bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolomics Unveiled the Potential Role of N1-Acetylspermidine As a Biomarker in T-Lymphoblastic Lymphoma/Leukemia Monitoring
Authors: Liu Qinyu , Yang Yunfan , Xu Caigang
Published: December 2023

Objective: For adult patients with T lymphoblastic leukemia/lymphoma (T-ALL/LBL), current methods for therapeutic response monitoring based on bone marrow examinations lack convenience. A biomarker in blood with high sensitivity can make daily monitoring easier. Our team attempted to identify easily obtained and highly sensitive T-ALL/LBL tumor biomarkers through metabolomics, and meanwhile explore potential metabolic therapeutic targets.

Methods: We performed non-targeted metabolomic analysis on archived plasma samples from 30 newly diagnosed T-ALL/LBL patients and matched controls from 2015-2018. Based on these results, we expanded the sample size to 50 patient and matched control plasmas for targeted metabolomic validation, and explored potential mechanisms using public databases.

Results: A total of 90 differential compounds were detected in non-targeted analysis. Orthogonal partial least squares discriminant analysis showed that the metabolic patterns of the patients and the controls were significantly different (R2=0.915, Q2=0.723, pR2=0.010, PQ2=0.010). KEGG pathway enrichment showed that the detected differential compounds were involved in 41 known metabolic pathways, and the methionine metabolism pathway was highly ranked. Random forest analysis verified significant differentiation between cases and controls based on metabolic differences (ROC curve AUC=0.928, p<0.001), with acetylspermidine contributing most significantly. Targeted validation in the expanded cohort showed decreased methionine, increased methylthioadenosine, and significantly increased N1-acetylspermidine in patient plasma. All these three metabolites could be localized in methionine and related polyamine metabolism pathways, with N1-acetylspermidine upregulation particularly pronounced (fold change=3.590, p<0.001). Plasma N1-acetylspermidine alone could effectively differentiate patients from controls (ROC curve AUC=0.888, p<0.001). Public database records (GSE109231) suggested that upregulated spermidine synthase may explain this alteration in N1-acetylspermidine.

Conclusion: N1-Acetylspermidine showed promising potential as a tumor biomarker for T-ALL/LBL therapeutic monitoring, while methionine and polyamine metabolism abnormalities may constitute new T-ALL/LBL metabolic therapeutic targets.
Atrial Arrhythmia in Sickle Cell Anemia: A Missing Piece to Prevent Cerebrovascular Complications?
Authors: d'Humières Thomas , Sadraoui Zineb , Savale Laurent , Boyer Laurent , De Luna Gonzalo , Habibi Anoosha , Messonier Laurent , Calvet David , Lellouche Nicolas , Derumeaux Geneviève , Bartolucci Pablo
Published: December 2023

Background: Although Sickle Cell anemia (SCA) patients carries an increased risk of stroke and an important left atrial (LA) remodeling, the reality of atrial arrythmia (AA) has never been prospectively assessed.

Purpose: The aim of this study was to identify the prevalence and predictors of atrial arrhythmia in SCA patients among Drepacoeur registry.

Methods: From January 2019 to November 2022, consecutive adult patients with SCA were referred to the physiology department to specifically analyze cardiac function and were prospectively included. They underwent a 24-hour electrocardiogram monitoring (ECG-Holter), transthoracic echocardiography, and laboratory tests on the same day. The primary end point was the occurrence of AA, defined by the presence of excessive supraventricular ectopic activity (ESVEA) on ECG-holter (i.e. >720 premature atrial contractions [PACs] or any run ≥ 20 PACs), recent history of paroxysmal atrial fibrillation (AFib), of persistant AFib.

Results: Overall, 130 patients were included. Mean age was 45±12 years, 48% were male. AA was observed in 34 (26%) patients (17 with more than 720 PACs/day, 6 with at least a run ≥ 20 PACs, 11 with recent history of paroxysmal AFib and 5 with persistant AFib). Ageing (52±9 vs. 42±12 years, P=0,004), LA dilation (LAV i, 71±24 vs. 52±14 ml/m², P<0.001) and history of stroke without underlying cerebral vasculopathy (23% vs. 7%, P=0.04) were independently associated with AA. Age and LAV i correlated with PAC load on ECG-holter (R=0,56, P<0,001 and R=0,33, P<0.001 respectively). Interestingly n age over 47 years or a LAV i >55ml/m² could predict AA with a positive prective value of 33% and a negative one of 92%.

Conclusion: Atrial arrythmia is common in adult SCA patients and is associated with ageing, LA remodeling and considerably increases the risk of ischemic stroke. This study provides tools for early detection of AA and prevent cardiac and cerebrovascular dramatic complications in this highly vulnerable population.
Prognostic Impact of TP53 Mutation in Adult Acute Lymphoblastic Leukemia Treated with Pediatric-Inspired Regimen
Authors: Ou Jiawang , Xu Xiuli , Zhou Ya , Liu Qifa , Zhou Hongsheng
Published: December 2023

Abstract

Background: TP53 is one of the most extensively studied genes in human cancer. However, the prognostic impact of TP53 mutations (TP53mut) in adult acute lymphoblastic leukemia (ALL) remained debatable, especially in those treated with pediatric-inspired regimen. Herein, we determined the characteristic of TP53mut in adult acute ALL patients and investigated the clinical significance of these TP53mut in newly diagnosed ALL.

Patients and Methods: We performed TP53 mutation analysis in 283 adult ALL patients (B-ALL n=227; T-ALL n=56) including 57 diagnose-relapse pairs using targeted next-generation sequencing (NGS). TP53 mutations were analyzed for their association with adult ALL enrolled in pediatric-inspired regimen evaluating clinical characteristics and treatment outcomes.

Results: A total of 35 TP53mut sites were detected in 31 diagnosed samples among 283 diagnosed patients and 17 among 57 paired diagnose-relapse samples, with a significant difference (11.0% vs 29.8%; c2=13.9, P<0.001). The major variant was missense mutation (n=32), followed by frameshift (n=11), nonsense mutation (n=4), in-frame (n=3), and splicing mutation (n=2). In paired diagnose-relapse samples, we identified acquired and/or loss of TP53mut in the samples at the time of relapse. In 283 newly diagnosed patients, patients with TP53mut had a higher proportion of the older population, complex karyotype, and MRD positivity before consolidation therapy (P=0.023, 0.002, 0.024). Survival analysis revealed that TP53mut was associated with inferior outcomes in the whole cohort of newly diagnosed ALL (4-year OS rates, 43.6% vs 63.6%, P=0.0086; 4-year EFS rates, 30.4% vs 52.2%, P=0.0056). Additional survival analysis showed that TP53mut did not confer poor outcomes in the AYA population (4-year OS rates, 60.6% vs 68.1%, P=0.55; 4-year EFS rates, 52.5% vs 55.5%, P=0.57). For the older patients, however, TP53mut predicted inferior OS and EFS in older patients (4-year OS rates, 18.2% vs 46.2%, P=0.0033; 4-year EFS rates, 0 vs 39.6%, P=0.00028).

Conclusion: Our data revealed that TP53mut was present at a low incidence at diagnosis and increase at relapse. TP53mut were potential biomarkers associated with poor prognosis in older patients with newly diagnosed ALL treated with pediatric-inspired regimen.

This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).

【 Key words 】TP53; Acute lymphoblastic leukemia; Pediatric-inspired regimen; Next-generation sequencing; Prognosis
Gender and Racial Disparities in Risk and Outcomes of Thrombotic Thrombocytopenic Purpura Admissions: An Analysis of the National Inpatient Sample 2016-2019
Authors: Jain Tripti , Kharel Himal , Abdelhay Ali , Mahmoud Amir
Published: December 2023

Introduction:

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder associated with severe deficiency in ADAMTS13 leading to microangiopathic hemolytic anemia, thrombocytopenia and end organ damage. The purpose of this study is to compare incidence and outcomes of TTP hospitalization between genders and races.

Methods:

We studied the National Inpatient Sample (NIS) from 2016 to 2019 for hospitalizations with the primary diagnosis of TTP. We fitted a multivariable logistic regression model to compare the risk of TTP amongst different races and genders. The model also accounted for age and comorbidities including solid or hematologic malignancies, history of thrombophilia, obesity, diabetes mellitus, hypertension, hyperlipidemia, chronic coronary artery disease, chronic liver disease, and chronic kidney disease. To compare mortality outcomes, we narrowed our analysis to TTP admissions only and fitted a multivariable logistic regression model with similar parameters. All reported confidence intervals were adjusted for multiplicity using the Bonferroni method.

Results:

A total of 7845 patients met the inclusion criteria of which 65.4% were female and 34.6% were males. The distribution of age and co-morbidities were different between the different racial groups. On adjusted analysis, females had higher rates of hospitalization due to TTP, with OR 1.32 (95% CI 1.24 to 1.41) compared to males, while there was no significant difference in mortality with OR 0.98 (95% CI 0.76 to 1.28). African American patients had significantly higher rates of hospitalization compared to Caucasian patients with OR of 3.62 (95% CI 3.38 to 3.88), followed by Asian and Hispanic patients respectively. Interestingly, the mortality in the African American patients was lower compared to Caucasian patients with OR of 0.74 (95% CI 0.55 to 0.98). There was no significant difference in mortality in other races.

Conclusion:

African American patients and females experienced significantly higher rates of hospitalization with TTP. However, African American patients experienced lower mortality. More research is needed to understand the cause behind these differences and modify our diagnostic and management to improve outcomes for patients with TTP.
Low-Dose IA with Venetoclax Regimen As Induction Therapy for Newly Diagnosed Acute Myeloid Leukemia
Authors: Zheng Weiyan
Published: December 2023

Abstract

Background: The IA regimen (combination of idarubicin and cytarabine) is used as the most common induction of remission therapy for acute myeloid leukemia, with the complete response (CR) rates of up to 70%. Addition of the BCL-2 inhibitor venetoclax(Ven) to chemotherapy can increase apoptosis priming. In order to further improve the remission rate and prolong survival, our center uses a low-dose IA regimen combined with Venetoclax to treat newly diagnosed primary acute myeloid leukemia under 60 years old.

Methods: We retrospectively analyzed 15 patients with newly diagnosed AML, who was under 60 years old. Patients received idarubicin (6mg/m2 IV for 3-days) and cytarabine (60mg/m2 IV for 5-days) with oral venetoclax (400mg daily for 2 weeks) for induction, followed by the same chemo-free regimen for consolidation if patients responded to induction therapy. And then analyze the effects of this regimen on complete remission (CR) rate, minimal residual disease (MRD) negative CR rate, relapse-free survival (RFS), overall survival (OS), and adverse events.

Findings: Between January, 2021 and June, 2023, 15 patients were treated with this regimen. The median age was 43 years (IQR, 36-43) and the median follow-up was 4.25 (IQR, 2.73-15.6) months. Among all patients, the ORR was 86.7% (95% CI 62, 96), the CR rate was 80.0% (95% CI 55, 93), and the MRD negative rate was 66.7% (95% CI 42, 85). According to 2022 ELN risk classification by genetics, the ORR in favorable risk patients were 50.0% (1/2), intermediate risk patients were 100% (7/7), adverse risk patients were 83.3%(5/6). Those who had epigenetic modification mutations (NPM1, FLT3-ITD, CEBPA) were more likely to benefit from this regimen. The most common grade 3 and 4 adverse reactions were neutropenia, thrombocytopenia, and anemia.

Conclusion: As induction and consolidation therapy whose adverse reactions were tolerable, the low-dose IA with Venetoclax regimen produces deep remission for the patients with newly diagnosed primary AML.
Integrative Genome and Transcriptome Sequencing Analysis Indicates Genetic and Epigenetic Dysregulation in DS-AML
Authors: Ma Xiaotu , Ries Rhonda E , Tran Quang , Liu Yanling , Kolekar Pandurang , Alsallaq Ramzi , Liang Zhikai , Shaw Timothy , Devineni Meghana , Deslattes Mays Anne , Lau Ching , Hitzler Johann K. , Meshinchi Soheil
Published: December 2023

Down Syndrome related AML is driven by GATA1 alterations in patients with trisomy 21. Using exome or targeted sequencing, prior studies identified GATA1 alterations in ~80-90% of patients. We performed whole genome sequencing coupled with whole transcriptome sequencing on 207 cases to study the genomic basis of Down Syndrome AML. We detected GATA1 alterations in 96.1% of cases, with additional structural rearrangements in GATA1 in 15% of cases that may have been missed in prior studies. For GATA1, although substitutions and small indels occur nearly uniformly across exon 2, we observed that internal tandem duplications (ITDs) are significantly enriched in the second half of exon 2, suggesting a specific mutational mechanism for these cases. We also detected exon 3 (instead of exon 2) deletion in one case, where the resultant truncated GATA1 protein is different from the commonly recognized sGATA1. Our study further revealed that mutations in genes mediating JAK-STAT signaling (JAK1/JAK2/JAK3), RAS pathway (KRAS/NRAS/NF1), Cohesin complex (STAG2/CTCF/RAD21/SMC3), as well as MBNL1, KANSL1, IRX1, and NFIA. By integrating the genome with transcriptome sequencing data, we discovered that GATA1 exon 2 skipping to be a significant event in DS-AML. Although exon 2 is nearly completely skipped in cases with exon 2 deletion or splice site alterations, significant exon 2 skipping is also observed in cases where the alteration is small and is in the middle of exon 2. Further, exon 2 skipping is also observed in cases wither the alteration is a single base substitution that results in stop codon in the middle of exon 2 (therefore splicing is unlikely affected by these alterations in such cases). Based on this observation, we propose a hybrid genetic-epigenetic model on the development of Down Syndrome AML. In DS-AML, GATA1 exon 2 skipping during transcription/splicing might be a developmentally (epigenetically) regulated event in early fetal development that is destined to be silenced in the postnatal period that results in activation of the canonical long GATA1. This epigenetic silencing of sGATA1 is overridden by secondary genetic events, thus maintaining sGATA1 as the predominant GATA1 protein. Notably, the sGATA1 have variable isoforms as a result of exon 2 or exon 3 loss. In summary, our integrated whole genome and transcriptome approach has resulted in discovery of novel and high-prevalence structural alterations in GATA1 and potentially novel genes involved in pathogenesis of DS-AML. Our integrated analysis provided evidence on the epigenetic/developmental regulation of GATA1 exon 2 skipping via alterative splicing in the context of trisomy 21 that warrants further investigation.
CLL Incidence Based-Mortality By Gender: Is There a Change in the Probability of Dying from CLL Today Among Men and Women?
Authors: Kenmoe Jerry , Ghimire Calvin , Yadav Monica , Vinjam Tejaswi , Kunadi Arvind
Published: December 2023

CLL Incidence Based-Mortality by Gender: Is there a change in the probability of dying from CLL today among men and women?

Background:

About one-fourth of newly diagnosed cases of leukemia are CLL. The lifetime risk of developing CLL is approximately 1 in 175 (0.57%) for the average person. Men are slightly more at risk than women are.

We looked at the incidence-based mortality rates (probability of dying from) of CLL by gender in adult populations in the United States from 2000-2019 via SEER.gov database.

Methods:

We used Incidence -Based Mortality SEER Research Data, 17 Registries, Nov 2021 Sub (2000-2019), which provides the broadest geographic coverage for incidence-based mortality rates and is roughly 26.5% of the US population (based on the 2020 Census) for the calculation of incidence rates of CLL. SEER*Stat 8.4.1 was used to obtain age-adjusted rates for different age-groups, races and genders. We used Join-point software, version 5.0.2. by the National Cancer Institute, annually to create log-linear time trends.

There are no P-values noted for the CI as Joinpoint does not currently produce a test statistic or p-value for Empirical Quantile confidence intervals.

Results:

Fig 1: CLL Incidence Based Mortality Rate per 100,000 and age-adjusted to the 2000 US standard population for males and females 2000-2019

Our study showed increasing incidence based mortality rates, with higher rates in males compared to females. We also noted significant Joinpoints in 2002, 2005 and 2012 for males and2003, and 2010 for females. It is of note that at the Joinpoints, the slope for the rate significantly changes or drops.

The Average Annual Percent Change (AAPC) for males and females were 10.64%*(95% CI 9.95 to 11.53) and 10.09%*( 95% CI 9.41 to 11.44)

Conclusion:

Our study reveals that the slope of incidence-based mortality has significantly reduced over the years from 2000-2019. This means the probability of dying from CLL has also significantly dropped over the years.

This pattern points to changes in guidelines or therapy that have significantly impacted the probability of dying from CLL. This suggests that more investigation is warranted to understand the underlying causes for the trends appreciated.
Distinguishing the Variances in Patient Care between Hematologists and Hospitalists for Individuals with Sickle Cell Disease Hospitalized Due to Vaso-Occlusive Crisis
Authors: Bou Zerdan Maroun , Niforatos Stephanie , Ashok Kumar Prashanth , Siegenthaler Alanna , Ombada Mulham , Kirk Melanie , Jones Andrulisa , Poudyal Bhavya , Levine Elad , Liu Cathy , Repicky Joseph , Mammadli Mahinbanu , Sampat Parth , Sherazi Mahnoor , Ramm Matthew , Rao Gergal Gopalakrishna Rao Sanjay , Layoun Habib , Gentile Teresa
Published: December 2023

Introduction:

Sickle cell disease (SCD) is a chronic condition characterized by multiple vaso-occlusive complications. Patients often experience recurrent, severe pain that can be disabling and necessitate opioid treatment. Hospitalization for vaso-occlusive crisis (VOC) is a common occurrence for individuals with SCD. In recent times, the care of hospitalized SCD patients has increasingly shifted from adult hematology specialists to hospitalists. At our institution, we are yet to make this transition, with hospitalists rarely taking over the care of inpatients with SCD. Initially, recommendations to the hospitalist service were provided through informal opinions or formal consultations when requested.

Hospitalists have demonstrated efficient inpatient management; however, some may have knowledge gaps and biases that can influence their interactions with SCD patients. To gain a better understanding of the differences in care practices between hematologists and hospitalists and to identify potential areas for improvement in the care of SCD patients, we conducted a formal comparison of their approaches.

Methods: We performed a single-institution, retrospective review of patients with SCD hospitalized for VOC between January 1, 2014, and September 31, 2022.

Results: Table 1 portrays the significant results.

Conclusion: We observed significant distinctions in the care provided by hematologists and hospitalists to patients admitted for VOC in SCD. Hematologists tended to transfer fewer patients to the intensive care unit compared to hospitalists. On the other hand, hospitalists more frequently sought consultations from the pain service than hematologists. Interestingly, patients under the care of hematologists received longer hours of patient-controlled analgesia for pain management. Additionally, patients managed by hematologists exhibited higher hemoglobin levels at the time of discharge when compared to those treated by hospitalists.

Notably, only 39.8% of patients had a formal hematology consult requested during their hospital stay, indicating a potential need for better collaboration between hematologists and hospitalists. This study emphasizes the importance of enhancing cooperation between these two specialties to elevate the quality of care for patients hospitalized with VOC.
Impact of Srs-CoV2 Infection on Pain Crises and Acute Chest Syndome in Patients with Sickle Cell Anemia: A Retrospective Multi-Cohort Study Based on USA Data from 2020-2022
Authors: Onimoe Grace ifeyinwa , Yerigeri Keval
Published: December 2023

Objective: To determine the impact of SARS-CoV-2 infection on vaso-occlusive pain crisis (VOC) and acute chest syndrome (ACS), incidence, and outcomes in sickle cell anemia (SCA) patients.

Method: This retrospective study used the TriNetX USA health research network database to identify SCA patients (Hb-SS, Sβ0-thal) ages 1-50 with and without concomitant SARS-CoV-2 infection from May 2020 to May 2022. A total of 6 cohorts were created: pain crisis with/without SARS-CoV-2, ACS with/without SARS-CoV-2, and SARS-CoV-2 without pain crisis/ACS. Patients with SARS-CoV-2 and pain crisis/ACS were compared to 2 cohorts (SARS-CoV-2 without pain crisis/ACS) for demographic characteristics, baseline laboratory parameters, disease-modifying drug use, and influenza/COVID-19 vaccination status by t-tests. Pain crisis/ACS patients with SARS-CoV-2 were then compared to 2 cohorts (pain crisis/ACS without concomitant infection) for demographic characteristics, and relative risk for acute settings of care, pain control, laboratory parameters/outcomes (including hemolytic and inflammatory markers), procedures (blood transfusion) and mortality.

Results : The incidence of pain crises and ACS in SCA patients following SARS-CoV-2 infection was 34 and 27 per 100 patients, respectively. The risk of developing ACS was significantly increased by SARS-CoV-2 infection (2.57% vs. 1.17%, RR 2.2), but not the risk of developing a pain crisis (RR 1.04). Pain crisis and ACS patients with concomitant SARS-CoV-2 infection had a greater risk for inpatient services, subsequent hospital visits, opioid and non-opioid analgesia, blood transfusions, and concerning hemolytic and inflammatory markers compared to those without the infection. Patients with SARS-CoV-2 who did not develop pain crises/ACS had higher baseline hemoglobin levels prior to infection compared to patients who developed pain crisis/ACS. There was a higher rate of COVID-19 and influenza vaccination in the cohorts who did not develop pain crisis/ACS and might have improved pain crisis rates (but not ACS) following SARS-CoV-2 infection.

Conclusions: COVID-19 illness had an impact on the incidence of both pain crises and ACS, significantly increased the risk of developing ACS, and influenced morbidity outcomes for both pain crises and ACS. Prior vaccination against influenza and COVID-19 may represent a protective factor for developing pain crises.
Utility of Assessing Primary Hemostasis By Determining Platelet Function and Von Willebrand Factor in Patients with Myeloproliferative Neoplasms
Authors: Nomdedeu Meritxell , Moreno Castaño Ana Belén , Garrote Marta , Arellano-Rodrigo Eduardo , Carbonell-Ordeig Sara , de Moner Blanca , Escolar Ginés , Esteve Jordi , Tassies Dolors , Diaz-Ricart Maribel , Reverter Joan Carles , Alvarez-Larran Alberto
Published: December 2023

VWF

Changes in primary hemostasis have been implicated in thrombotic and bleeding complications in myeloproliferative neoplasms (MPN), so their evaluation could be useful in the management of these patients.

We studied primary hemostasis in 248 patients with essential thrombocythemia-type MPN (TE n=129), polycythemia vera (PV n=71) and myelofibrosis (MF n=48). Von Willebrand antigen (VWF:Ag) (normal: 60-160 U/dL), von Willebrand factor (VWF) activity (VWF:GPIbM) (normal: 60-160 U/dL) and closure time with the platelet function analyzer (PFA-200) (pathological: collagen-Epinephrine channel > 200 seconds; collagen-ADP channel > 140 seconds) were assessed. VWF:GPIbM < 60 U/dL and a VWF:GPIbM / VWF:Ag ratio < 0.7 were considered to be suggestive of acquired von Willebrand disease (aVWD). In antiplatelet patients with acetyl salicílic acid (ASA), we defined in vitro resistance as a PFA-200 Col-Epi time < 200 seconds. The results were correlated with the diagnosis, hematological values, conventional or NGS genotype (n=176) and treatment at the time of the study. Patients with thrombocytopenia < 50x10 9/L were excluded from the PFA-200 analysis.

Table 1 describes the clinical variables of the patients.

GPIbM was decreased in 14 cases, increased in 85 cases, and normal in the rest. We identified a direct correlation with age (β=0.29, R2=0.08, p=0.001), and an inverse correlation with the number of platelets (β=-0.45, R2=0.20, p<0.001), independent of the genotype. . We found elongated PFA-200 in the Col-Epi and Col-ADP channels in 129 (54%) and 63 (26%) cases, respectively. In 10 (4%) patients we found parameters suggestive of avWD. All of them had thrombocytosis. Elevated platelet count (>600x109/L) was associated with VWF values suggestive of aVWD, with a sensitivity and specificity of 90% and 83%, respectively (AUC: 0.938, 95%CI: 0.896-0.980).

Of the 99 patients not on antiplatelet therapy, 31 (31%) had an elongated PFA-200. Elongated PFA-200 was associated with lower Hb, higher leukocytes, higher platelets, higher JAK2 mutational load, lower VWF:GPIbM, and CALR genotype. This alteration was observed in 71% of patients with the CALR genotype. In multivariate analysis, decreased VWF:GPIbM (OR: 0.98, 95%CI: 0.97-0.99, p=0.001) and CALR mutation (OR: 0.98, 95%CI: 0.97- 0.99, p=0.001), maintained their value.

Of the 130 patients receiving ASA, in vitro resistance was found in 31 cases (24%) (PV 30%, TE 25%, MF 0%). ASA resistance was associated with a higher platelet count and higher VWF:GPIbM. 50% of the patients with increased VWF:GPIbM (>160 U/dL) had resistance to ASA, showing VWF:GPIbM as an independent variable in the multivariate analysis.
Patients with Sickle Cell Disease Can Demonstrate a Constellation of Symptoms Associated with Hyper-Hemolysis without Recent Transfusion
Authors: Garrett Erin R. , Chonat Satheesh , Briones Michael , Rollins Margo R.
Published: December 2023

Background

A hallmark characteristic in patients with Sickle Cell Disease (SCD) is chronic hemolysis, the severe exacerbation of which has been linked to RBC transfusion in some cases. This hyper-hemolysis (HH) is defined as a rapid decline of hemoglobin (Hb) and HbA% below pre-transfusion values. HH has been considered a severe form of antibody negative DHTR (Ab (-) DHTR) in patients with SCD and defined by the American Society of Hematology as hemolysis within 21 days of transfusion, negative DAT and absence of new alloantibody. Herein, we present a case series of 5 SCD patients with transfusion > 21 days from presentation demonstrating symptoms and lab findings consistent with HH. The purpose of this study is to characterize patients with SCD diagnosed with HH as a working diagnosis without temporal relation to transfusion. To our knowledge, this is the first and largest case series of its kind.

Methods

An IRB approved retrospective EMR review collected demographic and clinical data for patients with SCD admitted for concern for HH or DHTR to a large multi-site Pediatric Hospital in the Southeastern USA (2020-2023). All patients in this study were identified from Transfusion Medicine consults to investigate DHTR. Patient admission diagnosis was obtained from EMR review.

Findings

Cohort patients were 15-19 years with HbSS or HbS-beta thalassemia zero. All patients had transfusion >21 days from presentation. Of note, patient #5 received a transfusion during their first admission and was readmitted for signs and symptoms of HH/Ab (-) DHTR within 24hrs of discharge. All patients admitted for >1 day demonstrated an average 47% fall in hemoglobin (range: 24-69%), negative antibody screen/DAT, reticulocytopenia and mild to moderate thrombocytopenia. Four patients demonstrated elevated LDH. One patient died prior to discharge. Day of stay (DOS) of labs is in brackets []. Refer to table 1 for detailed patient data.

Conclusion

This case series demonstrates that patients with SCD can experience a constellation of symptoms identified in patients with HH without temporal relation to transfusion. These include hemolysis, reticulocytopenia, and thrombocytopenia as well as elevation of complement proteins. Given the overlap in presentation, HH in patients with SCD should be considered independently of proximity to transfusion for prompt diagnosis. Further study should include a retrospective review for further characterization. In addition, given the finding of elevations in C5a, further study into complement as a mechanism and target of therapy would be valuable.
Increased Proliferative Drive of Lymphocytes in Sickle Cell Disease
Authors: Ginda Ashley , Zhang Jingyue , Meng Wenzhao , Kearns Charlotte , Weissman Samuel , Swiggard Liam , Richards Clarice , Moore Jeffrey , Murter Melissa , Luning Prak Eline T. , O'Doherty Una
Published: December 2023

Introduction

Patients with sickle cell disease (SCD) have higher levels of inflammation which plays a prominent role in disease pathogenesis. It is well known that individuals with SCD have a higher erythropoietic drive given the ~20 day life span of their red blood cells. We asked whether this increased proliferative drive also occurred in white blood cells (WBC). To characterize WBC turnover we focused on the longest-lived CD4+ and CD8+ T cells.

Methods

Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll gradient from red cell waste products from consented individuals with sickle cell disease and from leukapheresis products of healthy donors. In ten healthy donors and ten donors with SCD, CD4 and CD8 T cells were purified using EasySep Cell Isolation, labeled with eFluor 670 proliferation dye, and cultured in RPMI with 30% FBS for seven days. Samples were collected daily and stained with naïve and memory T cell markers. CountBright beads were added to obtain absolute cell counts and eFluor 780 live/dead dye was used to capture daily snapshots of cell death. Flow cytometric analysis was performed to track absolute cell numbers, cell division and indirectly monitor cell death. B cells, NK, macrophages, and dendritic cells were similarly tracked. To further probe T cell turnover, T cell receptor (TCR) sequencing was performed on twelve separate aliquots from purified CD4+ T cells at two different timepoints in healthy donors and individuals with SCD. Turnover of clonal sequences was analyzed using the Morisita index.

Results

CD4+ and CD8+ lymphocytes from individuals with SCD experienced more death in culture by day 7 compared to healthy donor controls. In addition, T lymphocytes from donors with SCD were observed to undergo 15-fold more proliferation compared to healthy donors (p=0.0002, unpaired t-test). Immunophenotyping performed on the CD4 and CD8 T lymphocytes showed a propensity for memory cells to undergo proliferation. We also found individuals with SCD had higher turnover in TCR sequences in two timepoints compared to healthy donors (p=0.05, Chi-square). Notably, we also saw increased proliferation of B cells, NK cells, macrophages, and dendritic cells in individuals with SCD.

Conclusion

Our data suggest that T lymphocytes and other PBMCs undergo faster turnover in SCD than in healthy donors, suggesting a stronger hematopoietic drive. Our findings may have important implications for gene therapy since an increased proliferative drive may contribute to an increased risk of developing leukemia in SCD.
Efficacy and Safety Profile of CPX-351 in Secondary Acute Myeloid Leukemia (sAML): A Systematic Review
Authors: Ibrahim Ahmed , Yousaf Muhammad Abdullah , Ikram Mariam , Khalid Huma , Anum . , A Safdar Omar , Anwer Zain , Faraz Fatima , Rehman Mohammad , Saad Muhammad
Published: December 2023

Secondary Acute Myeloid Leukemia (sAML) is a subgroup of Acute Myeloid Leukemia (AML) associated with poor outcomes despite recent advancements in chemotherapy. CPX-351 (United States: Vyxeos®), a 1:5 liposomal encapsulation of daunorubicin and cytarabine was approved in 2017 by the US Food and Drug Administration (FDA) for the treatment of newly diagnosed Secondary AML. Previously, the conventional 7+3 Regimen (7 days of cytarabine and 3 days of daunorubicin) was considered first line for the treatment of sAML. However, the pivotal study that led to approval of CPX-351 demonstrated increased Overall Survival (OS) with CPX-351. We report a systematic review of published literature on the efficacy and safety of CPX-351 in patients with sAML, including data from post-market real-world experiences of patients.

Materials and Methods Following PRISMA guidelines, we performed a comprehensive literature search for articles published after 2017 using PubMed, Embase, Clinical Trials.gov, Cochrane Library, and Web of Science. Initially 63 articles were identified, and after a thorough screening, we finalized 9 studies including 767 patients, illustrated in Table 1. We analyzed data from patients who received CPX-351 chemotherapy as first-line therapy for sAML. MeSH terms and keywords were 'CPX-351' and 'Leukemia, Myeloid, and Acute'.

Results The median age of patients was 65.9 years. Patients could receive up to two cycles of induction, and those who achieved complete remission (CR) or complete remission with incomplete recovery (CRi) could receive up to 2 cycles of consolidation with CPX-351. CPX-351 treatment showed median overall survival (mOS) of 12.20 months, CR rate of 43.66%, and an overall remission rate (ORR) of 51.1%. Hematopoietic Stem Cell Transplantation (HSCT) was performed in 39.1% patients. The mean time to absolute neutrophil count >500/mL (mANC) and platelet count >50,000/mL (mPC) recovery in patients who achieved OR was 34.4 days and 32.9 days, respectively. The most frequently reported greater than grade 2 adverse events (AEs) were febrile neutropenia (NF), opportunistic infections including pneumonia, and hypoxia.

Conclusion In sAML patients, the CPX-351 regimen is more effective and well tolerated as compared to the conventional 7+3 Regimen. The real-world data also points to CPX-351 as an efficient therapeutic agent for sAML patients facilitating HSCT in many patients with promising outcomes after transplantation. CPX-351 is a treatment of choice for patients aged >60 years. Future randomized prospective trials with longer follow-up periods are needed to consolidate these findings, and help us better understand the efficacy and survival outcomes of CPX351 regimens for sAML treatment.
Preclinical and Early Clinical Results Indicate a Role for the Oral p300/CBP Inhibitor Inobrodib (CCS1477) in T-Cell Lymphoma
Authors: Campbell Victoria , Walter Harriet , Gibb Adam , Davies Andrew S. , Elmusharaf Nagah , Pegg Neil , West Will Henry , Knurowski Tomasz , Frese Kris , Haynes Debbie , Clegg Karen , Somervaille Tim
Published: December 2023

Inobrodib (CCS1477) is a potent, selective, and orally bioavailable inhibitor of the bromodomains of CBP and EP300, two homologous histone acetyltransferases with critical roles in cellular growth and differentiation. Lymphomas can harbor multiple putative predictive biomarkers for inobrodib, including deleterious mutations in CBP/EP300 that convey synthetic lethality and expression of the lineage transcription factors IRF4 and GATA3.

The preclinical efficacy of inobrodib was assessed in a range of solid cancer and hematological cancer cell lines. Select models, including multiple myeloma, acute myeloid leukaemia, and lymphoma cell lines were sensitive to submicromolar concentrations of inobrodib. These in vitro results were extended to xenograft models in which inobrodib demonstrated dose-dependent efficacy.

Based on these results, we initiated a clinical trial to test the safety and efficacy of inobrodib in advanced hematological malignancies (NCT04068597). Dose escalation was conducted in multiple myeloma patients and select B and T-cell lymphomas. The safety profile was similar to other hematological and solid tumour indications with readily manageable and reversible thrombocytopenia as the main toxicity. The recommended phase 2 dose was established at 35mg bidaily on a 4 days on/3 days off intermittent schedule.

Initial data in peripheral T cell lymphoma - not otherwise specified (PTCL-NOS) shows a potential benefit with objective responses in 3 of 4 patients as of data cut-off date (20 Jul 2023). These included a complete metabolic response in a patient (with previously refractory disease) continuing on treatment for over 1.5 yrs and 2 patients with minor responses. Translational investigations indicate that responders all express IRF4 and GATA3, but do not harbour CBP/EP300 mutations.

Together these data support the further development of inobrodib for the treatment of peripheral T cell lymphoma. Expansion continues with a focus on T-cell lymphomas, which may be driven by IRF4 and GATA3.
Pre-Clinical Developmental Hematopoiesis Demonstrates the Heterogeneity of KMT2A-Rearranged Infant Acute Lymphoblastic Leukemic Populations
Authors: Ulloa Bianca A , Nizhnik Anastasia , Bowman Teresa V.
Published: December 2023

KMT2A-rearranged (KMT2A-r) infant acute lymphoblastic leukemia (ALL) has a poor prognosis with increased risk of relapse when diagnosed at younger ages. Understanding the origin of these leukemic cells is crucial to comprehend disease development and prognosis differences. The unclear delineation of the identity of early blood populations in humans is a challenge in defining the cell type(s) driving this infant ALL. Recent pre-clinical studies revealed that definitive hematopoietic stem cells (HSCs) have minimal contribution to embryonic hematopoiesis, while independently arising embryonic hematopoietic progenitors (HPCs) that possess more limited self-renewal and/or multilineage differentiation capacities, are both necessary and sufficient to sustain the developing embryo. Here, we aim to leverage pre-clinical knowledge on the markers that distinguish HSCs from HPCs to investigate the potential contribution of HPCs in driving prenatal and infant leukemias. We defined transcriptional signatures from developmental HSC and HPC populations using thirteen single cell RNA sequencing (scRNA-seq) datasets from zebrafish, eight datasets generated by our research group and five from independent published studies. We then employed a neural network approach to define the orthologous cell type signatures most likely correlating with human healthy and blast cells from publicly available data of 18 KMT2A-r infant ALL patients. In accordance with previous literature, HSC and lymphomyeloid progenitor signatures are both highly represented in the leukemic blast populations. Additionally, we found subpopulation differences in gene expression within leukemic blasts cells including lymphoid progenitor, granulocytic, and T cell signatures, possibly suggesting heterogeneity in either their cell type of origin or developmental differentiation potential. Our findings support the ability to use orthologous scRNA-seq to decipher new understanding on the role of HSCs and HPCs in hematological malignances affecting infants and children.
Outcomes Among Hospitalized Patients with Acute Chest Syndrome and Concomitant Clinical Depression: A United States Population-Based Cohort Study
Authors: Syal Arshi , Arya Yajur , Casipit Bruce Adrian , Dourado Claudia , Mayo Ryan J , Casipit Carlo
Published: December 2023

Background

Acute chest syndrome is a life-threatening complication of sickle cell disease, seen in both children and adults. Hospitalization and immediate treatment are necessary to prevent morbidity and mortality. Clinical depression is quite prevalent in patients with sickle cell disease, and review of literature reveals association of depression with increased annual emergency department visits, hospitalizations, and blood transfusions in patients with sickle cell disease. Whether this leads to worse outcomes is yet to be ascertained.

Methods

We utilized the 2018-2020 National Inpatient Sample (NIS) Database in conducting a retrospective cohort study. We identified hospitalized patients with acute chest syndrome and concomitant clinical depression using appropriate ICD-10 CM codes. We stratified patients based on whether they had clinical depression during the hospitalization or not. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (OR) for the primary and secondary outcomes. A p value of <0.05 was considered statistically significant. The aim of this study is to investigate the outcomes among hospitalized patients with acute chest syndrome and comorbid clinical depression looking primarily at the in-hospital mortality and hospital length of stay (LOS).

Results

We identified a total of 5271 hospitalized patients with acute chest syndrome, of which 10.72% (565/5271) had comorbid clinical depression. The overall in-hospital mortality among those with acute chest syndrome was 3.70% (195/5271). Among those with clinical depression, the overall in-hospital mortality rate was not significantly higher at 5.31% (30/565) (p=0.385). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, clinical depression among hospitalized patients with acute chest syndrome did not significantly increase the risk for in-hospital mortality (adjusted OR 1.39, 95% confidence interval [CI], 0.49-3.91; p=0.533) or prolong hospital LOS (median LOS 6 days versus 7 days, p=0.631)

Conclusion

Acute chest syndrome continues to be an important cause of hospital admissions in patients with sickle cell disease. Our analysis revealed that clinical depression is commonly encountered in this subset of patients. Clinical depression did not have a statistically significant impact on outcomes including increased in-hospital mortality or prolonged hospital LOS. Prospective studies with large sample sizes are needed to better understand these outcomes.
Identifying Inflammatory and Immune Markers Associated with Vasoocclusive Crisis in Patients with Sickle Cell Disease
Authors: Li Wei , Pucka Andrew , Debats Candice , Reyes Brandon , O'Brien Andrew Ross Wickman , Yu Qigui , Wang Ying
Published: December 2023

Background: Sickle cell disease (SCD) is an inherited disorder that can cause a range of clinical complications, featured by unpredictable and recurrent acute painful episodes associated with vasoocclusive crises (VOCs). Individuals with SCD experience frequent VOCs and require high doses of opioids for pain control. Thus far, studies on biomarkers associated with VOCs in SCD are very limited and the known markers are hardly considered as critical end points in studying VOCs in SCD. This study aimed to comprehensively analyze immune and inflammatory characteristics of patients with SCD to understand the disease-specific pathogenesis and develop targeted diagnostic and therapeutic strategies related to VOCs.

Methods: The study cohort consisted of 40 patients with SCD aged 14-73 years (23 female, 58%), recruited for an ongoing clinical trial (ClinicalTrials.gov Identifier: NCT05045820). Twenty-three ethnicity-, age- and gender-matched pain-free participants were also enrolled as healthy controls (HCs) (Table 1). Multiplex immunoassays were used to profile 80 inflammatory cytokines/chemokines/growth factors and 18 autoantibodies in plasma samples from patients with SCD and the matched HCs. Peripheral blood mononuclear cells were used to profile immune cells. Statistical analysis was performed using GraphPad Prism with Mann-Whitney test, χ 2 test, and Spearman's correlation. P < 0.05 was considered statistically significant.

Results: Patients with SCD exhibited significantly higher plasma levels of 34 analytes, including 12 pro-inflammatory/anti-inflammatory cytokines (IFN-γ, IL-1α, IL-2, IL-8, IL-9, IL-18, TNF-α, TNF-β, IL-4, IL-5, IL-6, and TSLP), 10 chemokines (CCL21, CCL23, Eotaxin-2, Gal-3, GRO-α, IP-10, MCP-2, MIP-1α, MIP-1β, and MIP-3α), 8 growth factors (bNGF, G-CSF, GM-CSF, HGF, IL-7, IL-20, IL-34, and LIF), 2 effectors (granzymes A and B), and 2 soluble receptors (PTX3, TREM-1). Higher activation levels of B cells, CD4 T cells, CD8 T cells, and MAIT cells were seen in patients with SCD. Autoantibody profiles were also altered in patients with SCD, with elevated levels of antibodies against SSA/Ro60, Ribosomal P, Myeloperoxidase, and PM/Scl-100. Levels of cytokines/chemokines/growth factors were correlated with time interval between blood draw and occurrence of VOCs. Four soluble factors (Eotaxin-2, GRO-α, IL-6, and LIF) were positively associated with time interval after VOCs, while two factors (IL-18 and granzyme A) showed negative associations with time interval, suggesting that the altered inflammatory mediators were associated with the occurrence of VOC events.

Conclusion: Our results provide novel and comprehensive understanding of the immune and inflammatory dysregulation in patients with SCD and their relationship with occurrence of VOCs, offering insights into potential SCD-specific biomarkers for further investigation.
Exploring the Utility and Significance of an Adult Academic Non-Cancer Hematology Clinic
Authors: Thomas Melissa , Gibson Spencer , Quy Ray , Pakbaz Zahra
Published: December 2023

Background:

Current projections suggest that the demand for adult hematologists will exceed the existing supply in the United States. Despite this, academic centers' hiring practices and fellows' future career choices appear to place an emphasis on oncology over non-cancer hematology.

Objective:

The primary objective of this study was to assess the overall utility and importance of a clinic dedicated to non-cancer blood disorders within a single academic center by analyzing referral characteristics and select patient demographics.

Methods:

This study is a retrospective chart review of 755 adults seen in a new single-provider clinic for adults with non-cancer blood disorders within the division of hematology oncology at an academic center between February 2020 and July 2023. This clinic was telemedicine only (video visit or phone visit) between February 2020 and August 2022, after which the clinic switched to a hybrid format. Data analysis included specialty of referring provider, reason for referral, and patient demographics including age, sex, and geographic location. Financial returns for the clinic in the fiscal years 2020-2023 were also analyzed.

Results:

Of the 755 patients analyzed, 318 were male and 437 were female, with a median age of 53 years (minimum 17 years and maximum 100 years). Referred patients were from 209 unique zip codes in 92 unique cities with a catchment radius of 340 miles to the north and south, and 94.5 miles to the east and west. One third of referrals were from outside of the UCI Health system. Of the 31 referring specialties, Family Medicine (21.25 %), Internal Medicine (18.19 %), and Hem Onc (17.75%) were the top referrers. The most common reason for referrals were anemia (30.58%), cytopenia (23.23%), and thrombosis/hemostasis (including pre-op clearance) (22.32%). The productivity averaged over the last 3 years the clinic was open was 40% above the defined clinic operation target benchmark. The top 3 common health insurances for the fiscal year 22-23 were managed care (33.78%), Medicare (31.65%), and commercial contracted (28.12%).

Conclusion:

This data analysis demonstrates the growing need for adult hematologists with expertise in non-cancer blood disorders and the high utility and financial revenue potential for non-cancer hematology clinics. Given the vast catchment area of patients being seen, the expertise necessary in the diagnosis and management of non-cancer blood disorders truly shows its value. Furthermore, with such a sizable proportion of referrals originating from other hematology/oncology doctors (3rd highest volume of referrals), it can be inferred that a 2nd opinion from a benign hematologist is valued by those in the field as critical in the diagnosis and management of their patients.