bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utilizing HealthTree ® Cure Hub's Real-World Data to Assess Treatment Management of Patients with Multiple Myeloma during the COVID-19 Pandemic
Authors: Sweeney Nathan W. , Ahlstrom Jennifer M. 
Published: November 2021

Abstract
Background: Patients with multiple myeloma (MM) are uniquely susceptible to viral and bacterial illnesses, including COVID-19, due to their immunocompromised state, age, treatments, and comorbidities. With the advent of COVID-19, changes to treatment were recommended whenever possible, in order to reduce visits to the clinic. The total effect of these changes on cancer patients with multiple myeloma remains unclear. The aim of this project was to assess treatment management by changes to treatment of patients with MM during the COVID-19 pandemic.
Methods: We utilized HealthTree ® Cure Hub for Multiple Myeloma (healthree.org) and invited patients with active MM cancer or precursor conditions to participate in an online survey. We analyzed patient responses to questions regarding their myeloma treatments during the COVID-19 pandemic.
Results: 978 MM patients participated in the survey between February to June 2021. Since March 2020, 151 patients (15%) either delayed, postponed, or stopped a myeloma treatment because of COVID-19. The four most common treatments were daratumumab (20%), lenalidomide (15%), stem cell transplant (13%) and zoledronic acid (11%). There were 110 patients that canceled a planned myeloma treatment. Of these patients, 55 (50%) canceled a planned chemotherapy, 15 (14%) canceled a stem cell transplant, 1 (1%) canceled radiation and 39 (35%) indicated other. Eight patients replaced an intravenous or subcutaneous treatment with an oral treatment because of COVID-19. There were 9 patients that started a new myeloma treatment because of COVID-19, the most common being daratumumab (44%), ixazomib (22%), lenalidomide (22%) and carfilzomib (11%). Finally, 15 patients had their lenalidomide (50%), steroid (42%) and carfilzomib (8%) dose changed.
Conclusions: Our results show that decision-making regarding treatment changes were made on an individual basis and that patients who required a change in treatment were the minority. Aggregating real-world data can provide evidence that despite the changes, patients with MM still received and efficacious treatment and avoided putting these patients at risk or mortality.

Disclosures
Ahlstrom: Bristol Myers Squibb: Other: Patient Advisory; Janssen: Other: Patient Advisory; Pfizer: Other: Patient Advisory; Takeda: Other: Patient Advisory.
Meta-Analysis of Chemotherapy-Induced (Febrile) Neutropenia and Chemotherapy Disruptions Associated with Same-Day Versus Standard (24-72h) Pegfilgrastim Administration in Non-Hodgkin Lymphoma Patients
Authors: Alrawashdh Neda , McBride Ali , Abraham Ivo 
Published: November 2021

Abstract
Background: While the product label and international guidelines recommend pegfilgrastim administration 24-72 hours following completion of chemotherapy, increasingly clinicians administer pegfilgrastim using a same-day protocol. We performed a meta-analysis to compare the incidence of febrile neutropenia (FN), chemotherapy-induced neutropenia (CIN) grade 4, and CIN/FN-related chemotherapy delays and dose reductions in non-Hodgkin lymphoma (NHL) patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab (R±CHOP) who were provided with pegfilgrastim on the same-day of chemotherapy versus the standard 24-72h post-chemotherapy time window.
Methods: Six databases were searched for studies that compared same-day pegfilgrastim with the standard regimen in NHL patients. Given the low heterogeneity (I 2&lt;50%, Cochrane Q test P&gt;0.10, fixed-effect model was used to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for all outcomes of interest.
Results: We identified 7 studies, including one clinical trial (Burris et al. 2010) and six retrospective cohort studies (Woods et al. 2010, Ibrahim et al. 2011, Karol et al. 2013, Cheng et al. 2014, Bartels et al. 2021, McBride et al. 2021), that evaluated same-day versus standard 24-72h administration of pegfilgrastim in NHL patients. Results were statistically non-significant for all outcomes (Figure 1): FN across all chemotherapy cycles (OR=1.48, 95%CI= 0.98-2.23, P=0.06, N of studies=7); FN after the first cycle (OR=1.98, 95% CI=0.80-4.90, P=0.14, N=4); CIN grade 4 across all cycles (OR=0.73, 95% CI=0.37-1.47, P= 0.38, N=3); CIN grade 4 after the first cycle (OR=2.58, 95%CI= 0.86-7.73, P=0.09, N=3); and chemotherapy dose delays or reductions (OR=2.25, 95%CI=0.42-11.97, P= 0.34, N=2).
Conclusion: In this independent study, the likelihood of developing FN and CIN grade 4 in the first cycle or across all chemotherapy cycles, and the likelihood of chemotherapy dose delays or reductions were statistically not different in NHL patients treated with R±CHOP and administered pegfilgrastim same-day or 24-72h post-chemotherapy. In the setting of NHL treated with R±CHOP, administering pegfilgrastim on the day of completion of chemotherapy may be a safe and effective method of prophylaxis.
Figure 1 Figure 1.

Disclosures
Alrawashdh: Genentech: Current Employment. McBride: BMS: Current Employment. Abraham: Matrix45, LLC: Current holder of individual stocks in a privately-held company.
Phage Display Functionally Defines Variants in the Von Willebrand Factor Platelet Binding Domain
Authors: Yee Andrew , Arslantas Guzel Melda , Dai Manhong , Meng Fan , Ginsburg David 
Published: November 2021

Abstract
Missense variants in the von Willebrand factor (VWF) platelet binding domain, A1, may pathologically hyperactivate or weaken interactions with its platelet receptor, GPIbα, and lead to von Willebrand disease (VWD) subtypes 2B or 2M, respectively. Variants identified in VWD patients and tested as recombinant VWF have supported genotype-phenotype associations and subtyping of VWD by genetic analyses. However, novel variants, most classified as variants of uncertain significance (VUS) are poorly defined. To functionally characterize a large subset of VWF A1 variants (P1254-L1460), we screened a phage display library for binding to a recombinant form of GPIbα used to clinically assess VWF platelet binding activity, GPIbM. Comprised of ~5x10 6 independent clones, the phage display library contained 1,427 unique, missense variants (~36% of all possible single amino acid substitutions) which could be scored for significant enrichment, depletion, or no change following selection for GPIbM binding. The enrichment of phage displayed VWD variants previously classified as VWD subtype 2B significantly segregated from reported 2M variants (mean fold change from preselected phage ~1.06 for 2B vs. ~0.68 for 2M, p &lt; 0.005). To further validate these findings, five depleted, four unchanged, and seven enriched VWF A1 variants were introduced into the full length VWF sequence by site-directed mutagenesis and expressed by transient transfection of HEK293T cells. Conditioned media were collected and analyzed for VWF level (VWF:Ag) and activity (VWF:GPIbM). Of the sixteen variants examined, fourteen (87.5%) exhibited a VWF GPIbM:Ag ratio that was concordant with the phage display findings. Furthermore, the VWF GPIbM:Ag ratios were well correlated with the degree of enrichment by phage display (Pearson R = 0.69, p&lt; 0.01). Taken together, these findings demonstrate phage display as a high content approach to measure and functionally define the platelet-binding activity of genetic variants within the VWF A1 domain.

Disclosures
Ginsburg: Takeda: Patents & Royalties.
The Krüppel-like Factor 4 Sustains a Leukemic Gene Expression Profile in MLL-AF9-Driven Acute Myeloid Leukemia
Authors: Lewis Andrew , Bridges Cory Seth , Moorshead David , Du Wa , Zorman Barry , Sumazin Pavel , Puppi Monica , Lacorazza H. Daniel 
Published: November 2021

Abstract
Among hematological malignancies, acute myeloid leukemia (AML) confers poor prognosis and limited progress has been made in the translation of decades of research into improved clinical outcomes. The current paradigm is that eradication of leukemia stem cells (LSCs) represents an avenue for overcoming relapse and refractory disease, but therapy focusing on eradicating this leukemic population has not been developed to-date. Further studies of unique signaling pathways and vulnerabilities in LSCs are warranted to design targeted therapies that could impact patient outcomes. To evaluate whether the stemness transcription factor Krüppel-like Factor 4 (KLF4) is important in the progression of AML, we retrovirally transduced MLL-AF9 into Klf4 fl/fl(fl/fl)and Klf4 fl/flVav-Cre (Δ/Δ) lineage − Sca-1 + c-Kit + (LSK) bone marrow cells and transplanted into C57BL/6 recipients. Here we report that the KLF4 promotes disease progression in the MLL-AF9-driven syngeneic AML mouse model. Strikingly, Δ/Δ AMLs exhibited improved disease latency and penetrance, and a seven-fold reduction in leukemia-initiating cell frequency in a secondary transplantation study. Δ/Δ LSCs, defined as leukemic granulocyte macrophage progenitors (L-GMP), demonstrated lessened clonogenicity in methylcellulose cultures and reduced representation of cells in the G 2/M phase of the cell cycle. RNAseq analysis of L-GMP revealed decreased expression of hematopoietic and leukemic stemness gene sets such as RAS signaling, and induction of inflammatory response gene (TNF-α, IFNα, IFNβ) pathways in Δ/Δ LSCs. To evaluate human relevance, we used CRISPR-Cas9 based targeted deletion of the human KLF4 gene in a MLL-AF9 PDX line and observed improved survival and defects in expansion as seen in the syngeneic mouse model . Lastly, to correlate KLF4-associated signaling present in murine AML LSCs with human AML, we used CRISPR-Cas9-based targeted deletion of KLF4 in MOLM-13 (KO) to generate two validated clones. MOLM-13 KO cells showed reduced cell proliferation in vitro and in vivo. Further, RPPA analysis revealed reduced RAS pathway activity (IR-β, β-Raf), accumulation of proteins associated with the S and G 1 phases (e.g., CDKN2A, p21, Histone H3, CENP-A), and decrease expression in regulators of the G 2/M checkpoint (e.g., Aurora A, B, Chk1, Plk1, Wee1, Cyclin B, pCDK1). Collectively, our data suggest a mechanism in which KLF4 contributes to AML disease by establishing a gene expression profile supporting stemness of AML LSCs.

Disclosures
No relevant conflicts of interest to declare.
In Depth Analysis of Blastic Plasmacytoid Dendritic Cell Neoplasm Based on a Comprehensive Literature Database of Cases
Authors: Ohgami Robert S. , Aung Phyu , Gru Alejandro Ariel , Hussaini Mohammad O , Querfeld Christiane , Yao Kelou , Small Corinn , Gollapudi Sumanth , Jaye David L , Wang Sa A , Pullarkat Sheeja T , George Tracy I. 
Published: November 2021

Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcome. BPDCN diagnostically overlaps with entities such as acute myeloid leukemia, histiocytic/dendritic cell neoplasms, and NK/T cell lymphomas. Unfortunately, large patient centered studies that comprehensively analyze clinical, pathologic and other diagnostic features are lacking. As such, there is an incomplete understanding of this disease. To better characterize BPDCN, a multicenter working group consisting of hematopathologists and dermatopathologists gathered in-person and remotely to review the current understanding of BPDCN, discuss specific issues regarding the diagnosis and differential diagnosis, and perform a retrospective analysis of the literature. A curated database of published BPDCN patient cases (BPDCN Network literature database) was generated. By conducting an in-depth analysis, not only did we confirm known findings in BPDCN such as frequent skin involvement and male predominance amongst older patients, but we also identified a number of under-recognized features, such as significant central nervous system involvement (35% of cases), and a roughly equal female to male prevalence amongst patients &lt; 40 years old. Furthermore, with the large database, we were able to accurately summarize the immunohistochemical, cytogenetic, and molecular features of this disease. The BPDCN Network literature database serves as a central data repository of archived published aggregated and individual cases and facilitates an in-depth characterization of this rare disease. Continual updates from the consortium and beyond will allow for prospective refinement of our understanding of this orphan disease.

Disclosures
Ohgami: Stemline Therapeutics: Research Funding. Aung: Stemeline Therapeutics: Honoraria. Gru: Innate Pharma: Research Funding; StemLine: Honoraria, Research Funding, Speakers Bureau; CRISPT Therapeutics: Research Funding. Hussaini: Stemeline Therapeutics: Honoraria. Jaye: Stemline Therapeutics: Honoraria. Wang: Stemline Therapeutics: Honoraria. Pullarkat: Stemline Therapeutics: Honoraria. George: Bristol Meyers Squibb: Consultancy; Incyte Corporation: Consultancy; Blueprint Medicines: Consultancy; Celgene: Consultancy.
Transfusional Iron Overload in Sickle Cell Patients:Outcomes of Chelation Therapy
Authors: Adamkiewicz Daniel , Mangaonkar Abhishek A. , Son James , Xu Hongyan , Wells Leigh , Bowman Latanya , Kutlar Abdullah 
Published: November 2021

Abstract
Iron (Fe) overload is not rare among sickle cell disease (SCD) patients. It results from either chronic transfusions for primary or secondary stroke prevention, or more commonly sporadic, mostly unnecessary transfusions and are associated with significant morbidity, secondary to hepatic, cardiac and renal Fe deposition. Previous studies at our Center showed that 12% of the adult SCD population had Fe overload, and vast majority of these (80%) resulted from episodic transfusions (Son et al, 2013). Subsequent studies showed that the Fe regulatory peptide, hepcidin was appropriately upregulated in SCD subjects with Fe overload, and the plasma levels of the glycoprotein hormone erythroferrone (ERFE) was not as high as that found in patients with transfusion dependent beta thalassemia (TDT) due to the absence of significant ineffective erythropoiesis in SCD (Thawer et al, 2017, Mangaonkar et al, Brit. J. Haematol, 2020). We report on the utilization and outcomes in Fe overloaded SCD patients who were prescribed the oral chelating agent deferasirox.
22 patients were prescribed deferasirox; median age was 38, 12 female 10 male. 21 had Hb SS, and 1 had s-b 0 thalassemia. Deferasirox dose ranged from 720-2500 mg/day (12 to 28 mg/Kg/day). Nonadherence was ascertained by patients' own admission. Figures 1-3 show the pre and post ferritin levels in subjects who were on deferasirox, and in controls; patients who took deferasirox had a more pronounced decrease in their ferritin (p=.004 vs p=.74). Although hepatic MRI for liver iron content (LIC) was not available on all patients, in those who underwent MRI there was a correlation between LIC and serum ferritin obtained at close temporal proximity (Fig. 4). Most common side effects of deferasirox were gastrointestinal (abdominal pain, nausea, vomiting, diarrhea), which were seen less commonly with the newer oral formulation (Jadenu).
Several conclusions can be drawn from our observation on relatively small number of patients: 1) Deferasirox is effective in decreasing Fe overload as shown by serum ferritin levels 2) Second generation of oral deferasirox is better tolerated, and therefore is associated with improved adherence, 3) Documentation of a decrease in LIC with chelation will be important for the reversal of Fe induced organ damage, and 4) Parallel studies of the levels of Fe regulatory peptides hepcidin and erythroferrone (ERFE) will clarify the effect of chelation therapy on biomarkers of Fe metabolism.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
COVID-19 Incidence in Asymptomatic Cancer Patients Undergoing Chemotherapy
Authors: Monteiro Claudia , Gomes Cecília , Marani Leticia , Colli Leandro , Calado Rodrigo T. , Figueiredo-Pontes Lorena 
Published: November 2021

Abstract
COVID-19 is an infectious disease caused by the virus SARS-CoV-2, which was first described at the end of 2019. Since then, it has affected a growing portion of the world's population because of its high transmissibility. Most patients are asymptomatic or present with mild symptoms, but approximately 5-10% of cases can develop more serious manifestations, such as severe acute respiratory syndrome, acute kidney injury, shock, myocardial injury and even death. These features seem to occur more commonly in patients with essential hypertension, diabetes mellitus, obesity and chronic pulmonary disease. However, there are few studies that clarify the natural history of the disease and its broad clinical spectrum owing to the fact that it is a new entity. Since individuals with malignancies tend to present some degree of immunological deficiency and are more prone to opportunistic infections, especially those being treated with immunosuppressive drugs, it is possible that this group has a higher incidence of COVID-19. The current recommendations of oncology specialists advise to postpone treatments and to use less toxic drugs when possible. However, we still do not know how much these measures will affect in cancer mortality. Also, the incidence of COVID-19 in this population remains undetermined. We do not know if infectious symptoms are a good parameter to motivate these therapeutic changes or if there is benefit to test asymptomatic patients. In this context, this research submitted 100 patients with hematological malignancies or solid tumors on chemotherapy at the Ribeirão Preto Medical School of the University of São Paulo's Hospital, asymptomatic for COVID-19, to RT PCR to determine the SARS-CoV-2 infection incidence in this population. Only two patients were diagnosed with COVID-19. Both had gastrointestinal cancer. One of them developed symptoms, but none presented severe manifestations. Both had their treatment postponed initially and reinitiated after the appropriate period of isolation. Hence, we believe that it's reasonable not to test every asymptomatic patient when the resource for that is scarce, prioritizing those at greater risk of infection and those more prone to severe outcomes as long as the appropriate preventive measures are being taken.

Disclosures
Calado: Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Instituto Butantan: Consultancy; Alexion Brasil: Consultancy; AA&MDS International Foundation: Research Funding; Novartis Brasil: Honoraria.
The Synergistic Anticancer Effect of a Combination of Chidamide and Etoposide Against NK/T Cell Lymphoma
Authors: Song Wenting , Chen Zhan , Shi Cunzhen , Gao Yuyang , Feng Xiaoyan , Li Hongwen , Li Zhaoming , Zhang Mingzhi 
Published: November 2021

Abstract
Natural killer/T cell lymphoma (NKTCL) is a highly aggressive hematological malignancy. However, there is currently no consensus on first-line therapies for refractory/relapsed patients. Chidamide is a self-researched and developed HDACs inhibitor, and when combined with DNA-damaging agents, exhibited a clinical synergistic effect for the treatment of some solid tumors and hematological malignancies. Thus in this study, a series of in vitro and in vivo experiments were conducted to explore the efficacy and potential mechanisms of combined chidamide and etoposide treatment in NKTCL. We demonstrated that chidamide or etoposide alone dose- and time-dependently inhibited the cell viability of NKTCL cell lines, YT, NKYS and KHYG-1. Functional experiments suggested that combined chidamide and etoposide treatment exerted synergistic antiproliferation effect and enhanced cell apoptotic death both in vitro and in vivo. Furthermore, the expression of DNA damage related proteins was detected and we also examined the alternations in histone acetylation, cell cycle progression, and mitochondrial membrane potential (MMP). The results suggested that increased histone acetylation, cell cycle arrest at the G2/M phase and loss of MMP, converging to greater DNA damage, might account for the synergism of the combination of chidamide and etoposide in NKTCL. Taken together, our study supplements the clinical application of combining HDACs inhibitors and DNA-damaging agents on treating hematological malignancies but also provide an experimental basis for improved therapeutic efficacy and decreased complications for patients with NKTCL.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Hypomethylating Agents As Maintenance Treatment Following Allogeneic Hematopoietic Transplant in Children's Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome: A Single Center Study
Authors: Ruan Yongsheng , Xie Danfeng , Liu Xuan , Liu Qiujun , Li Chunfu , Wu Xuedong , He Yuelin , Feng Xiaoqin 
Published: November 2021

Abstract
Regarding children's patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), disease relapse remains the most common reason for transplant failure and patient death. We implemented a single center study to investigate hypomethylating agents (HMA) as maintenance treatment after HSCT for children AML or MDS. We retrospectively analyzed 30 patients with AML or MDS including 63 courses of azacytidine (AZA) and 69 courses of decitabine (DEC) from January 1, 2018 to June 30, 2021 (Figure 1A). Either AZA (37.5mg/m 2 to 75 mg/m 2 for consecutive 5-7 days) or DEC (5 mg/m 2 for consecutive 5 days) was administrated 90 days post-transplantation as first course. Furthermore, the interval of HMA treatment was 1.5-month hereafter for in total of a year (Figure 1B). Patients that received at least one course of HMA treatment were included in this study. The patient characteristics was shown in Table 1. We found that the disease-free survival (DFS) and overall survival (OS) were 82.96±6.95% and 85.51±6.72%, respectively (Figure 1C, D). Based on Common Terminology Criteria for Adverse Events (CTCAE) criteria, only Grade 1 to 2 leukopenia (P&lt;0.001), anemia (P=0.043), and thrombocytopenia (P=0.033) were found between complete blood count (CBC) of pre-treatment and post-treatment. Subgroup analysis indicated that the difference was mainly come from DEC group [leukopenia (P&lt;0.001), anemia (P=0.001), and thrombocytopenia (P=0.190)] instead of AZA group [leukopenia (P=0.476), anemia (P=0.443), and thrombocytopenia (P=0.095)]. No nausea/vomiting, or elevated ALT, or elevated creatinine, or rash, or de novo/exacerbated GVHD were observed. Moreover, there were no difference of activation T cells populations (CD25 and HLA-DR) among 7 courses except CD3+HLADR+/CD3+ and CD8+HLADR+/CD8+ in course 1 vs course 4 (P= 0.0354 and P=0.0163, respectively, Figure 1E). Furthermore, a trend of increased percentage of CD3+HLADR+/CD3+, or CD4+HLADR+/CD4+, or CD8+HLADR+/CD8+ and decreased percentage of CD3+CD25+/CD3+, or CD4+CD25+/CD4+, or CD8+CD25+/CD8+ was found in relapsed group, despite there was no significant difference. Interestingly, DEC significantly reduced population of CD3+HLADR+/CD3+, or CD4+HLADR+/CD4+, or CD8+HLADR+/CD8+ compared to AZA (P&lt;0.001, P&lt;0.001, or P&lt;0.001, respectively). In conclusion, both AZA and DEC as HMA maintenance treatment following HSCT in children AML or MDS was safe, and the outcome was encouraging. A further large cohort of randomization of AZA and DEC study is required.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.