bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation-Based Drug Value Framework in Hodgkin Lymphoma
Authors: Oren Ohad 
Published: October 2019

Abstract
Background
Currently available drug value frameworks integrate data about a medication's benefits and risks. However, the strength of the research data supporting the use of one medication versus another is highly variable. The greater the number and quality of well-conducted trials underlying a certain intervention, the stronger its potential favorable contribution to public health. Drug value should therefore also be a function of the magnitude of clinical evidence gleaned from high-quality clinical trials.
Methods
We propose an investigation-driven value framework that determines the merit of a drug based on the overall available evidence, including the rigour of relevant trials. The NCCN Hodgkin Lymphoma guidelines were reviewed and data collected about commonly used regimens for Classic HL. Value scores were determined for each drug combination.
Results
A model was designed incorporating information about the number of RCTs conducted, the total number of participants enrolled, and the generalizability to real-world populations, in addition to the drug's efficacy, significant toxicity and cost (Figure 1). Practice-changing trials supporting each of the currently-endorsed regimens were collected from the HL NCCN guidelines (ABVD, 4; Stanford V 4; Esc BEACOPP 2). The average number of participants per trial was higher for ABVD (1,126) and Esc BEACOPP (1,890) than for Stanford V (267). The generalizability score for the three compounds was 0.5 (ABVD), 0.25 (Stanford V) and -1 (Esc BEACOPP). The mean 5-year overall survival rate was higher in the case of ABVD (96.2%) and Esc BEACOPP (96.1%) compared with Stanford V (92.0%). The toxicity score was 1.24 (ABVD), 3 (Stanford V) and 2.5 (Esc BEACOPP). Using a multi-factorial value scoring system, ABVD, Esc BEACOPP and Stanford V obtained 11.5, 9.5 and 8.5 points, respectively. A scoring system that focused on traditional factors alone (efficacy, toxicity, cost) yielded different scores (ABVD, 7.7; Stanford V 6.7; Esc BEACOPP, 6.5).
Conclusion
The robustness of clinical trials investigating anti-cancer regimens deserves special consideration when defining drug value. Three high-quality trial characteristics help stratify common regimens in HL into higher/lower value strata using a simple, easy to use algorithm.

Disclosures
No relevant conflicts of interest to declare.
Allogeneic Stem Cell Transplantation after Exposure to Checkpoint Inhibitors: Graft Versus Host Disease and Non-Relapse Mortality in Pooled Analysis
Authors: Dada Reyad , Binyam Usman 
Published: October 2019

Abstract
Objectives: Relapsed cHL patients after autologous stem cell transplantation with treatment sensitive disease are usually potential candidates for curative allogeneic stem cell transplantation (HCT). However, there are some concerns around performing such procedure after treatment with checkpoint inhibitors.
Methods: We collected published data of patients undergoing allogeneic (HCT) after treatment with checkpoint inhibitors. Abstracts of recent conferences (2015-2017) (ASCO, ASH, EBMT) were also included. Results (cohort 1) were compared with safety of recent studies with allogeneic HCT in cHL (2015-2018) without prior exposure to checkpoint inhibitors (cohort2). Only studies reporting on outcome of ≥3 patients were considered. Two reviewers studied the publications independently and matched extracted data. In case of author/group duplication, the publications were jointly rescanned by the reviewers and unified decision was taken whether the reported cohorts are the same. In case of confirmed duplication, the most recent report or the one with more detailed information was chosen. End points were rates for grade 3-4 acute GVHD, chronic GVHD and Non-relapse mortality (NRM).
Results: Total of 259 records with 1100 patients were screened. Mean number of checkpoint inhibitors cycles received prior to allogeneic HCT was nine (range 1-38). Grade 3-4 acute GVHD in cohort 1 was 28% (95% CI, 20-37%) in comparison with 8% (95% CI, 6-10%) in historical cohort. Chronic GVHD was observed in 26% (95% CI, 19-36%) versus 29% (95%, CI 26-31%) respectively. In cohort 1, NRM rate was 15% (95% CI, 9-23%) which remained relatively stable after 6 months of allogeneic HCT versus 19% in cohort 2. Only 6.6% deaths were attributed to GVHD while the remaining 7.4% deaths were due to other complications of allogeneic HCT. Other relevant results will be presented at the 60th Annual Meeting of the American Society for Hematology in December 2018.
Conclusions: This is the largest pooled analysis of its kind published so far. Our results suggest that allogeneic stem cell transplantation after checkpoint inhibitors is feasible and not associated with higher mortality. However, careful consideration should be given for prevention, early detection and effective treatment of GVHD in these cases.

Disclosures
No relevant conflicts of interest to declare.
Early Diagnosis of an Infant with Gaucher's Disease Type 3. Case Report
Authors: Bello Adriana C. , Cortez Rossana 
Published: October 2019

Abstract
Background
Gaucher's disease is a rare autosomal recessive disorder that results from the deficiency of the enzyme glucocerebrosidase, causing deposition of glucocerebroside in cells of the macrophage-monocyte system.
Type 3 disease has varied presentations, with neurologic involvement, in addition to progressive hepato-splenomegaly, anemia, thrombocytopenia and skeletal manifestations.
Case Report
2 month old infant girl, was noted to have abdominal enlargement, and was taken to the local rural provider. She was referred to a pediatrician. From there, she was transferred to our institution, after a red blood cell transfusion.
Past history is noteworthy for early passage of a first degree cousin, at the age of 3 months, with hepatosplenomegaly and transfusion requirements.
Parents deny consanguinity. However, they live in a very rural, closed population. A detailed pedigree chart was not obtained.
Physical exam revealed an infant in regular overall conditions, grade IV hepatosplenomegaly. Pale, fussy, hyporexic, with mild breathing difficulty, from enlarged abdomen. She had oculomotor apraxia, at the horizontal gaze. Rest of neurological examination was uneventful.
Dry blood sample was obtained and sent to a specialized laboratory (Greenwood Genetic Center, USA). Bone marrow biopsy showed almost total replacement of normal hematopoiesis, with Gaucher cells.
Beta glucosidase activity was low. GBA gene sequencing, at chromosome 1q21-22, revealed homozygous pL483p mutation, on exon 11. She was 5 months old, when diagnosis of Gaucher's disease type 3, was genetically confirmed.
Imiglucerase was initiated, biweekly, at 60 unit/kg. Dose was increased, on a monthly basis, up to 120 unit/kg. Ambroxol was also started, as a chaperone therapy 15mg/kg/d, as per recent literature (Narita et al, Ann Clin Transl Neurol 2016 Feb 2;3(3):200-15), providing increased glucocerebrosidase activity, in the cerebrospinal fluid, with improvement of neurologic symptoms.
Blood counts, including platelets, normalized shortly after starting enzyme replacement therapy. Neurologic milestones, growth and constitutional features, are adequate for age.
Hepatosplenomegaly has decreased with ongoing therapy, and we expect it will continue to ultimately improve, with treatment. She is now 14 months old.
Conclusion
Gaucher's disease is a rare condition that should be considered in an infant with hepato-splenomegaly and low blood counts, and or bleeding manifestations. Gold standard for diagnosis should be sought by the enzyme measurement, and molecular confirmation.
Enzyme replacement therapy is the therapy of choice, in these patients.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
A Heterozygous Mutation of G-Protein-Coupled Receptor 25 in a Family with Inherited Thrombocytopenia and Thrombosis
Authors: Yamanouchi Jun , Ikeda Yuichi , Hato Takaaki , Yasukawa Masaki , Takenaka Katsuto 
Published: October 2019

Abstract
Background
Inherited thrombocytopenia is associated with bleeding tendency and no association with thrombotic tendency has been reported. We found a Japanese family with autosomal dominant form of thrombocytopenia associated with arterial and venous thrombosis.
Aims
To identify a causative gene for hereditary thrombocytopenia with thrombosis.
Methods
A propositus was a 42-year-old Japanese woman with thrombocytopenia and deep vein thrombosis (DVT). She had normal activities of antithrombin, protein C, and protein S, and negative results for lupus anticoagulant and anti-cardiolipin antibodies. She has suffered from thrombocytopenia (20 - 50 x 109/L) for at least 20 years. Six members among her family pedigree had thrombocytopenia, and also suffered from thrombosis including mesenteric artery thrombosis, young-onset myocardial infarction, femoral artery thrombosis, repeated cerebral infarction, DVT, and pulmonary embolism. Importantly, the family members with these thrombotic disorders had exclusively thrombocytopenia. Whole exome sequencing was performed with venous blood from the 6 affected and 6 non-affected family members to identify a causative gene for thrombocytopenia.
Results
We identified a heterozygous change (c.764G>T:p.G255V) in GPR25 gene, an uncharacterized G protein-coupled receptor. The mutation was completely linked with thrombocytopenia. The mutated residue was located at the transmembrane domain of GPR25. We generated anti-GPR25 monoclonal antibodies and confirmed that GPR25 was expressed on the platelet surface. The patient's platelets showed the same level of PAC1 (a monoclonal antibody recognizing the active conformation of integrin αIIbβ3) binding and P-selectin expression as platelets from healthy subjects. However, ADP-induced aggregation of patient's washed platelets was enhanced as compared with normal washed platelets. Moreover, the patient's platelets had an increase in thrombin + collagen-induced and A23187-induced Annexin V binding compared with platelets from healthy subjects.
Conclusion
We identified a novel gene mutation responsible for inherited thrombocytopenia and thrombosis that may induce platelet hyper-reactivity.

Disclosures
No relevant conflicts of interest to declare.
Outpatient Autotransplants for Persons with Multiple Sclerosis
Authors: Gomez-Cruz Gisela B. , Gale Robert Peter , Olivares Gazca Juan Carlos , Leon-Peña Andres , Gomez-Almaguer David , Gomez De Leon Andres , Gonzalez-Lopez Elias Eugenio , Ruiz-Argüelles Alejandro , Soto-Vega Elena , Muñoz-Perez Maria Jose , Ruiz-Delgado Guillermo J. , Ruiz-Argüelles Guillermo J. 
Published: October 2019

Abstract
Background. High-dose cyclophosphamide and a haematopoietic cell autotransplant is an effective therapy of multiple sclerosis (MS). This is often done in an inpatient setting using frozen blood cells either blood or bone marrow cells.
Objective. Determine if this procedure can be safely and effectively simplified.
Methods. We developed an autotransplant protocol actionable in an outpatient setting using refrigerated blood cells collected after giving cyclophosphamide, 50 mg/kg/d x 2 d and filgrastim, 10 μg/kg/d. A 2nd identical dose of cyclophosphamide was given 9 d later followed by infusion of blood cells stored at 4º C for 1-4 d. Subjects received rituximab after bone marrow recovery, 100 mg, every 2 mo for 1 y or rituximab, 1 g in 1 dose based on the subject's residence country (Figure 1). The co-primary outcomes were rate of bone marrow recovery and therapy-related mortality (TRM). Secondary outcomes included MS relapse-free survival (MS-RFS) and survival. Cumulative dose of cyclophosphamide was 200 mg/Kg
Results. We treated 426 consecutive subjects. Median age was 47 y (range, 21-68 y). 145 (34%) were male. 84 (20%) had primary progressive MS, 173 (41%), relapsing remitting MS and 169 (39%), secondary progressive MS. Median blood cell storage time was 1 d (range, 1-4 d). Median intervals to granulocytes >0.5 x10E+9/L was 8 d (range, 2-12) and to platelets >20 x10E+/L, 8 days (range, 1-12). 412 subjects (96%) were treated as outpatients. Median follow-up is 6 mo (range, 3-30 mo). There was 1 death from TRM. In 304 subjects (71%) with data from neurologic evaluations ≥3 posttransplant median MS RFS is 27 mo (95% confidence interval [CI], 24, 30 mo). Estimated 1 y MS RFS is 85% (80, 90%) with no significant difference between the 3 MS variants. Median survival will exceed 30 mo. An unusual aspect of our study was giving two 2-d blocks of cyclophosphamide 8 days apart rather than 4 d continuously done for 3 reasons: (1) use of cyclophosphamide to mobilize blood cells for the autograft; (2) facilitate using a refrigerated rather than frozen autograft; and (3) decrease toxicity. Our finding of rapid bone marrow recovery using refrigerated grafts is like our experience in persons with plasma cell myeloma and lymphomas receiving high-dose therapy and an autotransplant.
Conclusion. The strategy we developed was actionable in an outpatient setting with rapid recovery of granulocytes and platelets and only 1 early death. Estimated MS-RFS and survival were good. MS variant type did not correlate with MS-RFS or survival.

Disclosures
Gomez-Almaguer: AbbVie: Consultancy; Novartis: Consultancy.
Race, Socioeconomic Status, and Time to Transplantation in Multiple Myeloma
Authors: Pan Darren , Coltoff Alexander , Ozbek Umut , Lin Jung-Yi , Afshar Solmaz , Steinberg Amir 
Published: October 2019

Abstract
Race, Socioeconomic Status, and Time to Transplantation in Multiple Myeloma
Background: Multiple myeloma is the most common hematologic malignancy in blacks. Previous studies have found that black patients undergo autologous stem cell transplant (ASCT) less frequently than their white counterparts, though the reasons for this have not been fully elucidated. To identify whether racial differences in timing of referrals to transplant centers and transplantation may play a role in this observed disparity, we analyzed data from transplants undergone at The Mount Sinai Hospital between 2011 and 2016.
Methods: We retrospectively analyzed 416 black and white patients who received their first autologous stem cell transplant for multiple myeloma at The Mount Sinai Hospital between 2011 and 2016. We compared the time from initial diagnosis to stem cell harvest and the time from harvest to transplant between the two groups while controlling for age, socioeconomic status, and functional status.
Results: In total, 264 white patients and 152 black patients were identified as receiving their first transplant between 2011 and 2016. Data regarding each patient's demographic, date of diagnosis, date of harvest and transplant, and functional status were available. Age, socioeconomic status (as assessed through census data of median income of the patients' zip code), and functional status were considered possible confounders. Linear regression analysis was used to assess differences in transplant timing between races while controlling for these factors. We found that between racial groups, neither the time from diagnosis to harvest (528 days vs. 406 days respectively, p=.95) nor the time from harvest to transplant (113 days vs. 150 days respectively, p=.31) was significantly different. Age and socioeconomic status also did not significantly affect either time point, although patients with higher socioeconomic status had a decreased time from diagnosis to harvest which approached significance (p=0.07) regardless of their race. Finally, better functional status was associated with a shorter time from diagnosis to harvest (p=0.003).
Conclusion: Based on these findings, race and socioeconomic status did not significantly affect expediency of referral to and completion of transplantation following initial disease diagnosis. Further studies are needed to clarify the factors contributing to observed differences in ASCT utilization between blacks and whites.

Disclosures
No relevant conflicts of interest to declare.
Preclinical Evaluation of MAX-40279, a FLT3/FGFR Dual Kinase Inhibitor for Treatment of Acute Myeloid Leukemia
Authors: Wang Yuguang , Bao Hanying , Zhang Nong , Wang Feilan , He Yunsong , Wu Tianzhi 
Published: October 2019

Abstract
Background: In newly diagnosed AML patients, the prevalence is about 30% for FLT3-ITD. FLT3-ITD is associated with disease progression, increased risk of relapse and shorter overall survival. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research.
FLT3-ITD AML patients treated with AC220 developed increased FGF2 expression in marrow stromal cells, which peaked prior to overt clinical relapse and detection of resistance mutations which indicated that inhibition of both FLT3 and FGFR is highly desirable for the development of the next generation of FLT3 inhibitors. We discovered MAX-40279, a dual inhibitor of FLT3 and FGFR for the potential AML treatment.
Methods: MAX-40279 has been tested in the enzyme assays, cellular assays, signal transduction assays and xenograft assays to evaluate their FLT3 and FGFR inhibitory activity; At the enzyme level, FLT3-wt, FLT3-ITD and FLT3-D835Y were compared, and the FGFR subtypes FGFR1, FGFR2 and FGFR3 were profiled. MAX-40279 was dosed orally to SD rats and the drug AUC was calculated and the comparison was made in plasma and bone marrow. KG-1 xenograft model known to have FGFR1-FGFR1 QP fusion and the MV4-11 xenograft known to have FLT3 aberrant were developed to compare the in vivo efficacy as measured by tumor growth inhibition of MAX-40279.
Results: We report here the preclinical evaluation of MAX-40279, a potent, selective, and bioavailable FLT3/FGFR dual kinase inhibitor. MAX-40279 inhibited AML xenograft tumor growth by 58% to 106% without significant body weight loss. MAX-40279 has much higher drug concentration in bone marrow than in plasma. In addition, MAX-40279 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the urrent FLT3 inhibitors (e.g., AC220 and sorafenib).
Conclusion: MAX-40279 demonstrated superior FGFR inhibitory activity and higher bone marrow drug concentration while maintaining similar activity against FLT3-ITD. All of these results supported that MAX-40279 is the next generation FLT3-mutant inhibitor with great potential to overcome the drug resistance via FGF pathway in bone marrow. Now it is in the phase 1 clinical trial in Australia. In this presentation, we will describe the full preclinical profile of Max-40279 and some of the phase 1 clinical data.

Disclosures
No relevant conflicts of interest to declare.
Effects of Overexpressed P2X7 on Leukemia Progression in Mouse Acute Myeloid Leukemia Model
Authors: Feng Wenli , Yang Xiao , Wang Rong , Yang Feifei , Wang Hao , Liu Xiaoli , Wang Lina , Zheng Guoguang 
Published: October 2019

Abstract
P2X7 is one of the P2X family ligand-gated ion channel receptors. High level expression of P2X7 is reported in various malignant cells. High level expression of P2X7 was also detected in leukemia patients, especially in relapsed cases. A hyposensitive P2X7 mutant, N187D P2X7, was cloned from leukemia cells. However, the role of P2X7 on the progression of leukemia was poorly understood. In the present study, we studied the effects of P2X7 receptor in acute myeloid leukemia mouse model.
We established MLL-AF9 induced AML mouse model with high level expression of P2X7 (MA9-P2X7). High level of P2X7 significantly accelerated the progression of leukemia. Homing capability experiment demonstrated that MA9-P2X7 cells had lower homing potential. The apoptotic rate of freshly isolated leukemia cells had no significant difference between two groups. However, both in vitro culture experiments and in vivo BrdU incorporation assay demonstrated that MA9-P2X7 cells had enhanced proliferation potential, i.e. more S and G2/M phase cells but less G0/G1 phase cells. Moreover, upon treatment with Ara-C, though MA9-P2X7 cells were more sensitive to Ara-C, but the mice had shorter survival time. Furthermore, in vitro colony assay and limiting dilution transplantation experiments showed that MA9-P2X7 cells formed more colonies and had a 7.25-folds increase in LICs frequency. We also detected the expression of c-Kit, and the results showed that the majority of MA9-P2X7 cells were c-Kit+, whereas control cells have two populations and more than half of them were c-Kit-. Leukemia mice in MA9-P2X7 group had shorter survival time than those in the c-Kit+ control group.
Our results suggested that leukemia cells overexpressing P2X7 possessed the characteristics of both greater proliferation potential and higher LICs frequency, which contributed to the accelerated progression of leukemia.
This work was supported by grants 81570153, 81770183 and 81170511 from the National Natural Science Foundation of China (NSFC); programs 2016-I2M-2-006 and 2017-I2M-1-015 from the CAMS Innovation Fund for Medical Sciences (CIFMS); grant 17JCZDJC35000 from the Tianjin Natural Science Foundation; and Graduate Student Innovation Fund (2014-0710-1021) from Peking Union Medical College. Z.GG. is a recipient of the New Century Excellent Talents in University (NCET-08-0329).

Disclosures
No relevant conflicts of interest to declare.
Socioeconomic Status and Outcomes Among Mexican Patients Undergoing Allogeneic Stem Cell Transplantation
Authors: Leon Rodriguez Eucario , Rivera Franco Monica M 
Published: October 2019

Abstract
Background: Some specific patient and donor demographic factors have been described and associated with outcomes of hematopoietic stem cell transplantation (HSCT). However, associations with the socioeconomic status (SES) remain controversial as some studies including allogeneic HSCT (allo-HSCT) patients have reported that SES associates with worse long-term outcomes and other studies, including both, allogeneic and autologous HSCT have not found an association between SES and overall survival (OS), non-relapse mortality (NRM) or other outcomes. More importantly, these studies have been performed in developed countries and data from developing regions remains scarce.
Objective: To associate the SES with outcomes in Mexican patients undergoing allo-HSCT at a National Institute of Health located in Mexico City.
Patients and Methods: A retrospective study was performed including 124 consecutive patients undergoing allo-HSCT at the National Institute of Medical Sciences and Nutrition "Salvador Zubiran", from May 1999 to March 2018. SES was established according to the classification assigned by the Department of Social Work (levels I-VII); the lowest level corresponds to 7% out-of-pocket expense (93% subsidized by the Institution) and the highest to 120% (private health insurances). Patients were dichotomized into low SES (levels I-II) and high SES (levels ≥ III). Disease risk index was classified as low, intermediate or high using standard definitions and the HCT-CI score was assigned to each patient. Graft-versus-host disease (GVHD) was evaluated according to NIH guidelines. Endpoints included OS and NRM.
Results: Patient characteristics by SES are shown in Table 1. Age, educational attainment, employment status, and financial support were the sociodemographic characteristics that differed between both groups. There were no differences in GVHD between the two groups. For all the cohort, 30, 100-days, and 1-year NRM was 3.2%, 8.8%, and 14.5%, respectively. Figure 1 shows NRM and OS by SES group.
Conclusion: Although there were differences regarding diagnosis between the two groups (low and high SES), the DRI was the same between them, as well as the HCT-CI. Further, there were no differences between low and high SES in NRM or OS, demonstrating that our HSCT approaches are standardized and all patients can benefit from them despite their financial status, also highlighting that patients with low SES probably had good outcomes as a result of substantial governmental, NGO, and/or institutional subsidy.

Disclosures
No relevant conflicts of interest to declare.