bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 1b Study of ELA026, a Monoclonal Antibody Targeting Signal Regulatory Protein-α/β1/γ, in Patients with Newly Diagnosed and Previously Treated Secondary Hemophagocytic Lymphohistiocytosis
Authors: Maiti Abhishek , Daver Naval , Iyer Swami P. , McCall David , Gohil Satyen H , Lopez Jimenez Javier , Lane Hayley , Kim Benjamin , Dao Kim-Hien , Patou Gary , Panicker Sandip , Covert Kelly , Parry Graham Carl , Allen Carl E 
Published: December 2023

Introduction: ELA026 is under investigation in secondary hemophagocytic lymphohistiocytosis (sHLH), a life-threatening, hyperinflammatory condition that is most often triggered by malignancies, autoimmune disorders, and infectious diseases. There are no approved therapies for sHLH, and current treatment approaches, particularly for malignancy-associated HLH (mHLH), are suboptimal. For example, in adult patients with mHLH, median overall survival (mOS) is approximately 2 months (Lee et al. 2023). ELA026 is a monoclonal antibody directed against signal regulatory protein-α/β1/γ and is intended to target the activated myeloid and T cells that drive sHLH.
Methods: This is an open-label, single-arm, Phase 1b global multicenter study (NCT05416307) to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of ELA026 in newly diagnosed and previously treated sHLH patients, aged 12 years or older (6 years or older in select countries including the US). In Cohort 1, an intra-patient dose escalation of ELA026 occurs in the absence of a dose limiting toxicity (DLT) and optimal biomarker response. Response is evaluated as described in Locatelli et al. 2020.
Results: Six mHLH patients enrolled in Cohort 1 with median age of 50 years (range 21-67). Three patients were refractory to etoposide-based therapies and/or anti-cytokine therapies. No DLTs or study drug-related serious adverse events occurred. Five patients were deemed evaluable for efficacy based on &gt;1 week of ELA026 exposure (efficacy assessment is pending). All 5 patients received concurrent chemotherapy for their malignancies. As of July 31, 2023, 3 patients are alive and 2 patients have died from complications of malignancy (mOS has not been reached but has exceeded 3 months). Three patients who had periods of ELA026 monotherapy displayed early, progressive monocyte and lymphocyte reductions with associated improvements in C-reactive protein and other sHLH-associated biomarkers. Updated study results and progress will be provided at the meeting.
Conclusion: Preliminary data suggest ELA026 is well tolerated in sHLH patients and induces early biomarker changes that warrant further clinical investigation.
TET2-Mediated Dysregulation of Heterochromatin in Age-Related Clonal Hematopoiesis
Authors: Hong Tingting , Li Jia , Guo Lei , Cavalier Maryn , Wang Tianlu , Fang Shaohai , Guzman Anna , Wohlan Katharina , Kapadia Chiraag , Yang Yaling , Yin C. Cameron , Li Shaoying , You M. James , Cheng Xiaodong , Zhou Yubin , Goodell Margaret , Huang Yun Nancy 
Published: December 2023

Aging is one of the major negative factors of normal hematopoiesis, characterized by a decline in the self-renewal capabilities of hematopoietic stem and progenitor cells (HSPCs), alongside a myeloid lineage bias, thereby sabotaging the immune system and increasing the risk of malignant transformation. Epigenetic deregulation is a hallmark feature representative of aging and significantly contributes to age-related dysfunction in multiple systems. DNA methylation drifting is commonly observed during aging, especially within the partially methylated domains (PMDs). PMDs are intriguing heterochromatin regions featured by their late-replicating, lamina-associated, and B-compartment localized properties in HiC analysis. While heterochromatin is generally considered devoid of genes, it nonetheless plays a pivotal role in maintaining genomic stability. However, the link between age-related DNA methylation loss in PMDs and heterochromatin dysfunction remains elusive.
In this study, we juxtapose the influence of aging on both wild-type (WT) and Tet2 knockout (KO) HSPCs. Tet2 depletion was found to counteract the functional deterioration typically associated with aging by preserving robust self-renewal and repopulation capacities in aging HSPCs. This resistance to functional decay may account for the age-related clonal hematopoiesis observed in Tet2KO HSPCs. At a molecular level, we identified distinct epigenetic regulatory mechanisms mediated by Dnmt3a and Tet2 at heterochromatin. These mechanisms are associated with alterations in 3D genome architecture during HSPC aging. Age-related dysregulation of heterochromatin leads to the upregulation of endogenous retroviruses (ERVs), which subsequently activate intracellular innate immune response and contribute to the functional decline of aging HSPCs. The application of reverse transcriptase inhibitors was shown to suppress ERV production and interferon-stimulated genes (ISGs) expression, thereby ameliorating age-related defects in aged HSPCs. Our findings provide compelling evidence supporting the intricate interplay between DNMT and TET in regulating DNA (de)methylation equilibrium in heterochromatin and euchromatin during stem cell aging. Moreover, our study offers critical insights into the mechanisms underlying age-related heterochromatin dysfunction, which contributes to the functional deterioration of HSPCs during aging.
Safety and Efficacy of GPRC5D CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma Patients
Authors: Li Shiqi , Yuan Zhongtao , Liu Lin , Li Yu , Luo Le , Chen Yingnian , Zhang Lihua , Li Guangchao , Luo Min , Zeng Kaikai , Ma Donghui , Wang Sanbin 
Published: December 2023

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have shown breakthrough therapeutic effects in treating relapsed/refractory (R/R) multiple myeloma patients. However, relapses, including some that are BCMA negative, remain a challenge.
Here we have developed a second-generation GPRC5D CAR-T, composed of a GPRC5D-binding scFv (derived from a humanized rabbit monoclonal antibody), a 4-1BB costimulatory domain, and a CD3ζ signaling domain. Following pre-clinical studies, we initiated a phase 1 dose-escalation clinical trial. Lymphodepletion with fludarabine and cyclophosphamide was performed before administering 3E6, 6E6, or 1E7/kg anti-GPRC5D CAR T cells.
To date, we have enrolled a total of 7 R/R MM patients, including 3 patients with prior BCMA CAR-T treatment. All patients received autologous CAR T-cell infusions and were clinically evaluated between February 7th, 2023, and June 26th, 2023. No dose-limiting toxicities (DLT) were observed, even at the highest dose of 1E7/kg. Grade 3 or higher adverse events (AEs) were mainly hematological toxicities, such as neutropenia (6 [85.7%]), anemia (3 [43%]), and thrombocytopenia (3 [43%]). Cytokine release syndrome occurred in 6 (85.7%) of 7 patients, with all cases classified as grade 1 or 2. Notably, no neuro-toxicities were observed in any of the seven patients.
The overall response rate was 85.7% (6/7 patients), comprising 3 complete responses or better, 3 partial responses, and one no-response (NR). The NR patient had previously shown no response to BCMA CAR-T therapy, with FACS analysis confirming the absence of both BCMA and GPRC5D on their tumor cells. Interestingly, the other two patients previously treated with BCMA CAR T-cell therapy, one reached complete response (CR), and the other reached partial response (PR). Remarkably, one patient diagnosed as COVID-19 positive two days before CAR-T infusion still received the CAR-T cell product, which led to a dramatic in vivo expansion of CAR-T cells, resulting in CR within one month after cell infusion.
In conclusion, GPRC5D CAR T-cell therapy demonstrated promising clinical efficacy and tolerable safety in patients with R/R MM. For those who relapsed after anti-BCMA CAR T-cell therapy, GPRC5D CAR T-cell therapy offered an effective option (NCT05739188).“
A Phase 1 Study to Assess the Effect of Supratherapeutic Doses of Iptacopan on Cardiac Conduction Parameters and Safety
Authors: Schmouder Robert , Kaetterer Noemi , Kulmatycki Kenneth , Nidamarthy Prasanna Kumar 
Published: December 2023

Introduction: Iptacopan is a first-in-class, oral, selective inhibitor of factor B, a key component of the complement system alternative pathway. Inhibition of the complement system represents a potential mechanism for treatment of several diseases including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. The purpose of this randomized, participant-blinded, placebo-controlled phase 1 study was to assess the effect of supratherapeutic doses on the exposure-response relationship of iptacopan concentration and cardiac conduction, and to assess the cardiac safety and tolerability of ascending, supra-therapeutic single doses of iptacopan.
Methods: Supratherapeutic doses of iptacopan 400, 800, and 1200 mg were included in this study, representing ≤6-fold higher dose than the planned clinical dose of 200 mg. The primary endpoints were change from baseline in Fridericia-corrected QT interval (QTcF) and safety endpoints. The analyses included data from this study pooled with part 1 data (single dose) from the first-in-human (CLNP023X2101) study (n=86). The study population included healthy men and women aged 18-55 years. The relationship between iptacopan plasma concentration and change from baseline in QTcF was estimated using a linear mixed effects model.
Results: Thirty-two patients were randomized and received placebo (n=8) or iptacopan (n=24). The median age of participants in the 400-mg, 800-mg, 1200-mg, and placebo groups was 51.5, 35, 36, and 37 years, respectively. The upper bound of the 2-sided 90% CI for linear mixed effects model-derived placebo-adjusted change from baseline in QTcF at the geometric mean C max was 2.82 ms for 400-mg, 2.94 ms for 800-mg, and 3.22 ms for 1200-mg doses. Hence, there was no evidence of clinically meaningful QTc prolongation ( Table). The exposure-response analysis of PR and QRS intervals showed no iptacopan concentration-related effects. While the pre-specified and more simple exposure-response analysis of heart rate using change from day 1 baseline (0 hour) revealed an increase of 3 to 5 beats per minute, in a post hoc analysis using 24-hour, time-matched comparison for each participant at each time point before and after study treatment (the more common and gold-standard analysis), iptacopan had no effect on heart rate. No deaths, no moderate or severe treatment-emergent adverse events, and no treatment cohort discontinuations due to adverse events were reported.
Conclusions: Three supratherapeutic doses were well tolerated and were not associated with any relevant change in QTcF. Iptacopan did not affect PR or QRS intervals and a time-matched post hoc analysis showed no effect on heart rate. These results indicate that the anticipated clinical dose of iptacopan (200 mg twice daily) has no adverse clinical effects on cardiac function.
Prior Daratumumab Exposure and It's Correlation to Parameters Related to Apheresis Prior to Hematopoietic Stem Cell Transplantation in Multiple Myeloma
Authors: Unis Graham D , Gudiel Cesia , Philon Ernest , Finn Laura E. 
Published: December 2023

A number of recent studies have brought to light the potential detrimental effect the biologic monoclonal antibody daratumumab, directed towards CD38, may have on the collection of stem cell collection for hematopoietic stem cell transplantation (HSCT). In our evaluation of this claim, we retrospectively reviewed multiple myeloma patients who underwent autologous HSCT at a major tertiary transplant center between 2017 and 2022. A total of 240 patients were identified which included 62 patients who received daratumumab prior to stem cell collection and 178 patients who had no prior daratumumab exposure. Basic demographic data was collected as well as radiation, chemotherapy, and smoking history. No significant differences were identified between the groups based on demographics, smoking, or radiation exposure. Parameters related to peripheral stem cell collection were identified and recorded. We found that in patients exposed to daratumumab prior to apheresis, the mean number of days of apheresis required to reach the target collection goal was statistically increased compared to control (1.42 days ± 0.07 vs 1.26 ± 0.03; p&lt;0.05). Furthermore, medications used to increase peripheral stem cell collection yield were also increased. It was demonstrated that the mean number of doses of plerixafor and G-CSF analogs were increased in the daratumumab group vs the control (1.08 ± 0.12 vs 0.6 ± 0.05; p&lt;0.001 and 5.98 ± 0.31 vs 5.17 ± 0.06; p &lt;0.001 respectively). Total number of stem cells collected both as an absolute number and controlled for the number of days of apheresis were lower in the daratumumab group compared to the control (5.31x10^6 ± 0.31 vs 6.68x10^6 ± 0.20; p&lt;0.05 and 4.16x10^6 ± 0.32 vs 5.84x10^6 ± 0.21; p &lt; 0.001 respectively). These results suggest that pre-apheresis exposure to daratumumab has a detrimental effect on peripheral stem cell collection. These results have a significant implications for both long term patient care and healthcare system resource utilization. The clinical outcome implications of daratumumab are currently not well known and further study is needed to determine if alterations in stem cell collection protocols would result in improved stem cell collection yields for patients with pre-collection daratumumab exposure.
All data is expressed as mean ± SEM
Bendamustine Bridging Versus Standard of Care Chemotherapy on Toxicity Profile for Multiple Myeloma Patients Undergoing CAR T Cell Therapy
Authors: Leyfman Yan , Rajeeve Sridevi , Sheng Tianxiang , Diniz Marcio , Richard Shambavi , Jagannath Sundar , Rossi Adriana C 
Published: December 2023

Introduction
Multiple myeloma (MM) remains an incurable malignancy arising from plasma cells, however great promise has been seen with the use of Chimeric Antigen Receptor (CAR) T cells. Autologous CAR-T products require bridging therapy, however little is known about different agents used in this manner. Some studies indicate decrease in disease burden is crucial, while others note an association with higher rates of toxicity and negative effect on survival. As commercial CAR T cell therapy is indicated after failure of at least 4 prior treatments, careful consideration of bridging therapy is crucial, particularly in patients with aggressive and high-risk disease. This study aims to compare the impact of bendamustine to standard of care (SOC) bridging therapy in MM patients undergoing CAR T cell therapy.
Methods
A single-center retrospective chart review of 19 adult patients with relapsed/refractory multiple myeloma treated with CAR T cells, who also received bridging therapy with either bendamustine (n=9) or SOC/Other (n=10) was conducted at Mount Sinai Hospital. Patient demographic information (gender, race, MM subtype, history of prior transplant) was collected and toxicity profiles (infection, pancytopenia, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS)) were compared. Descriptive statistics were used to analyze demographic characteristics and toxicity profiles between the two cohorts.
Results
Comparative analysis of demographics showed that both cohorts were predominantly males with IgG MM subtype, and varied in terms of race ( Figure 1a). The Other cohort had a higher proportion of patients with a history of autologous stem cell transplant (ASCT) (70%) compared to the bendamustine group. In the SOC group, two patients developed infections, whereas none were observed in the bendamustine cohort ( Figure 1b). Pancytopenia was observed in both groups, but interestingly, 100% of patients experienced it in the SOC cohort. CRS and ICANS were comparable between the two groups ( Figure 1b). Comparative statistics demonstrated no significant difference between the two groups ( Figure 1c).
Conclusion
Our study findings indicate that there was no significant difference in toxicity profiles between the two pre-conditioning therapy groups. Given our limited sample size, future studies with a larger are indicated to validate these results.
Screening Cerebrospinal Fluid for Aggressive B-Cell Lymphoma: Significance of Clonal Populations Found with 8-Color Flow Cytometry
Authors: Ho Carrie I , Lopedote Paolo , Lin Olivia , Fromm Jonathan R , Gopal Ajay K , Milano Filippo , Smith Stephen D 
Published: December 2023

Background: Secondary central nervous system (CNS) lymphoma confers a poor prognosis, and prompt identification is critical for guiding management. Over the last decade, we have employed cerebrospinal fluid (CSF) analysis with 8-color flow cytometry (FCM) in screening patients deemed at risk of CNS relapse. However, there is little data to guide interpretation and management of positive results, and concurrent clinical and radiographic features of FCM positive (FCM+) patients, remain areas of uncertainty.
Methods: We analyzed newly diagnosed (ND) and relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBCL) patients who underwent a screening lumbar puncture (LP) from 2011-2020. Clinical, imaging, and CSF findings (differential, cytology, FCM) were collected. Patients with prior CNS involvement or FCM showing CLL/low-grade B-NHL were excluded. “FCM-only” patients were defined as FCM+ but without any other evidence of CNS spread (negative cell count/cytology, MRI, and no symptoms), whereas others were deemed to have overt CNS disease.
Results: There were 415 LPs among 361 patients (243 ND, 172 R/R). 21 (5%) patients were FCM+, 10 ND and 11 R/R patients (Table 1). Four had FCM-only involvement (2 ND, 2 R/R). Among these, the clonal population was 1.63% of WBC (range, 0.3-2.7%), and 3 had concurrent bone marrow (BM) or peripheral blood (PB) involvement. All 4 received intrathecal (IT) therapy. At median follow up of 23 months, 3 (75%) have died (2 from CNS disease progression, 1 unknown due to loss in follow up), and 1 remains alive in remission 44 months later following IT methotrexate (MTX) and CAR T-cell therapy.
17 had overt CNS disease (8 ND, 9 R/R). The clonal population was 9% (range, 0.2-98%). Eight (47%) had concurrent BM or PB involvement. Twelve (70%) received IV high dose MTX, and the remainder received only IT therapy. At median follow up of 42 months, 9 (53%) have relapsed (2 CNS only, 1 systemic, 6 both), and 9 have died. Median time to CNS relapse was 5 months.
Conclusions: CSF 8 color FCM screening of DLBCL/HGBCL patients yields a low proportion of positive results, mostly in the setting of overt CNS disease. However, even FCM-only patients had poor outcomes (2/4 with CNS progression), suggesting that blood contamination does not explain CSF findings, and that these patients should be approached as secondary CNS involvement. Better pt selection for CSF screening is needed to reduce unnecessary LPs. Intensified or novel approaches for all FCM+ patients are needed.
Flumatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: An Open-Label, Multi-Center Study
Authors: Wen Ziyu , Zhao Ying , Li Guowei , Su YongZhong , Chen FeiHeng , Tao HongFang , Zheng ZhengJin , Lin Wuqiang , Chen XiuLi , Meng Meili , Yu Lian , Chen LongTian , Huang JianQing , Wu Guocai , Zhao Mengxia , Liu Zhenfang , Zhu Hongqian , Jiang Yirong , Liu Qifa , Liu Xiaoli , Xu Na 
Published: December 2023

Background Tyrosine kinase inhibitors (TKIs) ushered in the era of targeted therapy for chronic myeloid leukemia(CML), which greatly improved the prognosis of patients with CML. Flumatinib is a second-generation tyrosine kinase inhibitor (TKI), which is currently approved for patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in China. And some current clinical trials revealed that flumatinib has been shown to be a more potent inhibitor of BCR::ABL than imatinib.
Methods In this open label, single-arm, multicenter study, 127 patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML) treated with flumatinib were enrolled. The primary endpoint of this study was early molecular response (EMR) rates at 3 months. The secondary were the rates of complete cytogenic response (CCyR), major molecular response (MMR) at 3, 6, 12 months and treatment-related adverse events (AEs). The trial is registered with ClinicalTrials.gov NCT04591197.
Results From October 2020 to December 2022, a total of 158 patients with CP-CML were assessed for eligibility, of whom 127 were followed up for more than 3 months. 79(62%) patients were men and 48 (38%) were women. The median age was 47 years (range, 19-82 years), The median time from diagnosis to treatment was 6 days (0-176 days) and the median follow-up was 9.7 months (range 3.1-26.6 months). Of evaluable 127 patients, EMR was achieved by 85% (95% confidence interval [CI], 77.6%-90.7%) of patients at 3 months. After the initiation of flumatinib treatment, the incidence of MMR at 3, 6, and 12 months was 24%, 59%, and 73%, respectively. Patients receiving flumatinib had higher rates of CCyR at 6 months and MMR 12 months than the data from DASISION (dasatinib) and ENESTnd (nilotinib) therapy (85% vs 73% vs 67% and 73% vs 46% vs 44%). Progression-free survival (PFS) rate at 1-year was 97.2%. Diarrhea (34%) were the most commonly reported adverse events. Most treatment-related adverse events were grade 1/2. None of the patients discontinued or died due to AEs.
Conclusion Flumatinib as first-line therapy in patients with newly diagnosed CP-CML was not inferior to nilotinib and dasatinib and well tolerated.