bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eltrombopag As Initial Monotherapy for Transfusion Dependent Patients with Low to Intermediate Risk-1 Myelodysplastic Syndrome: Single Center Experience
Authors: Shen Yingying , Li Hangchao , Xiang Jingjing , Zhu Ni , Li Yuzhu , Liu Qi , Dong Huijie , Wang Bo , Ye Baodong , Lin Shengyun , Shen Yiping , Wu Dijiong 
Published: November 2021

Abstract
Myelodysplastic syndrome (MDS) is a group of disorders involving hematopoietic dysfunction, with a leukemic transformation characteristic. The risk based therapeutic strategy was well applied in clinical. And for patients with IPSS low or intermediate risk-1, NCCN guideline recommended hematopoietic stimulation therapy, immune suppression therapy (IST), as well as demethylation therapy, along with best supportive care. Eltrombopag (EPAG) was firstly approved as the second line option for immune thrombocytopenia (ITP), and recently it was also investigated for treatment of aplastic anemia and MDS. In MDS, based on available reports, the EPAG was mostly used along with hypomethylating-agent, or as salvage treatment after treatment failure. However, there was study showed that the combination of EPAG to azacitidine (AZA) may worsen platelet recovery, with lower response rate and increased trend of leukemic transformation. The successful EPAG monotherapy for MDS case was report, with complete hematologic remission and blasts elimination.
To date, limited study was focus on investigating the benefit of EPAG as initial monotherapy for transfusion dependent (TD) patients with low to intermediate risk-1 MDS, as well as its safety. Herein, we reviewed cases of elderly TD-MDS patients who received EPAG as front-line single treatment in our center, and 7 patients was enrolled from July, 2019 to September, 2020. Patients received EPAG 25mg to a maximum 75mg. The side effects, numbers of transfusion, improvement of peripheral blood and bone-marrow blast were recorded.
The 12weeks overall response rate was 85.7%, with 2 robust response (RR), and 4 hematologic response. In patients got response, 66.7% (4/6) became platelet transfusion independent, with an answering period from 19 days to 55 days. No drug adverse events were observed within 12 week-treatment, and no obvious increased blasts as well as myelofibrosis were observed. 2 patients repeated the next-generation sequencing, and no new mutations were found. After the 12-week treatment, the 2 RR patients were still taking EPAG and got continued complete remission with a median follow up of two years. Two patient (No.3 and No.4) relapsed after EPAG withdrawn and became transfusion depend again. Patient No.1 and No.6 died of infection and cerebral hemorrhage during the follow up.
In summary, EPAG may improve the hematopoiesis of TD-patient with low to intermediate risk-1 MDS, and was well tolerant with a dose of 25mg to 75mg for Asian population.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
T-Cell Phenotype Varies in Distinct Tumor Microenvironments and CD57 + T FH Cells Are Associated with Disease Progression and Inferior Survival in Follicular Lymphoma
Authors: Yang Zhi-Zhang , Kim Hyojin , Wu Hongyan , Tang Xinyi , Krull Jordan E. , Villasboas Jose , Novak Anne J. , Ansell Stephen M. 
Published: November 2021

Abstract
The tumor microenvironment plays a crucial role in mediating the tumor immune response, thereby affecting patient outcomes in follicular lymphoma (FL). Using CyTOF, we analyzed single cell suspensions created from pre-treatment biopsies in a cohort of 82 FL patients and retrospectively extracted patient clinical parameters. Hierarchical analysis of the tumor microenvironment composition stratified these patients into 4 groups: group 1 represents patients with high percentage of monocyte/macrophages/NK cells; patients from group 2 and 3 are rich of intratumoral T and B cells, respectively. Patients with intermediate number of T and B cells are classed into group 4. Intratumoral T cells from these 4 groups exhibited distinct phenotypical characteristics. Group 1 was enriched with KLRG1 +CD8 + T cells, while group 4 showed increased number of CXCR3 - T EM and CD4 + T N cells. Patients from group 2 and 3 featured with increased number of ICOS + T reg cells and CD57 + T FH cells, respectively. We observed that higher numbers of T cells significantly correlated with early disease stage, lack of B-symptoms, event-free survival at 24 months (EFS24) and a favorable overall and EFS survival in patients with histological grade 1 and 2. However, this association was not seen in patients with histological grade 3a and b, suggesting that T cell-mediated anti-tumor immunity is preserved in low grade patients, but overridden in higher grade patients. CITRUS analysis revealed that a cluster that is CD57 + and PD-1 high was significantly more abundant in patients who had disease progression than patients who had a complete response to therapy, suggesting a role of CD57 + T FH cells in promoting malignant cell growth in FL. Consistent with this finding, we observed that higher number of CD57 + T FH cells correlated with an inferior survival in FL. Using CITE-seq technology, we found that CD57 + T FH cells exhibited a substantially different transcriptome when compared to CD57 - T FH cells. Genes that were differentially upregulated in CD57 + T FH cells when compared to CD57 - T FH cells included genes involved in cell survival, compromised inflammatory response, and metabolism activation including GZMK, CCL4, CST7, DUSP2, LGALS3, CYTOR, CHI3L2, SYNE2, CXCL13, CD27 and FABP5. Taken together, our results indicate different tumor microenvironments among FL patient groups that is associated with variable T-cell phenotype. We found that CD57 + T FH cells play an important role in predicting disease progression and patient prognosis in FL.
Figure 1 Figure 1.

Disclosures
Novak: Celgene/BMS: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.
Subcutaneous Marzeptacog Alfa (Activated) Versus Intravenous rFVIIa for Treatment of Episodic Bleeding in FVIII Deficient Hemophilia a Rats
Authors: Knudsen Tom , Johansen Peter , Reckless Jill , Desai Shraddha , Blouse Grant E. 
Published: November 2021

Abstract
Background: FVIII deficient knock-out (F8 -/-) rats mimic the bleeding incidents seen in severe human hemophilia A (HA). Subcutaneous (SQ) marzeptacog alfa activated (MarzAA), a novel, engineered recombinant activated coagulation Factor VII (rFVIIa) has been shown to effectively treat episodic bleeding in a pilot experiment in HA rats. This study evaluated the effect of single SQ doses of MarzAA and a single intravenous (IV) dose of rFVIIa on episodic bleeding in F8 -/- rats. Moreover, it compared the effect of SQ MarzAA and IV rFVIIa directly.
Methods: Animals were allocated to treatment with either SQ vehicle, SQ MarzAA (60, 180 or 385 µg/kg) or IV rFVIIa (NovoSeven ®) (580 µg/kg) immediately after the bleeding was diagnosed. Doses were based on allometric scaling from humans (Nair AB and Jacob S. J Basic Clin Pharm 2016; 7: 27-31). The primary endpoint of the study was clinical efficacy as rated by a well-defined 4-point scale (Excellent, Good, Fair or Poor), and the efficacy assessment was either treatment success (Excellent or Good) or treatment failure (Fair or Poor) at the 24-hour timepoint. All personnel handling or assessing animals were blinded to the treatment status of each animal except those dosing animals who knew the route of administration.
Results: A total of 86 F8 -/- rats was enrolled in the study. Of these, 61 rats presented treatment eligible bleeds between 3 and 10 weeks of age. No statistically significant difference in bleeding severity score were found across groups on diagnosis. As assessed by the clinical outcome at 24 hours, all three SQ MarzAA dose groups exhibited a statistically significant effect on treatment response when compared to SQ vehicle treatment (Figure 1). Conversely, no statistically significant effect could be identified when the single IV rFVIIa 580 µg/kg dose group was compared to vehicle. The overall treatment success rates at 24 hours were: SQ vehicle: 8%, SQ MarzAA 60 µg/kg: 58%, SQ MarzAA 180 µg/kg: 67%, SQ MarzAA 385 µg/kg: 85%, and IV rFVIIa 580 µg/kg: 33%. When compared directly using allometric scaling of clinical doses, SQ MarzAA at 385 µg/kg exhibited a statistically superior effect compared to IV rFVIIa at 580 µg/kg (p=0.0154, Fischer's exact test).
Conclusion: Single doses of SQ MarzAA were effective in treating episodic bleeding in HA rats and statistically distinguishable from vehicle at all dose levels tested. When clinically relevant doses were compared directly to rFVIIa, SQ MarzAA compared favorably to IV rFVIIa. Taken together, these data provide robust nonclinical evidence that a single dose of SQ MarzAA may be successful in treating episodic bleeding when administered after bleeding has started.
Figure 1 Figure 1.

Disclosures
Knudsen: Catalyst Biosciences: Current Employment, Current holder of individual stocks in a privately-held company. Blouse: Catalyst Biosciences: Current Employment.
Genetic Screening of Patients with Evans Syndrome: A Single Centre Analysis
Authors: Miano Maurizio , Guardo Daniela , Grossi Alice , Palmisani Elena , Fioredda Francesca , Terranova Paola , Lupia Michela , Cappelli Enrico , Dell'Orso Gianluca , Lanciotti Marina , Ceccherini Isabella , Dufour Carlo 
Published: November 2021

Abstract
Background:
Evans syndrome (ES) is a rare disorder defined as the simultaneous or sequential presence of autoimmune haemolytic anemia and immune thrombocytopenia but it can also be considered as the presence of at least two autoimmune cytopenias. Recent reports have shown that ES is often a manifestation of an underlying congenital immune dysregulation syndrome that, in some case, can benefit from specific treatments.
Aims:
The aim of this study is to investigate the clinical/immnunological characteristics and the underlying genetic background of a single centre cohort of patients with ES.
Methods:
Data were obtained from a retrospective charts' review of patients with a diagnosis of ES in our centre. Genetic studies were performed with NGS analysis of 315 genes related to both hematologic and immunological disorders as congenital bone marrow failure syndromes, primary immunodeficiencies, and primary immune regulatory disorders.
Results:
Fourteen patients (23 males, 17 females) with a median age at onset of 6 years (range 0-16) were studied. ES was concomitant and sequential in 18 (45%) and 22 (55%) patients, respectively. Nine/40 (8%) patients had a family history of autoimmunity. Other abnormal immunological features and signs of lymphoproliferation were present in 24/40 (60%) and 29/40 (72%) of cases, respectively. Seventeen out of 40 (42%) children fitted the ALPS diagnostic criteria. The remaining 15 (37%) and 9 (22%) were classified as having an ALPS-like phenotype and an isolated ES, respectively. Twenty patients (50%) were found to have an underlying genetic defect on TNFRSF13B, FAS, CTLA4, IKBGK, CARD11, LIG4, LRBA, STAT3, CASP10 and ADA2 genes. Table 1 shows the details of clinical/immunological characteristics of patients with or without a genetic diagnosis. No significant differences were noted between the two groups.
Conclusions:
This study shows that half of patients with ES have a genetic background, secondary to Primary Immunodeficiencies. Therefore, an immunological screening and an extended molecular evaluation should be offered to all patients, since specific genetic diagnosis may benefit from targeted treatments.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Online Patient-Reported Platform Detects Trend of Increased COVID-19 Risk and Severity for Multiple Myeloma Patients on Active Lenalidomide-Based Therapy
Authors: Liu Emily I. , Sweeney Nathan W. , Ahlstrom Jennifer M. 
Published: November 2021

Abstract
Background: Since the start of the COVID-19 pandemic, "high-risk" patients, such as cancer patients, have had to reconsider their current medical treatments and other treatment alternatives to best minimize their risk for contracting COVID-19. Lenalidomide has immunomodulatory properties that stimulate the production of T-cells which help combat against infections which may include diseases such as COVID-19. In this abstract, we investigate whether lenalidomide protects multiple myeloma (MM) patients from contracting COVID-19 and whether lenalidomide decreases the severity of COVID-19 events (including hospital or intensive care unit [ICU] admissions, and need of assisted ventilation) for patients that contract the virus (PMID: 32950467, PMID: 32353254).
Methods: MM patient data was collected through HealthTree ® Cure Hub for Multiple Myeloma (healthtree.org) and the relative risk was calculated to compare the risk of contracting COVID-19 between patients taking lenalidomide and those who were not at the time of contracting COVID-19. The odds ratio was calculated to measure lenalidomide's effect on the severity of COVID-19 if contracted. These events include whether a patient was hospitalized, had to go to the ICU, or required oxygen therapy.
Results: There were 1,123 patients involved in comparing lenalidomide with the risk of contracting COVID-19, including patients that never tested positive for COVID-19. Surprisingly, our results showed that patients who are taking lenalidomide have a 10% higher risk for contracting COVID-19 than those who are not; however, these findings were insignificant. Furthermore, 40 patients were involved in investigating lenalidomide's effect on decreasing severe COVID-19 symptoms for MM patients. Our results showed that the odds of patients experiencing severe COVID-19 were 1.95 times more for those on lenalidomide than those who were not.
Conclusions: Despite the insignificance of lenalidomide during COVID-19, our results indicated that taking lenalidomide may not be beneficial in lowering the risk for MM patients in contracting COVID-19. Furthermore, lenalidomide may also not decrease the severity of COVID-19 symptoms for MM patients that did contract COVID-19. Our results may help MM patients and their providers decide whether to continue their use of lenalidomide or to seek alternative treatment options.

Disclosures
Ahlstrom: Pfizer: Other: Patient Advisory; Janssen: Other: Patient Advisory; Takeda: Other: Patient Advisory; Bristol Myers Squibb: Other: Patient Advisory.
Activity of Limited-Schedule Bendamustine and Methylprednisolone in Chronic Lymphocytic Leukemia
Authors: Quan Walter JR , Kadakia Meet , Krishnan Nithya , Stack Anthony , Rogers Christy , Quan Francine Marie 
Published: November 2021

Abstract
Bendamustine was approved by the United States Food and Drug Administration in 2008 for the treatment of Chronic Lymphocytic Leukemia (CLL). Corticosteroids have been administered in regimens with chemotherapy for CLL for more than 40 years. Despite this, the combination of Bendamustine and Methylprednisolone has not been explored in CLL. We describe our experience with Bendamustine 100 mg/m2 and Methylprednisolone 125 mg IV on days 1 and 2 and Peg-filgastrim 6 mg subcutaneously on day 3 every 28 days for 3-4 cycles in 12 patients with CLL. Cycles have been limited to attempt to prevent cumulative marrow toxicity due to Bendamustine. Patient characteristics: 7 males/5 females, median age-58, Binet stage B (8), C (2), A (2); ZAP70/CD38+ (5), Trisomy 12 (3), 13q- (2), normal cytogenetics (2); median ECOG status 1, no prior therapy in 8. Median number of cycles received = 3 (two received 4 cycles). Most common toxicities: nausea/emesis (5), fever/flu-like symptoms (4), arthralgia/myalgia (4). There have been no treatment-related deaths. One patient was briefly hospitalized for pneumonia. Complete responses have been seen in 6 patients (median duration = 50.7 months; range: 12.1+ to 87.3 months). Partial responses have been seen in 4 patients (median duration = 17.3+ months; range: 3.3 to 26.9+ months). The combination of Bendamustine and Methylprednisolone given in a limited schedule is well-tolerated and is active in CLL.

Disclosures
No relevant conflicts of interest to declare.
Post-Transfusion Takotsubo Cardiomyopathy
Authors: Badami Krishna G 
Published: November 2021

Abstract
In three recent cases an initial transfusion-related adverse event (TRAE) occurred that had a significant respiratory component, and other features suggesting a severe allergic reaction. All were treated as such. Shortly after treatment the nature of the event changed to something resembling transfusion-associated circulatory overload (TACO).
These cases suggest the possibility that a severe TRAE that is not TACO may precipitate TACO. In other words, some transfusions, sometimes, may deliver a 'double whammy'. A possible mechanism might be through the development of Takotsubo, or stress, cardiomyopathy - a cause of acute, reversible, heart failure. Takotsubo cardiomyopathy typically presents with chest pain or shortness of breath. Ventricular wall dysfunction occurs, and characteristic echocardiographic abnormalities are seen. ECG and biochemical features suggest cardiac ischaemia. It is commoner in post-menopausal women. A range of 'stressors' - hypotension, asthma attacks, accidents, medical procedures, pain, bad news, etc. - may precipitate it. 1 Catecholamines such as adrenaline are believed to play a central role. They cause direct toxicity to the myocardium, and also coronary artery spasm, and increased cardiac workload. 2 One other such case is reported. There, a 48 years old post-menopausal woman developed acute reversible heart failure with the features of Takotsubo cardiomyopathy, following urticaria and pruritus, whilst having a platelet transfusion. No adrenaline was given, but the authors postulate that adrenergic and histaminergic elements may have combined to produce the effect on the heart. 3 Thus, in some patients the 'perfect storm' compounded of borderline cardiac function,catecholamine release (secondary to the stress of the underlying disorder, the transfusion, and the TRAE),histamine release (in allergic TRAE),the treatment of the allergic reaction with adrenalinerecent or ongoing volume overload
may be sufficient to precipitate or exacerbate TACO. Careful consideration of cases with similar features is needed. Potential precipitating factors are modifiable or preventable.
References:
1. https://www.health.harvard.edu/heart-health/takotsubo-cardiomyopathy-broken-heart-syndrome
2. https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.116.027121
3. Zhou JQ, Choe E, Ang L, et al. Stress-induced cardiomyopathy associated with a transfusion reaction: A case of potential crosstalk between the histaminic and adrenergic systems. Exp Clin Cardiol.2011; 16: 30-32
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
PDGF-BB and Its Role in Megakaryopoiesis and Thrombocythemia
Authors: Yang Mo , Li Liang , Luo Yi , Su Weiqing , Kong Huimin , Chong Beng H , Ye Jieyu 
Published: November 2021

Abstract
Background: Essential Thrombocythemia (ET) is characterized by persistently elevated platelet counts in the context of a normal red cell mass. However, the molecular mechanism of ET is still under investigation. Our previous studies demonstrated the presence of functional PDGF receptors (PDGFR) on megakaryocytes and their ability to mediate hematopoiesis and megakaryopoiesis (Ye et al, Haematologica, 2010). The role of PDGF-BB on megakaryocytic progenitors (CD41+, CD34+ cells) and its mechanisms on ET will be further studied in this project.
Methods: ELISA, CFU assay, immunofluorescence microscope, flow cytometry and NOD/SCID mice were used in this study.
Results: Bone marrow plasma levels of PDGF-BB in ET patients (n=18) and normal control (n=10) were tested and found an increased PDGF-BB levels in ET patients (2071.2±124.8 pg/ml), compared with normal control (1382.5±128.3pg/ml) (P=0.002). In vitro experiment, PDGF-BB promoted the ex vivo expansion of human hematopoietic stem (CD34 +) and progenitor (CD41 + CD61 +) cells. More significantly, PDGF enhanced the engraftment of human CD45 + cells and their myeloid subsets (CD33 +, CD14 + cells) in NOD/SCID mice. PDGF-BB stimulated megakaryopoiesis via PDGFR and its signalling. It also showed a direct stimulatory effect of PDGF-BB on c-Fos, GATA-1 and NF-E2 expressions in megakaryocytes. We speculate that these transcription factors might be involved in the signal transduction of PDGF-BB on the regulation of megakaryopoiesis. PDGF-BB also enhanced platelet recovery in mice model with radiation-induced thrombocytopenia. Studies showed that PDGF, like TPO, significantly promoted platelet recovery and the formation of CFU-MK in this irradiated-mouse. An increased number of hematopoietic stem/progenitor cells and a reduction of apoptosis were found in the bone marrow histology sections. In the CHRF apoptotic model, PDGF-BB had a similar anti-apoptotic effect as TPO on megakaryocytes. We also demonstrated that PDGF-BB activated the p -Akt , p-Jak2 and p-Stat3 expression, while addition of imatinib mesylate reduced p-Akt, p-Jak2 and p-Stat3 expression in CHRF cells.
Conclusion: Our findings suggested that PDGF-BB is likely to be mediated via PDGF receptors with subsequent activation of the Akt and Jak2/ Stat3 pathways in megakaryopoiesis. These studies provide a possible explanation that PDGF-BB and its signaling may be involved in the molecular mechanism of essential thrombocythemia.

Disclosures
No relevant conflicts of interest to declare.