bluuebunny/crossref_metadata_2025 huggingface dataset:
“I Really Wish We Had a Talk on Advocacy That Wasn't Boring”: Toward a Health Advocacy Curriculum That Meets the Needs of Canadian Hematology Residents
Authors: Chaudhary Mitali , Trinkaus Martina , Tseng Eric , Schneider Francine , Scott Michael Douglas
Published: December 2024

Background: There is an ongoing need to incorporate health advocacy training into postgraduate medical education. In Canadian hematology training, there are no existing dedicated health advocacy curricula. As a first step toward the development of such curricula, we sought to determine what the health advocate role entails for hematologists, identify necessary health advocacy competencies in hematology, and understand how these competencies could be learned in hematology residency training.

Methods: Semi-structured interviews were conducted with practicing hematologists in Ontario, Canada to elicit key health advocacy competencies for hematologists and learn how these are acquired. Participants were selected using a purposeful, maximal variation sampling strategy. Interviews were recorded in their entirety and transcribed by hand. Data were deidentified after collection and a computer software (NVivo) was used to create codes through an iterative approach. The codes were analyzed using the thematic analysis technique outline by Braun and Clarke (Braun & Clarke, 2006). A deductive approach was employed, incorporating the CanMEDs framework and previously described conceptual frameworks pertaining to health advocacy.

Results: 8 hematologists (5 academic-based, 3 community-based; 4 malignant hematologists and 4 non-malignant hematologists) were included. Hematologists engage in advocacy activities at the clinical, paraclinical, and supraclinical levels and conduct advocacy work most commonly through a directed agency strategy. Drug access was the most prominent advocacy challenge encountered by hematologists. Health disparities that were identified included the rural/remote divide and socioeconomic status. Health advocacy competencies employed by hematologists closely resembled those used by other physicians, with some difference on emphasis. Skills that hematologists found were important to advocacy training were leveraging interprofessional connections, using research as advocacy, and acquiring health systems knowledge. Early exposure to advocacy in training, effective mentorship, and learning from practical examples and experience were viewed as the most effective ways to learn health advocacy skills.

Conclusion: This study identified the breadth of advocacy activities conducted by hematologists and identified numerous competencies that are important to being an effective health advocate. Health advocacy education in hematology training programs should start early, be practical and engaging, be integrated longitudinally into existing teaching and learning activities, and harness the power of mentorship relationships. This work is the first step in addressing the informational gap required to design a novel health advocacy curriculum for hematology residents.
RGT-61159, Best-in-Class Small Molecule Inhibitor of MYB Via Selective RNA Splicing Alteration, Showed Robust Anti-Tumor Activity across AML Tumor Models Harboring Common Genetic Lesions
Authors: Lu Norman , Soulard Patricia , Kay Ibrahim , Li Kai , Gu Xiubin , Sadlish Heather , Lee Jay , Elhawary Mariam , Rotelli Michael , Hasson Sam , Wynn Thomas , Yates Chris , Weng Zhiping , Xi Simon , Wager Travis
Published: December 2024

MYB gene encodes a transcription factor that acts as a master regulator of cells self-renewal, proliferation and differentiation processes. MYB is frequently upregulated or aberrantly activated in a variety of solid cancers (e.g., adenoid cystic carcinoma [ACC], colorectal cancer [CRC], and liquid tumors). In leukemias, high MYB RNA levels are especially frequent (90%) in acute myeloid leukemia (AML). In addition, in T-cell acute lymphoblastic leukemia (T-ALL), MYB is overactivated in 20-30% of patient population due to well characterized genetic lesions (e.g., chromosomal translocations [c-MYB/AHI1; TCRB-MYB 8%], gene duplication [19%]), or somatic mutations. Importantly, a genome-wide CRISPR-Cas9 screen identified MYB as an essential gene for leukemia/lymphoma cell lines viability. Altogether, data strongly suggest MYB as a promising therapeutic target to treat blood cancers.

RGT-61159 is a potent, selective oral small molecule inhibitor of the MYB oncogene via the inclusions of a cryptic exon into MYB RNA transcripts, resulting in the activation of the nonsense-mediated decay pathway promoting MYB mRNA depletion and sequentially MYB protein degradation. RGT-61159 Phase 1 study in adults with relapsed/ refractory ACC or CRC has been initiated (NCT 06462183)

Here, we report RGT-61159 robust MYB RNA & protein knockdown and cell-killing activity across a broad range of different AML cell lines with different oncogenic abnormalities. Such a data set supports that RGT-61159 killing activity of leukemic cells is driven by MYB signaling inhibition and confirms MYB dependency across a broad AML patient population. In addition, we report proteomic and genomic analyses of different AML cell lines treated with RGT-61159 that provided further lights on key oncogenes (e.g., BCL2, NOTCH, MYC) directly regulated by MYB in a cell genetic context dependent.

To further evaluate RGT-61159's potential to treat leukemia, RGT-61159 single agent was profiled in a battery of murine models of AML harboring the most common genetic lesions (e.g., AML-1-ETO, MLL-fusion and NPM1 mutation). RGT-61159 showed highly significant anti-tumor activity across the different AML tumor models tested along with robust MYB RNA depletion in tumor cells (up to 90% tumor growth inhibition [TGI]) in a dose dependent manner and at tolerated doses.

In summary, MYB oncogene represents a therapeutic target of relevance to AML and other hematological malignancies. RGT-61159 is a potent and selective oral small molecule inhibitor of MYB RNA and protein and an attractive therapeutic avenue to treat cancers overexpressing the oncogenic MYB protein.
Markers of Activated Coagulation Factor XII Are Inversely Associated with Progression of Atrial Fibrillation in the Race V Study
Authors: Nagy Magdolna , Weberndoerfer Vanessa , Posma Jens , Van Kuijk Sander , Nguyen Bao-Oanh , Ten Cate Hugo , Van Gelder Isabelle C , Crijns Harry , Rienstra Michiel , Spronk Henri M.H.
Published: December 2024

Background: Paroxysmal atrial fibrillation (PAF) is a common cardiac arrhythmia which may cause stroke and heart failure, especially in case of AF progression. Recent studies have suggested that hypercoagulability may play a significant role in the pathophysiology of PAF by facilitating initiation and progression of PAF. Most evidence for the hypercoagulable state originates from elevated levels of D-dimer, prothrombin fragment 1+2 or thrombin-antithrombin complexes, however whether this originates from the intrinsic (FXII) or the extrinsic (FVII) pathway is not known. Therefore, we aimed to systematically investigate the association of the activation of single coagulation factors with the progression of AF.

Methods: In this sub-study of RACE V (Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical Remodelling, and Vascular Destabilisation in the Progression of Atrial Fibrillation, NCT02726698) study, 417 patients with PAF were included. At baseline extensive phenotyping was performed including blood samples drawn. During follow-up continuous monitoring for AF progression defined as either development of persistent or permanent AF during follow-up or an increase of >3% AF burden over the first 6 months or total follow-up, was performed for at least one year. Hypercoagulability was monitored through activated coagulation factors (FXIIa, FXIa, FIXa, FXa, pKa and thrombin) in complex with their natural inhibitors (antithrombin (AT), C1-esterase inhibitor (C1Inh), or alpha-1-antitrypsin (a1AT)) utilizing ELISA. Multivariable logistic regression analysis was used for the association of coagulation markers with AF progression.

Results: 51 out of 417 study subjects showed AF progression within the follow-up time period. Patients with AF progression showed significantly lower FXIIa complexes in comparison to patients without AF progression (759 pM [660-879] vs. 886 pM [765-1007]. The activation state of the other coagulation factors showed no statistically significant differences. Multivariate analysis identified that FXIIa complexes (odds ratio [OR] 0.998, 95% confidence intervals [CI] 0.997-0.999, p<.001.) are associated with AF progression. FXIa (OR 0.734, 95%CI 0.521-1.033, p=0.76), FXa (OR 0.532, 95%CI 0.201-1.405, p=0.203), FIXa (OR 1.101, 95%CI 0.789-1.538, p=0.572), thrombin (OR 1.022, 95%CI 0.997-1.048, p=0.086) and kallikrein (OR 0.969, 95%CI 0.903-1.039, p=0.372) showed no relationship with AF-progression.

Conclusion: In patients with PAF FXIIa was inversely related to AF progression. Downstream activation of the intrinsic cascade, however, was not related to AF progression. Whether this means that FXII is over-proportionally auto-activated or has a protective role or in AF-progression needs to be further investigated.
Characteristics and Therapeutic Response of Erdheim-Chester Disease Associated with Myeloid Neoplasm, an Observational Multicenter Study
Authors: Le Pogam Ambroise , Papo Matthias , Hirsh Pierre , Emile Jean-Francois , Duffau Pierre , Razanamahery Jerome , Lazarro Estibaliz , Roos-Weil Damiens , Cohen-Aubart Fleur , Jachiet Vincent , Mekinian Arsene , Fain Olivier , Amoura Zahir , Hadjadj Jerome , Haroche Julien
Published: December 2024

Introduction : Erdheim-Chester disease (ECD) is L-group histiocytosis with adult-onset and life-threatening multisystemic involvement. ECD is frequently reported in association with clonal hematopoiesis and myeloid neoplasm (MN). Due to its rarity, clinical, hematological, and mutational characteristic of ECD associated with MN, as well as their evolution under targeted therapy, are actually not known.

Methods : We performed a retrospective study of 67 patients with ECD or mixed histiocytosis associated with MN. All data were collected from medical records before and under treatment. Therapeutic response was assessed by CRP and FDG-PET-CT at 6 and 12 months. Characteristics were compared to a control cohort of 348 ECD without MN. The mutational profile was obtained at MN diagnosis and under kinase inhibitor (KI i.e. BRAF and/or MEK inhibitors) through deep targeted sequencing analysis.

Results : A total of 67 patients with ECD and MN were reported, including 33 chronic myelomonocytic leukemia (CMML), 18 with myelodysplastic syndromes (MDS), 15 with myeloproliferative neoplasms (MPN) and one acute myeloid leukemia (AML). MDS cases and CMML cases had low blasts and favorable prognosis score respectively.

ECD patients with MN were significantly older at histiocytosis diagnosis (65 years vs. 59 years, p <0.0001) and exhibited more frequent cardiac (54% vs. 37%, p < 0.01), pulmonary (48% vs. 31%, p < 0.01), perirenal (84% vs. 64%, p = 0.004), and digestive (34% vs. 11%, p < 0.0001) involvement than those without MN. The most frequent myeloid mutations in the cohort were TET2, KRAS, SRSF2, ASXL1, NRAS and CBL. There was an increase in the number of myeloid mutations from 78 to 99 mutations after a mean reassessment time of 25 months under KI. MN progression or transformation occurred in 25% of patients, similarly in those treated with kinase inhibitor or IFN. Median survival-rate of ECD patients with MN was 76 months compared to 163 months in ECD without MN (p < 0.001).

Conclusion : ECD associated with MN affects older patients, with more frequent cardiac, pulmonary, and digestive involvement, as well as increased mortality compared to ECD without MN. Our study shows no evidence of increased risk of progression of underlying myeloid neoplasm under kinase inhibitor.
Temporal Trends and Demographic Disparities in Mortality from Heart Failure with Co-Existing Iron Deficiency Anemia in the United States, 1999-2020
Authors: Zafar Fatima , Najafi Syed Muhammad Ali , Fazal Muhammad Imtanan , Shubhangi Fnu , Mukhtiar Vaibhavi P , Talal Umer , Safdar Malik Ahsan , Manan Muhammad Romail , Nawaz Iqra , Naeem Ammad
Published: December 2024

Introduction

Heart failure (HF) is a rapidly prevalent issue and affects individuals across diverse demographics. Various comorbidities can exacerbate HF symptoms in certain populations and may predict poorer outcomes. The aim of this study was to conduct a retrospective analysis of mortality trends stratified by gender, race, geographic distribution, and urbanization in HF patients with iron deficiency anemia (IDA).

Methods

The CDC WONDER multiple causes of death database was used for analysis of HF with IDA-related mortality in adults (≥25 years of age) from 1999 to 2020. Age-adjusted mortality rates (AAMRs) per 100,000 population were computed using ICD-10 codes I50 (HF) and D50 (IDA). Joinpoint regression was used to visualize the mortality trends and calculate the average annual percentage change (AAPC) and annual percentage change (APC).

Results

Between 1999 and 2020, HF with IDA caused 7226 deaths in the US adult population. The mortality rate showed an initial decline (1999-2012), but later (2012-2020) a significant up-rising trend was appreciated in the AAMR, with an APC of -2.4% (95% CI: -3.6–1.3, p<0.001) to 13% (95% CI: 11.2-15.5, p<0.001). Males exhibited a consistently higher AAMR with an AAPC of 3.6% (95% CI: 2.6-4.7, p<0.001) against 3.1% (95% CI: 2.4-3.9, p<0.001) in females. The analysis also indicates that the white population has the highest mortality among all races, with an AAMR of 0.16 (95% CI: 0.15-0.16), followed by 0.14 (95% CI: 0.09-0.2) in the American Indian/Alaska Native population. Census records from all the regions showed upward trending, with the West and Northeast regions displaying AAPC values of 3.95% (95% CI: 2.6-5.6, p<0.001) and 3.5% (95% CI: 2.2-5.2, p<0.001), respectively. Stratification based on urbanization displayed a significantly higher mortality trend among the rural population when compared with the urban population.

Conclusion

A significant upsurge has been observed in the mortality trends of HF with IDA in recent years. When stratified by gender, race, census region, and rural/urban area, disparities in mortality rates were observed. This highlights the need to identify vulnerable populations, determine modifiable and non-modifiable variables, and implement proactive healthcare policies aimed at reducing the rising mortality burden among HF patients with IDA.
Role of Macrophage TLR4 Expression in the Immunopathogenesis of Severe Aplastic Anemia
Authors: Gao Mengran , Deng Ling , Zhang Xinrui , Liu Chunyan , Fu Rong
Published: December 2024

By studying the expression level of TLR4 in macrophages of patients with severe aplastic anemia (SAA) and its impact on CD8+ T cells, we explored the role of macrophages with high TLR4 expression in the immunopathogenesis of SAA. Mononuclear cells were isolated from the bone marrow samples of untreated and remissive SAA patients as well as healthy controls, and macrophages were cultured in vitro. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western Blot were used to detect the expression level of TLR4 in macrophages. The effect of TLR4 level changes on macrophages and CD8+ T cell cytotoxicity was studied by knocking down TLR4 or using TLR4 inhibitors in the bone marrow macrophages of untreated SAA patients. The results showed that: 1. The relative expression level of TLR4 mRNA and protein in the bone marrow macrophages of untreated SAA patients was significantly higher than that in the remission group and control group, and was negatively correlated with clinical indicators. 2. RNA-seq of macrophages with knocked-down TLR4 showed that differential genes were enriched in innate immune and inflammatory chemotaxis signaling pathways. 3. After TLR4 knock-down or TLR4 inhibitor addition in bone marrow macrophages of untreated SAA patients, the mRNA and protein expression levels of pyroptosis markers IL-1β, IL-18, NLRP3, caspase-1, and GSDMD were significantly lower than those in the control group. 4. When CD8+ T cells were co-cultured with TLR4-knocked-down or inhibitor-added macrophages, the expression of perforin and granzyme B in CD8+ T cells was significantly reduced, and CD8+ T cell cytotoxicity decreased. Therefore, the high expression of TLR4 in macrophages of SAA patients is positively correlated with pyroptosis levels, and inhibiting TLR4 expression can reduce macrophage pyroptosis levels, thereby alleviating the overactivated cellular immune response in SAA patients.
Efficacy and Safety of Venetoclax Added to Arsenics Plus All-Trans-Retinoic Acid Combination Salvage Regimen for Patients with Relapsed/Refractory Acute Promyelocytic Leukemia
Authors: Lou Yinjun , Jin Jie , Tong Hongyan , Suo Shanshan , Wang Huafeng , Mao Liping , Meng Haitao , Yu Wenjuan
Published: December 2024

Background: Despite high cure rates in acute promyelocytic leukemia (APL), treatment outcomes in patients with relapsed/refractory (R/R) APL, particular with central nervous system (CNS) involvement relapse remains challenge. Recently, venetoclax (VEN, a selective BCL2 inhibitor) plus azacitidine has shown superior efficacy to azacitidine monotherapy in newly diagnosed unfit patients. However, data of venetoclax in APL patients were Limited. Here, we aim to analysis the efficacy and safety of VEN plus arsenics (arsenic trioxide or oral arsenic drug, realgar-indigo naturalis formula) plus ATRA based salvaged regimen in R/R APL from our center.

Patients and methods: We retrospectively analyzed cases with R/R APL who received VEN plus arsenics and ATRA based regimen at our institution from July 2021 to December 2023. During the reinduction cycle, patients received 0.15 mg/kg/day intravenous infusion of Arsenic trioxide or oral RIF daily 60 mg/kg/day. ATRA was administered 25 mg/m2/day. VEN was administered using a daily ramp-up strategy (100 mg on day 2, 200 mg on day 3, and 400 mg on days 4-28). The last date of follow-up for this analysis was May 2024.

Results: Thirty-one patients with R/R APL were enrolled, 10 patients has co-occurred with CNS relapse, and 1 patient with CNS relapse only. Four patients had ≥ 2 therapies. All patients had prior exposure to arsenics and ATRA. The median age was 44 years (ranges, 18-72).

After once cycle of reinduction, the overall response rate (complete remission/complete remission with incomplete count recovery) was 97% (30 of 31), CR was achieved in 27 patients. No early death was occurred. Side effects were manageable. With the median follow-up of 15 month, the 1-year event-free survival and overall survival rates is 78.7% and 96.7%, respectively.

Conclusions: Our results showed that the combination of VEN plus arsenics and ATRA appeared to be a highly effective therapy option for patients with R/R APL, and underline its potential activity also in patients with CNS involvement.
In Vivo panCAR-Mediated Depletion of B Cells in Non-Human Primates Using a Circular (oRNA®) Anti-CD20 CAR
Authors: Crabtree Juliet , Emmanuel Akinola , Sankaran Ganapathy Subramanian , Dutta-Simmons Jui , Kosakowska Karolina , Dimezzo Tracy , Langer Ian , Vyas Prapti , Soto David , Thakkar Akshi , Chen Grace , Sedic Maja , Barros Scott , Horhota Allen , Dalkilic-Liddle Isin , Thiruneelakantapillai LT , Jayaraman Muthusamy , Hoban Megan , Neumann Frank , Mabry Robert
Published: December 2024

While traditional ex vivo-generated chimeric antigen receptor (CAR) T cell therapies have had tremendous success in the clinic, manufacturing, safety, and accessibility challenges remain. The prospect of an in vivo CAR therapy without the need for patient cell isolation and culture and the safety risks associated with conditioning regimens remains a therapeutic goal. Orna Therapeutic's panCAR™ combines a synthetic, circular coding RNA platform (oRNA®) and proprietary immunotropic lipid nanoparticle (LNP) to drive CAR expression on the surface of immune effector cells (e.g. T cells, NK cells) after in vivo administration, promising a transient, re-dosable, and scalable immune cell therapy without the need for preconditioning lymphodepletion. Orna's panCAR technology leverages both a high-throughput LNP discovery engine, capable of unlocking LNP-mediated RNA delivery to extra-hepatic tissues, with a proprietary FoRCE platform capable of identifying oRNA-required IRES sequences that initiate protein translation in target cells.

Our lead immunotropic LNP, LNP-6, delivers RNA cargo to 60% of splenic and 84% of peripheral blood T cells in non-human primates (NHP) using a reporter RNA cargo. When paired with an oRNA cargo, LNP-6 demonstrated up to ~70% delivery of an anti-CD20 CAR to NHP T cells and human T cells in vitro, maintaining expression over 72 hours. In cytotoxicity assays, both an anti-CD20 CAR and anti-CD19 CAR construct were able to kill human B lymphoblast cell lines in vitro. Using a humanized mouse model, an LNP-6-delivered anti-CD20 CAR oRNA showed significant B cell depletion in peripheral blood, spleen, and bone marrow at 24 hours (75-80% reduction) and sustained B cell depletion 7 days after dosing in the peripheral blood and bone marrow compartments. In NHPs, LNP-6 delivery of an anti-CD20 CAR oRNA resulted in a 95% reduction in B cells with sustained depletion (82%) 7 days after a single dose. These data support the opportunity for exploration of in vivo CAR therapies in oncologic disease settings.
Classical Hematology: Not so Easy! Call for Expert!
Authors: Thomas Melissa , Gibson Spencer , Moss Arianna S , Quy Ray , Zhao Eva , Wang Angelina , Debeusscher Ben P , Pakbaz Zahra
Published: December 2024

Background:

Studies have previously shown that the addition of a sickle cell specialist to the management team for patients with Sickle Cell Disease improved health outcomes and healthcare utilization (1). This data analysis evaluates the patient outcome when a classical hematologist is added to the management team for patients with non-cancer blood disorders, given that current projections suggest the demand for adult hematologists will exceed the existing supply in the United States (2).

Methods:

This study is a retrospective chart review of 759 adults (mean age +/SD of 52.5 years +/- 18.4, 447 females) seen between February 2020 and July 2023 in a single-provider non-cancer hematology clinic at an academic center. Data collected included type of referring provider specialty, referral reason or diagnosis, diagnosis made by the classical hematologist, new additional contributing diagnoses, and new unrelated incidental findings discovered during the work up.

Results:

Of the 759 patients seen by the classical hematologist, 356 patients (group A) were referred for management advice or confirmation of the diagnosis, andremainingpatients (group B) were referred seeking a diagnosis. Of note, 18% of the 759 referrals were from another hematologist/oncologist seeking a second opinion. During work up for group A, the diagnosis was changed in 34 patients (9.6%), one or more new contributing causes for their referral reason were discovered in 89 patients (25%) and 80 patients (22.47 %) were found to have one or more new unrelated but clinically significant diagnosis. In 99.26% of patients in group B, a visit to the classical hematologist led to a new diagnosis to address the reason for referral; 55% of patients had only one diagnosis while in remaining patients' the diagnosis was found to be multifactorial. During workup for group B, at least one new incidental but clinically significant finding was discovered in 16% of patients.

Conclusion:

This data demonstrates that adding classical hematologists to the care team improves diagnostic evaluation and management of patients with non-cancer blood disorders and their overall quality of care. The significant number of referrals from hematology/oncology to classical hematologists indicates their value seen from within the field and the clear need for their expertise.

References Deva Sharma, Natalie Wallace, Erik A. Levinsohn, Ariela L. Marshall, Karen Kayoumi, Johanna Madero, Morgan Homer, Robby Reynolds, Janet Hafler, Nikolai A. Podoltsev, Alfred Ian Lee; Trends and factors affecting the US adult hematology workforce: a mixed methods study. Blood Adv 2019; 3 (22): 3550-3561. doi: https://doi.org/10.1182/bloodadvances.2019000307Mainous AG 3rd, Rooks B, Tanner RJ, Carek PJ, Black V, Coates TD. Shared Care for Adults with Sickle Cell Disease: An Analysis of Care from Eight Health Systems. J Clin Med. 2019 Aug 2;8(8):1154. doi: 10.3390/jcm8081154. PMID: 31382365; PMCID: PMC6723540.
IFN1 Blockade Enhances Non-Activated CAR T Cell Anti-Tumor Function Via Inhibiting the Innate Anti-Viral Response
Authors: Durgin Joseph , Kazmi Shadab , Kelly Andre , O'Connor Roddy S. , Ghassemi Saba
Published: December 2024

Chimeric antigen receptor (CAR) T cells have demonstrated unprecedented success in treating blood-based cancers. However, the durability of response is often hindered by challenges related to long-term T cell persistence and engraftment. The efficacy of CAR T cell immunotherapy relies on the differentiation status and overall fitness of the CAR T cell product. Current protocols involve the activation and ex vivo expansion of patient T cells, however, activation leads to irreversible differentiation, compromising their therapeutic potency.

Manufacturing protocols utilizing non-activated T cells results in superior differentiation characteristics and reduced exhaustion, with concordant benefits in long-term tumor control. Nevertheless, as quiescent T cells are highly resistant to lentiviral infection, CAR T manufacturing yield is a significant limitation with non-activated T cells. In this study, we investigated the impact of IFN1 blockade on CAR lentivirus transduction and function of non-activated T cells.

Quiescent T cells were treated with an IFN1 binding protein, or vehicle, and transduced with CAR19 lentiviral vectors. Our findings demonstrate that lentiviral vector transduction triggers an innate immune response in non-activated T cells, resulting in reduced transduction efficiency, and altered T cell differentiation. Inhibiting the anti-viral response via blockade of IFN1 during transduction promotes a more naïve and central memory phenotype. We further investigate the effect of IFN1 blockade by lentiviral-mediated expression of CAR as well as a secreted IFN1-binding protein. These CAR T cells show enhanced cytolytic activity and cytokine production against target cells after repeated antigen exposure.

We, therefore, tested the effect of IFN1 blockade in a preclinically validated xenograft NALM6 model of leukemia. After establishing xenografts, a suboptimal dose of CART19 (1e6 T cells), generated in the presence of IFN1 binding protein, was infused. These CAR T cells demonstrated enhanced tumor control relative to standard CAR T cells. Our studies in vivo suggest that the sustained secretion of the protein to block IFN1 may enhance the therapeutic activity of T cells in tumors reliant on IFN-mediated immune evasion.

Our results identify a novel approach to enhance non-activated CAR T cell transduction and fitness by countering anti-viral defenses triggered during gene delivery. Mechanistically we show that blocking IFN1 signaling with a binding protein improves transduction and anti-tumor function of non-activated CAR T cells during repeated antigen exposure. Given the therapeutic promise of non-activated CAR T cells, our findings have immediate translational relevance for broadening their appeal against cancer.
Retrospective Study of Intraarticular Synovectomy in Chronic Synovitis in Person with Hemophilia
Authors: Pechetty Priyanka , Shanmukhaiah Chandrakala , Mohanty Shubhranshu Shekhar , Pawar Shwetal Ghule , Patil Kirti Amol , Y Dileep
Published: December 2024

Aim

To evaluate the safety and efficacy of Radiosynoviorthesis in Chronic Synovitis in Persons with Hemophilia.

Materials and Methods :

This retrospective observational study reviewed all radiosynoviorthesis conducted in persons with Hemophilia (PWH) from June 2016 to May 2024. Yttrium-90 (68%) was used for knee and shoulder joints. Lutetium-177(32%) was used for elbow, wrist and ankle joints.

The inclusion criteria were patients of any sex, ³8 years or older, with stage 2 and 3 haemophilic arthropathy and target joint. Exclusion criteria included patients <8 years, pregnant females, those with acute bleeds, local infections, and stage 4 haemophilic arthropathy. Data were collected on resolution of target joints, functional (FISH and HJHS)and radiological score (Denver) before the procedure and at 1, 3, 6 months and 12 months post-procedure to assess the efficacy of the intervention.

Results

A total of 115 procedures were performed in 81 PWH. The median age of patients was 22 years (range: 8-62). Of all the cases, Haemophilia A were 85.3% (n=98), Haemophilia B were 10.4% (n=12), Hemophilia A with Inhibitor were 4.3% (n=5). Among all 94.4% were severe haemophiliacs and 5.6% were moderate haemophiliacs. Of 115 procedure, 57% (n=41) were knee, 25%(n=22) were elbow 13.8% (n=16) were Ankle, 3.4%(n=2) were shoulder joints. The majority 69% of patients had a good Caviglia score, while 31% had a poor score. Out of 81 PWH, 37 PWH with 56 (48.6%) procedures followed up regularly at the defined time-points and assessment was done accordingly. Out of 56 joints 50 had resolution of target joints. Median FISH, HJHS and VAS Scoring at pre procedure, 1 month, 3 months and 6 months are (27, 25, 25 and 24), (18,16,15 and 15) and (6, 5, 5 and 5) respectively with statistically significant improvement (P <0.001). The Denver score didn't show any statistical difference post procedure. The procedure was safe, with two episodes of skin burns reported.

Conclusion : People who followed regularly has a decrease in the Annual Joint Bleed Rate. Radiosynovectomy is safe and effective intervention for patients with chronic haemophilic arthropathy irrespective of the type of radionuclide used
Effect of Monoferric Transferrins on Fetal Iron Homeostasis and Erythropoiesis
Authors: Shapleigh Benjamin , Ali Faris , George Nisha Ajit , Karahodzic Adin , Parrow Nermi L. , Fleming Robert E.
Published: December 2024

Introduction: Marked changes in maternal iron metabolism and erythropoietic activity are required to meet fetal iron needs in pregnancy. Maternal iron deficiency, with or without anemia, is common despite prescribed iron supplementation. Dysregulated fetal iron accrual occurs in multiple conditions despite adequate maternal iron status and absence of anemia. These include maternal diabetes, placental insufficiency and fetal liver disease. Abnormal fetal iron status is associated with negative fetal outcomes. The processes regulating fetal/maternal iron transfer are incompletely understood. We hypothesize that signaling properties of transferrin regulate fetal-maternal iron homeostasis and fetal erythropoiesis.

Methods: We investigated the effect of lobe specificity of iron binding to the transferrin (Tf) N or C lobe on fetal iron homeostasis. We utilized female mice homozygous for either the wild-type TF allele, N-blocked TF allele (permitting iron binding only to the TF C-lobe), or C-blocked TF allele (permitting iron binding to only the TF N lobe). These were mated to mice which were either wild-type or heterozygous for the TF N-blocked or the C-blocked TF allele. At E17.5 pregnant dams were sacrificed. Placenta and fetuses were genotyped and analyzed for tissue iron concentration, expression of selected genes participating in iron homeostasis, and hematologic parameters.

Results: Litter sizes, distribution of genotypes, fetal weights and placental weights were similar in pregnancies of wild-type, N-blocked and C-blocked mice. Homozygous N-blocked fetuses (N/N) had lower hematocrits (27.5% +/-6.3) compared with homozygous C-blocked (C/C) fetuses (33.7+/-5.8%; p<0.05) and wild type (WT) fetuses (42.0% +/- 3.7, p<0.001). N/N fetuses had significantly higher liver iron concentrations (484.9+/-24.4 µg Fe/g dry wt) compared with C/C (322.1+/-40.1) and WT (345+/-41.0), p<0.002. N/N fetuses had significantly higher hepatic Bmp6 and Hamp1 mRNA expression compared with C/C and WT fetuses. Although no significant differences were detected in placental ferroportin protein across strains, N/N fetuses had higher placental ferroportin mRNA expression compared to C/C.

Conclusions: Whereas placental iron concentration is unaffected, iron distribution across fetal hepatic and erythroid compartments is strongly influenced by the transferrin lobe occupied by iron. Despite blunted iron utilization for hemoglobin production, N/N mice accrue iron–leading to fetal hepatic iron loading, and consequently increased liver Bmp6 and Hamp1 expression. Despite the higher liver Hamp1 expression in N/N fetuses, placental ferroportin protein is similar to that observed in placentas from C/C fetuses. We speculate that any inhibitory effect of hepcidin on ferroportin protein might be offset by a hypoxia mediated upregulation of ferroportin gene expression in the setting of fetal anemia.
Racial Disparities in Survival Outcomes of Diffuse Large B Cell Lymphoma: A Retrospective Cohort Study from 2000 to 2021
Authors: Ogedegbe Oboseh John , Cheema Asfand Yar , Sukhera Ahmed Bashir , Erazo Gloria , Rodriguez Vazquez Jorge , Unlu Serhan , Godfrey Tabowei
Published: December 2024

Introduction

Diffuse Large B Cell Lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), accounting for 25-30% of all cases of NHL. DLBCL is an aggressive disease that can be cured in up to 50% of the patients who achieve complete remission following treatment with first-line therapy.

In this study, we described the effect of race/ethnicity on survival outcomes among patients with DLBCL in the United States.

Methods

We extracted data on patients with a primary diagnosis of DLBCL from the Surveillance, Epidemiology and End Results (SEER) Registry. These patients had a primary diagnosis of DLBCL. We excluded patients with missing or unknown deaths, and Kaplan-Meier methods were used to estimate 5-year survival rates. Cox proportional hazards regression was used for multi-variable modelling of the survival database. The difference between the observed number of events between each group was compared using a log-rank statistical test.

Results

Our analysis revealed 99,415 patients with DLCBL. 82.8% (82,356) of patients were white, 7.2% (7244) of patients were black, 0.6% (602) were American Indian/Alaska Native, and 9.3% (9213) were Asian or Pacific Islanders. The one and five-year survival by race/ethnicity was White (75.9%, 64.0%), Black (72.6%, 60.6%), American Indian/Alaska Native (72.6%,61.1%) and Asian/Pacific Islander (76.5%,63.5%). Race/ethnicity proved to be a predictor of worse outcomes, with Asian/Pacific Islander HR 0.96 (95% CI; 0.92-0.99, p = <0.001), Black HR 1.01 (95% CI; 0.98-1.04, p = 0.629), American Indian/Alaska Native HR 1.06 (95% CI; 0.95-1.18, p = 0.294). There was no survival disparity by sex, male, HR 1.00 (0.98-1.02) p = 0.93.

Conclusion

Race plays a significant role in survival outcomes, with certain races associated with improved outcomes in patients with DLBCL. Asian/Pacific Islanders demonstrated a statistically significant improved survival outcome compared to whites. Of note, there was no disparity in survival outcomes by sex.
Ph− ALL: immunotherapy in upfront treatment
Authors: Stelljes Matthias
Published: December 2024

Antibody-based and cell-based novel immunotherapies, such as bispecific T-cell engagers (BiTE), antibody-drug conjugates, or chimeric antigen receptor (CAR) T cells are currently standard treatment options for patients with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). To date, CD20-targeting monoclonal antibodies and the CD19-targeting BiTE's blinatumomab have been established elements of frontline therapy, either in patients with CD20+ ALL or in patients with measurable disease (MRD) following conventional chemotherapy. Recently, blinatumomab has also demonstrated a survival benefit in patients with MRD-negative ALL. Based on the observed high response rates and improved survival outcomes in patients with R/R ALL, antibody-based immunotherapies are being prospectively studied in the upfront setting, particularly in older adult patients, where even age-adapted conventional chemotherapies are still associated with significant rates of early death, treatment-related toxicity, and poor prognosis. In these approaches, conventional chemotherapy has been replaced or reduced and supplemented by immunotherapeutic agents, resulting in promising outcomes that form the basis for evaluating and defining new treatment standards.
Transplant in ALL: who, when, and how?
Authors: Marcoux Curtis , Kebriaei Partow
Published: December 2024

Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a cornerstone in the treatment of high-risk acute lymphoblastic leukemia (ALL), yet optimal patient selection is challenging in the era of rapidly changing modern therapy. Refined molecular characterization allows for better risk assessment, sparing low-risk patients from allo-HCT toxicity while identifying those who may benefit from intensified approaches. Measurable residual disease (MRD) has emerged as a powerful predictor of relapse irrespective of treatment strategy, challenging the necessity of transplant in MRD-negative patients. Further, expanded donor options, particularly haploidentical transplantation coupled with reduced intensity conditioning, have extended the applicability of allo-HCT to a broader range of patients. Finally, immunotherapies and targeted treatments are increasingly integrated into both initial and relapsed treatment protocols yielding deep remission and allowing for successful transplant in patients with a history of advanced disease. In this review, we provide an overview of the contemporary role of transplant in adult patients with ALL, focusing on indications for allo-HCT in first remission, optimal sequencing of transplant with novel therapies, and advancements in donor selection and conditioning regimens.
Mitigating and managing infection risk in adults treated with CAR T-cell therapy
Authors: Tabbara Nadeem , Dioverti-Prono M. Veronica , Jain Tania
Published: December 2024

Chimeric antigen receptor T-cell therapy (CAR-T) has transformed the treatment paradigm of relapsed/refractory B-cell malignancies. Yet, this therapy is not without toxicities. While the early inflammation-mediated toxicities are now better understood, delayed hematopoietic recovery and infections result in morbidity and mortality risks that persist for months following CAR-T. The predisposition to infections is a consequence of immunosuppression from the underlying disease, prior therapies, lymphodepletion chemotherapy, delayed hematopoietic recovery, B-cell aplasia, and delayed T-cell immune reconstitution. These risks and epidemiology can vary over a post-CAR-T timeline of early (<30 days), prolonged (30-90 days), or late (>90 days) follow-up. Antibacterial, antiviral, and antifungal prophylaxis; growth factors and stem cell boost to expedite count recovery; immunoglobulin replacement therapy; and possibly revaccination programs are important prevention strategies to consider for infection mitigation. Assessment of risk factors, evaluation, and treatment for pathogen(s) prevalent in a particular time frame post-CAR-T are important clinical considerations in patients presenting with clinical features suggestive of infectious pathology. As more data emerge on the topic, personalized risk assessments to inform the type and duration of prophylaxis use and planning interventions will continue to emerge. Herein, we review our current approach toward infection mitigation while recognizing that this continues to evolve and that there are differences among practices stemming from data availability limitations.
Patient-reported outcomes after CAR T-cell therapy in patients with hematological malignancies
Authors: Wang Xin Shelley , Srour Samer A.
Published: December 2024

The remarkable improvement in survival among individuals with hematological malignancies receiving chimeric antigen receptor (CAR) T-cell therapy has highlighted the growing unmet need to incorporate patient-centered assessments in management guidelines for these patients. That CAR T-cell therapy is associated with unique toxicities and relatively high symptom burden in the first few weeks after cell infusion is well known. Magnifying the patient's voice by using patient-reported outcomes (PROs) might support personalized intervention in the acute-care setting, optimize the use of medical resources, improve satisfaction with therapy, and enhance survival benefit. However, various factors impede PRO use in routine patient care: (1) the feasibility of PRO assessment during the acute phase of treatment, especially in patients experiencing neurological toxicities, is not well established; (2) although PROs are widely used in drug- development trials, the assessment tools used in clinical trials primarily inform quality-of-life or safety comparisons among study arms and are rarely the proper tools for assessing and capturing clinically meaningful adverse events that should be monitored in routine patient care; (3) PRO data that could guide how best to monitor and capture the delayed effects of CAR T-cell therapy in long-term survivors are limited. There is a pressing need to overcome these barriers to integrating evidence-based PROs into standard-of-care guidelines for patients receiving CAR T-cell therapy. In this review, we present the current state of PRO utilization in CAR T-cell therapy. We also discuss practical approaches and future directions for successful implementation of PROs in the care of patients receiving CAR T-cell therapy.
Beyond FAScinating: advances in diagnosis and management of autoimmune lymphoproliferative syndrome and activated PI3 kinase δ syndrome
Authors: Rao V. Koneti , Pittaluga Stefania , Uzel Gulbu
Published: December 2024

Refractory autoimmune mutilineage cytopenias can present in childhood associated with chronic nonmalignant lymphoproliferation (splenomegaly, hepatomegaly, and/or lymphadenopathy). Cytopenias due to peripheral destruction and sequestration have been well recognized since the 1950s and are often lumped together as eponymous syndromes, such as Evans syndrome and Canale-Smith syndrome. Though their clinical and genetic diagnostic workup may appear daunting, it can provide the basis for early intervention, genetic counseling, and empirical and targeted therapies. Autoimmune lymphoproliferative syndrome (ALPS), activated phosphatidylinositol 3-kinase delta syndrome (APDS), and many other related genetic disorders are otherwise collectively known as inborn errors of immunity (IEI). They present in early childhood as refractory autoimmune cytopenias due to immune dysregulation leading to lymphadenopathy, splenomegaly, and increased susceptibility to lymphoma. More recently, controlled clinical trials have shown that some of these immune system disorders with hematological manifestations might be more readily amenable to specific targeted treatments, thus preventing end-organ damage and associated comorbidities. Over the last 20 years, both rapamycin and mycophenolate mofetil have been successfully used as steroid-sparing long-term measures in ALPS. Current therapeutic options for APDS/PASLI (phosphoinositide 3-kinase [PI3K]-associated senescent T lymphocytes, lymphadenopathy, and immunodeficiency) include the orally bioavailable PI3Kδ inhibitor, leniolisib, which was licensed by the US Food and Drug Administration (FDA) in 2023 for use in individuals older than 12 years as a targeted treatment. Paradigms learned from patients with rare genetic disorders like ALPS and APDS may help in exploring and streamlining molecular therapy strategies in the wider group of IEIs presenting with refractory cytopenias and lymphoproliferation.
Large granular lymphocyte leukemia: a clonal disorder with autoimmune manifestations
Authors: Marchand Tony , Pastoret Cédric , Moignet Aline , Roussel Mikael , Lamy Thierry
Published: December 2024

Large granular lymphocyte (LGL) leukemia is a rare lymphoproliferative disorder characterized by an expansion of clonal T or natural killer lymphocytes. Neutropenia-related infections and anemia represent the main manifestations. LGL leukemia is frequently associated with autoimmune disorders such as rheumatoid arthritis, Sjögren's syndrome, autoimmune endocrinopathies, vasculitis, or autoimmune cytopenia. Recent advances in the phenotypic and molecular characterization of LGL clones have underscored the pivotal role of a chronic antigenic stimulation and a dysregulation of the Jak/STAT signaling pathway in the pathophysiology linking leukemic-cell expansion and autoimmunity. In more than half of patients, there is a somatic STAT3 mutation. The disease is characterized by an indolent course, but approximately half of all patients will eventually require therapy. The first-line treatment for LGL leukemia is historically based on immunosuppressive agents (methotrexate, cyclophosphamide, or cyclosporine). However, cytokines blocking molecules or Jak/STAT inhibitors represent a new conceptual therapeutic approach for LGL leukemia. In this review, we present an overview of the spectrum of LGL proliferations, potential links between LGL expansion and autoimmunity, and therapeutic approaches.
Mutation- and MRD-informed treatment decisions for the transplant-eligible AML patient
Authors: Heuser Michael , Shahswar Rabia
Published: December 2024

Acute myeloid leukemia (AML) is classified by risk groups according to a number of genetic mutations, which may occur alone or in combination with other mutations and chromosomal abnormalities. Prognosis and appropriate therapy can vary significantly based on a patient's genetic risk group, making mutation-informed decisions crucial to successful management. However, the presence of measurable residual disease (MRD) after induction and consolidation therapy, before hematopoietic cell transplant, and during posttransplant monitoring can be even more significant to patient prognosis than their genetic subtype. Clinicians must select MRD-monitoring methods most appropriate for a patient's genetic profile and a treatment regimen that considers both a patient's primary genetic subgroup and other risk factors, including MRD information. Recent clinical trial data and drug approvals, together with advances in the validation of MRD using next-generation sequencing, require a deeper understanding of the complex AML mutation and MRD matrix, enabling more insightful monitoring and treatment decisions for intensively treated AML patients. Here, we provide an overview on methods and clinical consequences of MRD monitoring in genetic subgroups of patients with AML. As treatment options become more personalized, on-treatment MRD monitoring will become even more important to effective AML care.