Of note, early donor T-cell chimerism at D100 was not significantly different between MRD and non-MRD groups [27.0 (18.0 - 50.0) % vs 37.5 (3.0 - 80.0) %, p=0.83] whereas at 1-year, MRD group donor T cell chimerism was significantly lower [53.5 (17.0 - 65.0) % vs 82.7 (69 - 90), p=0.01]. Conclusion: We demonstrate excellent outcomes with 100% survival and no graft rejection following matched and mismatched unrelated donor HSCT for adult patients with severe SCD. Larger cohorts are needed to confirm these results and further delineate the impact of T-cell subset reconstitution on early-post transplant complications. Disclosures Assal: Incyte corporation: Consultancy, Research Funding; boston biomedical: Consultancy. Bhatia:BMS: Consultancy; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Bhutani:Sanofi: Membership on an entity's Board of Directors or advisory committees. Lentzsch:Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy. Reshef:Magenta: Consultancy; Kite: Consultancy, Research Funding; Atara: Consultancy, Research Funding; Pfizer: Consultancy; BMS: Consultancy; Pharmacyclics: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Shire: Research Funding.

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.