bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age of Red Blood Cell Units Transfused in Canada.
Authors: Kokolo Madzouka , Tinmouth Alan , Fergusson Dean , Giulivi Antonio , Hebert Paul 
Published: October 2019

Abstract
Abstract 3143
Poster Board III-80

Background
During storage, red blood cells (RBCs) undergo well-described biochemical and biomechanical changes, termed the red cell storage lesion. These changes may affect the ability of stored RBCs to deliver oxygen or have other adverse consequences. The transfusion of older RBCs has been associated with increased morbidity/mortality, and planned or on-going randomized controlled trials are exploring a possible causal relationship between the age of RBCs and mortality/morbidity. However, the age-related characteristics of the RBCs units in hospital inventories and of the RBCs units transfused are largely unknown.

Method
A descriptive observational study from 9 centres from 5 Canadian provinces was conducted. Using a randomly generated schedule, data was collected on one weekday for 30 consecutive weeks. Reports of the RBCs inventories and the transfused RBCs units for all ABO and Rh blood groups were collected and analyzed.

Results
Academic centers contributed more than half of the collected data, both for inventory and for transfused units. Overall, the median age of RBCs units in inventory was 14 days (IQR=10-20) and their median age upon transfusion was 16 days (IQR=12-22). The cumulative proportion of younger blood (less than 8 days) in inventory was 9% (range for individual centres: 5 to 20%) for units in inventory and 5% (range for individual centres: 1 to 17%) for transfused units. The cumulative proportion of older blood (more than 28 days) was 8% (range for individual centres: 6 to 14%) for units in inventory, and 13% (range for individual centres: 9 to 23%) for transfused units. Community centres tended to have the largest proportion of younger units transfused (12%) as well as in inventory (14%).

Conclusion
This study provides important data that may contribute to decision-making regarding blood bank inventory management and age-based transfusion practices. If the results of ongoing studies demonstrate an adverse effect from transfusing older RBCs, then significant changes to the inventory management may be required. In Canada, shortening the shelf-life for storage of RBC units to 28 days may be less problematic, but restricting the age of RBCs transfused to less than 8 days for all RBC units may pose significant challenges.

Disclosures
Tinmouth: Canadian Blood Services: Consultancy; Novartis: Research Funding; CSL: Research Funding; Bayer: Research Funding; Wyeth: Research Funding.
Exploratory in Vitro Study of Red Blood Cell Storage Container with An Alternative Plasticizer.
Authors: Dumont Larry J. , Baker Sharry , Waters Susan L , Herschel Louise , Dumont Deborah F , David Raymond M , Otter Rainer 
Published: October 2019

Abstract
Abstract 3149
Poster Board III-86

Background
The plasticizer di-2-ethylhexyl phthalate (DEHP) is a common component in medical plastics. Unique to the storage of RBC, DEHP is a necessary component of these storage bags, and is required to prevent excessive hemolysis over storage. Due to concerns related to the long term effects of DEHP exposure and issues related to disposal of these materials, there is a drive to replace this component. Our objective is to evaluate a candidate replacement plasticizer (Hexamoll TM DINCH, Cyclohexane-1,2-dicarboxylic acid, dinonylester, branched and linear) compared to control DEHP in an in vitro feasibility study. We hypothesize that the candidate will provide at least equivalent protection against hemolysis for RBC stored in additive solution for 42 days, and periodic mixing of RBC stored in additive solution for 42 days will add additional protection against hemolysis.

Methods
Whole blood was collected into CPD in standard collection sets (Terumo), combined into pools of 2 ABO identical RBC, divided, leukocyte-reduced, centrifuged and separated into plasma and packed RBC, then additive solution (AS-5) was added to the RBC, and the RBC/AS-5 were transferred into 2 study bags (matched pair) for storage up to 42 days under standard blood bank conditions of 4°C. In the first part, both study bags were Hexamoll TM DINCH, and one bag of each pair was mixed once per week, the other was held undisturbed. In the second part, DEHP bags were used as control held 42 days undisturbed, and the DINCH test bag was mixed once per week during storage. Standard in vitro RBC characteristics were determined at days 0 and 42.

Results
DINCH bags mixed weekly retained RBC morphology better, had lower extracellular potassium and had lower hemolysis compared to static storage. There were no detectable differences between DEHP static stored bags and DINCH bags mixed weekly when comparing in vitro parameters.

Conclusion
Periodic mixing of RBC stored in DINCH bags provides additional protection against hemolysis over 42 days of storage. DINCH plasticizer provided at least equivalent protection against hemolysis and potassium leakage for RBC stored in additive solution for 42 days. These initial observations should be extended to larger sample sizes and to in vivo autologous RBC recovery studies. The need for periodic mixing will need to be evaluated further. The plasticizer DINCH may be a viable candidate for replacement DEHP in RBC storage bags.

Disclosures
Dumont: BASF: Research Funding. Baker:BASF: Research Funding. Waters:BASF: Research Funding. Herschel:BASF: Research Funding. Dumont:BASF: Research Funding. David:BASF: Employment. Otter:BASF: Employment.
E3 Ligase c-CBL Mediates Ubiquitination-Proteasomal Degradation of BCR-ABL and Therapeutic Effects against BCR-ABL Leukemia.
Authors: Mao Jianhua , Sun Xiaoyan , Zhang Qun-Ye , Huang Qiu-Hua , Liu Ping , Xie Yinyin , Lu Jing , Chen Saijuan , Chen Zhu 
Published: October 2019

Abstract
Abstract 3257
Poster Board III-1
We previously demonstrated that the cellular level of the fusion oncoprotein BCR-ABL in chronic myelogenous leukemia (CML) could be regulated by the proteolysis via ubiquitin-proteasome pathway and arsenic sulfide (As4S4) could enhance this process to exert therapeutic effects against CML. However, the exact biochemical mechanism and molecules involved, including the ubiquitin E3 ligases of BCR-ABL, their modification sites and the topologic type of ubiquitination remain uncovered. In this work, by using immunoprecipitation (IP) /2D-nano-HPLC/MALDI-TOF-TOF, we found a number of components in ubiquitination process, such as ubiquitin, E1, E2 and E3 ligases in the BCR-ABL protein complex. Particularly, several E3 ligases including the CBL family E3 ligase c-CBL were identified. The in vitro ubiquitination experiments indicated that c-CBL was one of the E3 ligases of BCR-ABL. Overexpression and knockdown experiments of the c-CBL gene revealed it participated in the process of endogeneous BCR-ABL ubiquitination and turnover. The enforced overexpression of c-CBL could enhance the degradation of BCR-ABL and apoptosis of CML cells whereas the down regulation of c-CBL generated opposite effects. Furthermore, we mapped a domain of c-CBL as the interface to form complex with BCR-ABL based on the protein structure prediction. Either the identification of BCR-ABL ubiquitination sites or the interaction experiment among the c-CBL and BCR-ABL are undergoing. Our data thus suggest that induction of c-CBL may be a new therapeutic approach for CML.

Disclosures:
No relevant conflicts of interest to declare.
Loss of Growth Arrest DNA Damage 45a,b (GADD45a,b) Enhances Oncogenicity in BCR/ABL-Driven Chronic Myelogenous Leukemia.
Authors: Sha Xiaojin , Liebermann Dan A. , Hoffman Barbara 
Published: October 2019

Abstract 3264
Poster Board III-1
The bcr/abl oncogene causes chronic myelogenous leukemia (CML) in human. BCR/ABL induces the transformation of myeloid lineage through MAPK, JNK/SAPK, PI3K signaling pathways. Growth arrest DNA damage 45A (GADD45A) and GADD45B are upregulated during myeloid lineage terminal differentiation. They are involved in G2/M cell cycle arrest and apoptosis in response to exogenous stress stimuli through MAPK and JNK/SAPK pathways. To investigate the effect of GADD45A and GADD45B in the development of CML, syngeneic wild type lethally irradiated mice were reconstituted with wild type, gadd45a or gadd45b null myeloid progenitors transduced with a retrovirally expressed 210-kD BCR/ABL fusion oncoprotein. We found that loss of gadd45a or gadd45b accelerated the development of CML-like disease in wild type recipients. BCR/ABL transformed gadd45a or gadd45b deficient progenitor recipients exhibited a significantly accelerated kinetics of increase in the number of WBC and percentage of myeloid blasts in blood compared to mice reconstituted with the same number of wild type bone marrow cells transduced with BCR/ABL. There was also increase in the rate of accumulation of CD11b+Gr1+ cells in the bone marrow and spleen. Using in vitro and in vivo BrdU assays, enhanced proliferation capacity was observed for both BCR/ABL transduced gadd45a and gadd45b deficient myeloid progenitors. BCR/ABL transduced gadd45a and gadd45b deficient primary myeloid progenitors formed more and bigger colonies compared to BCR/ABL transformed wild type progenitors. Impaired apoptosis was showed in BCR/ABL transduced gadd45a deficient myeloid progenitors. These results indicate that both gadd45a and gadd45b function as suppressors of the development of BCR/ABL driven CML, where gadd45a appears to suppress CML via mechanism involving inhibition of cell proliferation enhancement of apoptosis, whereas gadd45b appears to only inhibit cellular proliferation. Dissecting the molecular nature of signaling paths involved in the suppressive function of gadd45a and gadd45b in BCR/ABL driven CML, as well as analysis of Gadd45 in CML patients, is underway.

Disclosures:
No relevant conflicts of interest to declare.
Sub-Morphologic Evidence of Disease Prior to Stem Cell Transplantation Correlates with Inferior Post Transplant Outcome in Childhood Acute Myeloid Leukemia.
Authors: Rosenberg Abby R. , Leisenring Wendy , Sanders Jean E , Woolfrey Ann E , Carpenter Paul A. , Wells Denise A. , Loken Michael R. , Meshinchi Soheil 
Published: October 2019

Abstract
Abstract 328
Hematopoietic cell transplantation (HCT) is utilized in the treatment of a subset of children with acute myeloid leukemia (AML). Although presence of minimal residual disease (MRD) has been associated with a high relapse rate in children with AML, the clinical implications of MRD prior to HCT have not previously been defined. We explored the clinical outcomes associated with the presence of morphologic or sub-morphologic disease prior to HCT. In the period of 1995-2007, 89 patients age 1-18 years received myeloablative conditioning and allogeneic HCT from related (N=36) or unrelated (N=53) donors at Fred Hutchinson Cancer Research Center. At the time of HCT, 63 patients received transplants in complete remission (CR) and 26 had morphologic disease. Among those in morphologic CR, 43 were in 1st CR, 17 in 2nd CR and 3 were in 3rd CR. All patients had bone marrow evaluation for MRD by multi-dimensional flow cytometry (MDF) 2-4 weeks prior to HCT. MDF testing showed that 10 of 63 patients (16%) who received transplants in morphologic CR had MRD levels ranging from 0.3% to 12% (median 3.7%) while the remaining 53 patients had no detectable MRD. The median follow up for the 38 survivors is 6 years (range 1 – 12). Actuarial overall survival at 3 years from HCT for patients who received HCT with and without morphologic disease was 12% vs. 59%, (p<0.001) with corresponding relapse rates of 62% and 24%, (p<0.001), respectively. We subsequently evaluated clinical outcomes for patients who received HCT in morphologic CR with and without evidence of MRD by MDF. Actuarial overall survival for patients who received transplants in morphologic CR with MRD was 15% vs. 67% for those without MRD, p=0.001. The corresponding relapse rate for those with MRD was 65% vs. 17% for those without MRD (p<0.001). Among the 10 CR patients with MRD, 4 had high risk cytogenetics and 6 patients had standard risk cytogenetics. In 53 MRD-negative patients who received HCT in CR, 10 (19%) had high risk, 7 had favorable risk cytogenetics and the remaining 37 (69%) had standard risk cytogenetics. It is notable that the relapse and overall survival probabilities for patients who were received HCT in morphologic CR but with MRD appear similar to those for subjects in morphologic relapse. This data demonstrates that presence of sub-morphologic disease prior to HCT portends high relapse risk and worse post transplant survival. Larger studies are evaluating the full impact of pre-transplant MRD as well and the clinically significant threshold of MRD prior to stem cell transplantation in AML.

Disclosures:
No relevant conflicts of interest to declare.
Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia: Similar Efficacy of Non-Myeloablative and Myeloablative Conditioning; Long-Term Evaluation From the University of Minnesota.
Authors: McClune Brian , Burns Linda J. , DeFor Todd E. , Slungaard Arne , Bachanova Veronika , Brunstein Claudio , Weisdorf Daniel J. 
Published: October 2019

Abstract
Abstract 3385
Poster Board III-273
Allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) is increasingly utilized. We retrospectively analyzed outcomes of HCT for 43 patients with CLL at the University of Minnesota from February 1985 through March 2009 using myeloablative (MA, n=19) (total body irradiation [TBI] 1320 cGY in 8 fractions and cyclophosphamide [Cy] 60 mg/kg x 2 days) and non-myeloablative (NMA, n=24) preparative regimens (fludarabine 40 mg/m2 × 5 days or cladribine 50 mg/m2 IV with TBI 200cGy in 1 fraction and either oral busulfan [Bu] 8 mg/kg divided every 6 hours over 2 days or Cy 50 mg/kg x1 day). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine (CSA) and methotrexate in most MA patients and CSA and mycophenolate mofetil (MMF) for all NMA patients. Median follow up for survivors was 3.3 years. Nine-two percent of NMA HCT took place after 2000 whereas only 26% of MA HCTs happened during this time. Most patients were male (15/19 MA, 20/24 NMA). Time from diagnosis to treatment was nearly twice as long in NMA vs. MA patients (median 72 vs. 39 months) with MA patients progressing through a median of 3 regimens (range, 1-5) and NMA 4 (1-7). Poor-risk cytogenetics (11q-, 17p-) were found in 5 MA and 10 NMA patients. Seven and 13 patients were fludarabine refractory in the MA and NMA groups, respectively. Eighteen patients in the MA group had matched related donors (MRD), while only 10 MRD were amongst the NMA patients. Umbilical cord blood stem cells were used in 12 NMA patients. Neutrophil recovery was slightly faster after NMA HCT vs. MA (median 12.5 vs. 18.5 days; p=0.14). Incidence of acute GVHD, grades II-IV, was similar (p=0.11) but grades III-IV at day 100 was more frequent in the NMA than the MA group (33% vs. 5%, p=0.04). The chronic GVHD incidence was 43% (95% CI, 18-68%) in MA and 29% in NMA (11-47%, p=0.08) patients. Transplant-related mortality (TRM) at 1 year was 42% (20-64) in the MA arm vs. 25% (8-42) (p=0.34) for the NMA group. Relapse rates at 3 years were higher in the NMA HCT group (MA 18% [0-36] vs. NMA 26% [8-44]). Three-year progression-free survival (PFS) was similar in MA (33% [13-55]) and NMA (39% [19-58]) patients (p=0.61). Overall survival at three years was also similar (MA 37%, [15-60] vs. NMA 52%, [30-70]) (p=0.28). While these data suggest that dose intensity may affect TRM and relapse, NMA HCT yields equivalent and encouraging PFS and OS as compared to MA HCT. Our results support further investigation of the role of allogeneic transplantation in the treatment of high risk and advanced CLL.

Disclosures:
No relevant conflicts of interest to declare.
Nonmyeloablative Allogeneic HCT From Unrelated Donors for Multiple Myeloma (MM).
Authors: Rotta Marcello , Storer Barry E , Lange Thoralf , Pulsipher Michael , Shizuru Judith , Bruno Benedetto , McSweeney Peter A. , Agura Edward , Chauncey Thomas , Appelbaum Frederick R , Bensinger William , Sandmaier Brenda M , Storb Rainer F , Georges George E. , Maloney David G 
Published: October 2019

Abstract
Abstract 3391
Poster Board III-279

BACKGROUND:
We previously reported on the outcome of unrelated donor nonmyeloablative hematopoietic cell transplantation (HCT) in 24 patients (pts) with poor-risk multiple myeloma treated by Seattle Consortium Centers (Georges et al BBMT 2007). Here we update our observation to 43 pts with a median follow up of 3.3 years after allografting.

PATIENTS:
Pts with stage II-III MM (n=43) received AlloHCT at 9 centers between May 2000 and September 2008. Forty pts (93%) were matched with their donors for 10 of 10 HLA alleles, and 3 (7%) had single HLA-C allele-level mismatches. Median age at allotransplant was 53 (range 35–67) years. Median number of prior treatments was 2 (1–3), and median number of prior treatment cycles was 8 (5–22). All pts but 2 received at least 1 (range 1-3) high dose-Autograft regimen. Fifteen pts (35%) received planned tandem Auto/AlloHCT as consolidation to first line therapy. Allogeneic conditioning was with 2 Gy TBI plus fludarabine 90 mg/m2 and post allografting immunosuppression was with mycophenolate mofetil (MMF) and cyclosporine or tacrolimus. Disease status at allogeneic HCT included complete remission (CR, 6 pts, 14%), very good partial remission (VGPR, 12 pts, 28%), partial remission (PR, 14 pts, 33%) and refractory disease (RD, 11 pts, 26%).

RESULTS:
All pts had sustained donor engraftment. Twenty-eight (65%) developed grade 2 to 4 acute graft-versus-host-disease (GVHD) and 6 pts (14%) developed 3 to 4 acute GVHD. Twenty-six pts (60%) had extensive chronic GVHD. The overall response rate was 86%, with 18 pts (42%) achieving CR, 14 (33%) VGPR and 5 (12%) PR. With a median follow-up of 3.3 (0.3–8.1) years from allografting, median time to progression was 1.1 years. Median overall survival (OS) has not been reached. Median progression-free survival (PFS) was 1.5 years. Five-year estimated OS and PFS were 51% and 21% respectively. Cumulative incidence of nonrelapse mortality (NRM) at 100 days, 1 and 5 years were 2%, 16% and 19% respectively. The subgroup of 15 pts receiving upfront tandem Auto/AlloHCT had five-year estimated OS and PFS of 72% and 37%, respectively. These results are similar to the outcomes we observed in a series of 102 patients with MM who received upfront tandem Auto/AlloHCT from HLA-identical sibling donor (Rotta et al, Blood 2009) where five-year OS and PFS were 64% and 36%, respectively.

CONCLUSION:
The use of unrelated donors leads to sustained donor engraftment and is associated with a low 1-year NRM (16%). As consolidation of first remission, Tandem Auto/Allo HCT leads to similar 5-year outcomes as HCT from HLA-identical sibling donors.

Disclosures:
No relevant conflicts of interest to declare.
Outcome of HLA-Mismatched Unrelated Donor Allogeneic Stem Cell Transplantation Depends On the Intensity of the Conditioning Regimen.
Authors: Ayuk Francis , Zabelina Tatjana , Bacher Ulrike , Wolschke Christine , Lellek Heinrich , Eiermann Thomas , Erttmann Rudolf , Kröger Nicolaus , Zander Axel R. 
Published: October 2019

Abstract
Abstract 3393
Poster Board III-281

Background:
HLA-mismatched unrelated donors are increasingly becoming a graft source for both standard myeloablative (MAC) and reduced intensity conditioning (RIC) hematopoetic stem cell transplantation (HSCT).

Patients and methods:
We retrospectively analysed the effects of HLA-mismatching in 553 patients undergoing MAC (n = 342) or RIC (n = 211) unrelated donor HLA-matched (n = 289) or -mismatched (n = 264) HSCT with antithymocyte globulin as part of conditioning. Patient characteristics well matched between HLA-matched and –mismatched groups of MAC and RIC patients.

Results:
Median follow-up was 1946 days for MAC patients and 765 days for RIC patients. In MAC patients, there was no difference in the incidence of aGvHD, treatment related mortality (TRM) and overall survival (OS) between recipients of HLA-matched vs. –mismatched allografts. In RIC patients on the contrary, the incidence of aGvHD II-IV (46%, vs. 32.0% p = 0.05), III-IV (18%, % vs. 9.0 p = 0.07) and TRM (35% vs. 20%, p = 0.04) were higher and OS lower (31% vs. 50%, p = 0.001) for recipients of HLA-mismatched vs. –matched transplants. In the RIC patients, female donor gender (RR: 1.8; p = 0.02) and HLA-mismatch (RR: 1.8; p = 0.02) negatively influenced TRM while female donor gender (RR: 1.58, p = 0.03), HLA-mismatch (RR: 1.82, p = 0.003) and bad risk disease (RR: 2.14, p < 0.001) negatively impacted OS.

Conclusion:
Our analyses surprisingly reveal that the positive effect of ATG in HLA-mismatched transplants is only limited to patients undergoing standard myeloablative conditioning. HLA-mismatching and female donor gender negatively impact outcome of RIC allogeneic unrelated donor HSCT despite the use of ATG, highlighting the need for improved strategies.

Acknowledgments
We thank the staff of the BMT unit for providing outstanding care to our patients and the medical technicians for their excellent work in the BMT laboratory.

Disclosures:
Off Label Use: Antithymocyte globulin for prevention of severe GVHD.
Effect of the Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) On Chronic Lymphocytic Leukemia Cells: Apoptosis, Migration Impairment and Drug Sensitization.
Authors: Stamatopoulos Basile , Meuleman Nathalie , De Bruyn Cécile , Delforge Alain , Bron Dominique , Lagneaux Laurence 
Published: October 2019

Abstract
Abstract 3435
Poster Board III-323
Chronic lymphocytic leukemia (CLL) is a neoplastic disorder that arises largely as a result of defective apoptosis leading to chemoresistance. Furthermore, SDF-1 and its receptor CXCR4 has been shown to play an important role in CLL cell trafficking and survival. Since histone acetylation is involved in the modulation of gene expression, cellular differentiation, and survival, we evaluated the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on CLL cells in vitro and in particular on cell survival, CXCR4 expression, migration and in combination with different chemotherapies. Here, we showed that a 48-hour treatment of SAHA induced a dose-dependent decrease in CLL cell viability via apoptosis (n=20, p=0.0032). This effect was also seen in previously untreated and chemoresistant CLL patients. Using specific caspase inhibitors, we demonstrated the participation of caspases-3, -6 and -8, suggesting an activation of the extrinsic pathway. Additionally, SAHA decreased actin polymerization (about 45%) in response to SDF-1 (n=6, p=0.0313). SAHA also significantly decreased CXCR4 mRNA (n=10, p=0.0010) and protein expression (n=25, p<0.0001). Consequently, CLL cell migration in response to SDF-1 (n=17, p=0.0003) or through bone marrow stromal cells (pseudoemperipolesis) was dramatically impaired. Finally, SAHA at low concentration (5μM) could increase sensitivity of CLL cells to fludarabine, flavopiridol, thalidomide or bortezomib. In conclusion, SAHA induces apoptosis in CLL cells via the extrinsic pathway and downregulates CXCR4 expression leading to decreased cell migration. SAHA (alone or in combination with other drugs) represents thus a promising therapeutic approach to inhibiting migration, inducing apoptosis in CLL cell and potentially overcoming drug resistance.

Disclosures
No relevant conflicts of interest to declare.