bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 2, Open-Label Study to Assess the Pharmacokinetics, Pharmacodynamics and Safety of Orally Administered Epeleuton in Patients with Sickle Cell Disease
Authors: Andemariam Biree , Sheehan Vivien A. , Hamza Moayed , Kelly Kirsty , Climax John 
Published: December 2023

Background.
Sickle cell disease (SCD) is a rare hereditary multi-system disorder that is caused by a single mutation in the beta allele of the hemoglobin gene, leading to the production of sickle hemoglobin (HbS). HbS polymerizes when deoxygenated, resulting in red blood cell (RBC) sickling and membrane damage, ultimately leading to a cascade of events which include hemolysis, chronic anemia, inflammation, and vaso-occlusion. Despite recent progress, there is a need for additional disease-modifying therapeutic options.
Epeleuton is 15-hydroxy eicosapentaenoic acid (15(S)-HEPE) ethyl ester, a novel synthetic second generation w-3 fatty acid which targets key drivers of hemolysis and multicellular adhesion. In preclinical studies in Townes humanized SCD mice and SCD patient RBCs, epeleuton acts as a disease-modifying agent by simultaneously decreasing (a) systemic and local inflammatory activation, (b) endothelial adhesion, (c) organ damage and (d) intravascular hemolysis and sickling. Epeleuton has been administered to 343 subjects in clinical trials, with a favorable safety and tolerability profile.
Objective
To evaluate the pharmacokinetics, pharmacodynamics and safety of orally administered epeleuton in patients with SCD.
Study Design and Methods.
This open-label, phase 2, multicenter study (NCT05861453) will enroll approximately 30 adult patients with a confirmed diagnosis of SCD (HbSS and HbSß0-thalassemia). Participants must have hemoglobin levels of 5.0-9.5g/dL at screening, 2-10 vaso-occlusive crises (VOCs) in the past 12 months, and a high adhesion index at screening defined as RBC laminin adhesion &gt; 400 cells. Concomitant treatment with a stable dose of hydroxyurea is permitted during the study. Key exclusion criteria include receiving an RBC transfusion within three months of enrolment, receiving voxelotor, crizanlizumab or l-glutamine within six weeks of enrolment and, prior hematopoietic stem cell transplant.
The trial has a 28-day screening period, followed by a 16-week treatment phase and a 30-day post-treatment follow-up period. Study participants will attend the clinic on 6 occasions at screening, baseline, weeks 4, 8 and 16 (end-of-treatment) and the week 20 post-treatment follow-up visit. Enrolled patients will receive epeleuton 2g BID (4g daily) for 16 weeks. Study endpoints include change from baseline in hemoglobin levels, hemolytic markers, assessments of RBC health, soluble adhesion molecules, RBC adhesion, whole blood adhesion and rates of VOC.
Conclusion:
Treatments that can simultaneously target hemolysis and cellular adhesion may have an important disease-modifying utility for patients with SCD. The results of this study are anticipated to confirm the potential of epeleuton to address multiple aspects of SCD and to guide the design and conduct of future studies in patients with SCD.
Mega-Dose Decitabine Intensified Regimen Is More Effective at Eliminating Pre-HSCT Measurable Residual Disease Compared to the Bu/Cy Regimen: A Multicenter Prospective Phase II Study
Authors: Zheng Hao , Lv Meng , Yan Chenhua , Liu Jing , Zhang Yuanyuan , Mo Xiao-Dong , Sun Yuqian , Wang Yu , Zhang Xiaohui , Xu Lanping , Huang Xiao-Jun 
Published: December 2023

Background:
Acute myeloid leukemia (AML) patients with high-risk pre-HSCT measurable residual disease (MRD, KMT2A-r, etc.) have a high relapse rate (&gt;50%) even after allogeneic hematopoietic stem cell transplantation(allo-HSCT). In 2018, we developed two multi-institutional, single-arm, prospective phase II trials, to investigate the efficacy and safety of a novel intensified conditioning with “Mega-Dose 400mg/m 2” decitabine following allo-HSCT for high-risk MRD AML (NCT03793517).
Method：
Inclusion: 1) Detectable pre-HSCT MRD detected by recurrent genetic abnormalities (KMT2A-r, DEK, etc.) in ELN adverse-risk AML; or high-level pre-HSCT MRD in all risk groups, defined as the reduction of recurrent genetic abnormalities ≤1 log compared to initial diagnosis (RUNX1:RUNX1T1, etc.); 2) Age≥18; no HSCT history, available donor; ECOG 0-2, HCT-CI 0-3. Uniform conditioning regimen: intravenous decitabine (200mg/m 2/day) on days-12, -11, intravenous cytarabine+ busulfan+ cyclophosphamide (Bu/Cy) on days -10 to -2 (Blood. 2015;125(25):3956-62). The primary endpoint was cumulative incidence of relapse (CIR). Competing risk analysis and time-dependent Cox model were constructed in R software 4.21. Contemporary MRD+ AML patients with the same recurrent genetic abnormalities following Bu/Cy regimen or relapsed/refractory AML patients following 400mg/m 2 decitabine regimen (NCT03799224) were enrolled as nest-control to compare the post-HSCT kinetics of recurrent genetic abnormalities.
Results: Between Dec 2018-Feb 2023, twenty-one patients received allo-HSCT from HLA-matched siblings (n=2), and haploidentical donors (n=19), including 13 patients with KMT2A-r genes. Median follow-up was 19 (4.6-58) months after HSCT. The cumulative 30-day neutrophil (median 13 days) was 100.0% and 100-day platelet engraftment and 95.2% (median 21 days); all patients reached negative MRD by flow cytometry after HSCT. This conditioning regimen was well tolerated without irreversible grade III-IV toxicity peri-engraftment.
Primary endpoint: 2-year CIR was 5.6% (95%CI: 0.3-23.3). Secondary endpoint: 2-year NRM was 4.8% (0.3-20.2); 2-year LFS was 89.6% (77-100); 2-year OS was 89.3% (76.2-100). The median fold reductions (log10) of leukemia burden with recurrent genetic abnormalities were 3.6 (range 1.3-5.1) one month after HSCT (Figure).
Conclusion: Compared to Bu/Cy regimen, “Mega-Dose” decitabine (400mg/m2) is a novel conditioning regimen with improved efficacy to eradicate pre-HSCT MRD and reduce post-HSCT relapse.
Statin Use and Its Effects on Survival Outcomes and Rates of Gvhd in Allogeneic Stem Cell Transplant Patients: Results from Real-World Cohorts
Authors: Fuqua Jacob , Abonofal Abdulrahman , Safi Danish , Khan Maimoona , Khan Hiba , Yingling Spencer , Safi Salah Ud Din 
Published: December 2023

Introduction:
The effect of statin use in allogeneic stem cell transplant remains unclear. There have been conflicting results in studies examining the impact of statins on engraftment, graft-versus-host-disease, survival, and long-term outcomes in stem cell transplant recipients.
Methods:
Retrospective data was extracted using the TriNetX database. The primary endpoint was overall survival at 5 years, risk of death, and graft-versus-host-disease in the two cohorts.
Results:
5045 patients were identified in cohort-1 (statin cohort) and 10,181 patients were identified in cohort-2 (non-statin cohort). Table-1 shows patient characteristics at baseline. Propensity-score-matching was used to balance the two cohorts. Patient count in each group after matching was 3702 (Table-2). Overall survival was 59.32% in cohort-1 versus 48.55 % in cohort-2, with HR of 0.685 (95% CI 0.634, 0.740) in favor of cohort 1 (Figure-1). Median OS for cohort-1 was not reached versus 1593 days for cohort-2. Risk of death in cohort-1 and 2 was 0.311 and 0.4 respectively (Figure-2), with a risk difference for the death of -0.089 (95% CI, -0.110, -0.067, p-value &lt;0.001), in favor of cohort-1. Risk of graft-versus-host-disease was 0.648 and 0.674 in cohort-1 and 2 respectively (Figure-3), with a risk difference of -0.026 (95% CI -0.054, 0.002, p-value 0.065), and risk ratio of 0.961 (95% CI 0.921, 1.003). Survival-probability was higher at 5 years in cohort-1 regardless of presence or absence of GVHD.
Conclusions:
Our retrospective analysis of a large patient cohort showed improved OS and decreased risk of death with statin use in allogeneic stem cell transplant patients, regardless of presence or absence of GVHD, even though the average total and LDL cholesterol levels were higher in statin-group. The difference in graft-versus-host-disease was not statistically significant in both cohorts, however, there was a trend towards decrease GVHD in statin-cohort. To the best of our knowledge, this is the first large database based study evaluating the effect of statin use on outcomes in patients undergoing allogeneic stem cell transplant. Phase 3 clinical trials are needed to further answer this question.
Revumenib Maintenance Therapy Following Revumenib-Induced Remission and Transplant
Authors: Zucenka Andrius , Issa Ghayas C. , Arellano Martha , Khazal Sajad , Khera Nandita , Stock Wendy , Cuglievan Branko , Gu Yu , Nguyen Huy Van , Smith Angela R. , Stein Eytan M. 
Published: December 2023

Background: The potent and selective oral menin-histone-lysine N-methyltransferase 2A (KMT2A) inhibitor revumenib (SNDX-5613) induced complete remissions with clearance of residual disease in acute leukemias refractory to multiple previous lines of therapy ( Nature. 2023;615:920-924). Here we report outcomes following the resumption of revumenib after hematopoietic stem cell transplant (HSCT).
Methods: Patients aged ≥30 days with relapsed or refractory (R/R) acute leukemias with genetic alterations associated with HOXA overexpression, including KMT2A-rearranged ( KMT2Ar) or nucleophosmin 1 ( NPM1)-mutated leukemias, were enrolled in the AUGMENT-101 phase 1/2, multicenter, open-label, dose-escalation study (NCT04065399). Patients received revumenib every 12 hours (q12h) in 28-day continuous cycles. Patients who achieved a complete response (composite definition [CRc]), morphological leukemia-free state, or partial response could undergo HSCT without leaving the study. Revumenib was stopped before the HSCT conditioning regimen but, per a protocol amendment, could be resumed after HSCT if the patient was in CRc. Measurable residual disease (MRD) was assessed using multiparameter flow cytometry and/or polymerase chain reaction.
Results: Between November 5, 2019, and June 28, 2023, a total of 131 phase 1 patients were enrolled and treated in the AUGMENT-101 study. Nine patients with acute myeloid leukemia (AML) from the AUGMENT-101 study resumed revumenib (8 after transplant and 1 after a stem cell boost [Table 1]). Seven patients had KMT2Ar and 1 patient each had nucleoporin 98 rearranged (NUP98r) and mutated NPM1. Revumenib was resumed 59 to 180 days after HSCT (Table 2). Dose was reduced for 4 of 9 patients to mitigate adverse events of thrombocytopenia (n=3) and leg pain (n=1), and revumenib was discontinued in 4 of 9 patients because of progressive disease (n=2), cytopenias (n=1), and not reported (n=1). Revumenib duration of treatment (DOT) in the maintenance setting at the time of this analysis ranged from 23 to 588 days, with treatment ongoing for 5 of the 9 patients. CRc was maintained in 6 of 9 patients after HSCT and maintenance revumenib. One patient with reported MRD after HSCT converted to MRD-negative status following initiation of revumenib maintenance therapy. Overall, MRD-negative remissions were maintained in 5 patients as of the data cut off.
Conclusions: With 3 patients on revumenib maintenance therapy for more than a year, long-term responses, including conversion to MRD-negative status, were seen in these heavily pretreated patients with AML. Resuming revumenib post HSCT had a tolerable safety profile consistent with that previously reported for the AUGMENT-101 study.
Outcomes of Treosulfan Vs. Busulfan Based Conditioning Regimens in Adult Patients Undergoing Allogeneic HSCT: Real Life Data from a Single Center
Authors: Uzay Ant , Gündogdu Yasemin , Kartı Süleyman Sami , Koşan Barış , Yetiş Tuğba 
Published: December 2023

Introduction
The type of conditioning regimen has a great impact on the outcome of patients who undergo allogeneic HSCT since graft versus host disease (GVHD), infections, regimen related organ and tissue toxicities are among the most important causes of post-transplant mortality. Despite the regimen related toxicity profile of busulfan, supported by information from the results of clinical trials and real-world data, it is still commonly used worldwide. Treosulfan has advantages in terms of dose of administration, lower incidence of sinusoidal obstruction syndrome and lower neurotoxicity. We aimed to retrospectively investigate outcomes and compare results of patients who underwent matched and haploidentical allogeneic HSCT with treosulfan based or busulfan based reduced intensity conditioning, non-myeloablative conditioning and myeloablative conditioning regimens in our institution.
Methods
From September 2016 to November 2022, treosulfan was administered to 94 patients while 85 patients received busulfan. We analyzed outcomes as regimen related-toxicity, chronic and acute GVHD, overall survival, non-relapse mortality, relapse related mortality and fungal infection. The myeloablative dose of busulfan was 12.8 mg/kg while it was 9.6 mg/kg for the non myeloablative regimen which was combined with fludarabine. The myeloablative dose of treosulfan was 42 mg/m2 while a dose range of 30-36 mg/m2 was administered for the reduced intensity conditioning.
Results
The median follow up was 14 months for the treosulfan group while it was 11 months for the busulfan group (p = 0.16). Regimen related toxicity, which was monitored during the hospital stay and 3 months after discharge were 11.7% and 7.1% for treosulfan and busulfan respectively and were similar between two groups. Extensive chronic GVHD was encountered in 15.7% of the patients in the treosulfan group compared to 32.1% in the busulfan group (p &lt; 0.001). Similarly, chronic skin GVHD was observed in 3.6% of the patients who received treosulfan while it was seen in 22.6% of the busulfan group (p &lt; 0.001). Acute GVHD (grade 3 or higher) was encountered in 32.2% of the patients within the treosulfan group while it was encountered in 31.6% of the patients in the busulfan group. Overall survival was 47.5% and 36.5 % in the treosulfan group and busulfan groups respectively. The relapse-related mortality was 17 % in the treosulfan group while it was 34% in the busulfan group. Fungal infection was observed in 23.4% and 36.5% of the patients in treosulfan and busulfan groups respectively.
Conclusion
Treosulfan, with a lower chronic GVHD incidence and similar regimen related toxicity profile appears to be a safe alternative to busulfan and prospective randomized controlled trials are needed to confirm the results in our study.
Keywords: Busulfan; treosulfan; conditioning regimen; stem cell transplantation
Palmitoleic Acid Extracted from Fish Oil Inhibit aGVHD By Immune Regulation
Authors: Xu Jingjing , Zhu Haojie , Chen Dabing , Kong Hui , Chen Shaozhen , Ye Chenjing , Hu Jianda , Yang Ting 
Published: December 2023

Objective: This study aims to explore the immunosuppressive effect of palmitoleic acid (POA), derived from fish oil extract, on lymphocytes in vitro and its potential impact on the clinical outcome and survival prognosis of rodents with acute graft-versus-host disease (aGVHD).
Methods: In vitro experiments involved using CCK8 to determine the influence of various concentrations of POA on the growth and proliferation of lymphocytes. Flow cytometry was employed to assess POA's inhibitory effect on T lymphocyte activation triggered by fluorobol ester (PMA) and ionomycin (IM). For evaluating the therapeutic effect of POA on aGVHD, C57bl/c mice were used as donors and BALB/C mice as recipients. The aGVHD mouse model was established to observe the impact of POA on aGVHD treatment, survival, and prognosis.
Results: In vitro experiments demonstrated that POA concentrations ranging from 250uM to 500uM inhibited the proliferation of PMA and IM-activated T lymphocytes and reduced the proportion of CD4+CD25+ cells without causing significant cytotoxicity. The aGVHD mouse model exhibited clinical symptoms like bristling, depilation, anal redness and swelling, and loose stools, along with characteristic pathological changes in the liver and small intestine. Treatment with POA significantly extended the survival period and reduced the clinical score of aGVHD in the model mice.
Conclusion: Palmitoleic acid derived from fish oil shows promise as a potential treatment for acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation, warranting further research on its immunosuppressive properties.
Keywords: Fish oil extract, palmitoleic acid, acute graft-versus-host disease, allogeneic hematopoietic stem cell transplantation, immunosuppression.
Malaria in Children with Sickle Cell Anaemia in Areas with Low, Moderate and High Transmission in Uganda
Authors: Namazzi Ruth , Idro Richard , Kalibala Dennis , Ssenkusu John , Akun Pamela , Mboizi Vincent , Gondwe Thandile Nkosi , Munube Deogratias , Kasirye Philip , Nabaggala Catherine , John Chandy C. , Green Nancy S. , Robberstat Bjarne , Hensbroek Boele van , Kuile Feiko ter , Phiri Kamija S. , Opoka Robert 
Published: December 2023

Background. Few large prospective studies have evaluated burden and outcomes of malaria in children with sickle cell anaemia (SCA) in malaria endemic countries. We evaluated the incidence, complications and outcome of malaria in three cohorts of Ugandan children with SCA in three areas with differing malaria transmission.
Methods. Cohort 1 were SCA aged 3-9 years, enrolled in the hydroxyurea therapy for neurological and cognitive protection in Uganda (BRAINSAFE II) trial at Mulago Hospital, a low transmission area, while cohort 2 and 3 aged 6 months to 15 years, were enrolled in the dihydroartemisinin-piperaquine (DP) or sulphadoxine-pyrimethamine (SP) for the chemoprevention of malaria in SCA (CHEMCHA) trial at Jinja Hospital (moderate transmission) and Kitgum Hospital (high transmission). In cohort 1, all received SP for malaria chemoprophylaxis and hydroxyurea at 20-30mg/kg/day, while cohorts 2 and 3, received either DP or SP for malaria chemoprevention, and a proportion (10%) received hydroxyurea in the study.
Results. A total of 706 participants were enrolled: 267, 249 and 190 at Mulago, Jinja and Kitgum respectively. The mean age was 6.5 (SD 3.4) years; 5.1 (1.7), 7.9 (4.3) and 6.8 (3.5) years for Mulago, Jinja, and Kitgum respectively. Incidence of malaria was 13 (95% CI 6, 20) per 100 child years in low, 38 (95% CI 26, 51) in moderate and 104 (95% CI 64, 144) in the high transmission area, p&lt;0.001. Adjusting for hydroxyurea treatment, incidence of malaria was 33 (95%CI 14, 52) per 100 child year on hydroxyurea and 51 (95%CI 40, 62) per 100 child years without hydroxyurea, p=0.001. The most common SCA-related complications were anaemia (39.6%, 133/336), and pain (27.7%, 93/336) among children with malaria. Over a period of 1042.8 person years, there were 115 admissions for malaria, with an overall incidence of 11 per 100 child year (95% CI 9, 13), and this differed across sites, p&lt;0.001. Overall, 1.5% (11/706) children died, and 18.2% (2/11) deaths were directly related to malaria infection.
Conclusion. Malaria incidence remains high among Ugandan children with SCA, and differs by transmission patterns. Prevention strategies should be strengthened, especially in high transmission areas.
Neurocognitive Performance Changes with Chimeric Antigen Receptor T-Cell Therapy in Patients with Hematologic Malignancies
Authors: Giri Smith , Giri Smith , Ubersax Clare , Tucker Abigail , Bal Susan , Godby Kelly , Costa Luciano , Bhatia Smita , Williams Grant , Ravi Gayathri , Narkhede Mayur , Murdaugh Donna 
Published: December 2023

Introduction:
Chimeric antigen receptor (CAR) T cell therapy is a transformative therapy that has revolutionized the care of patients with hematologic malignancies. However, CAR-T cell therapy is associated with several short-term toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The impact of CAR-T cell therapy on neurocognitive outcomes is unknown. Here, we report on our prospective study examining the changes in neurocognitive performance before and after CAR T cell therapy.
Methods:
This single-center prospective cohort study recruited consecutive recipients of CAR-T cell therapy enrolled in a prospective study NCT05556928 and a phase II clinical trial NCT04975555. Patients underwent neurocognitive assessment using the NIH Toolbox Cognition Battery (NIHTB-CB). Baseline assessment was done within 3 weeks before receiving CAR-T cell therapy. Follow up assessment was conducted at 90 days of receiving CAR T therapy. Domain specific T-scores adjusted for age, sex, race/ethnicity, and education were calculated. Change in T-scores between pre and post assessments were evaluated, with significant cognitive change defined as +/- 0.5 standard deviations from the mean.
Results:
Twenty-six eligible patients were identified, of which 9 completed both pre and post assessments. The median age was 66 years (range 45-79) at the time of CAR T cell therapy with 76.9% males and 38.5% being Non-Hispanic Black. Cancer types included diffuse large B-cell lymphoma (46.2%), multiple myeloma (38.5%), and follicular lymphoma (11.5%). Our baseline cognitive assessment showed that our eligible patient cohort had a median total composite T-score of 42 (range 30-64); twelve (46%) patients were one or more standard deviations below the mean. Of the 9 patients that completed a follow up assessment, a decline in one or more cognitive domains was seen in 89% of patients. Largest declines were seen in the cognitive domain of processing speed (66.7%, Figure 1).
Conclusion:
CAR T cell therapy recipients experienced a short-term cognitive decline in multiple domains. These findings can be used to educate future patients on potential toxicities of CAR T-cell therapy. We continue to enroll participants into our study and updated data will be presented at the meeting.