bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enrollment of Black Americans in Pivotal Clinical Trials Supporting Food and Drug Administration (FDA) Chimeric Antigen Receptor (CAR)-T Cell Therapy Approval in Hematological Malignancies
Authors: Al Hadidi Samer , Schinke Carolina , Thanendrarajan Sharmilan , Zangari Maurizio , van Rhee Frits 
Published: November 2021

Abstract
INTRODUCTION
Black Americans are under-represented in clinical trials that supported FDA drug approvals of various hematological malignancies. (Al Hadidi et.al. Ann Intern Med 2020) CAR-T cell therapy, a new significant advancement in hematological malignancies, is currently approved for use in multiple myeloma (MM), acute lymphoblastic leukemia (ALL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and follicular lymphoma (FL). Enrollment of Blacks in clinical trials that supported those approvals are not well described.
METHODS
We conducted a retrospective analysis of 7 pivotal clinical trials that resulted in approval of of tisagenlecleucel for ALL in 2017, axicabtagene ciloleucel for DLBCL in 2017, tisagenlecleucel for DLBCL in 2018, brexucabtagene autoleucel for mantle cell lymphoma in 2020, lisocabtagene maraleucel for DLBCL in 2020, axicabtagene ciloleucel for follicular lymphoma in 2021 and idecabtagene vicleucel for multiple myeloma in 2021. Prevalence-corrected estimates for enrollment of Blacks were calculated as the percentage of Blacks among clinical trial participants divided by the percentage of Blacks in the disease population (participation to prevalence ratio [PPR]).A range between 0.8 and 1.2 reflects similar representation of Black Americans in the trial and disease population Data on drug products and demographic subgroups were extracted from Drugs@fda which include publically available data from the FDA.
RESULTS
Efficacy was reported in 74% (782 of 1051 patients) of enrolled patients across all the approved CAR-T products. Blacks constituted only 3.6% (28 of 782) of treated patients. Most treated patients had DLBCL (58%) or MM (16%). Two of seven studies (29%) didn't report ethnicity/race and/or included Blacks under others ethnic category. Blacks constituted only 4% of DLBCL patients, 6% of MM patients and 1% across other indications. Adjusted prevalence measures showed very low PPR in MM (0.17), a disease that is more common in Blacks and relatively better enrollment, though still sub-optimal, in DLBCL (PPR: 0.6).
CONCLUSIONS
Blacks are under-represented in clinical trials that supported CAR-T therapies for various hematological malignancies especially in MM. Efforts should be made to enroll more Blacks in clinical trials that include novel, potentially beneficial CAR-T products.

Disclosures
No relevant conflicts of interest to declare.
Ixazomib Based Maintenance Therapy for the Patients with Newly Diagnosed Multiple Myeloma in Real-World Practice
Authors: Zhong Liye , Wei Yongqiang , Ping Baohong , Li Xin , Peng Hongling , Li Yongqain , Tian Yuyang , Liu Zelin , Luo Jun , Su Yongzhong , Chen Haifei , He Yanjuan , Li Hongliang , Wu Congming , Sun Zhiqiang , Shi Keqian , Li Xiaoliang , Zhang Qing , Hu Guoyu , Huang Gang , Huang Zhenqian , Wang Weida , Xia Zhongjun 
Published: November 2021

Abstract
Background
The Phase III TOURMALINE-MM4 Trial demonstrated that the oral proteasome inhibitor, Ixazomib maintenance significantly improved progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing ASCT. However, patient recruitment for clinical trials is highly selective so the extent to which study populations represent real-world patients is unclear. Currently, data validating the use of ixazomib maintenance in clinical practice in Chinese landscape is scarce.
Methods
we conducted a retrospective, observational study of NDMM patients meeting International Myeloma Working Group (IMWG) criteria, who received ixazomib-based maintenance therapy. Data was collected from 26 medical centers in southern China. Enrollment was stratified by risk stage, transplant status and maintenance regimens. The characteristics, toxicities and survival outcomes were recorded.
Results
We included 105 NDMM patients who received ixazomib-based maintenance treatment. Mean age at diagnosis was 59.82 ± 9.80 years, with 62.9% male patients. MM International Staging System (ISS), stage 3 was the most common with 49.04% of patients; 62.86% had an Eastern Cooperative Oncology Group performance score ≥2, and 81.9% with concomitant diseases. By the end of over 70 months follow-up since initial diagnosis, median PFS was 69.45 (95%CI: 31.42-107.48) months, and median OS was not achieved yet. We explored potential influencing factors of progression at the post-maintenance evaluation with a crude model using logistic regression. Difference in PFS was not statistically significant by status at pre-maintenance response, transplantation, maintenance therapy regimens (single/two/three-agent) and dexamethasone in maintenance regimens (p &gt;0.05). Eight patients (7.62%) had grade≥3 treatment-emergent adverse events (TEAEs); 5.7% discontinued treatment because of TEAEs. Common any-grade TEAEs included fatigue (18.1%), diarrhea (16.19%), and peripheral neuropathy (11.43%).
Conclusion
Although there are certain differences in maintenance treatment options for newly diagnosed multiple myeloma patients in real-world practice, the results of our retrospective study support that the ixazomib-based maintenance therapy was effective with acceptable toxicity and single-agent ixazomib maintenance provided enough clinical benefit compared to two or three agents.
Keywords: multiple myeloma, ixazomib, maintenance therapy, real-world practice
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Clinical and Molecular Biology Analysis of Patients with Mantle Cell Lymphoma Resistant to BTK Inhibitor
Authors: Wang Lingli , Yang Ping , Zhang Weilong , Wang Jing , Jing Hongmei 
Published: November 2021

Abstract
Background. BTK inhibitor(BTKi) has transformed the therapeutic landscape for mantle cell lymphoma(MCL). Results of clinical trials demonstrate the efficacy of BTKi to salvage patients with MCL progression, however, mechanism of MCL patients resistant to BTKi is still lack of study.
Aim In order to describe the clinical and molecular characteristics of BTK inhibitor resistance and guide the clinical rational application of BTK inhibitor.
MethodsWe retrospectively evaluated the 19 consecutive patients(relapsed/refractory MCL ,n=15;Primary MCL,n=4) who received a BTKi(Ibrutinib, n = 13; Zanubrutinib, n = 2; Orelabrutinib, n=4;Acalabrutinib,n=1) ,while the MCL still progressed.Fully detailed information of patients, disease characteristics, treatments and the next generation sequencing collected.
Results Median time of taking BTKi and median time of BTKi efficiency were 10 months and 5 months, respectively. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 14 months and 21 months, respectively. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 19 MCL patients, top 10 genes including ATM(47%)、TP53(47%)、KMT2D(32%)、NOTCH2(26%)、BTK(16%)、NSD2(16%)、BIRC3(11%)、CCND1(11%)、NOTCH1(11%)、KMT2C (11%).B cell activation, histone modification, inflammatory response to antigenic stimulus genes were increased in patients with mantle cell lymphoma resistant to BTKi according to Kyoto Encyclopedia of genes and Genomes pathways on gene-set enrichment analysis.
Conclusions Demonstration of ATM and TP53 genes mutations and related pathways opens the door for future investigations in BTKi resistance in MCL patients.

Disclosures
No relevant conflicts of interest to declare.
Response Kinetics of Daratumumab-Based Regimens in Patients with Newly Diagnosed or Refractory/Relapsed Multiple Myeloma
Authors: Wang Jiasheng , Arroyo-Suarez Raul , Tse William 
Published: November 2021

Abstract

Background: It is controversial in multiple myeloma (MM) whether early and late responders to therapies have similar clinical outcomes. Daratumumab (DARA) is a human anti-CD38 antibody that has been increasingly used in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). The association between response kinetics to DARA and clinical outcomes remains unexplored.
Methods: Individual-participant data were obtained from phase 3 trials: POLLUX (Dimopoulos, NEJM, 2016), CASTOR (Palumbo, NEJM, 2016), and MAIA (Facon, NEJM, 2019). Patients were divided into early and late response groups based on the median time to the response of interest. Modified PFS (mPFS) and OS (mOS) were calculated from the time of first response of interest. Minimal residual disease (MRD) negativity was defined as less than 10 5 tumor cells by NGS assays.
Results: After a median follow up of 16.1 months, 670 patients achieved a response of very good partial response (VGPR) or better, and 213 achieved MRD negativity. The median time to achieving VGPR or better was similar between NDMM and RRMM (86 vs. 84 days, respectively), while the median time to MRD negativity was longer among NDMM than RRMM (407 vs. 197 days, respectively). Among patients achieving VGPR or better, there was no significant difference of mPFS (HR 1.00, 95%CI 0.69 to 1.44) (fig. a), duration of response (DOR) (HR 1.02, 95%CI 0.68 to 1.53) (fig. b), or mOS (HR 0.98, 95%CI 0.54 to 1.75) (fig. c) between early and late responders. In the subgroup analysis, no significant difference of DOR was observed across all prespecified groups, including sex, age, cytogenetic risk groups, lines of previous therapy, types of measurable disease, NDMM vs. RRMM, prior treatment with autologous hematopoietic cell transplant, immunomodulatory drugs, or proteasome inhibitors. Among patients with NDMM achieving MRD negativity, there was no significant difference of mPFS (p=0.66) (fig. d), DOR (p=0.21) (fig. e) or mOS (p=0.87) (fig. f) between early and late responders. However, among patients with RRMM achieving MRD negativity, late responders had significantly longer mPFS (p=0.038) (fig. g) and DOR (p=0.043) (fig. h) than early responders; mOS was not significantly different (fig. i). In the multivariable Cox analysis among patients achieving MRD negativity, only lower baseline LDH level, NDMM, and IgG type MM were independently associated with later response.
Conclusions: For patients with NDMM or RRMM achieving VGPR or better, early and late responders had similar survival; for patients with RRMM achieving MRD negativity, late responders had significantly longer mPFS and DOR. Our data support that in patients who failed to achieve an early or deep response to daratumumab based regimens, therapies should be continued with the goal of achieving ongoing and stepwise improvement of response.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
A Real World Study of Venetoclax Combined with Azacitidine in 64 Chinese Patients Newly Diagnosed Acute Myeloid Leukemia
Authors: Qian Jiejing , Xu Jieyu , Hong Qing , Lou Yinjun , Mao Liping , Xu Weilai , Yang Min , Yu Wenjuan , Meng Haitao , Mai Wenyuan , Ye Xiujing , Zhu Honghu , Jin Jie 
Published: November 2021

Abstract
Background: Venetoclax combined with azacitidine has been demonstrated to have a favorable overall response rate and tolerable safety in acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy.
Methods: This study retrospectively recruited 64 Adults (≥18 years) with newly diagnosed AML ineligible for intensive chemotherapy who had received at least one cycle of treatment with venetoclax plus azacitidine. The primary endpoint was overall survival (OS). Secondary endpoints were remission rates. Safety was evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Results: The median age of the enrolled patients was 69 years. The median OS for the cohort was 15.5 months, with 21.2 months for complete responders as opposed to 13.3 months for those who did not achieve a complete response. 39 (60.9%) patients achieved composite complete remission (complete
remission (CR) + CR with incomplete count recovery (CRi)) and 7/64 (10.9%) achieved morphologic leukemia-free state (MLFS) with a median follow-up time of 14.7 months. The median CR+CRi duration was 10.9 months. It is noteworthy that 43/64 (67.2%) patients achieved the best response after one cycle with a median time of 1.2 months. Normal karyotype (P=0.015) was significantly associated with extended OS in multivariate analysis, while higher white blood cell count (P=0.032), lower platelet count (p=0.018) and antifungal drug combination (P=0.013) were predictors of shortened OS in univariate analysis. Common grade 3/4 Adverse Events (AEs) included infection (68%) and hematological AEs consisting of neutropenia (93%), anemia (90%), leukopenia (86%), thrombocytopenia (77%) and febrile neutropenia (52%). The median neutropenia duration was 16 days.
Conclusions: The novel venetoclax-azacitidine combination regimen showed prolonged survival period, promising efficacy, sound and rapid response, and superior tolerance in Chinese patients newly diagnosed AML.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Clinicopathologic Characteristics and Genomic Profiling of De Novo CD5 Positive Diffuse Large B-Cell Lymphoma: A Multicenter Retrospective Study in China
Authors: Sang Wei , Ma Yuhan , Wang Xiangmin , Shen Ziyuan , Xu Linyan , Qiao Jianlin , Xu Kailin , Liu Hui 
Published: November 2021

Abstract
De novo CD5 positive diffuse large B cell lymphoma (CD5+ DLBCL) has poor survival in the era of immunochemotherapy. We conducted a multi-center retrospective study to explore the clinicopathologic characteristics, genomic profiling and prognostic elements of 61 CD5+ DLBCL and 60 CD5- DLBCL patients in China. In contrast with CD5- DLBCL, elderly onset, advanced stage, central nervous system (CNS) involvement, as well as MYC/BCL-2 and P53 overexpression were more prevalent in CD5+ DLBCL. In addition, most of CD5+ DLBCL patients were of non-germinal center B-cell-like (non-GCB) and activated B-cell-like (ABC) subtype according to immunohistochemistry and Lymph2Cx assay. Genetic analysis by next generation sequencing (NGS) showed the proportion of MCD subtype in CD5+ DLBCL was higher than that of CD5- DLBCL (50% vs 5%, p = 0.0007). Compared with CD5- cohort, CD5+ DLBCL patients showed poorer 5-year overall survival (OS) (70.9% vs 39.0%, p&lt;0.001), independent of cell-of-origin and MYC/BCL-2, P53 and BCL-6 status. Multivariate analysis showed that age &gt;76 years, advanced stage, CNS involvement and hypoalbuminemia were independent factors associated with poor prognosis in CD5+ DLBCL. In conclusion, CD5+ DLBCL conveyed poor prognosis and showed distinctive clinicopathologic characteristics and predominant genetic features of ABC and MCD subtypes.

Disclosures
No relevant conflicts of interest to declare.
G-CSF Upregulates the Expression of Aquaporin-9 through C/EBP-Beta to Enhance the Cytotoxic Activity of Arsenic Trioxide to Acute Myeloid Leukemia Cells
Authors: Fu Wanbin , Xu Lan , Liu Jia , Han Xiaofeng , Wang Junying , Wang Xinpeng , Zhao Huanbin , Hou Jian , Hu Jiong , Zhong Hua 
Published: November 2021

Abstract
Arsenic trioxide (ATO) is the first-line drug for the treatment of acute promyelocytic leukemia (APL). Aquaporin-9 (AQP9), a transmembrane transporter, is required for leukemia cells to uptake ATO. APL cells express high levels of AQP9, while other types of acute myeloid leukemia (AML) cells express much lower levels of AQP9, which limits the transportation and the cytotoxic activity of ATO in those types of leukemia. Recently, we found that granulocyte colony stimulating factor (G-CSF) can significantly upregulate the expression of AQP9 in AML cell lines (THP-1 and HL-60), and can significantly enhance the intracellular concentrations of ATO, when compared with the treatment with ATO alone. We also found that the combination of ATO and G-CSF inhibited the cell proliferation and induced cell apoptosis more significantly than the treatment with ATO or G-CSF alone. The overexpression of AQP9 with lentivirus in HL-60 or THP-1 cells significantly enhanced the cytotoxic activity of ATO, while the knock-down of AQP9 gene with small interfering RNA (siRNA) significantly attenuated the combination effect of G-CSF and ATO. Moreover, we found that the upregulation of AQP9 by G-CSF depends on the upregulation of C/EBP-beta, the transcription factor downstream of G-CSF. In conclusion, our study suggests that the pretreatment of G-CSF could significantly enhance the cytotoxic activity of ATO in AML cells through the upregulation of AQP9, and that the combination of G-CSF and ATO would be a potential therapeutic strategy for AML patients.

Disclosures
No relevant conflicts of interest to declare.
The Serine Threonine Kinase Inhibitor Ots-167 Improves Erythropoiesis through Suppression of Nlk Activity in Diamond Blackfan Anemia Models
Authors: Shibuya Aya , Wilkes Mark C , Serrano Manuel , Flygare Johan , Glader Bert , Narla Anupama , Sakamoto Kathleen M. 
Published: November 2021

Abstract
Diamond Blackfan Anemia (DBA) is associated with a hypoproliferative anemia, congenital abnormalities, and cancer. The disease typically presents within the first year of life with the majority of patients carrying mutations in one of at least 17 ribosomal proteins, with RPS19 being the most common. Current therapies for DBA have undesirable side effects, including iron overload from repeated red cell transfusions, chronic effects from long term corticosteroid use, or complications from stem cell transplantation.
The serine threonine kinase Nemo-like Kinase (NLK) is an atypical member of the MAP kinase family of enzymes and has been shown to be chronically hyper-activated in RPS19- and RPL11-haploinsufficient murine and human models of DBA, as well as in erythroid progenitors from DBA patients. In RPS19-insufficient human hematopoietic stem and progenitor cells, genetic silencing of NLK by shRNA increased erythroid expansion by 220.3% (SD = 6.6%), indicating that aberrant NLK activation may contribute to the pathogenesis of the disease and is a potential target for DBA therapy.
A number of clinically approved or advanced compounds have been developed to inhibit MAP kinases with various degrees of cross reactivity among its family members. We therefore screened a number of compounds that inhibit NLK as an off-target and found that these NLK inhibitors improved erythroid expansion in DBA models. Of these inhibitors, OTS-167 performed optimally, improving erythropoiesis by 2-fold at 300nM, with an EC50 of 146nM.
Previous studies of OTS-167 in xenograft models of neuroblastoma for one month did not result in neutropenia, suggesting very little to no toxicity to myeloid cells. The goal in treating DBA patients with NLK inhibitors is to sufficiently raise the hemoglobin to prevent the need for chronic red cell transfusions or treatment with steroids. Our results suggest that pharmacologic inhibition of NLK is a potential approach to treat patients with DBA. We are currently investigating other NLK inhibitors in preclinical models for future clinical application.

Disclosures
Glader: Agios: Consultancy.
Difference in Therapeutic Effects between Roxadustat and Daprodustat, HIF-Ph Inhibitors, Depending on the Blood Type in Hemodialysis (HD) Patients
Authors: Funakoshi Satoshi 
Published: November 2021

Abstract
Human blood group antigens are glycoproteins and glycolipids expressed on the surface of red blood cells and a variety of human tissues. This study aimed to determine if there is an association between ABO blood type and the efficacy of HIF-PH inhibitors. Roxadustat and daprodustat are potent inhibitors of HIF-PH and capable of stimulating erythropoiesis in patients on patients with impaired renal function. These two compounds are reported to act mechanistically similar but display differences in their effects on cells, and the differences may affect their efficacy in the treatment of renal anemia in HD patients. In this study we compared the response rate by blood type between roxadustat and daprodustat, respectively.
Sixty-eight HD patients treated with roxadustat (20-100mg, 3/week) and ninety-five treated with daprodustat (1-12mg, daily) were recruited in our observational study. We defined &gt;1.5g/dL increase in hemoglobin as effective, and &lt;1.5g/dL decrease as ineffective.
As shown in the figure, type A had a significantly high response rate at 47% in HD patients treated with roxadustat. On the other hand, type O had a significantly high response rate at 55% in those who were treated with daprodustat.
We found the association in the effectiveness of roxadustat on the treatment for anemia in HD patients in type A, while the effectiveness was higher in type O treated with daprodustat. The results suggest that the therapeutic effect of HIF-PH inhibitors may differ depending on the blood type.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Targeting Metabolic Dysregulation for Ruxolitinib Failure in MPN
Authors: Xu Na , Luo Jie , Luo Dongmei , Liang Hanying , Tan Yaxian , Liu Qifa , Liu Xiaoli 
Published: November 2021

Abstract

Background:Metabolic alterations are increasingly recognized as an important pathogenic process that underlies fibrosis and cancer cells. MPN models were demonstrated to exhibit metabolic vulnerabilities due to a high dependence on enhanced levels of glycolysis and oxidative phosphorylation. MPN patients often gain weight during ruxolitinib treatment effects on leptin signaling. Ruxolitinib provides symptomatic relief and can improve survival but generally fails to resolve the malignant clone,nealy 50% patients resistance to ruxolitinib.Here,we will study transcriptomic and metabolomic program in JAK2-mutant MPN who resistance to ruxolitinib.
Methods:The collection of blood samples and clinical data from MPN patients, Mice used in this study were kept in accordance with Swiss federal regulations. Multi-omics detection by transcriptome sequencing and liquid chromatography .
Results: We found that active lipid metabolism obviously in patients resistance to ruxolitinib in comparison with patients sensitive to ruxolitinib.Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of key regulatory enzyme of Fatty acid metabolism gene(SREBP,FASN, ACC, SCD1) and found that pharmacological inhibition of SREBP(Betulin) reduced hematopoietic manifestations of MPNs.
Conclusion: Our findings reveal the contribution of metabolic alterations to JAK2 inhibitor failure and suggest that abnormally active lipid metabolism of mutant cells represent vulnerabilities that can be targeted for treating MPNs.
Keywords: metabolomic;resistance;resistance;Myeloproliferative

Disclosures
No relevant conflicts of interest to declare.