bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence of Parkinsonism As a Complication of Anti-BCMA CAR-T Cell Therapy in Multiple Myeloma
Authors: Singh Vaishnavi , Master Samip 
Published: December 2023

Introduction: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) therapy has revolutionized the treatment for relapsed/refractory multiple myeloma (RRMM). Two BCMA-directed CAR T products, Idecabtagene Vicleucel (ide-cel) and Ciltacabtagene Autoleucel (cilta-cel), have received approval from the U.S. Food and Drug Administration (FDA). While these therapies have demonstrated remarkable efficacy, concerns regarding treatment-related neurotoxicities have emerged. The specific adverse effect of Parkinsonism associated with BCMA-directed CAR T therapy has not been adequately studied.
Methods: We conducted an analysis utilizing the FDA Adverse Events Reports System (FAERS) database, covering the years 2021-2023. Our search focused on the reported incidence of Parkinsonism associated with BCMA-directed CAR T therapy.
Results: Upon reviewing the FDA data, we identified a total of 177 patients with reported nervous system disorders related to Ide-cel therapy. Out of these patients, 2 had reported incidents of Parkinsonism. Similarly, for Cilta-cel therapy, there were 81 patients with reported nervous system disorders, with 5 reported incidents of Parkinsonism. Out of the total 7 reported patients with Parkinsonism, 5 were males, 2 were females, the average age was 67, the average weight was 68.9 kg, and 3 patients were also noted to have associated cytokine release syndrome.
Conclusion: Our analysis of FAERS data highlights the occurrence of Parkinsonism associated with BCMA-directed CAR T-cell therapy. Further studies are required to quantify the need for neurological surveillance after initiating treatment with these novel agents.
Quantification of ADA of Humanized CD19 CAR-T Cell Therapy in R/R LBCL
Authors: Huang Zhongpei , Mei Heng , Li Chenggong , Hu Yu 
Published: December 2023

Purpose: Humanized CD19 chimeric antigen receptor (CAR) T-cell therapy results in a high response rate in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). And many clinical trials have discovered the impact of anti-drug antibody (ADA) on CAR-T efficacy. But the ADA has yet been quantified. And its influence in patients with CAR-T infusion is still unknown.
Patients and methods: We enrolled 30 patients with R/R LBCL treated with humanized CD19 CAR-T cells between April, 2022 and July, 2023, and collected their plasma at pre-FC, day7, 14, and follow up months for ADA testing using flow cytometry.
Results: The detection of ADA within plasma of humanized CAR-T was performed using flow cytometry, and the relative quantification of ADA was achieved by setting up a calibration curve with CD19 protein as a standard. R 2 of the calibration curve can be 0.999 (Figure 1a). The physiologic threshold was determined as 0.1nM (95%CI) by using plasma from 10 normal subjects.
27/30 patients who experienced only one infusion and did not relapse had mostly low ADA (&lt;3nM). Only one exception having a maximum value higher than 5nM with PFS maintained 1 year. All of the 27 patients had ADA presence before FC, but it did not affect CAR-T amplification.
3/30 patients who received second CAR-T cell infusion, 2 of which had 2 infusions of the same product, and 1 of which relapsed after relma-cel infusion and followed by the humanized product. 2 of the 3 patients (P08 and P09) who had a high ADA before the second infusion (of 3.52 and 3.27) had extremely limited CAR-T expansion after the second infusion (maximum CAR copies of 470 and 3950, respectively), and both relapsed 1 month after the second infusion (Figure 1b-1c). The other one patient (P18) had a low ADA both before and after the second infusion (maximum is before infusion, 0.65 nM), and had normal subsequent CAR copies amplification (maximum 60800 and minimum 10850), and did not relapse during the follow-up period (Figure 1d). We consider that ADA &gt;3nM suggests poor CAR-T amplification and poor prognosis, but further validation is needed due to the small number of patients.
Conclusions: The quantification of ADA is essential and credible, which contributes to the unification of standard. Pre-existing ADA does not affect CAR-T amplification for the first infusion but possibly suggests a negative impact on CAR-T efficacy and amplification of multiple-infusion. However, further research is needed.
Outcomes of Paediatric Acute Promyelocytic Leukaemia in the UK
Authors: Vedi Aditi , Memon Irum , Van Risjik Else , Uparkar Urmila , Shenton Geofffrey , Trinquand Amélie , Clesham Katherine , Mclelland Vanessa , Campbell Helen Jane , Patrick Katharine , Thompson Lyndsey , Baird Susan , Connor Philip , James Beki 
Published: December 2023

Acute Promyelocytic Leukaemia (APL) is characterized by unique genetic and molecular abnormalities, clinical features, and treatment strategies. It accounts for 5-10% of paediatric acute myeloid leukaemia (AML) cases. APL is defined by the t(15;17)(q24;q21) chromosomal translocation, leading to the formation of the PML-RARA fusion protein, which plays a crucial role in leukemogenesis. All-trans retinoic acid (ATRA) has revolutionized APL management by targeting the PML-RARA fusion protein and inducing complete remission in the majority of patients. Arsenic trioxide (ATO) has emerged as an effective therapeutic agent, particularly in cases with ATRA resistance or relapse. ATO is now widely recommended as part upfront treatment. However, access to ATO has been limited by funding sources in certain countries.
This retrospective national study presents the treatment strategies, complications, and survival outcomes of 50 paediatric patients, aged 1 to 18 years, diagnosed with APL in the UK over an 8-year period, between 1 st November 2014 and 31 st October 2021. There were 21 (42%) high risk (HR) patience and 29 (58%) non-HR patients in the cohort. The majority of patients received a chemotherapy-free regimen comprising ATRA and ATO, with additional agents used selectively. Chemotherapy was usually given to patients in the event of lack of access to ATO or clinical urgency. Availability to ATO varied between countries within the UK.
Event-free survival (EFS) and overall survival (OS) were evaluated, with a minimum 2 years follow up from diagnosis and median follow-up of 8 years. Overall, the cohort demonstrated a high OS of 94%, with no significant difference observed between HR and non-HR patients. However, HR patients experienced significantly lower EFS, with all relapses occurring in this group. Relapsed patients received varied treatment regimens, including ATRA, ATO, and chemotherapy, with favourable outcomes.
This study contributes valuable insights into the management and outcomes of paediatric APL in the UK, emphasizing the importance of early diagnosis and risk stratification for optimal treatment decisions. Addressing disparities in ATO availability and promoting consistent funding across NHS Trusts will be crucial in further improving patient outcomes and reducing relapse rates in APL. Future research should focus on refining treatment protocols and exploring novel therapeutic strategies to enhance the long-term survival of paediatric APL patients. The study highlights the challenges associated with ATO availability across NHS Trusts, impacting treatment decisions and outcomes for APL patients.
High Disease-Free Survival in Patients with High-Risk MDS Treated with Orca-T
Authors: Gandhi Arpita , Hoeg Rasmus T. , Patel Sagar S. , Waller Edmund K. , Pantin Jeremy M. , Oliai Caspian H. , McClellan J. Scott , Pavlova Anna , Agodoa Irene , Fernhoff Nathaniel B. , Meyer Everett H. 
Published: December 2023

BACKGROUND
Allogeneic hematopoietic cell transplant (alloHCT) may be a curative treatment option for patients with myelodysplastic syndrome (MDS). The use of investigational therapies that potentially reduce transplant toxicity could improve outcomes in this patient population with difficult to treat disease. Per CIBMTR, survival after alloHCT for MDS using matched donors is approximately 65% at 1 year and relapse-free survival at 1 year was ~69% in MDS patients in the RICMAC trial who received myeloablative conditioning (MAC).
Orca-T is a high-precision cell therapy biologic that includes stem and immune cells, derived from allogeneic donors, that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses. In this phase 1b study, Orca-T was evaluated in MDS patients who were eligible for transplant per 2017 International Expert Panel recommendations.
METHODS
As of 03/31/23, 16 patients with intermediate to very high risk (HR) MDS with ≤10% blasts in the bone marrow at the time of transplant had received Orca-T in the phase 1b study. IPSS-M prognostic scores were Low (6%), Moderate Low (6%), Moderate High (19%), High (44%), and Very High (25%). Baseline HCT-CI scores were 0 (n=6), 1 (n=3), 2 (n=2), 3 (n=3), and 4 (n=2). The median f/u was 19.1 months (range 6.3 - 32.2). Patients were aged 43 - 65 (median 59) and 56% female. Donors were 8/8 HLA-matched related (n=7) or unrelated (n=9). Patients received a busulfan-based myeloablative chemotherapy regimen prior to Orca-T, followed by single-agent GvHD prophylaxis with tacrolimus.
RESULTS
Orca-T was successfully manufactured in a single, centralized GMP manufacturing facility for all patients enrolled, distributed, and infused throughout the U.S. Orca-T was delivered within &lt; 72 hours vein-to-vein (i.e. time between end of donor apheresis to start of recipient's Orca-T infusion).
Disease-free survival (RFS) at 12 months was 94% (Figure). At 1 year, no patients had experienced grade ≥ 3 acute GvHD and moderate to severe chronic GvHD had occurred in 2 patients. Modified GRFS (survival free of Grade 3-4 aGvHD, moderate-to-severe cGvHD and relapse) at 12 months was 75%. Non-relapse mortality (NRM) and overall survival (OS) were 0% and 94%, respectively, at 12 months.
Additionally, one MDS patient with very poor prognosis, characterized by mutated TP53 and complex karyotype, remains in CR without active signs of acute or cGvHD at 500 days post-alloHCT.
CONCLUSIONS
Orca-T demonstrated promising results in this HR-MDS patient population, including high RFS, low incidence of GvHD, and very high OS at 1 year. A randomized controlled phase 3 multi-center trial comparing Orca-T to SOC in patients with MDS, AML, and ALL is currently enrolling across the US (NCT05316701).
Early Initiation of Ketamine Infusion for Pain Management in Pediatric BMT Patients with Mucositis
Authors: Utley Kaylyn , Azadegan Ali , Rosenbaum Adam Rene , McGinn Brenna , Deis Amanda , Hamer Katie , Barthelmess Erin , David Alexandria , Southworth Debra , Trawick Cyndi , Tan Gee Mei , Fabrizio Vanessa A. 
Published: December 2023

Background: As many as 90% of children undergoing hematopoietic stem cell transplant (HSCT) will experience painful mucositis. The mainstay of treatment for these children has been opioid analgesia which can be associated with sedation and respiratory depression. Additionally, these children may experience heightened opioid tolerance and physiologic dependence contributing to lengthy admissions. Ketamine is an anesthetic and analgesic which has been used successfully in conjunction with opioids in the treatment of painful mucositis. This study aimed to reduce total opioid use per day by 10% and overall pain scores by 2 in pediatric patients with mucositis undergoing HSCT through initiation of ketamine at the same time as an opioid patient-controlled analgesia (PCA).
Methods: Beginning April 2022, HSCT patients (both autologous and allogeneic) at Children's Hospital Colorado were started on ketamine infusion in conjunction with an opioid PCA for management of painful mucositis. Mucositis severity and duration, opioid consumption, pain and functional scores, time of initiation of ketamine therapy, ketamine side effects, and duration of PCA and ketamine therapy were recorded for a retrospective (April 2021- March 2022, n=6) and a prospective cohort (April 2022- April 2023, n=17). A 2-sample-T-test was used to calculate the difference in mean cumulative opioid use per day and the mean 24-hour average pain scores between the retrospective and prospective groups.
Results: 71% of children in the prospective group underwent ketamine initiation alongside an opioid PCA. Patients in this group had a 46% reduction in mean cumulative opioid use per day (CI 1.265-2.318, p=0.000). Reduction in 24-hour pain scores between the retrospective and prospective groups was 1.18, failing to meet our goal of 2.0. However, there was still a statistically significant difference in mean scores (CI 0.499-1.860, p=0.001). Additionally, this intervention was tolerated well and only 1 patient (16%) was intolerant of ketamine side effects in the prospective cohort.
Conclusions: Initiation of ketamine alongside an opioid PCA for the treatment of mucositis pain is safe and significantly reduces cumulative opioid exposure and 24-hour pain scores in children undergoing HSCT.
Comparison of Maintenance Therapy Regimens of Patients Treated for Multiple Myeloma
Authors: Wani Kashmira , Gutta Radhika , Mittal Aayush , Jamil Maria , Springer Kylie , Kuriakose Philip 
Published: December 2023

Background: Despite significant progress in treatment modalities and improved survival and response rates in patients diagnosed with multiple myeloma (MM), it remains an incurable disease with a poor outcome, especially in high-risk groups. Though not all patients are eligible, autologous stem-cell transplantation (ASCT) remains an integral part of the treatment of patients with both newly diagnosed and relapsed MM. Regardless of whether patients receive a transplant, they do receive maintenance therapy, and recent evidence has demonstrated that maintenance therapies offer an advantage in progression free and overall survival. While Revlimid is the standard of care, data regarding the specifics of maintenance therapy in high-risk patients is limited and the overall impact of various regimens on survival needs to be further investigated. In our retrospective chart review we reviewed all adult patients with advanced MM within Henry Ford Cancer Institute in the last 10 years to determine the impact of maintenance therapy on progression free survival (PFS) and overall survival (OS).
Methods: We conducted a retrospective chart review of adult patients with MM who underwent ASCT between January 1, 2012 to December 31, 2022. Those who received maintenance chemotherapy after transplant were included in the study. Patients who were lost to follow-up or who had largely incomplete records were excluded. Data points including age, ethnicity, cytogenetic analysis, risk category, maintenance regimen after transplant, last chemotherapy regimen, last follow-up, and date of death (if applicable) were recorded. Maintenance chemotherapy regimens were recorded as Revlimid versus other. Patients were split into 2 categories based on risk - high risk and standard risk. Kaplan-Meier plots were used to illustrate overall survival and time to relapse between groups for various variables. Statistical significance was set at p&lt;0.05
Results: 158 patients were included in the study of which 44 were considered high-risk based on cytogenetics, 106 were standard-risk and 8 were missing. Most of the patients (n=137, 87.3%) received Revlimid, while 20 (12.7%) received maintenance therapy other than Revlimid, and for 1 patient, the type of maintenance therapy was unknown. Within the high-risk group, no statistical significance in OS or PFS was found between patients that received Revlimid versus those that did not. Furthermore, there was no statistical significance in OS and PFS within high risk versus standard cytogenetic risk groups.
Conclusions: We did not see a difference in outcome based on risk and believe all patients would derive equal benefit from maintenance therapy We also did not see a difference in outcome between high and standard risk patients, and for the high-risk subgroup, there was a separation in curves suggesting that maintenance therapy has benefit compared to no maintenance.
IPSS-M Predicts Survival Outcomes Significantly Better Than IPSS-R in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Neoplasms
Authors: Yang Tingting , Jiang Bingqian , Luo Yi , Zhao Yanmin , Ouyang Guifang , Yu Jian , Lan Jianping , Lu Ying , Lai Xiaoyu , Ye Baodong , Chen Yi , Liu Lizhen , Xu Yang , Guo Qunyi , Shi Pengfei , Xiao Haowen , Hu Huixian , Fu Huarui , Ye Yishan , Wang Xinyu , Sun Jie , Zheng Weiyan , He Jingsong , Zhao Yi , Wu Wenjun , Cai Zhen , Wei Guoqing , Huang He , Shi Jimin 
Published: December 2023

Background
The newly published molecular International Prognostic Scoring System (IPSS-M) represents a powerful risk stratification tool for treatment decision-making in myelodysplastic neoplasms (MDS); however, its utility in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains to be fully explored.
Methods
We retrospectively analyzed a large multicenter cohort of 347 MDS patients who underwent allo-HSCT between January 2017 and October 2022. The prediction accuracy of IPSS-M at diagnosis for 3-year survival outcomes was assessed and compared to that of the conventional revised International Prognostic Scoring System (IPSS-R).
Results
Among the 347 patients, median age at transplant was 48.3 years and 41.2% of patients were female. According to IPSS-M, patients were clustered as very low risk (1.2%), low risk (11.2%), moderately low risk (11.5%), moderately high risk (18.2%), high risk (33.4%), and very high risk (24.5%), resulting in a restratification of 49.3% of the entire cohort when compared with IPSS-R. Of these reclassified patients, 52.6% patients were upstaged and 47.4% were downstaged. Median follow-up time among the survivors was 28.6 (range, 4.7 to 76.6) months. With the IPSS-M model, overall survival (OS) and leukemia-free survival (LFS) discrimination was refined relative to the IPSS-R as evidenced by a 7.0 percentage- and 5.7 percentage-point increase in the concordance index (C-index), which was further supported by the lower Akaike Information Criterion and higher C-indexes in multivariate analyses. Among patients undergoing haploidentical HSCT, IPSS-M model also demonstrated significantly improved prognostic performance for LFS versus IPSS-R (C-index, 0.707 vs 0.604) which was validated by multivariate analyses. When restricting our analyses to younger patients (&lt;49 years) and patients carrying detectable mutations, IPSS-M retained greater prognostic value with respect to OS and LFS; while it failed to stratify individual probability of OS and LFS in their counterparts.
Conclusions
IPSS-M was confirmed to increase prognostic discrimination at the individual level and is applicable to transplant-specific settings, which also had an advantage for subjects carrying mutations and younger patients.
Transient CDK9 Inhibition with AZD4573 Effectively Induces Apoptosis in Burkitt Lymphoma As a Monotherapy in Pre-Clinical Models
Authors: Potter Danielle S , Ott India , Saeh Jamal , Fawell Stephen , Drew Lisa , Roderick-Richardson Justine 
Published: December 2023

Burkitt Lymphoma (BL) accounts for almost two thirds of all B-cell non-Hodgkin lymphoma cases in children and adolescents. It may affect the jaw, bones of the face, bowel, kidney, ovaries and in some cases spread to the central nervous system. Nearly all types of BL are characterized by c-MYC gene translocation of chromosome 8 with immunoglobulin genes at chromosome 2, 14 or 22 resulting in high levels of the transcription factor. Recently, MCL-1 was shown to be overexpressed in BL and is a critical survival factor in pre-clinical BL models using genetic and chemical approaches.
CDK9, a serine/threonine kinase, regulates transcription elongation through phosphorylation of RNA polymerase II at serine 2 (pSer2-RNAPII). AZD4573 is a highly potent and selective CDK9 inhibitor that results in downregulation of short-lived transcripts and labile proteins such as c-MYC and key survival proteins including MCL-1 and BFL-1, resulting in apoptosis in several hematological malignancies (Cidado et al. 2020 & Boiko et al. 2021)
We selected several preclinical BL models to assess the rapid apoptogenic potential of AZD4573 in vitro and in vivo. To measure apoptosis, we evaluated cleaved caspase-3 (CC3) induction following acute treatment (6h) using Caspase-Glo 3/7. Using this assay, we found that 3 BL models were sensitive to CDK9 inhibition (EC50 &lt; 100nM; max. CC3 &gt; 50%) and 2 were resistant (EC50 &gt; 100nM; max. CC3 &lt; 50%). Treatment with AZD4573 in these sensitive BL cell line models decreased pSer2-RNAPII, and downregulation of MCL-1 and c-MYC within 6 hours. In AZD4573 resistant lines we observed relatively higher levels of anti-apoptotic proteins BCL2 and BCL-xL, compared to the sensitive cell lines. These increased levels potentially lead to the decreased sensitivity to AZD4573, which does not reduce levels of BCL-2 and BCL-xL due to their longer half-life. Using CRISPR genetic knockouts we demonstrate that BL cell lines are dependent on c-MYC and MCL-1 and that loss of these protein decreases caspase induction after AZD4573 treatment, highlighting the importance of these proteins in driving the efficacy of AZD4573. In vivo AZD4573 dosed on a once weekly schedule resulted in tumor growth inhibition in aggressive BL cell line xenografts Namalwa and Ramos (40-60%) and decreased pSer2-RNAPII, MCL-1 and c-MYC and increased CC3 8 hours after treatment. AZD4573 is currently in a phase 2 study (NCT05140382) to assess the efficacy, safety, and PK of AZD4573 in patients with relapsed or refractory Peripheral T-cell lymphomas (pTCL). Our findings demonstrate that targeting CDK9 with AZD4573 can effectively induce apoptosis in pre-clinical BL models and could be an effective therapy for BL patients.