bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-Driver Genomic Alterations and Venous Thromboembolism in Myeloproliferative Neoplasms
Authors: Ajufo Helen , Leader Avi , Derkach Andriy , Chrysafi Pavlina , Singh Rohan , Rampal Raajit , Mantha Simon , Zwicker Jeffrey I.
Published: December 2024

Introduction: The most common cause of morbidity and mortality in the myeloproliferative neoplasms (MPNs) is thrombosis. Current risk scoring systems for essential thrombocythemia (ET) and polycythemia vera (PV) predict the risk of thrombosis. The influence of non-driver co-mutations such as those affecting epigenetic regulation in thrombosis is not established. This study seeks to further characterize the genomic landscape and genomic predictors of venous thromboembolism (VTE) in a comprehensive cohort of MPNs that may have implications for the use of cytoreductive therapy and antithrombotic therapy.

Methods: We assessed clinical and molecular risk factors of VTE in a cohort of patients from Memorial Sloan Kettering Cancer Center from 2017 to 2023 with annotated myeloid molecular data. VTE were identified through the use of the CEDARS+PINES natural language processing platform (Mantha et al, 2024) and instances were manually reviewed. Univariate and multivariate (stratified by MPN subtype) was conducted using cause specific Cox regression analysis to identify factors associated with VTE while adjusting for competing event of death. Cumulative incidences of thrombosis were estimated from date of genomic testing with death considered as a competing risk as well.

Results: The cohort included 656 patients with MPNs: 103 (16%) with essential thrombocythemia (ET), 117 (18%) with myelofibrosis (MF), 100 (15%) with polycythemia vera (PV), and 336 (51%) with an unclassified MPN. JAK2, CALR, and MPL mutations were present in 68%, 18% and 6% of patients, respectively. The most common non-driver somatic mutations identified were ASXL1 (14%), DNMT3A (11%), and TET2 (18%). The overall cumulative incidence of VTE at 3 years was 5.7% (95% confidence interval [CI] 3.7-8.4%). In a univariate analysis the factors associated with increased risk of VTE were older age (>72 vs <55 years; hazard ratio [HR] 6.12, 95% CI 1.38-27.13), MF (HR 3.84, 95% CI 1.02-14.37), prior history of VTE (HR 7.12, 95% CI 2.47-20.54), and presence of mutations in ASXL1 (HR 3.2, 95% CI 1.44-7.08), NRAS (HR 4.15, 95% CI 1.25-13.78), and TP53 (HR 5.43, 95% CI 1.27-23.22). In a multivariable model stratified by type of MPN, the HR for VTE associated with non-driver mutations was 5.39 for TP53 (p=0.029), 3.51 for NRAS (p=0.056), and 1.98 for ASXL1 (p=0.13). The risk was not further influenced by the presence of JAK2 mutations. Associations were similar when excluding patients with a history of VTE prior to genomic assessment.

Conclusions: Non-driver mutations appear to influence the risk of VTE in patients with MPN. Future studies are needed to evaluate how inclusion of non-driver mutations can improve the accuracy of thrombosis risk prediction models in MPNs and identification of patients most likely to benefit from antithrombotic prophylaxis.
Review of Rare Association between Chronic Lymphocytic Leukemia and Chromic Myeloid Leukemia
Authors: Abdalla Elmustafa , Fadul Abdalla , Osman Ahmed Elmudathir , Mohamed Gihan , Soliman Dina Sameh , Shawayli Hawra , Abuasab Tareq , Almahmood Motaz , Saied Amin , Mohamed Mohamed , Ahmed Shahd , Singh Kalpana , Mohamed Shehab
Published: December 2024

Introduction:

Chronic lymphocytic leukemia (CLL) and chromic myeloid leukemia (CML) are the most found in elderly patients, with CLL being the most prevalent type of leukemia among older adults in Western nations. CML is the most common myeloproliferative neoplasm (MPNs). However, coexisting in a single patient is very rare and there are few documented cases of this in medical literature. Cases reported as sequential, where CML followed CLL diagnosis, vise versa or at the same time .

Methodology:

we preformed systematic literature review Our inclusion criteria included articles that presented cases of confirmed CLL associated with CML, whether diagnosed simultaneously or sequentially. Cases of CLL associated with Philadelphia negative MPNs were excluded from this review The search strategy used during our review with specified terms on both PubMed and Google Scholar.

Results

Twenty- six articles were found. All of them were cases reports. each case included one patient who had CML and CLL. Males were sightly predominant with 13/23(57%) compared to 10 females (3 cases they did not report) and mean age was 63.1. The mean of initial laboratory investigations at diagnosis showed HB 14.9 g/dl, WBC 52.6x10^3/uL, uL, Platelet 440x10^3/uL, . B symptoms were reported in 8 out 15 patients 57 %. The examination, a total of 13/21 (62%) found to have splenomegaly. CLL diagnosed first before CML in 13/26 (50%) of all cases and most common sequence. The second most common were concomitant presentation of CML and CLL presented at same time with 7 patients (27%). last group with 23 % those who had CML before CLL. The mean time difference between the two-diagnosis wither CLL first or CML around 44 months while the median was 48 (2 years). Cases of CLL First treated with wait and watch or chemotherapy 7/13 (54%) , chemotherapy protocols were FCR or Chlorambucil as most of reported cases before Bruton Tyrosine Kinase Inhibitors (BTK) era. The median exposure to chemotherapy was 36 months. Overall survival was 77 %, 6 patients died from different reasons including disease progression or febrile neutropenia and others.

Conclusion

CLL and CML associations is very rare only 26 cases reported in the literature till the moment. Both diseases can occur before each other or simultaneously.Since, majority of cases CLL diagnosed firstraising the possibility of therapy related mechanism secondary to chemotherapy previous exposure, specially most of them happened before BTKs . More studies and collaboration with large number is needed to study the mechanism and pathophysiology of this association. Currently there is no guidelines on how to treat patients with simultaneously CLL and CML .
Abbv-453: A Highly Potent and Selective Next Generation Small Molecule Inhibitor of BCL-2
Authors: Phillips Darren C , Robles-Cardona Luzivette , Alvey Cory , Ingram Justin , Lam Lloyd T , Yang Ziping , Riehm Jacob J , Chen Jun , Kurnick Matthew , Kovar Peter , Wang Jin , Doherty George , Bhat Vikram , Dai Yujia , Judd Andrew , Souers Andrew
Published: December 2024

Evading apoptosis is a hallmark of cancer that is achieved by altering the dynamic binding interactions between pro-survival (BCL-2, BCL-XL, BCL-W, MCL-1, BFL-1) and pro-death (e.g., BAX, BAK, BAD, BIM, NOXA, PUMA) BCL-2 family members. BCL-2 itself plays a dominant role in survival of malignant hematologic cells; a dependency which has been exploited therapeutically as exemplified by the established clinical activity of BCL-2 inhibitors in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), multiple myeloma (MM), and acute myeloid leukemia (AML) (Fowler-Shorten et al., 2024).

ABBV-453, a next-generation BCL-2 inhibitor, was designed for enhanced molecular and biological properties to improve upon the patient experience relative to available therapies. Specifically, incorporation of macrocyclic elements into the hot-spot binding regions of BCL-2 afforded a constrained molecule with high potency, selectivity and durable in vivo activity at low doses. In vitro, ABBV-453 possesses sub-nM affinity for BCL-2 (KI = 0.228 nM) and high selectivity over family members BCL-XL and MCL-1. The high affinity and selectivity of ABBV-453 translates to potent cell killing activity human tumor cell lines dependent upon BCL-2, including the acute lymphocytic leukemia (ALL) cell line RS4;11 (EC50 = 4.7 nM in the presence of 10% human serum), and greatly decreased activity in human tumor cell lines dependent on BCL-XL (Molt-4 EC50 = 2.85 µM) and MCL-1 (H929 EC50 >10 µM) for survival. Moreover, the cellular activity of ABBV-453 is on-target and mechanism-based as demonstrated by the disruption of BCL-2:BIM complexes and the rapid activation of the intrinsic apoptosis signaling pathway (as evidenced by caspase-3-7 activation and dissipation of the inner mitochondrial membrane potential) and the caspase dependent externalization of annexin-V at the plasma membrane of ABBV-453 treated tumor cells.

Activity of ABBV-453 monotherapy was compared to other clinically relevant BCL-2 inhibitors in an in vivo subcutaneous xenograft model of ALL. ABBV-453 demonstrated superior growth inhibition of the RS4;11 xenograft compared to both sonrotoclax or lisaftoclax at equivalent doses and schedule. ABBV-453 has the potential to be the best-in-class next-generation BCL-2 inhibitor and is actively being investigated in phase 1 clinical trials in relapsed or refractory (R/R) MM (ClinicalTrials.gov ID, NCT05308654) and R/R CLL/SLL (NCT06291220).
Desiccation Stress Triggers and Exacerbates Experimental Ocular Graft-Versus-Host-Disease
Authors: Steven Philipp , Gehlsen Uta , Maass Martina , Pasparakis Manolis , de Paiva Cintia S. , Holtick Udo , Scheid Christof , Stern Michael E.
Published: December 2024

Introduction:

Ocular Graft-versus-Host Disease (oGVHD) is a rapidly progressing, sight-threatening condition of the eye following allogeneic hematopoetic stem cell transplantation (aSCT). Previously we reported in two retrospective studies, adverse environmental stress (AES) such as high air flow and low humidity during the stay on the transplant unit may be a risk factor for chronic oGVHD. To investigate which pathophysiological processes may be triggered by AES in the early phase after transplantation, we performed experiments using a mouse model of oGVHD under different environmental conditions.

Methods:

A minor mismatch-mouse model (129S2->C57BL/6) was used where mice either remained in standard housing (>50% humidity, no air flow) or were subjected to AES (<30% humidity, constant air flow) for 18 days after bone marrow transplantation (BMT). Systemic and ocular GVHD were monitored for up to 28 days and histological, immunohistochemical and flow-cytometric analyses of ocular tissue, tear film, lacrimal gland, ocular draining-lymph nodes and spleen were performed.

Results:

AES led to a significantly higher systemic and oGVHD score than in animals without AES at days 7 and days 14 after BMT. Corneal staining and blepharitis remained significantly elevated after discontinuation of AES until day 28. Tear film analysis demonstrated early elevation of Tumor Necrosis Factor (TNF), whereas increase of CD8+ T-cells, higher activation of dendritic cells and early loss of Treg activity was detected in cervical lymph nodes together with an early corneal lymphangiogenesis in desiccated animals, but not in animals kept under normal housing conditions.

Conclusions:

These data confirm the hypothesis that AES is an independent risk factor for oGvHD. Low humidity conditions after aSCT in the mouse model worsen the severity of systemic GVHD in the mouse model, implicating that AES has not only a local effect.

Therefor avoiding AES and targeting early activation of ocular surface immune mechanisms could help to reduce both oGVHD and systemic GvHD in patients undergoing aSCT.
Post-Transplant Bendamustine Extends Survival and Reduces GvHD in a Xenogeneic NSG Transplant Model Compared to Post-Transplant Cyclophosphamide
Authors: Cracchiolo Megan , Davini Dan , Simpson Richard , Katsanis Emmanuel
Published: December 2024

Acute graft-versus-host disease (GvHD) is a significant complication following allogeneic hematopoietic stem cell transplantation. This process begins with the activation of donor T-cells that recognize host tissue antigens as foreign, resulting in an immune attack primarily targeting the skin, gastrointestinal tract and liver. Post-transplant cyclophosphamide (PT-CY) has significantly reduced GvHD in haploidentical and other allogeneic transplant settings, although relapse, viral reactivations, hemorrhagic cystitis and cardiotoxicity remain common. Our laboratory has investigated the use of bendamustine, another nitrogen mustard agent, as a post-transplant GvHD prophylaxis. The goal is to reduce GvHD while preserving graft-versus-leukemia (GvL) effects and avoiding the significant side effects associated with PT-CY.

Using a xenogeneic GvHD (xGvHD) model of irradiated NSG mice infused with human peripheral blood mononuclear cells (PBMCs), we found that a day +3 dose of 30 mg/kg of post-transplant bendamustine (PT-BEN) confers better survival and reduces xGvHD more effectively than PT-CY (50 mg/kg). These results were also maintained in a xGvHD model of NSG mice receiving PT-CY (25 mg/kg) on days +3 and +4 as compared to PT-BEN (15 mg/kg). Engraftment of human lymphocytes on days +7, +14, +21, +28, +42, and +70 was tracked using flow cytometric analysis of peripheral blood samples. Interestingly, we observed higher rates of human engraftment in PT-CY treated mice which was associated with a more pronounced reduction in murine CD45+ cells in the peripheral blood. Our findings indicate that a dose of 25 mg/kg PT-CY on days +3 and +4, previously reported to be optimal in mice, or a single PT-CY dose of 50 mg/kg on day +3 does not significantly extend survival in our xGvHD model. Additionally, PT-BEN can significantly prolong survival and reduce acute GvHD, although this may be partially attributed to a reduced circulating number of engrafted human lymphocytes. Ongoing experiments include investigation into the early deleterious effects of PT-CY on murine CD45+ populations and use of xenogeneic GvL models to examine whether the engrafted cells maintain a GvL effect in the presence of reduced GvHD. Additionally, single cell RNA-sequencing on engrafted hCD45+ cells will be performed to assess changes in gene expression across T-cell populations in xGvHD mice treated with either PT-CY or PT-BEN.
Enhancing Compliance to a Bloodless Management Protocol for Severe Anemia through Avomd Technology Integration
Authors: Imhoff Santiago , Bag Angila , Pope Danielle , Kaufman Margit , Gandhi Nisha
Published: December 2024

Background

Englewood Hospital (EH) has over 25 years of experience in patient blood management (PBM) for patients who decline blood transfusions due to religious or personal reasons. The Bloodless Medicine and Surgery Institute has developed a comprehensive protocol for managing severe anemia in bloodless patients, aiming to optimize patient hematopoietic capacity. [1] This approach has been shown to reduce costs, transfusion reactions, and hospital stays. [2] However, the progressive nature of bloodless medicine has presented challenges in physician compliance with hospital guidelines and policies, leading to frequent referrals to the specialized PBM department for guidance. Tools like AvoMD, a clinical decision support (CDS) platform, have helped reduce referrals by providing structured guidance on evidence-based algorithms.

Methods

EH collaborated with AvoMD to integrate our customized PBM protocol into an interactive interface. This platform enables physicians to select among various clinical conditions, such as patients who are actively bleeding, critically ill or those undergoing a surgical intervention. Management recommendations are then provided based on hemoglobin values according to established protocols. In this study, we closely monitored the number of referrals to the PBM department over a 12-month period after implementation of our PBM protocol via AvoMD.

Results

The implementation of the AvoMD platform led to a 73% decrease in referrals to the PBM department.

Conclusion

Managing severe anemia when transfusion is not an option can be challenging. CDS systems integrate patient information with a digital knowledge base to enhance clinical decision-making processes and can be particularly helpful in unique scenarios such as severe anemia in bloodless patients. These systems have shown to decrease misdiagnosis rates and improve patient safety. [4] AvoMD is designed to streamline clinical decision-making by simplifying evidence-based guidelines and algorithms. The implementation of AvoMD decreased the number of PMB referrals in our hospital by empowering physicians with point-of-care recommendations. This CDS integration has proven to reduce the need for specialist consultations and improve guideline adherence in other institutions. [3, 5]

Integrating EH PBM protocols into the clinical workflow through the AvoMD platform represents a significant advancement in patient care quality. This project highlights the potential of technology to deliver comprehensive care, enhance patient safety and improve clinical outcomes. The field of CDS is evolving rapidly, and the advent of artificial intelligence (AI) is set to accelerate this transformation. Numerous studies are exploring how AI can improve decision-making processes, increase accuracy, and ultimately lead to better clinical outcomes. [6,7]
Cytoreductive Paradigms for Hyperleukocytosis in Acute Leukemia (AL) Using Venetoclax based Regimen. Single Center Experience from United Arab Emirates
Authors: Alam Arif , Alam Nida , Al Qawasmeh Khaled , McCarthy Philip L.
Published: December 2024

Introduction:

Hyperleukocytosis is traditionally defined as White Blood Count (WBC) greater than 100000/microliter. It is seen in Acute Leukemia (AL) and Chronic Leukemia (CL). However, the complications of leukocytosis with leukostasis, Diffuse Intravascular Coagulation (DIC) and tumor lysis (TLS) are usually hallmarks of AL particularly Acute Myeloid Leukemia (AML). There is no standard for management and controversy exists regarding the use of leukapheresis (Stahl M et al Leukaemia 2020) versus initiation of chemotherapy (Zhao J et al. Leuk Lymphoma 2021). Venetoclax is a bcl2 inhibitor that is being used in the management of AL. Here we report our experience using novel combination targeted therapy with Venetoclax for cytoreduction.

Methods:

This is a retrospective analysis of AL patients seen in a public tertiary care hospital in the emirates of Abu Dhabi in United Arab Emirates. The study period is between January 2023 to June 2024. Data was abstracted from the electronic medical records including patient demographics, diagnosis, laboratory values and treatment.

Results:

During the study period sixty-five patients presented with clinical features suggestive of AL. Fourteen (21 %) patients had hyperleukocytosis. The median age of the patients was 30 years (range 19 to 60 years). The median WBC was 134000/microliter (range 104-432,000/microliter).

Diagnostic work up included bone marrow biopsy with flow cytometry, karyotype analysis, Fluorescence in situ hybridization (FISH) and molecular studies (30 gene panel and FLT3 PCR).

The median period of reporting of the bone marrow result was 3 days (range 0-7 days).

Cytoreductive therapy was given with Dexamethasone 20 -40 mg intravenously daily with Hydroxyurea 2000 mg orally daily and Venetoclax orally (escalating from 100 mg day 1, 200 mg day 2 and 400 mg day 3 and onwards) while awaiting diagnosis.

There was a 50 % reduction of WBC by day 3 in most patients (64%). A WBC of less than 50000/microliter was achieved by day 4 in 57% of the cohort.

There was biochemical evidence of tumor lysis. This was managed medically by hydration, prevention of hyperuricemia and correction of electrolytes. Dialysis and critical care were not required.

Six patients refused further therapy and were lost to follow-up. Three patients died during induction period. Two patients went for allogeneic hematopoietic stem cell transplant, two patients had relapsed and refractory disease while one patient is in sustained remission post consolidation chemotherapy.

Conclusion:

The current experience using dexamethasone, Hydroxyurea and Venetoclax gives an alternate (leukapheresis and Cyclophosphamide/Cytarabine) and safe option for cytoreduction prior to exact diagnosis and initiation of therapy.
Efficacy of Axatilimab in the Management of Chronic Graft-Versus-Host Disease
Authors: Shahzad Moazzam , Javed Muhammad Jawad , Irfan Sohaib , Khan Muhammad Atif , Amin Muhammad Kashif , Vyas Abhinav , Chaudhary Sibgha Gull , Anwar Iqra , Nelson Maggie , Abhyankar Sunil , McGuirk Joseph P. , Mushtaq Muhammad Umair
Published: December 2024

BACKGROUND

Chronic graft versus host disease (cGVHD) is a major cause of late non-relapse morbidity and subsequent mortality in patients with allogeneic hematopoietic stem cell transplant (HSCT). Despite various treatment options, therapy failure is common which highlights the necessity for exploration of newer therapies. This systematic review aims to evaluate the efficacy of axatilimab, a monoclonal antibody that inhibits Colony-stimulating factor 1 receptor (CSF-1R), in managing refractory cGVHD.

METHODS

We conducted a systematic review per PRISMA Statement 2020 guidelines and included 3 studies after searching 5 major databases, PubMed, Cochrane, Medline, Embase, and Clinicaltrials.gov. Inter-study variance was calculated, and a pooled analysis was performed using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2).

RESULTS

A total of 292 patients from three studies were included in this systematic review and meta-analysis. The included studies were phase I 1(33.33%), phase I/II 1(33.33%) and phase II 1(33.33%). The median age of the patients was 58 years (range: 16-73) and 63% were male (184/292). The median time from cGVHD to the first dose of axatilimab was 3.57 years. The median time to response was 6 weeks (range: 4.5-12). The pooled overall response was 64% (95% CI 0.58-0.69, I²=0%, p=0.86) and the mortality rate was 6% (95% CI 0.04-0.10, I²=0%, p=0.72). One study reported that greater than 50 % of patients maintained a response for greater than 12 months. The gastrointestinal tract exhibited the most favorable response to treatment, whereas the eyes and skin showed modest improvement. The response rate in Esophagus was 74% (95%CI: 0.50-0.89, I²=74%, p=0.02), musculoskeletal was 67% (95% CI: 0.53-0.79, I²=51%, p=0.13) and skin was 26% (95% CI: 0.15-0.40, I²=50%, p=0.14). The pooled incidence of 7-point improvement in LEE score was 49% (95% CI 0.42-0.56, I²=0%, p=0.47) and the incidence of grade 3 or above treatment-related adverse effects was 28% (95% CI 0.17-0.42, I²=61%, p=0.11). AST elevation was the most common adverse effect with a pooled incidence of 35% (95% CI 0.30-0.41, I²=0%, p=0.42) followed by CPK elevation 34% (95% CI 0.29-0.40, I²=0%, p=0.45) and amylase elevation 20% (95% CI, 0.16-0.26, I²=14%, p=0.31). The pooled incidence of drug discontinuation due to treatment-related adverse events was 16% (95% CI: 0.12-0.20, I²=0%, p=0.94).

CONCLUSION

In this systematic review, axatilimab exhibited promising therapeutic outcomes for refractory cGVHD based on the findings from Phase I and II clinical trials, with an acceptable safety profile. However, prospective clinical trials with randomization are needed to consolidate these findings.
Moderate-Severe Thrombocytopenia Portends Poor Outcomes in Multiple Myeloma
Authors: Ferri Grace M. , Yildirim Cenk , Park Joseph , Do Nhan V. , Brophy Mary T. , Munshi Nikhil C. , Edwards Camille V. , Fillmore Nathanael R.
Published: December 2024

Malignant plasma cells in multiple myeloma (MM) reprogram the bone marrow microenvironment to support tumor expansion. In this transformative process, myeloma cells engage with hematopoietic stem cells to avoid apoptosis. The myeloma cell-hematopoietic stem cell interaction results in changes to the bone marrow microenvironment, decreased hematopoietic stem cells in the bone marrow, and suppressed differentiation of megakaryocytes, which can contribute to MM disease-related thrombocytopenia. Given the development of novel therapies for multiple myeloma and the need for prognostic markers that reflect the underlying bone marrow microenvironment, we evaluated peripheral blood platelet count at diagnosis and during treatment of MM. We retrospectively evaluated 14,425 patients diagnosed with MM between 2000 and 2019 at Veterans Administration hospitals using platelet count obtained closest to diagnosis and up to 2.5 years thereafter. Patients were stratified into 4 categories: moderate-severe thrombocytopenia, mild thrombocytopenia, normal platelets, and thrombocytosis (<100, 100-149, 150-349, and ≥350 per microliter, respectively). Thrombocytopenia was present in 25% of patients at MM diagnosis and was associated with inferior overall survival (OS). Median OS of patients with moderate-severe thrombocytopenia, mild thrombocytopenia, normal platelets, and thrombocytosis at diagnosis was 1.5, 3.0, 3.7, and 2.9 years (P < .001), respectively. During treatment and follow-up, persistent or new development of thrombocytopenia was also associated with inferior OS. Moreover, the negative prognostication afforded by baseline thrombocytopenia remained despite standard therapies such as lenalidomide and bortezomib, which were associated with worse outcomes among patients with moderate-severe thrombocytopenia (hazard ratio [HR] 1.80; 95% confidence interval (CI) 1.57-2.07; P < .01) relative to those with mild thrombocytopenia (HR 1.17; 95% CI 1.06-1.29; P < .01) or thrombocytosis (HR 1.25; 95% CI 1.02-1.54; P 0.03). Our findings support the use of peripheral blood platelet count in MM as a possible surrogate for the tumor microenvironment, an easily accessible biomarker of prognosis, and a tool to guide future risk-adapted therapies.
Anticoagulation for Patients with Essential Thrombocythemia or Polycythemia Vera-Associated Venous Thromboembolism
Authors: Tamdin Tenzin , Chang Yu-Cheng , Chiang Cho-Han , Song Junmin , Chi Kuan-Yu , Chang Yu , Peng Chun-Yu , Gao Wenli
Published: December 2024

Introduction: Essential thrombocytopenia (ET) and polycythemia vera (PV) are characterized by a high risk of thrombosis. Current guideline recommended low-dose aspirin for primary thromboprophylaxis in patients with ET or PV, but there is limited data describing the optimal anticoagulation strategies for managing venous thrombosis in these patients. We aimed to compare the effects of direct oral anticoagulant (DOAC) monotherapy versus DOAC-aspirin combined therapy on outcomes of patients with ET or PV-associated venous thrombosis.

Methods: We performed a retrospective, propensity score-matched cohort study by utilizing the TriNetX Analytics Network database. The TriNetX database is a collaborative research platform with de-identified electronic health records from more than 120 healthcare organizations. We included patients with a diagnosis of ET or PV who developed deep vein thrombosis (DVT) or pulmonary embolism (PE). Patients on a DOAC monotherapy were compared to those on a DOAC-aspirin combined therapy. The index date was defined as the start date of DOAC monotherapy or DOAC-aspirin combined therapy. Patients with atrial fibrillation before index date were excluded. The efficacy outcomes were recurrent venous thrombosis, which included PE and DVT, and arterial thrombosis comprising of ischemic stroke and acute myocardial infarction. The safety outcomes were gastrointestinal bleeding, intracranial bleeding, and hematuria.

Results: We identified 2839 patients eligible for inclusion. We matched 445 patients on a DOAC monotherapy to those on a DOAC-aspirin combined therapy. In Cox proportional hazards analyses, patients on a DOAC monotherapy had a similar efficacy in the prevention of recurrent venous thromboembolism (Hazard ratio (HR), 1.02 [95% CI: 0.67-1.54]), recurrent PE (HR, 1.13 [95% CI: 0.64-1.99]) and recurrent DVT (HR, 0.87 [95% CI: 0.49-1.56]) as well as ischemic stroke (HR, 0.68 [95% CI: 0.36-1.29]) and myocardial infarction (HR, 0.87 [95% CI: 0.42-1.80]) compared to patients on a DOAC-aspirin combined therapy. DOAC monotherapy was associated with lower risk of gastrointestinal bleeding (HR, 0.52 [95% CI: 0.28-0.97]) compare to DOAC-Aspirin combined therapy. There is no significant difference in the risk of intracranial bleed (HR, 0.95 [95% CI: 0.19-4.71]) and hematuria (HR, 1.02 [95% CI: 0.54-1.95]) between DOAC-aspirin combined therapy and DOAC monotherapy cohort.

Conclusion: DOAC monotherapy had a lower risk of gastrointestinal bleed but similar efficacy in the prevention of recurrent venous than DOAC-aspirin combined therapy among patients with ET or PV-associated venous thrombosis.
Dexamethasone and Daratumumab Impair T-Cell Mediated Killing in Multiple Myeloma: Implications for Sequential Therapies
Authors: Dulcamare Ilaria , Marino Sara , Parrinello Nunziatina Laura , Scandura Grazia , La Spina Enrico , Cambria Daniela , Scuderi Grazia , Giallongo Cesarina , Tibullo Daniele , Romano Alessandra , Di Raimondo Francesco
Published: December 2024

Background

For elderly patients the combination Daratumumab-lenalidomide-dexamethasone (D-Rd) is an emerging standard-of-care regimen, able to improve long-term outcomes in MM patients. Nevertheless, CD38 is ubiquitously expressed on both MM cells and immune cells, and the effect of daratumumab on MM microenvironment are still under investigation. Thus, we investigated the potential immunomodulatory effect of D-Rd on T-cells function in patients with newly diagnosed MM.

Material and methods

PB samples were collected from newly diagnosed MM patients receiving D-Rd (n=8) at baseline and after 2 months of therapy. PBMCs were obtained using Ficoll-Paque (GE Healthcare, Piscataway Township, NJ) and then used for in vitro experiments and flow cytometry analysis (T lymphocytes populations were identified as CD3+, CD4+/CD8+ cells). T-cells' activation was evaluated by flow cytometry (using a CD25, CD38, CD71, HLA-dr cocktail); mitochondrial mass was evaluated after cell staining with MitoTracker Green (Life Technologies); cell lysis was estimated by Annexin v FITC/7-ADD kit assay.

Results

Our data showed a redistribution of T cell subsets with decreased pool of terminal differentiated and highly differentiated end-stage CD8+ cells after 2 months of D-Rd (p<0.05) (n=4), associated with a loss of mitochondrial mass (p<0.0005) and an increase in percentage of dysfunctional mitochondria (p<0.05) in T lymphocytes compared to baseline (n=8). Additionally, we observed that both CD4+ and CD8+ cells from MM patients who received D-Rd therapy lose their ability to activate when stimulated in vitro with phytohemagglutinin (n=8), while no differences in proliferation capacity were observed (n=4). Thus, to explore the impact of D-Rd therapy on T lymphocyte fitness, we treated T lymphocytes from healthy donors and newly diagnosed MM patients in vitro with single agent (daratumumab, lenalidomide, dexamethasone) and their combinations, evaluating mitochondrial functionality, activation capacity, and proliferation in vitro. Our results showed that T lymphocyte fitness was negatively affected only in conditions with dexamethasone (p<0.0001). Furthermore, the tumor cell lysis capacity of T lymphocytes treated with dexamethasone, or its combinations, was significantly reduced. Finally, we observed that the negative effects on T lymphocyte functionality induced by dexamethasone were reversed by using a bispecific antibody, which enhanced tumor cell lysis capacity in vitro in T lymphocytes from healthy donor and newly diagnosed MM patients (p<0.0001).

Conclusions

Taken together, our data suggest an impairment in T-cell function occurring upon up-front treatment that should be considered when new combinations and sequential treatments are designed.
Circulating Tumour DNA Measurements As an Early Prognostic Indicator for Newly Diagnosed Diffuse Large B-Cell Lymphoma Treated with Pola-R-CHP Regimen
Authors: Wen Xiaolian , Su Liping , Guan Tao , Liu Jie , Shen Xuliang
Published: December 2024

Objective

The POLARIX trial showed that pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone) significantly improved 2-year event-free survival (EFS) and progression-free survival (PFS) compared with R-CHOP in DLBCL patients with intermediate- and high-risk. However, some patients still failed to achieve durable remission. Circulating tumour DNA (ctDNA) is a novel prognostic biomarker in diffuse large B-cell lymphoma, but its prognostic significance in DLBCL patients treated with pola-R-CHP has not been fully defined. This prospective multicentre study preliminarily evaluated the correlation between baseline ctDNA levels and early post-treatment ctDNA changes with efficacy in Chinese DLBCL patients receiving the pola-R-CHP regimen (ChiCTR2300077262).

Methods

Enrolled DLBCL patients were treated with the pola-R-CHP regimen. Patients' ctDNA samples were subjected to targeted next-generation sequencing (NGS) to analyse the mutational profiles of 168 gene panels. ctDNA testing was performed prior to treatment, on day 1 of cycle 2 (C2D1) and on day 1 of cycle 5 (C5D1), respectively, and imaging efficacy was assessed every 2 cycles.

Results

A total of 22 patients were enrolled between November 2023 and May 2024, of whom 21 (95.5%) had ctDNA mutations detected at baseline. The most frequently mutated genes were PIM1 (42%), TP53 (26%), TMSB4X (26%), BTG2 (26%) and TET2 (21%). Baseline ctDNA levels correlated with IPI but not with age, gender, lactate dehydrogenase(LDH), pathological subtype, stage, Bone marrow infiltration or not, and large masses. Patients in the IPI 4-5 group had significantly higher baseline ctDNA levels than those in the IPI 0-3 group (P = 0.0015). ctDNA was performed at C2D1 in 16 patients and all patients had a significantly lower ctDNA level, with the 8 patients with undetectable ctDNA in durable remission, while 1 of the 8 patients with detectable ctDNA had disease progression. In this case, the patient's ctDNA was found to be elevated from previous levels at C5D1, and was subsequently assessed as disease progression by imaging after 6 cycles, with the ctDNA elevation occurring earlier than the imaging assessment. With a median follow-up of 7.7 months (2.5-16.2), patients with ctDNA >1000 hGE/ml had better PFS than patients with ctDNA ≤ 1000 hGE/ml, but no statistical significance was seen between the two groups (P=0.0612), possibly due to the small sample size and shorter follow-up.

Conclusions

Sustained remission status in DLBCL patients receiving pola-R-CHP may be associated with early clearance of ctDNA, and non-invasive ctDNA assessment may allow risk stratification and outcome prediction in this group of patients. We will subsequently continue to enroll more patients with extended follow-up to further clarify the long-term prognostic significance of ctDNA.
Novel Insights into the Link between Rheumatoid Arthritis and Malignant Lymphoma: A Multi-Stage Study of Observational and Genetic Analyses
Authors: Yu Xinghao , Chen Yiyin , Lei Lei , Lu Huimin , Chen Jia , Fan Yi , Wu Depei , Xu Yang
Published: December 2024

Objective To investigate complex relationship between rheumatoid arthritis (RA) and malignant lymphoma (ML).

Methods Prospective analysis was conducted in participants from UK Biobank to evaluate associations between RA and subsequent ML risk. We estimated genome-wide genetic correlations by utilizing publicly available European genome-wide association (GWAS) summary statistics. Then cross-trait pleiotropic analysis was performed to identify shared signals and genes. Functional annotation, tissue-specific and cell-specific analysis were performed to determine biofunctions of shared genetic signals. Finally, two-sample Mendelian randomization (MR) was conducted to explore causal interactions between diseases.

Results Our results demonstrated strong positive associations between RA and ML and its subsets both in epidemiological and genetical evidence. Cross-trait pleiotropic analysis identified 20 shared loci (e.g., 11q23.3 and 20q13.12) with high colocalization evidence, which could be mapped to 67 pleiotropic genes, such as CD40, ITPR3, TNFRSF14 and MAPK3. CD40 was found to increase the risk of RA but reduce the risk of lymphoma. MAPK3 was identified as a potential drug target for both RA and lymphoma. Genome-wide gene-set enrichment analysis revealed shared mechanisms between different trait pairs, particularly in pathways related to B cell activation and T cell selection. Functional enrichment of pleiotropic genes highlighted lymphocyte proliferation, activation, and chromatin remodeling. These sharing mechanisms may be at work in tissues such as whole blood, spleen, terminal ileum, and EBV-transformed lymphocytes. We also identified co-localization evidence and enrichment in multiple immune cell subsets, especially B cells and T cells. Finally, MR analysis confirmed that RA onset increases the risk of lymphoma.

Conclusions These results support the shared genetic basis underlying RA and ML and have important implications for identifying potential intervention and druggable targets.
Effect of Efgartigimod IV on Immature Platelet Count Fraction in Primary Immune Thrombocytopenia
Authors: Matthijssens Filip , Miyakawa Yoshitaka , Nishiwaki Kaichi , Ayguasanosa Jaume , Lan Lan , Hultberg Anna , Ulrichts Peter
Published: December 2024

Immature platelet fraction (IPF%) is the number of immature platelets (PLT) relative to total PLT number and is a measure for enhanced PLT degradation. IPF% is increased in patients with primary immune thrombocytopenia (ITP) and in some countries, such as Japan, it is used as part of the ITP diagnostic criteria. ITP is a bleeding disorder caused by accelerated PLT destruction and impaired production facilitated in part by autoantibodies. Efgartigimod is a human IgG Fc fragment engineered to bind competitively to the neonatal Fc receptor (FcRn) with high affinity, preventing endogenous IgG recycling and reducing IgG levels, including pathogenic IgG autoantibodies. In 2024, intravenous (IV) efgartigimod was approved for the treatment of patients with chronic primary ITP in Japan.

Efficacy and safety of efgartigimod IV were evaluated in ADVANCE IV (NCT04188379), a phase 3, multicenter, double-blinded, placebo-controlled trial in adults with persistent and chronic primary ITP. Participants with an average of 2 PLT counts <30×109/L during screening were randomized to efgartigimod IV 10 mg/kg or placebo. Primary endpoint was the proportion of chronic ITP participants with a sustained PLT count response (defined as PLT counts of at least 50×109/L for at least 4 of the 6 visits between Weeks 19 and 24 of the study). IPF% was also measured as exploratory research to evaluate the effects of efgartigimod on PLT turnover. IPF% was measured locally in facilities equipped with a hematology analyzer that could determine this platelet subset.

In ITP participants (N=131), sustained PLT response was demonstrated in more efgartigimod IV-treated participants (25.6%) than placebo (6.7%; P=0.0108). In the 40 participants of which immature platelets were measured, mean [±SE] IPF% was reduced following efgartigimod IV treatment (baseline IPF%, 21.6 [±2.6]; Week 24 IPF%, 13.6 [±2.7]) while no decrease was noted for placebo (baseline IPF%, 29.2 [±5.3]; Week 24 IPF%, 33.8 [±4.5]).

Observed PLT count responses in efgartigimod IV-treated participants with primary ITP are likely mediated by a reduction in PLT degradation.
A Novel High-Effective Diagnostic Model of Chronic Myelogenous Leukemia By Flow Cytometry
Authors: Ma Yaokun , Du Wen , Shang Fangying , Song Liangliang , Ma Bin , He Shan , Zheng Jine , Huang Shiang
Published: December 2024

Flow cytometry plays a prominent role in immunophenotyping malignant hematological disorders. However, in the context of chronic myeloid leukemia in chronic phase (CML-CP), flow cytometry serves primarily as an auxiliary diagnostic tool. This study involved the analysis of 500 patients diagnosed with chronic myeloid leukemia (CML) and 106 patients without CML using flow cytometry. Significance testing between the CML and non-CML groups was conducted using logistic regression to assess diagnostic value. The analysis revealed significant differences (p<0.01) in markers such as Neu%, Baso%, CD10%, CD38%, CD56%, CD64+CD16-%, CD15+CD11b+%, and Eos% between the CML and non-CML groups. Five significant markers were identified and used to construct a formula for CML diagnosis. The area under the ROC curve (AUC) demonstrated a value of 0.989, with a sensitivity of 98.0% and a specificity of 96.2%. Notably, potential diagnostic markers for chronic myeloid leukemia in chronic phase (CML-CP) were identified, and a diagnostic formula was constructed. These findings suggest a potentially crucial role for flow cytometry in the initial diagnosis of chronic myeloid leukemia in chronic phase (CML-CP).
Copy Number Variants Identified By Shallow Whole-Genome Sequencing in Multiple Myeloma
Authors: Li Jiali , Xiang Xixi , Rao Jun , Zhou Sha , Zeng Yunjing , Zhang Xi , Gao Li
Published: December 2024

Background:

Multiple myeloma is a plasma cell neoplasm driven by primary and secondary chromosomal events. The detection of these copy number abnormalities (CNAs) are important, because they affect the prognosis, therapeutic response and disease survival.

Methods:

A total of 131 patients with newly diagnosed multiple myeloma were enrolled in this study to detect genome-wide CNAs by shallow whole-genome sequencing(sWGS). Risk stratification was performed following the Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART) criteria.

Results:

Compared with karyotyping and Fluorescence in situ hybridization (FISH), sWGS

significantly improved the detection rate of CNAs from 7.8% and 43.7%, respectively, to 75.6%. sWGS provided new CNA information for 75.6% of the patients, and changed the risk stratification for 19.1% of patients according to mSMART criteria. The concordance rate between sWGS and FISH in detecting the four conventional loci (1q21 gain, 13q14 del, 13q14.3 del, and 17p13 del) was 80.2%. A high concordance was observed in CNA between matched bone marrow and peripheral blood samples.

Conclusion:

sWGS can be regarded as an automated, convenient and cost-effective approach to describe genomic CNA profiles. With the advantage of detecting CNAs of short segments and incorporating routine diagnostic methods, sWGS can add value to conventional karyotyping with improved prognostic stratification.
The Clinical Characteristics and Prognostic Analysis of Prolonged Cytopenia after CAR-T Cell Therapy
Authors: Zhu Huiying , Zhao Danqing , Zhuang Zhe , Chen Chao , Zhang Wei , Zhou Daobin , Li Jian , Zhang Yan
Published: December 2024

ObjectiveThis research explores the clinical features and prognosis of prolonged cytopenia (PC) in diffuse large B-cell lymphoma (DLBCL) patients undergoing anti-CD19 CAR-T cell therapy. MethodsA retrospective study was conducted on DLBCL patients who received CAR-T cell therapy and had a minimum one-month follow-up at Peking Union Medical College Hospital's Hematology Department from March 2019 to December 2023. Patients were categorized into PC and non-PC groups based on cytopenia occurrence at 90 days post-infusion. ResultsThe study involved 27 patients, median age 58 years, including 18 males (66.7%). PC occurred in 19 patients (70.4%), including neutropenia (48.1%), anemia (37.0%), and thrombocytopenia (22.2%). In the PC group, there was higher chemotherapy sensitivity (95% vs 50%, P=0.006), lower cytokine release syndrome incidence (64% vs 100%, P=0.046), and lower baseline neutrophil levels (2.59±0.96 vs 4.20±1.93, P=0.007) compared to the non-PC group. Prior chemotherapy sensitivity was associated with PC (OR 18, 95% CI 1.56-207.45, P=0.02). The PC group had a lower overall response rate (80.0% vs 87.5%), increased infection risk (47.4% vs 12.5%), and shorter progression-free survival (19.3 vs 24.4 months), but these differences were not statistically significant (P>0.05). Conclusions PC is common post CAR-T cell therapy, associated with higher infection risk and poorer prognosis. Prior treatment sensitivity and lower neutrophil levels may be PC indicators.
Enhancement of mTORC1 Activity in Engineered Therapeutic CD4+ T Cells Amplifies Tumour Infiltration but Impairs Cytotoxicity
Authors: Sillito Francesca Emily , Holler Angelika , O'Neill Aideen T , Callender Lauren A , Henson Sian M , Stauss Hans , Chakraverty Ronjon
Published: December 2024

There is substantial interest in developing strategies to improve the intrinsic functions of engineered therapeutic T cells, for example by manipulating their metabolic fitness. Mammalian target of Rapamycin complex 1 (mTORC1) is a critical orchestrator of anabolic metabolism and effector functions in T cells. Our group has previously shown that overexpression of an mTORC1 positive regulator (Ras homologue enriched in brain; Rheb) in engineered CD8+ T cells increased anabolic metabolism, improved tumour infiltration and cytotoxicity, but reduced their long-term persistence (1). However, because of differences in baseline and activation-induced metabolism, it is less clear how manipulation of intrinsic mTORC1 activity might influence therapeutic CD4+ T cell function.

We therefore tested the consequence of overexpressing Rheb in a murine model of anti-tumour immunity that requires in vivo cytotoxic CD4+ T cell differentiation. As we have previously found for CD8+ T cells, Rheb overexpression in tumour-specific CD4+ T cells, engineered to express a class II restricted T cell receptor targeting melanoma antigen Tyrosinase-related protein- 1 (TRP-1), enhanced baseline and activated glycolysis and oxygen phosphorylation, promoted differentiation of T-bet high effector cells and significantly increased tumour infiltration in vivo. Conversely, mTORC1 inhibition using Proline-rich Akt substrate of 40kDa (PRAS40) produced a state of relative metabolic quiescence, rendered the cells in a less differentiated Th0 state and reduced tumour infiltration. Rheb-transduced tumour-specific CD4+ T cells showed reduced cytotoxic gene expression and failed to eliminate all tumours compared to control cells. Unlike CD8+ T cells, constitutive mTORC1 activation did not impair long-term persistence of CD4+ T cells, but the surviving cells expressed high levels of co-inhibitory receptors, especially Lymphocyte-activation gene 3 (LAG-3), and showed impaired proliferation in responses to antigenic re-challenge.

Together, these data highlight the need to address how engineering of intrinsic metabolic fitness might impact upon CD4+ versus CD8+ T cells in distinct ways and suggests the need for bespoke strategies to enhance their respective functions and survival.

References Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation. Veliça P, Zech M, Henson S, Holler A, Manzo T, Pike R, Santos E Sousa P, Zhang L, Heinz N, Schiedlmeier B, Pule M, Stauss H, Chakraverty R. 2015 Jul, Cancer Res. , pp. 1;75(13):2641-52.