bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safe and Effective Adoptive T-Cell Receptor Transfer with a High Affinity Single Chain p53(264–272)-Specific TCR
Authors: Echchannaoui Hakim , Petschenka Jutta , Antunes Edite , Theobald Matthias 
Published: October 2019

Abstract
Abstract 4226
Several studies have demonstrated the clinical efficacy of adoptive T cell therapy for targeting cancer. Using HLA-A2.1 transgenic mice, we have demonstrated the feasibility of T-cell receptor (TCR) gene transfer into T cells to circumvent self-tolerance to the widely expressed human p53(264–272) tumor-associated antigen and developed approaches to generate high-affinity CD8-independent TCR. A safety concern of TCR gene transfer is the pairing of endogenous and introduced TCR chains resulting in the potential generation of self-reactive T cells (off-target autoimmunity). Several strategies to favor matched TCR chains pairing and thus enhancing TCR cell surface expression, including optimization of TCR encoding nucleotide sequences, introduction of an additional inter-chain disulfide bond between the TCR α and β chain constant domains, coexpression of both TCR α and β encoding-genes using self-cleaving 2A virus peptide-based retroviral vectors have been applied. However, adoptive transfer of mouse T cells transduced with modified p53-specific TCRs into p53-deficient humanized (A2Kb) mice was inducing lethal autoimmunity due to the formation of self-reactive TCRs infiltrating vital organs, such as spleen, liver and bone marrow. Therefore, an optimized single chain (sc) p53-specific TCR was engineered to avoid the formation of mismatched TCR heterodimers. The safety and therapeutic efficiency of this approach were evaluated in humanized mouse models of adoptive T cell transfer and successfully demonstrated that optimized p53-specific scTCR-redirected T cells (i) do not induce OFF-target autoimmunity and (ii) mediate antitumor reactivity. Importantly, because the expression of p53 antigen on normal tissues raises the concern of potential on-target toxicity, we performed adoptive T cell transfer experiments in humanized mice expressing the Human p53 protein (Hupki mice) and did not observe any sign of TCR gene transfer-mediated GvHD in this model. In conclusion, these mouse studies suggest that the optimized p53(264–272)-specific scTCR could represent a safe and efficient approach for TCR-based gene therapy.

Disclosures:
No relevant conflicts of interest to declare.
Endocrine Sequelae and Metabolic Syndrome in Adult Long-Term Survivors of Childhood Acute Myeloid Leukemia
Authors: Blijdorp Karin , van Waas Marjolein , van der Lely Aart-Jan , Pieters Rob , van den Heuvel Marry M. , Neggers Sebastian J.C.M.M. 
Published: October 2019

Abstract
Abstract 4228

Background:
Survival of childhood acute myeloid leukemia (AML) has increased significantly over the past decades. Improved treatment strategies include intensive chemotherapy, by which stem cell transplantation (SCT) has been replaced in most of the current protocols for more than 80% of the cases. Limited data exist on endocrine late effects in AML survivors treated with chemotherapy only. The current study focuses on the effect of chemotherapy only on endocrine function and components of the metabolic syndrome (MetS) in adult survivors of childhood AML.

Methods:
In this prospective study with a cross-sectionally recruited controlgroup, endocrine function and components of the MetS were assessed in 12 AML survivors (3 females), treated with chemotherapy only, and in 9 survivors of myeloid leukemias treated with SCT, including TBI as conditioning regimen, after a median follow up time of 20 years (range 9–31). Data were compared with those of 60 controls (23 females).

Results:
In survivors treated with chemotherapy only no endocrinopathies were observed, although AMH and Inhibin B levels tended to be lower than in controls. In chemo-only survivors, frequency of the components of the MetS was not different from controls. In transplanted AML survivors one subject was growth hormone deficient, five had thyroid dysfunction and all survivors had gonadal dysfunction. SCT survivors had a higher risk for components of the MetS, especially a significantly higher frequency of dyslipidemia than controls (63% vs. 6%, P<0.001).

Conclusion:
At twenty years of follow up, survivors of AML treated with chemotherapy only did not show an increased risk at most endocrinopathies and metabolic syndrome as compared to healthy controls, which is in contrast to childhood AML survivors treated with SCT. Gonadal function should however be evaluated with care.
SCT: stem cell transplantation;
SCT: stem cell transplantation

Disclosures:
No relevant conflicts of interest to declare.
A Web-Based Decision Support Platform to Reduce Non Evidence-Based Treatment of Hodgkin Lymphoma
Authors: Grund Stephen , Forastiere Arlene , Flood William , Elaine Whyler 
Published: October 2019

Abstract
Abstract 4267

Background:
Published reports indicate 30–40% of oncology treatments deviate from evidence-based standards. Little is known about the extent of deviation from guidelines in Hodgkin Lymphoma, a highly curable cancer.

Methods:
eviti is a web-based decision support platform that incorporates all recognized guidelines (ASCO, NCI, NCCN, ASTRO and others) and supporting literature. An automated precertification code is issued if planned treatment is evidence based and meets payer language- Variances may be discussed in a peer to peer (P2P) with staff oncologists. We analyzed all treatment plans submitted for patients with stage I to IV Hodgkin's lymphoma (all pathology subtypes) between 1/1/2011 and 6/30/2012 to understand reasons for non-compliance with practice guidelines. There were six payers with a total of 605,412 covered lives encompassing 22 states.

Results:
124 treatment plans were submitted, including 37 with radiation treatment as part of the plan or as primary treatment. 48 (39%) received an automatic code, and another 63 (51%) were given preauthorization codes after submission of medical records. 25 treatment plans (20%) required a P2P and 7 (6% of all cases) were changed to evidence-based treatments as a result. 5 plans were deemed evidence-based as a result of the P2P, while13 plans (10%) did not meet evidence-based standards and did not receive a code for pre-certification even after a P2P. 3 of these were resubmitted with evidence-based plans. The most common deviations were; 1.Use of supportive drugs not consistent with guidelines 6 cases (6%); 2. Non evidence-based therapeutic regimens 2% (2 cases); 3. Non evidence-based variation in dose and/or schedule of chemotherapy 2% (2 cases). 4. Use of IMRT with IGRT.

Conclusions:
Decision support for automated pre-certification reduced non- evidence-based treatment of Hodgkin lymphoma from 16% (20 cases) to 8% (10 cases). A Web-based, point of care decision-support platform connecting providers and payers can reduce unwarranted variability, improve quality and reduce payment for unwarranted care. It facilitates analysis of variations from accepted standards of care for any hematologic malignancy at a granular level. Any such tool should promote compliance with evidence-based cancer care but allow flexibility for medically justified variances.

Disclosures:
Grund: eviti: Employment. Forastiere:eviti: Employment. Flood:eviti: Employment. Elaine:eviti: Employment.
Hospital Demand for Blood Components in Ontario Correlates with Selected Diagnostic and Procedural Activities
Authors: Pendergrast Jacob M , Zagorski Brandon 
Published: October 2019

Abstract
Abstract 4272

Introduction:
Demand for blood components in Canada is a significant and growing contributor to health care spending, but the drivers of this demand remain poorly characterized. While most institutions do not routinely monitor the transfusion requirements of individual diagnoses and procedures, an institution's overall demand for blood components and the types of clinical activities it provides are both well documented. Development of an institution-level inferential model may allow for more accurate demand forecasting for blood components.

Methods:
Hospital shipments of all blood components from Canadian Blood Services (red blood cells, platelets, plasma and cryoprecipitate) in the province of Ontario during the period 2006–2009 were merged with institution-level administrative data containing hospital characteristics and selected diagnostic and procedural codes as obtained from inpatient and ambulatory clinical databases maintained by the Canadian Institute for Health Information. Simple linear correlation and several nested multivariable linear regression models were fitted and compared.

Results:
From 2006–2009, our sample included 137 healthcare facilities, representing approximately 1.4 million units of RBCs, 400 000 units of plasma, 166 000 doses of platelets (defined as either one pool of whole blood-derived platelets or a single apheresis platelet), and 20 000 units of unpooled cryoprecipitate. Institutional demand for these blood components correlated with both hospital-level characteristics and diagnostic and procedural activity data. Institutional demand for red blood cells correlated most strongly with visits for cirrhosis and chemotherapy. Demand for plasma correlated most strongly with visits for cirrhosis and cardiac surgery procedures. Demand for platelets correlated most strongly with bone marrow and solid organ transplant procedures. Demand for cryoprecipitate correlated most strongly with visits for valvular heart disease and cardiac procedures. The strength of these correlations generally remained stable over the four years of analysis, during which time demand for red blood cells and platelets increased, demand for plasma decreased, and demand for cryoprecipitate remained stable.

Conclusions:
In the largest province of Canada, institutional demand for blood components correlate strongly with disease burden measured by diagnostic and procedural codes contained within administrative data.

Disclosures:
Pendergrast: Canadian Blood Services: Research Funding. Zagorski:Canadian Blood Services: Research Funding.
Acute Lymphoblastic Leukemia in Japanese Adolescents; Biology and Toxicity Profile
Authors: Suenobu So-ichi , Sato Atsushi , Takahashi Yoshihiro , Usami Ikuya , Nishimura Shin-ichiro , Hasegawa Daiichiro , Hashii Yoshiko , Suzuki Nobuhiro , Saito Akiko , Kawasaki Hirohide , Yagi Keiko , Horibe Keizo , Hara Junichi , Hori Hiroki , Oda Megumi 
Published: October 2019

Abstract
Abstract 4290

BACKGROUND
In the treatment for acute lymphoblastic leukemia (ALL), adolescents were reported to have worse prognosis than children because of their treatment compliance and response. In this study, we compared clinical features, treatment toxicity and outcome between children and adolescents treated with Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol.

METHODS
The dataset of 1246 eligible patients enrolled in the study between April 2002 and May 2008 was analyzed. The patients were assigned into five categories; SR (PGR, age between 1 and 9 years, WBC<10K and no CNS disease, HR (non SR with PGR; SR with t(1;19), 11q23 other than t(4;11), or M3 marrow on day15), ER (PPR, hypodiploid, unclassified, mixed-lineage, HR with M3 marrow on day15), T (T-lineage) and F (non CR on day 33, T with M3 marrow on day15, or t(4;11)). The patients with Ph+ ALL were excluded from this analyze. The data of 249 patients older than 10 years of age (adolescent group) were compared with those of 705 aged 1 to 5 years and 292 aged 6 to 9 years. The adolescent group included 28 patients older than 15 years of age. The survival rate was estimated with Kaplan–Meier method and two –sided log-rank test using SAS version 9.1.

RESULTS
ETV6-RUNX1 and hyperdiploidy were significantly less frequent in adolescents. The rates of PGR and CR on day 33 in adolescents were significantly lower than those in younger patients (82.7% vs. 90.5%, p<0.01, and 93.1% vs. 97.2%, Ap<0.01, respectively). Five-year overall survival (OS) and event-free survival (EFS) for adolescents were significantly lower than those for children aged 1 to 5 years (78.9% vs. 93.9%, p<0.01, 70.9% vs. 87.5%, p<0.01, respectively). In comparison of adverse effects between adolescent and children groups treated with HR protocol, Grade III and IV neurotoxicity was more frequently observed in adolescents than younger patients (1.99% vs. 0.39%, p<0.01) while infection, pancreatitis or liver toxicity was not significantly different between the two groups.

CONCLUSIONS
The results indicated that poorer outcome in adolescents with ALL may not result from severe treatment toxicities, but link with some specific biology of the leukemic cells.

Disclosures:
No relevant conflicts of interest to declare.
Drug Screening of Primary Human Pediatric Pre-B Cell Acute Lymphoblastic Leukemia (pre-B ALL) Cells in Their Stromal Niche
Authors: Shieh Jae-Hung , Su Tsann-Long , Shieh Jason , Moore Malcolm A.S. 
Published: October 2019

Abstract
Abstract 4295
Pre-B cell acute lymphoblastic leukemia (pre-B ALL) is the most common leukemia in children and is treatable. However, no in vitro nor in vivo models are available to investigate their pathophysiology other than a number of established cell lines that grow in the absence of any cytokine dependence or stromal interaction. We developed a serum-free MS-5 cell (a murine bone marrow stromal cell line) co-culture system that is capable of expanding human primary pre-B ALL CD34+CD19+ cells in vitro. To define a population of pre-B ALL initiating cells, our study reveals that a sorted CD34bright population displays a slow proliferation and maintains a high % of CD34+ cells. In contrast, CD34dim cells/CD34− cells fraction shows a higher proliferation but expanded cells lost CD34 antigens. A group of alkylating molecules (BO-1055, -1090, 1099, -1393 and -1509) was evaluated for proliferation of the pre-B ALL CD34+ cells, the pre-B ALL CD34− cells, human mesenchymal stem cells (hMSC), murine MSC (MS-5 cells and Op9 cells), human bone marrow derived endothelial cells (BMEC), and human cord blood (CB) CD34+ cells, as well as for a week 5 cobblestones area forming (CAFC) assay with CB CD34+ cells. BO-1055 molecule efficiently suppressed the growth of pre-B ALL CD34+ cells (IC50 = 0.29 μM) and CD34− cells (IC50 = 0.31 μM). In contrast, IC50 of BMEC, MSC, CB CD34+ cells and CAFC are >10, >25, 8, and >5 μM, respectively. Pre-B ALL cells expressing green fluorescent protein (GFP) and luciferase (GFP-Lu-pre-B ALL) were created, and a xenograft of the GFP-Lu-pre-B ALL cells to NOD/SCID IL2R gamma null (NSG) mice was established. The in vivo effect of BO-1055 to the GFP-Lu-pre-B ALL cells in NSG mice is under investigation. Our stromal culture system supports primary pre-B ALL cells and closely recapitulates the growth of primary human pre-B ALL cells in their niche in vivo. Based on this co-culture system, we identified BO-1055 as a potential therapeutic agent with an excellent toxicity window between pre-B ALL cells and normal tissues including BMEC, MSC and hematopoietic progenitor/stem cells. The in vitro stromal co-culture system combined with the xenograft model of GFP-Lu-pre-B ALL cells provides an efficient and powerful method to screen new drugs for pre-B ALL therapy.

Disclosures:
No relevant conflicts of interest to declare.
Design of the Hallmarq Trial, a Phase 3 Study of Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) in Adults with Newly Diagnosed, Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia
Authors: Deitcher Steven R. , Silverman Jeffrey A. 
Published: October 2019

Abstract
Abstract 4300

Background:
Adult acute lymphoblastic leukemia (ALL) is a lethal and fulminant disease and one distinct from childhood ALL. There are approximately 2400 new cases per year in the US; approximately 80% of these will be Philadelphia chromosome (Ph) negative. Despite remarkable success in treatment of childhood and adolescent ALL, adult ALL patients are underserved by existing treatment options as reflected by the poor survival rates and extremely poor outcomes in the relapsed setting. Complete response (CR) rates in the front-line setting range from 90% in patients <30 years old to 57% in patients >60 years old and 3-year disease free survival ranges from 47% to 12% respectively. The unmet medical need in adult ALL is most pronounced in those age 60 and older. VSLI was recently granted accelerated FDA approval as a single-agent for the treatment of adults with advanced, relapsed and refractory Ph-negative ALL and has successfully completed a Phase 2 trial as a component of multi-agent therapy.

Trial Design:
HALLMARQ (NCT01439347) is a Phase 3, multi-national, randomized study to evaluate the substitution of VSLI for standard vincristine (VCR) in the induction, consolidation, and maintenance phases of combination chemotherapy in the treatment of patients ≥ 60 years old with newly diagnosed Ph-negative ALL. The chemotherapy “backbone” utilized in this trial is modified from the Cancer and Leukemia Group B 8811 protocol. Asparaginase product usage is optional. The total duration of protocol-specified therapy is up to 24 months. VCR is dosed at 1.4 mg/m2 with a per dose cap at 2 mg. VSLI is dosed at 2.25 mg/m2without a dose cap. A protocol-specified dose reduction algorithm applicable to both VSLI and VCR will be used to minimize Grade 3 neurotoxicity while also facilitating continued dosing. Growth factors (e.g., granulocyte colony-stimulating factor) and bowel regimens (e.g., daily stool softener) are recommended and will be prescribed according to investigator preference and institutional guidelines. The primary endpoint is overall survival (OS) and the study is powered for superiority. Secondary endpoints include remission rate, overall response rate, event-free survival, and safety and tolerability. Minimal residual disease (MRD) at multiple time points and pharmacokinetic parameters are being assessed.

Conclusion:
The HALLMARQ Trial will provide new insights into the frontline treatment of ALL in adults ≥60 years old as well as confirm the clinical benefit of VSLI monotherapy demonstrated in the Phase 2 RALLY Study that supported the initial product approval. HALLMARQ is based on a Special Protocol Assessment with the FDA and is currently enrolling.
*On behalf of the HALLMARQ investigators.

Disclosures:
Deitcher: Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment.
A Phase II Trial of Decitabine and Vorinostat in Combination with Chemotherapy for Relapsed/Refractory Acute Lymphoblastic Leukemia
Authors: Burke Michael J , Lamba Jatinder , Weigel Brenda , Bachanova Veronika , Verneris Michael R. , Miller Jeffrey S. 
Published: October 2019

Abstract
Abstract 4307
DNA hypermethylation and histone de-acetylation are mechanisms involved in gene expression silencing and subsequent drug resistance in leukemia. Agents which target these mechanisms have been investigated in myeloid malignancies but few studies have addressed whether they have a role in lymphoid leukemia. We conducted a clinical trial evaluating the tolerability and efficacy of Decitabine and Vorinostat followed by chemotherapy for relapsed/refractory acute lymphoblastic leukemia (ALL). Patients 0–60 years of age were eligible. Protocol therapy included Decitabine (15mg/m2 iv) and Vorinostat (230mg/m2 PO div BID) days 1–4 followed by vincristine, prednisone, PEG-Asparaginase and doxorubicin. Fourteen patients with a median age of 16 (range, 3 – 54) years have been enrolled to date. Five patients failed prior allogeneic transplantation. The most common non-hematological toxicities (grade >3) at least possibly related to Decitabine and/or Vorinostat were infection (grade 3; n=6) and fever (grade 3; n=3). There was a single grade 5 toxicity related to the chemotherapy backbone. Bone marrow samples (n=11) were evaluated using the DNA LINE global methylation analysis. A decrease in total methylation was found in 10 patients comparing baseline and day 5 (4/10 showing significant reductions in hypermethylation (T-test p<0.01). Eight patients were evaluable for response. Complete remission without platelet recovery (CRp) was achieved in 4 patients, PR in 2 patients, SD and PD in 1 patient each for an overall response rate (CRp + PR) of 75%. Six patients were inevaluable for response based on not having an end of treatment marrow evaluation due to disease progression (n=2; days 4 and 16), toxic death (n=1), ineligibility (n=1) and physician/family request (n=2). The combination of Decitabine and Vorinostat for patients with relapsed ALL leads to changes in methylation patterns in the leukemic blasts. The use of these agents followed by chemotherapy appears tolerable and efficacious in patients with relapsed ALL. This study is continuing to accrual and is registered at www.clinicaltrials.gov as NCT00882206.

Disclosures:
Off Label Use: decitabine for relapsed ALL vorinostat for relapsed ALL.
Late Clearance of Circulating Leukemic Blasts (CBs) During Induction Therapy (IT) Is a predictive of Refractory Adult Acute Myeloid Leukemia (AML)
Authors: Muslimani Alaa , Rifai Aya , Chisti Mohammad Muhsin Muhsin , Margolis Jeffery , Nadeau Laura , Jaiyesimi Ishmael , Huang James 
Published: October 2019

Abstract
Abstract 4319

Background:
CBs are highly variable at diagnosis and during the course of IT in AML patients. Assessing response to IT carries a huge implication on the prognosis of individual patient with AML. Our study investigates whether late clearance of CBs during IT using standard cytarabine + anthracycline regimen is associated with refractory phenotype.

Methods:
We retrospectively reviewed the chart of 83 AML patients (43 males, 40 females, mean age 61.7) who received standard cytarabine and anthracycline regimen during induction between January, 2000-January, 2011 at William Beaumont Health System. Data collected include complete blood count with blast count during course of induction, and bone marrow response. AML is considered refractory if morphological evaluation, flow cytometry or cytogenetic study was positive in the first bone marrow post induction. Response to IT was assessed according to Cancer and Leukemia Group B (CALGB) criteria as complete remission versus residual leukemia or treatment failure (failing to achieve complete remission).

Results:
We noted that 57 of 83 patients (68.7%) showed CBs at the time of diagnosis. During the IT, CBs clearance occurred within 7 days (early clearance) in 38 of these 57 patients. The remaining 19 patients had CBs persistent more than 7 days (delayed clearance). The frequency of bone marrow residual disease at count recovery post IT was significant higher in patients with late clearance and those with early clearance (84% vs 42%, p=0.0015). Further analysis of data showed the frequency of bone marrow residual disease was not significantly different between patients with no CBs at the diagnosis and those with early clearance of CBs (38% vs 42%, p=0.8).

Conclusion:
Adult AML patients with persistent CBs >7 days during IT with standard induction cytarabine and anthracycline regimen are more likely to have induction failure. CBs clearance can be used as an early assessment of response to the IT.

Disclosures:
No relevant conflicts of interest to declare.