bluuebunny/crossref_metadata_2025_split huggingface dataset:
Automatic Generation of Alloreactivity-Reduced Donor Lymphocytes and Hematopoietic Stem Cells from the Same Mobilized Apheresis Product
Authors: Wiercinska Eliza , Quade-Lyssy Patricia , Hümmer Christiane , Beifuß Josephine , Akarach Karima , Poppe Carolin , Olevska Valeriya , Lahnor Heike , Dzionek Julia , Bosio Andreas , Papanikolaou Eleni , Bonig Halvard 
Published: December 2023

CONCLUSION
In vitro or in vivo depletion of alloreactive T cells can facilitate haplo-identical hematopoietic stem cell transplantation (HSCT). Very satisfactory transplant outcomes were thus reported for TCRαβ/CD19-depleted hematopoietic stem/progenitor cell (HSPC) grafts. However, the current semi-automatic manufacturing process, although robust, still requires a significant amount of time to be completed. Towards advancing and further facilitating large scale cell processing, a new TCRαβ/CD19 depletion module combined with a, previously described, CD45RA depletion module (to serve as allo-reactivity attenuated donor lymphocyte infusion) was established on the CliniMACS Prodigy.
We evaluated six apheresis products from G-CSF-mobilized volunteer donors which were split, one portion each depleted of CD45RA + or of TCRα/β + and CD19 + cells. Products were assessed for recovery of HSPCs and other mature subsets, as well as depletion of targeted cells using flow cytometry. Effects of apheresis and product age post 48 hours storage at 2-8 °C as well as freeze-thawing on product viability and recovery of WBC and HPSCs were assessed by flow cytometry.
Ten sequential depletions were technically uneventful, proceeding automatically with minimal hands-on time beyond tubing set installation. Depletion of CD45RA +, TCRα/β + and CD19 + cells was nearly complete, and at least equivalent to previous reports, achieving mean depletions of 4 log of targeted cells for both products. HSPC products retained TCRγ/δ + and NK cells. 48 hours storage of apheresis product was associated with the expected modest loss of HSPCs, but depletions proceeded efficiently. Depleted products were stable until at least 72 hours after apheresis with stem cell viabilities &gt;90%. Freeze-thawing resulted in loss of NK cells; post-thaw recovery of viable CD45 + and HSPCs was &gt;70% and in line with expectation.
The closed, GMP-compatible process generates two separate medicinal products from the same mobilized apheresis product. The CD45RA-depleted products contained functional memory T cells, whereas the TCRαβ/CD19-depleted products included HSPCs, TCRγ/δ + and NK cells . Both products are predicted to be effectively depleted of GvH-reactivity while providing immunological surveillance, in support of haplo-identical HSCT.
Dual Co-Stimulation with CD28 and ICOS Enhances T Cell Activation and Optimizes CAR-T Cell Antitumor Activity
Authors: Wu Jianghua , Luo Wenjing , Tang Lu , Chen Zhaozhao , Zhou Jie , Li Chenggong , Xiong Wei , Mei Heng , Hu Yu 
Published: December 2023

Background:
The Chimeric antigen receptor (CAR) T cell therapy for hematological malignancies has revolutionized anticancer therapy. CAR-T cell expansion and persistence are strikingly associated with the intrinsic programmes of T cells. However, the current process for CAR-T cells manufacturing resulted in high frequencies of exhausted and senescent CAR-T cells with reduced mitochondrial mass. T cell receptor (TCR) signaling cooperates with co-stimulatory signaling to regulate T cells activation and differentiation. Considering that ICOS has a well-defined role in T cell differentiation, especially with regard to the incorporation of ICOS into CAR to boost CAR-T cells antitumor activity, we therefore hypothesize that TCR activation in synergy with dual CD28 and ICOS co-stimulation rapidly triggers T cell activation and may be a potential approach to optimize CAR-T cells antitumor activity.
Methods: In this study, we established a culture system using plate-coated CD3 in combination with CD28 and ICOS mAbs to simultaneously stimulate T cells, and further studied whether dual CD28 and ICOS co-stimulation could reprogram the transcriptional, epigenetic and proteomic states of T cells and optimize CAR-T cells antitumor activity. In vitro CAR-T cell phenotype and cytotoxicity were detected via flow cytometry, co-culture killing assay and degranulation assay. NSG mice were inoculated with Raji cells to establish xenograft mouse model, and the tumor load and survival time were dynamically monitored after treatment with CAR-T cells.
Results: As expected, dual co-stimulation potently enhanced T cells activation and expansion via reprogramming their transcriptome, epigenome and proteome. Mechanistically, dual CD28 and ICOS co-stimulation rapidly upregulated the pathways such as ribosome, citrate cycle (TCA cycle) and oxidative phosphorylation (OXPHOS) to drive T cells exiting from quiescence. Moreover, metabolic pathways are rewired in CD28 and ICOS-stimulated T cells to guarantee sufficient energy for cell proliferation. Meaningfully, dual co-stimulation confers CAR-T cells with high lentiviral transfection efficiency, possibly correlating with highly open chromatin accessibility in CD28 and ICOS-stimulated T cells. CAR-T cells manufactured with dual CD28 and ICOS co-stimulation demonstrated significantly enhanced OXPHOS and mitochondrial biogenesis, resulting in a superior expansion and being more effective at killing tumor cells in immunodeficient animals.
Conclusions: Collectively, our data indicated that activating CD28 and ICOS signaling during CAR-T cells preparation is a potential strategy for optimizing CAR-T cells antitumor activity.
Estimation of Relapsed/Refractory Follicular Lymphoma Patients on Therapy in the United States
Authors: Johnston Karissa , Bennett Mark , Bains Chawla Savreet , Yang Shibing , Wang Anthony , Yu Junhua , Jun Monika 
Published: December 2023

Background: Follicular lymphoma (FL) represents approximately 20-25% of non-Hodgkin lymphomas (NHL). In contrast to patients with more aggressive NHL, patients with FL have a heterogenous course of disease in which some can spend extended periods in an initial watch-and-wait state and/or within a single line of treatment. As such, these patients may have multiple relapses and a variety of clinical features that may impact disease course (eg, double-refractory disease, increased Follicular Lymphoma International Prognostic Index (FLIPI) scores, high Ann Arbor disease stage, older age, etc.). The objective of this study was to estimate the number of treated patients with FL in each line of therapy (LOT) to better understand the proportion with relapsed or refractory (R/R) disease in the US while accounting for distributions of LOTs within a baseline prevalent population and annual trends in treatment initiation by LOT.
Methods: Two companion models were developed from a US perspective: 1) an epidemiologic model that utilized FL incidence and survival data from the Surveillance, Epidemiology, and End Results (SEER) program to project the size of the prevalent population; and 2) a state-transition model describing the proportion of patients with FL initiating treatment and time on treatment by line of therapy. Within the state-transition model, hypothetical incident cohorts were simulated annually to follow FL treatment patterns and survival trajectories until a “steady-state” was reached regarding the distribution of LOTs in the prevalent population. Model inputs were based on data from published literature. Several published sources were identified regarding estimates of treatment rates by line of therapy, with base-case values based on physician survey: 51% for first LOT, 32% for second LOT, and 31% for third and successive LOTs. This distribution was then applied to a baseline prevalent population and subsequent incident cohorts were modeled annually over a 3-year time horizon.
Results: In 2022, the estimated FL prevalent population in the US was 154,922. Over a subsequent 3-year period combining the prevalent patients with newly incident patients, the model projected 10,399 patients initiating first-line treatment, 3197 initiating second-line treatment, and 975 initiating third-line treatment.
Conclusions: While incidence of FL initial diagnosis in the US is well reported, there are limited data describing prevalence or population makeup with respect to LOT. While many patients can benefit from long remissions after first-line therapy, a portion of patients experience R/R disease and require further treatment. Estimation of the R/R FL population can support with planning of treatment needs as novel therapies emerge in the US.
Sorafenib Plus Triplet Therapy with Venetoclax, Azacitibine and Homoharringtonine for Refractory/Relapsed Acute Myeloid Leukemia with FLT3-ITD: A Multicentre, Phase 2 Study
Authors: Yu Sijian , Liu Qifa , Zhang Yu , Yu Guopan , Wang Yu , Shao Ruoyang , Liu Qiong 
Published: December 2023

Abstract
Background
Patients with relapsed or refractory acute myeloid leukemia (R/R AML) with FLT3 internal tandem duplication (FLT3-ITD) have an infrequent response to salvage chemotherapy. We aimed to investigate the activity of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as salvage therapy for this population.
Methods and findings
This multicentre, single-arm, phase 2 study was done at twelve hospitals in China, to investigate the activity and safety of sorafenib plus VAH. Eligible patients were R/R AML with FLT3-ITD (aged 18-65 years) with an Eastern Cooperative Oncology Group performance status of 0-2. Patients received venetoclax (100mg on day 1, 200mg on day 2, and 400mg on days 3-14) and azacitidine (75 mg/m² on days 1-7) and homoharringtonine (1 mg/m² on days 1-7). Sorafenib (400 mg twice daily) was given on 1-14 during each course and continuously during maintenance.The primary endpoint was composite complete remission (CRc) after 2 cycles. Secondary outcomes included overall response rate (ORR), safety and survival.Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom enrolled. Median age was 47 years (IQR 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 10.3 months (IQR, 6.6-16.5), median duration of CRc was not reached (NR) overall survival was 18.1 months (95% CI, 12.2-NR) and event-free survival was 13.2 months (95% CI, 7.3-NR). The grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92·2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%) and sepsis in 6 (11.8%) patients. Treatment-related death occurred in 2 (3.9%) patients.
Conclusions
Sorafenib plus VAH regimen is well tolerated and highly active for R/R AML with FLT3-ITD. This regimen might be a suitable therapeutic option for this population, and larger population trials are needed to be explored.
Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Acute Myeloid Leukemia Harboring KMT2A Rearrangement and Its Prognostic Factors
Authors: Jiang Bingqian , Zhao Yanmin , Luo Yi , Yu Jian , Chen Yi , Ye Baodong , Fu Huarui , Lai Xiaoyu , Liu Lizhen , Ye Yishan , Zheng Weiyan , Sun Jie , He Jingsong , Zhao Yi , Wei Guoqing , Cai Zhen , Huang He , Shi Jimin 
Published: December 2023

Background: KMT2A rearrangement ( KMT2A-r) in patients with acute myeloid leukemia (AML) is associated with poor outcomes; the prognostic factors after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear.
Methods: We investigated 364 adults with AML who underwent allo-HSCT between April 2016 and May 2022, and 45 had KMT2A-r among them. Propensity score analysis with 1:1 matching and the nearest neighbor matching method identified 42 patients in KMT2A-r and non- KMT2A-r cohorts respectively.
Results: The 2-year overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), and non-relapsed mortality (NRM) rates of patients with KMT2A-r were 59.1%, 49.6%, 41.5%, and 8.9%, respectively. With propensity score matching, the 2-year OS rate of KMT2A-r patients was lower than in those without KMT2A-r (56.1% vs. 88.1%, P=0.003), and in patients who achieved first complete remission (CR1), flow cytometry-based measurable residual disease (FCM-MRD) &lt;1% and KMT2A-r negative before HSCT, the difference in the 2-year OS rate was reduced (71.5% vs. 93.9%, P=0.065). Patients with KMT2A-r exhibited the prognostic advantage from transplantation while in CR1 with FCM-MRD &lt;1% and KMT2A-r negative which was reflected in OS, RFS, and CIR ( P&lt;0.001, P&lt;0.001, P=0.002, respectively). Besides, there were differences in OS, RFS, and CIR depending on KMT2A-r subtypes ( P=0.032, P=0.001, P=0.001, respectively). However, there was no difference regardless of the presence of mutations (all P&gt;0.05). Univariate and multivariate analyses demonstrated that achieving CR1, FCM-MRD &lt;1% and KMT2A-r negative before HSCT was a protective factor for OS (HR=0.242, P=0.007), RFS (HR=0.350, P=0.036), and CIR (HR=0.271, P=0.021), while AF6 was a risk factor for RFS (HR=2.985, P=0.028) and CIR (HR=4.675, P=0.004).
Conclusion: The poor prognosis of patients with KMT2A-r AML is associated with KMT2A-r subtypes, but not the presence of mutations. These patients can benefit from achieving CR1, FCM-MRD &lt;1% and KMT2A-r negative before HSCT.
Double-Negative T Cells Attenuate Acute Graft-Versus-Host Disease By Modulating CD4 + T Cell Activation Post-Allo-HSCT
Authors: Pan Tianzhong , Huang Aijie , Tang Baolin , Song Kaidi , Sun Guangyu , Wu Yue , Wang Dongyao , Zhu Xiaoyu 
Published: December 2023

Background: Acute graft-versus-host disease (aGVHD) is a major and life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Double-negative T cells (DNTs) have demonstrated potent cytotoxicity against various hematological tumors, and emerging evidence from animal experiments and clinical studies suggests their potential in predicting and treating aGVHD. Thus, DNTs may be a novel and versatile immunotherapy for aGVHD and relapse management post-allo-HSCT due to the function of harnessing the anti-leukemic effects and immune regulation. Nevertheless, the precise mechanisms underlying DNT-mediated aGVHD prevention remain unclear.
Results: In vitro, DNTs inhibited the proliferation of CD4 + T cells in a dose-dependent manner, and significantly inhibited the expression of CD25 on CD4 + T cells. CD4 + T cells inhibited by DNTs displayed decreased interleukin-2 secretion, reduced cell volume, nuclear condensation, and diminished mitochondrial number and volume. Transcriptome sequencing analysis verified significant downregulation of DNA replication, cell cycle, mitochondrial matrix metabolism, JAK-STAT, interleukin-17, and mitosis signaling pathways in CD4 + T cells co-cultured with DNTs. In addition, we found DNTs arrested CD4 + T cells at the G0/G1 phase, hindering their transition to the S phase, and inhibited CD4 + T cell proliferation by the CD25-JAK-STAT pathway. However, DNTs had no adverse effects on the activity and colony-forming capacity of allogeneic hematopoietic progenitor cells in vitro. Importantly, DNT infusion significantly improved the survival of mice in aGVHD model, reduced splenomegaly, downregulated CD25 expression on CD4 + T cells, and attenuated CD4 + T cell infiltration into host lungs, liver, and spleen, and effectively ameliorated organ damage (Figure 1).
Conclusion: Our findings suggest that DNTs attenuate acute aGVHD by affecting the proliferation and activation of CD4 +T cells via the CD25-JAK-STAT pathway, which is important to the prevention and management of aGVHD.
Retail Price of Imatinib Negotiated By Medicare Part D Plans with National or Regional Coverage at Large Chain and Mail Order Pharmacies
Authors: Kim Myung Sun (Sunny) 
Published: December 2023

Title
Retail price of imatinib negotiated by Medicare Part D plans with national or regional coverage at large chain and mail order pharmacies
Background
Direct-to-consumer pharmacies or websites such as Cost Plus or GoodRx has made imatinib more affordable even without prescription drug coverage. Wholesale acquisition cost (WAC) or list price is often used to compare drug prices. However, the pharmacy retail price negotiated by prescription drug plans and pharmacies is more relevant to patient as it directly impacts out-of-pocket costs and affects decisions on how to acquire oral cancer medications. The price of imatinib for Medicare beneficiaries through different Part D prescription drug plans is variable and not well known.
Methods
Part D Plan Finder was used to identify Medicare drug' plans offered in Portland, OR at zip code 97239. The monthly retail price of imatinib 400 mg was compared for all available Part D plans for a representative list of nationwide and regional large chain pharmacies (Walgreens, CVS, Rite Aid, Safeway) and for mail order pharmacy. The premium and deductible for each drug plan was extracted. The highest and lowest retail price available for each drug plan and the drug cost for first, second and third fill for each retail price was extracted. This drug cost of imatinib was compared to the out-of-pocket cost of imatinib available from Cost Plus pharmacy and GoodRx in zip code 97239.
Results
Nine insurance companies offered 24 drug plans in July, 2023. The premium ranged from $1.6 to $113 and the deductible was $0 to $505. All insurance companies offered 2-3 plans with low premium/high deductible or high premium/low deductible. Plans were categorized to low deductible plans (less than $100), medium deductible plans ($100 to $300) and high deductible plans (more than $300). There were 19 high deductible plans. The median retail price was $4340 (IQR 945-5467). The median drug cost for the patient at first fill was $1464 (IQR 583-1745). There were 4 low deductible plans with median retail price of $823 (IQR 187-6419) and median drug cost at first fill of $275 (IQR 61-1971). There was one medium deductible plan and the retail price was $4374 and patient drug cost at first fill was $1425. The lowest retail price was $77 for Asuris Medicare Script Enhanced (PDP) if prescription was filled at Safeway. The highest retail price was $8881 for Elixir RxPlus (PDP) if prescription was filled at Safeway, CVS or Rite Aid. The monthly imatinib from Cost Plus is $33 (+$5 shipping). GoodRx offered coupons for Walgreens at $150, Rite Aid at $64, CVS at $789 and Safeway $90.
Conclusions
The retail price of imatinib for patients with Medicare Part D drug plan is highly variable depending on the drug plan and filling pharmacy and the out-of-pocket drug cost is often higher than the cost of buying imatinib at Cost Plus by mail order or at the same pharmacy using a GoodRx coupon.
Radiotherapy Consolidation Reduces Risk of Relapse in Diffuse Large B-Cell Lymphoma Patients with Bulky Disease in Complete Response after Frontline Immunochemotherapy: Results from a Retrospective Single Center Study
Authors: Benevolo Savelli Corrado , Novo Mattia , Vassallo Francesco , Evangelista Andrea , Bisio Matteo , Legato Luca , Peri Veronica , Clerico Michele , Levis Mario , Bartoncini Sara , Cavallin Chiara , Nicolosi Maura , Boccomini Carola , Orsucci Lorella , Cavallo Federica , Bruno Benedetto , Freilone Roberto , Ricardi Umberto , Botto Barbara 
Published: December 2023

INTRODUCTION: The role of radiotherapy (RT) consolidation upfront in patients with diffuse large B-cell lymphoma (DLBCL) and bulky disease at diagnosis is controversial, especially in those in complete response (CR) after immunochemotherapy.
METHODS: All patients with DLBCL diagnosed between January 2010 and June 2021 at AOU Città della Salute e della Scienza di Torino and treated frontline with RCHOP-like regimens were retrospectively selected. Patients with primary mediastinal lymphoma were excluded. Clinical and biological features as well as treatment and survival data for the whole population were collected. All patients with bulky disease (defined as ≥6 cm) at diagnosis who obtained CR (defined as PET/TC Deauville score ≤ 3) at the end of systemic treatment were further selected. Progression free survival (PFS) and overall survival (OS) were compared between patients receiving consolidative RT on initial bulky mass and those who did not.
RESULTS: A total of 453 patients with DLBCL were identified. Median age was 68 years (IQR 58-77), 56% were males, 74% stage ≥3, 52% IPI ≥3. 140/451 (31%) had bulky disease at diagnosis. Median follow-up was 5 years. 5-year PFS and OS for the whole cohort were 59% and 66%, respectively. Bulky disease correlated with a significantly lower 5-year PFS (bulky 50% vs no bulky 64%, p = 0.0005) and OS (bulky 68% vs no bulky 60%, p = 0.01). 82 out of 140 patients with bulky disease (68/82 with a bulky ≥7 cm) were in CR after immunochemotherapy: 19/82 (23%) received RT (16/19 on bulky ≥7 cm), 63/82 (77%) did not (55/63 with a bulky ≥7 cm). There were no significant differences between the two groups regarding age, stage, ECOG PS, LDH levels, extranodal involvement and IPI. RT dose was 30 Gy in most patients (17/19); two patients received 36 Gy and 40 Gy. The 5-year PFS was 95% in the RT cohort and 58% in the no-RT cohort (p = 0.004); the 5-y OS was 95% in the RT cohort and 69% in the no-RT cohort (p = 0.038) (figure 1). A propensity score matching analysis confirmed the benefit of RT on PFS (HR 0.1, 95% CI 0.01-0.68, p = 0.019), and showed a non-statistically significant trend of better OS (p = 0.06). 14/24 relapses in the no-RT cohort occurred on the site of bulky disease.
CONCLUSIONS: With the limit of a non-randomized retrospective study, our data showed a benefit of RT consolidation on bulky disease in patients with DLBCL in RC after frontline immunochemotherapy, significantly prolonging PFS and with a trend of improved OS in a propensity score matching analysis.