bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive and Psychological Recovery from the Immune Effector Cell Associated Neurotoxicity Syndrome Following Chimeric Antigen Receptor T-Cell (CAR-T) Therapy
Authors: Kuznetsova Valeriya , Oza Harsh , Rosenfeld Hannah , Sales Carmela , van der Linde Sam , Roos Izanne , Roberts Stefanie , D'Aprano Fiore , Loi Samantha M. , Dowling Mark R , Dickinson Michael J. , Kalincik Tomas , Harrison Simon J , Malpas Charles B. , Anderson Mary Ann
Published: December 2024

Introduction:

Chimeric antigen receptor T-cell therapy has become standard of care treatment for several types of haematological malignancies. Immune effector cell associated neurotoxicity syndrome (ICANS) is a serious side-effect, with diverse neurocognitive symptom presentation. ICANS is typically considered an acute condition, however, the recovery trajectory has not been well-defined. The study aimed to investigate cognitive and psychological recovery from ICANS in adult haematology patients over 1 year after CAR-T therapy.

Methods:

Twenty patients completed a comprehensive cognitive assessment and a self-report measure of psychopathology and cognitive concerns before receiving commercial CAR-T for treatment of lymphoma (95%) or leukaemia (5%). The assessment was repeated 1-month, 6-months, and 1-year post-CAR-T. Seven (35%) patients experienced ICANS acutely. Bayesian repeated measures analysis of covariance examined the effect of interaction between ICANS group and time of the assessment on change in cognition and psychopathology. Models were adjusted for age, education, and sex.

Results:

ICANS patients declined in executive function post-CAR-T, while non-ICANS patients remained stable (BF10=524.0). The ICANS group had lower mean scores at the 1-month review (BF10=9.5, η2=0.4). No group difference was detected at 6-months or 1-year. Three (43%) ICANS patients had a clinically evident executive function impairment at 1-month, returning to baseline at 6-months and remaining normal at 1-year. In the non-ICANS group, all patients had normal executive function across all assessments. There was no evidence for an effect of ICANS group over time in any other cognitive domain. Analyses of individual psychometric measures, revealed evidence for an effect of ICANS group over time for tests of strategic lexical retrieval (BF10=8.1), verbal memory (BF10=67.3), and auditory attention span (BF10=9.2). The lowest mean scores were observed at 1-month in the ICANS group. There was no change in patient-reported cognitive concerns or symptoms of psychopathology over time, irrespective of ICANS group.

Conclusions:

ICANS patients had a reduction in executive function, verbal memory, and the auditory attention span 1-month post-CAR-T. There was no effect of ICANS on cognitive change at 6-months or 1-year, suggesting complete resolution of cognitive manifestation of ICANS. Stable self-reported symptoms of psychopathology indicate good psychological tolerance of neurological toxicity. Our findings provide a positive outlook for long-term cognitive recovery following CAR-T therapy. Cognitive monitoring, however, is indicated for ICANS patients for up to 6-months post-infusion.
Incidence of ITP before and after COVID-19: A Nationwide Inpatient Sample Study
Authors: Obeidat Khaldun , Turk Ekrem , Olafimihan Ayobami , Zia Maryam
Published: December 2024

Background/Purpose:

Since the onset of the coronavirus disease-2019 (COVID-19) pandemic in December 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been postulated as a potential trigger for numerous autoimmune disorders. Specifically, immune thrombocytopenia (ITP) has been reported following SARS-CoV-2 infection and vaccination. In this study, our objective was to compare the incidence of ITP in the pre- and post-COVID eras.

Methods:

The Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS) database were queried to identify admissions for ITP in 2018 and 2020, using ICD-10 codes for a primary diagnosis of ITP. The primary outcomes analyzed included mortality, length of stay (LOS), and total hospital charges (THC). Secondary outcomes encompassed acute kidney injury (AKI), intensive care unit (ICU) admission, and the need for blood transfusion. Statistical analyses were performed using t-tests, univariate and multivariate logistic regression analysis in Stata.

Results:

A total of 22,840 ITP patients were admitted in our study group, comprising 12,160 in 2018 and 10,680 in 2020 (53.2% and 46.7%, respectively). No significant differences were observed in patient sex (43% males and 56.8% females, P = 0.74), mean age (56.4 in 2018 and 55.8 in 2020), or race, except for a higher incidence among Native Americans in 2020 (0.2% vs. 0.6%, P = 0.004). There were no significant differences in medium household income, insurance, bed size, location/teaching status, and the region of the hospital.

In primary outcomes, total deaths in the main group numbered 264 (1.16%), with non-significantly higher mortality in 2020 (1.36% vs. 0.99%, OR 1.37, P = 0.24). Females had significantly lower odds of mortality (OR 0.46, P = 0.007, CI 0.26-0.80). Regarding secondary outcomes, there was no significant difference in the length of hospital stay. The incidence of AKI was non-significantly higher in 2020 (9.6% vs. 7.9%, P = 0.054) with a high need for ICU admission (1.1% vs. 0.7%, OR = 1.6, P = 0.14) and no significant need for blood transfusion.

Conclusion:

Despite multiple reported cases of ITP triggered by the virus and vaccines during the COVID-19 pandemic, our study did not reveal a significant increase in ITP cases in 2020 compared to 2018. Further studies are warranted to confirm the causality between COVID-19 and ITP, including analyses of incidence in years after 2020, considering the initiation of vaccinations at the end of that year.
Feasibility of Longitudinal Circulating Tumor DNA (ctDNA) Assessment in Patients with Peripheral and Cutaneous T-Cell Lymphomas
Authors: William Basem M. , Efebera Yvonne A.
Published: December 2024

T-cell lymphomas are a heterogeneous group of mature T-cell neoplasms. Outcomes of majority of peripheral T-cell lymphoma (PTCL) and advanced stage cutaneous T-cell lymphomas (CTCL) are poor. The value of ctDNA as a prognostic marker of chemosensitivity and disease-free survival has been validated in aggressive B-cell lymphomas but remain unclear in PTCL/CTCL and can be a useful tool for disease risk stratification and monitoring of treatment.

We performed a retrospective review of PTCL and CTCL patients treated at our center between April 2022 and June 2024; plasma samples were analyzed using a tumor-informed ctDNA assay as part of clinical care during diagnosis, treatment, and surveillance. Whole exome sequencing was performed on tumor tissue and matched normal blood samples to identify up to 16 patient- and tumor-specific, somatic single nucleotide variants using a clinically validated, tumor-informed mPCR NGS assay (SignateraTM). These variants were monitored in patients' subsequent plasma samples.

A total of 75 plasma samples were analyzed from 10 patients with PTCL/CTCL; lymphoblastic lymphoma (n=2), enteropathy associated T-cell lymphoma (n=2), ALK+ anaplastic large T-cell lymphoma (n=1), PTCL-NOS (n=1), angioimmunoblastic T-cell lymphoma (n=1), hepatosplenic T-cell lymphoma (n=1), and CTCL (n=2). After a median duration of follow-up of 6 (2-24) months, 7 (70%) patients remained alive. In patients with PTCL (n-8), persistence of ctDNA was strongly associated with disease progression and death (relative risk=6; 95% CI=1-35; p=0.04). In 5 patients with PTCL, ctDNA negativity showed 100% concordance with negative PET-CT results.

Our results, albeit with small numbers, suggest that ctDNA is strongly associated with clinical outcomes in patients with PTCL; ctDNA may serve as a useful tool to monitor and prognosticate patients with PTCL when validated in a large cohort of patients.
Small Molecule Inhibitor Screen to Identify Mechanisms Controlling Selective Clearance of Hemoglobin By Liver Sinusoidal Endothelial Cells
Authors: Sivanantham Ayyanar , Pradhan-Sundd Tirthadipa
Published: December 2024

Hemolysis and accumulation of cell free hemoglobin (Hb) is a major pathophysiological complication associated with hemolytic disorders such as sickle cell disease (SCD). In the absence of a functional spleen, the hepatic Kupffer cells play a large role in Hb clearance. We recently demonstrated that along with Kupffer cells, liver sinusoidal endothelial cells (LSECs) are also capable of Hb clearance. Based on this finding, we hypothesized that LSECs promote HbS clearance via endocytic trafficking. To evaluate the mechanism of HbS internalization, we performed an in vitro screen in primary LSECs using small molecule inhibitors or drugs of endocytic pathway blockers. Our in vitro screen results demonstrated that LSEC induced HbS clearance occurs through multiple endocytic routes simultaneously. Whereas micropinocytosis or fluid phase endocytosis is the predominant method of HbS clearance, blocking clathrin mediated endocytosis, receptor recycling, lipid vesicle formation as well as low pH can significantly impede HbS clearance by LSECs. Our screen also identified mannose receptor CD206 as a potent inhibitor of HbS clearance. We further demonstrated that blocking CD206 in vivo in SCD mice caused significant amelioration of hepatic Hb-heme-iron accumulation as well as hemolysis induced liver damage. Remarkably, this effect was also accompanied by a strong increase in Hb scavenger receptor CD163 in vivo in hepatic Kupffer cells. In conclusion, we identified various alternate methods of LSEC mediated HbS internalization that might provide useful therapeutic implications to combat hemolysis related liver damage in SCD and other hemolytic disorders. These findings also implicate a novel role of mannose receptor CD206 in mediating hepatic Hb clearance.
Disulfide Bond Heterogeneity in Factor VIII: Implications for Protein Function and Haemophilia a Therapy
Authors: Pijning Aster E. , Butera Diego , Flórido Manuela , Coxon Carmen , Metcalfe Clive , Hogg Philip
Published: December 2024

Haemophilia A is a chronic, life-threatening condition caused by the deficiency or dysfunction of plasma coagulation factor VIII (FVIII). Prophylactic treatments include regular intravenous infusion of exogenously derived FVIII concentrates or FVIII gene therapy. However, both of these therapies are limited by the inherent cytotoxicity of the FVIII protein and the generation of FVIII neutralizing antibodies (inhibitors). Protein engineering approaches have aimed to reduce FVIII cytotoxicity and immunogenicity to improve the durability of replacement and gene therapy. FVIII contains eight disulphide bonds that are covalent links between pairs of cysteine residues. Using differential cysteine alkylation and mass spectrometry, we observed that all eight disulfide bonds exist in unformed states in different proportions of plasma FVIII molecules, as has been observed in other blood proteins including fibrinogen, von Willebrand factor, and platelet αIIbβ3 integrin. The FVIII bonds were unformed in 1 in 10 (C172-C198 in the A1 domain) to 1 in 2 (C1918-C1922 in the A3 domain) molecules of the FVIII populations. The different disulfide-bonded states of FVIII were predetermined and not a result of post-secretion redox events, as recombinant FVIII exhibited the same disulfide status as the plasma protein. Using targeted cysteine mutations, we found that three disulfide bonds were dispensable for sustained FVIII expression and activity, and that a FVIII with an unformed bond in the A3 domain (C1918-1922) had increased plasma stability. Additionally, von Willebrand Factor (VWF) and a panel of 4 patient-derived FVIII-neutralizing antibodies showed binding selectivity to subsets of FVIII disulfide-bonded states. These findings indicate that FVIII is constitutively produced as multiple partially disulfide-bonded states that have different properties and may aid the engineering of a FVIII with improved therapeutic properties.
Predictive Value of Free Light Chain Burden in Patients Newly Diagnosed with AL Amyloidosis Treated with Cybord or Daracybord
Authors: Saunders Brendan , Theodorakakou Foteini , Evans Benjamin , Boullt Samuel , Fotiou Despina , Dimopoulos Meletios , Kastritis Efstathios , Bianchi Giada
Published: December 2024

Background: A difference between involved and non-involved free light chain (dFLC) exceeding 180 mg/L is part of the 2012 Mayo staging system. However, none of the 758 patients evaluated to develop this staging system received a bortezomib-containing regimen. We hypothesized that depth of response and overall survival in AL amyloidosis patients are independent of free light chain burden in the era of CyBorD and DaraCyBorD.

Methods: This is a retrospective, multicentre study including 223 newly diagnosed AL amyloidosis patients seen at our institutions between 2012 and 2024. In patient cohorts receiving CyBorD or DaraCyBorD therapy, we investigated 1) the relationship between baseline iFLC and dFLC at completion of cycle 1 (day 28) and 3, 6, 9 and 12 months ; 2) the overall survival of patients with baseline low (<180mg/L), medium (180-400 mg/L) and high (>400 mg/L) dFLC ; and 3) the validity of the 2004 and 2012 Mayo staging guidelines. The study was IRB approved.

Results: We identified 132 patients treated with CyBorD and 91 treated with DaraCyBorD. Forty patients in the CyBorD cohort and 3 in the DaraCyBorD cohort did not respond to therapy. Lack of response was independent of baseline iFLC. Following completion of cycle 1, we identified no correlation (r2=0.02) between baseline iFLC and dFLC response in the DaraCyBorD group and a moderate correlation (r2=0.53) in the CyBorD group. Similar trends were noted at 3, 6, 9 and 12 months from therapy start. Kaplan-Meier survival curves based on baseline iFLC were overlapping with a median follow up of 12.5 months. Mayo 2012 staging did not impact OS.

Conclusion: Overall survival, depth and rapidity of response appear to be independent from baseline iFLC in patients treated with bortezomib containing regimens. Our data questions the prognostic impact of free light chain burden in the era of CyBorD and DaraCyBorD.
iPSC-Derived CAR Neutrophils Possess Potent Activity Against Solid Tumors In Vivo
Authors: Majumder Aditi , Kabir MD Ehsanul , Jung Ho Sun , Jun Yuju , Zhang Jue , Huttenlocher Anna , Capitini Christian , Thomson James , Slukvin Igor
Published: December 2024

While chimeric antigen receptor (CAR)-T cells demonstrate high efficacy in eliminating liquid cancers (lymphoma, leukemia, multiple myeloma), and promise exists for CAR NK cells for lymphoma, many challenges remain in applying CAR lymphoid therapies for solid tumors including ineffective trafficking to the tumor microenvironment. Neutrophils provide a logical alternative to cellular immunotherapy since they can migrate to, and into, solid tumors better than any other cell type. However, neutrophils can have pro- or anti-tumor properties. Thus, enforcing anti-tumor properties through genetic engineering would be essential before successfully translating adoptive neutrophil immunotherapies into the clinic. Here, we established induced pluripotent stem cell (iPSC) technologies to generate anti-GD2 CAR neutrophils (iNeuts) using ETV2 modified mRNA and tested their anti-tumor potential. The disialganglioside (GD2) antigen is highly expressed in a variety of pediatric and adult tumors, including melanoma, and neuroblastoma, while its expression in normal post-natal tissues is low and limited to peripheral nerve pain fibers. The 3rd generation anti-GD2 CAR (14g2A-CD28-OX40-CD3z) construct was integrated into AAVS1 locus using CRISPR/Cas9. iNeuts generated from CAR iPSCs displayed typical neutrophil morphology and phenotype similar to unmodified wild-type (WT) WT-iNeuts, and retained CAR expression. Measurement of cytokine production by iNeuts in cultures without or with melanoma revealed that CAR-iNeuts produce higher levels of IFNg, TNFa, IL13, IL4, and IL10 after stimulation with tumor as compared with WT-iNeuts, while no differences were observed in IL12 and IL6 levels. GD2 CAR-iNeuts displayed cytotoxic activity against GD2-expressing neuroblastoma and melanoma in vitro,while cytotoxicity of GD2-negative cancers was minimal. Serial infusions of GD2 CAR-iNeuts exhibited strong antitumor activity against subcutaneous and metastatic melanoma in vivoleading to marked reduction in tumor burden and increased survival. Administration of iNeuts was safe and didn't produce toxicity as determined by clinical evaluation or histopathologic analysis. Overall, our data support the feasibility of clinical translation of GD2 CAR-iNeuts for solid tumors including melanoma.
Selinexor Synergizes with Decitabine in Mantle Cell Lymphoma through MAPK Signaling Pathway
Authors: Chen Yingtong , Yang Ping , Zhang Weilong , Wang Jing , Gao Shuang , Yang Yuan , Liu Shuozi , Li Chunyuan , Jing Hongmei
Published: December 2024

Background: Mantle cell lymphoma (MCL) is an incurable malignance, and MCL patients usually have high recurrence rate and poor prognosis. Additional therapeutic targets need to be discovered to improve the clinical outcome of MCL patients. This study aimed to explore the combined therapeutic effect of selinexor and decitabine in MCL.

Method s : MCL cells (Jeko, Mino, Rec1, and Z138) were treated with selinexor, decitabine, or in combination, and then cell proliferation, cell apoptosis, cell cycle were determined by CCK-8 and flow cytometry. RNA-seq was performed to elucidate the potential mechanism of the synergistic effect of selinexor and decitabine.

Result s : Monotherapy with either selinexor or decitabine could inhibit cell proliferation, promote cell apoptosis, and induce cell cycle arrest in MCL cells. The combined treatment of selinexor and decitabine achieved greater inhibitory effect of cell proliferation and significantly increased cell apoptosis rate compared to their single treatment. RNA-seq confirmed that the synergistic effect of selinexor and decitabine could activate the MAPK signaling pathway.

Conclusion s : The synergistic anti-tumor therapy of selinexor and decitabine is expected to be a powerful strategy for MCL treatment, which provides a new perspective for MCL patients.
Safety and Efficacy of Luspatercept for the Treatment of Refractory Anemia in Patients with Myelofibrosis
Authors: Wen Ziyu , Zhou Xuan , Lin Bingyu , Liu Xiaoli , Wang Qiang , Xu Na
Published: December 2024

BackgroundMyelofbrosis (MF) is a chronic and progressive myeloproliferative neoplasm accompanied by symptoms including, splenomegaly, fatigue, night sweats, fever, pruritis and anemia, and the treatment of myelofbrosis-associated anemia remains suboptimal, with no improved therapies.

Method We retrospectively collected MF with refractory anemia with luspatercept.

Result32 patients with MF treated with luspatercept were enrolled. Median age was 59 years (range, 48-83 years), and 62.5% were males. 28 (87.5%) of patients with hemoglobin below 60g/L. All patients previously were treated with a PTD regimen (prednisone, danazol, thalidomide). 20 (62.5%) were classified as intermediate-1 risk, and 12 (37.5%) as intermediate-2 risk based on Dynamic International Prognostic Scoring System (DIPSS). The median follow-up was 7.5 (3-16) months. 28 (87.5%) patients received luspatercept 50mg every three weeks, of these, 2 patients increased the dose due to poor response; and another 4 patients received luspatercept 25mg every three weeks. Erythroid response occurred in 18 patients (56.3%) at week 12, another 6 patients (18.8%) at week 24, and 25 (78.1%) at the end of follow-up. Patients had a significantly higher hemoglobin level at 12 weeks, 24 weeks, and at the end of follow-up, than at baseline (P=0.002, P=0.005, and P=0.01, respectively). Treatment-related adverse events occurred in 5 (15.6%) patients, with no serious adverse events. 3 (9.4%) patients treatment failure, and 4 (12.5%) patients relapse at week 21 and 24. No patient progressed to acute myeloid leukemia. No patients died by the end of follow-up.

Conclusion In patients with myelofibrosis, luspatercept improved anemia with a low relapse rate and good tolerance.

Keyword Luspatercept; refractory anemia; myelofbrosis
Evaluating the Effectiveness and Tolerability of Chimeric Antigen Receptor (CAR) T Cells Therapy in Patient with Systemic Lupus Erythematosus: A Systematic Review
Authors: Devi Amirta , Kumar Arun , Sah Ranjit , Shah Sangam , Paudel Amita , Sah Sanjit , Shah Ghulam , Solangi Ahda , Mirza Usama , Solangi Zeeshan
Published: December 2024

Background

Systemic Lupus Erythematosus (SLE) is a complex auto-immune disorder characterized by immune dysregulation leading to formation of autoantibodies and multiple organ dysfunction. Monoclonal antibodies targeting CD19 and CD20 on the B lymphocytes have demonstrated benefit, however, relapse is common. Chimeric antigen receptor (CAR) T cells targeting CD19 on B lymphocytes have shown to eliminate B lymphocytes both from the circulation and lymphoid organs leading to durable responses and have been approved for treatment for different forms of cancer including acute lymphoblastic leukemia, multiple myeloma and non-Hodgkin lymphoma. More recently, clinical trials are evaluating the effectiveness of CAR T-cell therapy in patients with SLE refractory to current lupus therapeutics.

Method

We did electronic search of the literature using Central Line (PubMed), EMBASE, and google scholar databases until July 2024. We searched for case-series, observational studies and randomized clinical trials to investigate the effectiveness of CAR-T therapy in SLE. PRISMA guideline was followed to conduct the study. Studies were filtered based on title and abstract, followed by the full text. Data extraction was done in Microsoft Excel.

Results

We evaluated a total of 3 studies which included a total number of 25 patients who received CART- Therapy for refractory SLE. All the included studies were case series. SLEDAI-2K score ranged from 1.5 to 0 and DORIS remission was achieved in all patients. C3 level was normalized, and dsDNA level were below cutoff for all the patients reflecting good treatment response. Most of the patients tolerated the treatment well and only mild cytokine release syndrome was reported. Immune-Effector Cell Associated Neurotoxicity Syndrome (IECANS) and infections rate were negligible.

Conclusion

Anti-CD19 CAR-T therapy has shown promising result in a small population to prevent relapses in patients with SLE by eliminating CD19 positive B lymphocytes and is relatively well tolerated with mild adverse effects. Future large studies including controlled clinical trials are expected to further evaluate safety and tolerability of CAR-T therapy in autoimmune conditions including SLE.
Inpatient Outcomes of Laparoscopic Cholecystectomy in Patients with Sickle Cell Disease
Authors: Dave Prashil , Uddin Anwar , Uddin Rahat , Ahad Afgal , Shastri Dipsa , Mahmoud Yasmin , Winer Andrew
Published: December 2024

Introduction: Cholelithiasis is a common complication in patients with sickle cell disease (SCD), making cholecystectomy one of the most common surgical procedures in this population. Up to 85% of SCD patients develop gallstones by their third decade, and chronic hemolysis caused by the disease can lead to gallstones that block the bile duct. This study aimed to evaluate the outcomes of laparoscopic cholecystectomy in hospitalized patients with SCD using data extracted from a nationwide database.

Methods: The Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS) was used to identify adult patients with SCD during 2016 - 2020 using ICD-10-CM codes (D57). ICD-10-PCS codes were used to identify patients who had laparoscopic cholecystectomy procedures. The main outcomes were in-hospital mortality, length of stay (LOS), and hospital costs, and secondary outcomes included acute pancreatitis, chronic pancreatitis, renal cancer, leukemia, lymphoma, Epstein-Barr virus (EBV), gastrointestinal (GI) bleeding, and pancreatic cancer. The association between laparoscopic cholecystectomy and outcomes was evaluated using survey-based multivariate logistic regression models for in-hospital mortality and secondary outcomes, Poisson regression for LOS, and a generalized linear model with gamma distribution and log link for hospitalization cost. Models were adjusted for age, sex, race and ethnicity, primary payer, Charlson comorbidity index, hospital bed size, hospital region, and hospital teaching status.

Results: A total of 899,610 SCD hospitalizations between 2016 and 2020 in the United States were identified, and 4,925 (0.55%) of them had laparoscopic cholecystectomy procedures. Out of 4925, 3620 (74%) patients were >18 years of age, and 3185 (65%) were female. Medicaid was the most common insurance source amongst those who had laparoscopic cholecystectomy (2410, 49%). Inpatient mortality and length of stay were not significantly different in SCD patients with laparoscopic cholecystectomy compared to those without laparoscopic cholecystectomy (inpatient mortality: 0.6% vs 0.6%, adjusted OR: 1.22, 95%CI: 0.55 - 2.72, p = 0.3; length of stay: 4.9 vs 5.1 days, p<0.001). SCD patients with laparoscopic cholecystectomy had an increased cost of hospitalization ($18,673 ± 475 vs $11,789 ± 106, p=0.004). SCD patients with laparoscopic cholecystectomy had increased odds of having acute pancreatitis (13% vs 0.5%, p < 0.001).

Conclusion: This analysis found that inpatient laparoscopic cholecystectomy is infrequent among SCD patients. However, they are associated with higher hospitalization costs and acute pancreatitis diagnoses. Further studies are needed to optimize surgical care in patients with SCD, mainly regarding cost implications, acute complications, and outcomes.
Risk of Depression and Anxiety Post Allogeneic Hematopoietic Stem Cell Transplant in Pediatric Patients with Cancer in a Low-Middle-Income Country (LMIC)
Authors: Boshra Sally , Hafez Hanafy , Hammad Mahmoud , Lehmann Leslie E. , Mohamed Taghreed , Hamdy Nayera , Mosa Ahmed , Elhaddad Alaa
Published: December 2024

BACKGROUND: Allogeneic Hematopoietic SCT (HSCT) is a potentially curative treatment option in patients with various hematological and lymphatic malignancies. Survival after HSCT has improved over the years but despite the possibility of cure for an otherwise terminal illness, allogeneic HSCT can be accompanied by high levels of morbidity, mortality, and immense psychosocial distress. This is reflected in the significantly increased risk of psychiatric conditions previously described; for example, depression and anxiety following HSCT are reported in 5% to over 40% of patients. However, pediatric patients are not routinely assessed for these complications and the incidence in children is not well understood.

METHODS: Prospective descriptive study assessing pediatric patients undergoing allogeneic HSCT at The Children's Cancer Hospital Egypt for hematologic malignancy from January 2018 to December 2021 and alive at the time of data collection. The primary objective was to assess the prevalence and severity of anxiety and depression post allogeneic HSCT. The secondary objective was to determine potential risk factors related to anxiety and depression.

Anxiety was assessed with the Spence Children's Anxiety Scale and Beck Anxiety Inventory, while Depression was assessed with the Child Depression Inventory and Beck's Depression Inventory. Anxiety and depression were categorized into 2 categories: Non-significant with scores in the normal to mild range and not requiring medical intervention or psychotherapy and Significant with scores in the moderate to severe range and needing medical intervention and /or psychotherapy.

RESULTS: A total of 100 patients were included. The prevalence of Significant anxiety was 35% and significant depression 60%. 27% of patients had both significant anxiety and depression. Among the whole cohort, age (as a continuous variable) was the only significant predictor of anxiety, with increasing likelihood of anxiety as age decreased.

The association with gender, stem cell source, presence of GVHD and time from transplant to test were evaluated and the primary diagnosis was the only significant predictor of depression identified with AML patients having a higher risk, likely due to intensive treatment pre-transplant therapy and long admission periods.

CONCLUSION: The high prevalence of anxiety and depression post allogeneic HSCT in pediatric patients transplanted for hematologic malignancy highlights the need for routine psychological assessment as an essential component of long-term follow-up, particularly in those treated at a younger age and those with a diagnosis of AML.

KEYWORDS: Anxiety, Depression, Allogeneic Hematopoietic SCT, LMICs
Single-Cell Multi-Omics Reveals Immune Characteristics of T Cells in Patients with Relapsed/Refractory Leukemia after Haplo+Cord HSCT
Authors: Li Nainong , Li Hua , Zhang Zheyang , Zhu Ming , Li Xiaofan , Chen Ping , Chen Fei , Chen Xianling , Yang Yiding , Yuan Xiaohong , Tang Ronghan , Zhu Zhijuan , Lin Hongli , Lin Ting , Tong Mengsha , Chen Tao , Zhong Chen , Huang Jialiang
Published: December 2024

Single-cell multi-omics reveals immune characteristics of T cells in patients with relapsed/refractory leukemia after haplo+cord HSCT

Background:

The treatment of relapsed/refractory leukaemia (R/R) is a significant challenge in medical oncology. Allogeneic haematopoietic stem cell transplantation has been demonstrated as the only cure method ; however, long-term survival rates for patients with R/R leukaemia remain low. Our current study's findings indicate that sequential transplantation of haploidentical stem cell and umbilical cord blood (haplo+cord HSCT) may result in enhanced survival outcomes for patients with R/R leukemia. Nevertheless, the underlying mechanisms remain largely unexplored.

Methods:

A comparative analysis of single-cell gene expression and chromatin accessibility was conducted in bone marrow samples from 16 patients who had undergone haplo+cord or single cord HSCT. Furthermore, flow cytometry was conducted to substantiate our findings.

Results:

Distinct compositions and functions of global immune landscapes were observed, with haplo+cord HSCT exhibiting effective anti-tumour and anti-viral immunity, mediated by type I interferon signalling. The analysis of T cells revealed the presence of a group of CD8+ T cells expressing GNLY and CX3CR1, which were observed to be enriched in recipients of haplo+cord HSCT. This finding was subsequently confirmed by flow cytometry. It is noteworthy that gene signature scoring indicates that haplo+cord-enriched CD8+ T cells possess a dual effector and memory property, which may provide long-term protection. Ultimately, an integrated single-cell multi-omics analysis elucidated the regulatory networks governing lineage-specific gene expression following transplantation. To illustrate, the expression of GNLY in CD8+ T cells enriched in haplo+cord transplants was found to be regulated by an enhancer network situated within a CTCF-mediated chromatin loop.

Conclusions: The collective findings of the single-cell multi-omics analyses demonstrate that CX3CR1+GNLY+ CD8+ T cells, which exhibit effector and memory properties, contributed to the enhanced survival of patients with R/R leukaemia who underwent haplo+cord HSCT.
Targeting YTHDC1 Inhibited the Progression of Mantle Cell Lymphoma By Inhibiting the Expression of MYC Gene through m6A Modification
Authors: Zhou Hui , Wang Li , Yang Ruicheng , Lin Guifeng , Zhang Hailin , Niu Ting
Published: December 2024

Objective

YTHDC1 (YT521-B homology domain-containing protein 1) is an in vivo nuclear RNA n⁶ -methyladenosine (m6A) reader with YTH domain. At present, YTHDC1 has been found to play an important role in the pathogenesis of various tumors, such as acute myeloid leukemia. However, there are no relevant studies on YTHDC1 in mantle cell lymphoma (MCL). Therefore, this study was to investigate the role and mechanisms of YTHDC1 gene in MCL.

Methods

The expression of YTHDC1 in MCL patients and normal human cells was compared in GEO database. JEKO1 cells with stable knockdown of YTHDC1 were constructed. MTT method, flow cytometry, western blot were used to investigate the effect of YTHDC1 knockdown on proliferation, apoptosis, cell cycle and proteins of apoptosis and G2M phase of cell cycle. MCL subcutaneous tumor model was used to explore the effect of knocking down YTHDC1 in vivo; HE staining and Ki-67 immunohistochemical staining were performed to value the tumor load. RNA-Seq analysis was performed to explore the possible mechanisms of YTHDC1 genes in MCL. MERIP-qPCR and YTHDC1-RIP-qPCR were used to investigate the mRNA level of the target gene of YTHDC1 modified by m6A in MCL. Additionally, qPCR was used to evaluate the mRNA stability of target genes, based on the principle of actinomycin D blocking mRNA synthesis.

Results

The expression of YTHDC1 in MCL was significantly increased compared to normal people. Knocking down YTHDC1 inhibited the proliferation of MCL cells, and promoted cell apoptosis, and leaded the cell cycle arrest at G2M stage, and decreased the expression of apoptosis-related proteins PARP, CASPASE 3 and G2M related proteins CDC25C and CYCLINB 1, while increased the expression of CLEVEAD CASPASE 3. In addition, the tumor growth was decreased and the tumor load was reduced after YTHDC1 was knocked down. There were 3333 differentially expressed genes in sh-YTHDC1 and control cells, including 2178 down-regulated genes and 1155 upregulated genes. The top down-regulated genes included MYC, etc. Enrichment analysis showed that YTHDC1 down-regulated gene may be located in cell membrane, down-regulated cancer pathway, ECM-receptor interaction, etc. Intersection analysis of RNA-Seq data, YTHDC1- iCLIP data and YTHDC1-miCLIP data revealed 174 differentially expressed genes with m6A modification that bind to YTHDC1 in MCL, including MYC. Furthermore, we demonstrated that YTHDC1 regulated the mRNA level of MYC target gene through m6A modification by regulating the stability of MYC mRNA.

Conclusion

The expression of YTHDC1 gene was higher in MCL patients than that in normal people and played a important role in the progression of MCL. Mechanically, YTHDC1 regulated the mRNA level of MYC target gene through m6A modification by regulating the stability of MYC mRNA.
Comparison of the Efficacy and Adverse Effects of Recipient-Derived Versus Donor-Derived CAR-T Cell Therapy for Post-Transplant Relapse in B-ALL
Authors: Liu Lichao , Huang Ruihao , Hu Yongxian , Tu Sanfang , Wang Na , Yi Hai , Gao Qiuying , Zhou Jian , Wang Xiaoqi , Zhang Cheng , Zhang Xi
Published: December 2024

Background

Chimeric Antigen Receptor T (CAR-T) cells have been demonstrated to be an effective treatment for relapsed acute B-cell lymphoblastic leukemia (B-ALL) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). T cells for CAR-T therapy can be derived from the patient's own peripheral blood (recipient) or from the donor's peripheral blood. Despite having identical genomes, the different maturation environments of these T cells can lead to functional differences. This study aims to compare the clinical outcomes of CAR-T cells derived from these two sources.

Methods

This multicenter, retrospective cohort study collected clinical data from 36 patients who experienced B-ALL relapse after allo-HSCT and received CD19 CAR-T cell therapy between January 2016 and October 2023 across seven centers. The primary endpoint was the complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate at 28 days post-CAR-T cell infusion. Secondary endpoints included the 2-year overall survival (OS) rate, 2-year event-free survival (EFS) rate, incidence of graft-versus-host disease (GVHD), cytokine release syndrome (CRS), and CAR-T cell-related encephalopathy syndrome (CRES).

Results

Retrospective analysis was performed on 36 patients: 12 in the recipient group and 24 in the donor group. The recipient and donor groups showed no significant differences in CR/CRi rates (83.33% vs. 100%, P=0.105), 2-year EFS rates (50.8% vs. 51.6%, P=0.617), and 2-year OS rates (49.5% vs. 63.6%, P=0.215). Additionally, the incidence of GVHD, CRS, and CRES did not significantly differ between the two groups. Further analysis within the donor group revealed 12 matched sibling donors (MSD) and 12 haploidentical donors (HID). The 2-year EFS rate was significantly higher in the HID group compared to the MSD group (75.0% vs. 30.7%, P=0.043), while no significant differences were observed in CR/CRi rates, 2-year OS, and the incidence of GVHD, CRS, and CRES between these subgroups.

Conclusion

Both recipient-derived and donor-derived CD19 CAR-T cell therapies are effective treatment options for B-ALL relapsed post-allo-HSCT. Haploidentical donor-derived CAR-T cells offer a longer EFS and may be considered the optimal choice.
A Phase I/II Study of AZD0305, a Novel Antibody-Drug Conjugate (ADC) Targeting GPRC5D, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Lim Sueh-Li , Augustson Bradley , Mian Hira S , Stadtmauer Edward A. , Iida Shinsuke , Slade Michael , Hazra Saswati , Chamoun Kamal , Cheung Patricia , Saeh Jamal , Shah Nina , Krishnan Amrita Y
Published: December 2024

Background and Significance: GPRC5D (G Protein-coupled Receptor, Class C, Group 5, Member D) is a known therapeutic target for multiple myeloma (MM). The GPRC5D bispecific T-cell-engager talquetamab was conditionally approved recently by the FDA and EMA for the treatment of RRMM in adults with at least 4 prior lines of therapy. However, there is still a need to explore additional approaches to target this protein without reliance on immune fitness. AZD0305 is a first-in-class ADC that binds specifically to GPRC5D. AZD0305 has shown preclinical activity against MM and has the potential to be active in patients with RRMM who have exhausted or cannot tolerate standard of care options. In addition to payload-mediated cytotoxicity, AZD0305 can potentially drive the killing of tumor cells through antibody-dependent cellular cytotoxicity.

Study Design and Methods: NCT06106945 is a modular Phase I/II, open-label, multicenter, dose escalation, and dose expansion/optimization study to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics, and preliminary efficacy of AZD0305 in patients with RRMM. Module 1 includes Phase Ia (Dose escalation) and Phase Ib (Dose expansion/optimization). The total enrollment is estimated to be approximately 84.

Patients with RRMM >18 years of age, treated with at least 3 prior lines of treatment including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody are eligible. Patients must have measurable disease by IMWG criteria and an ECOG performance status of ≤2. Patients with peripheral neuropathy Grade ≥2, known COPD, or previous history of interstitial lung disease, uncontrolled cardiovascular disease and primary refractory MM are excluded. Further, patients who previously received anti-GPRC5D or MMAE-containing treatment are excluded. The primary endpoints of the phase I include occurrence of dose-limiting toxicities (dose escalation only) and incidence and severity of adverse events and serious adverse events. Secondary endpoints include but are not limited to objective response rate, duration of response, progression free survival, pharmacokinetics of AZD0305 and immunogenicity of AZD0305. This study is currently recruiting patients for phase I in North America, Europe, Asia and Australia.
An Investigator Initiated Study of RCHOP in Combination with Selinexor (KPT-330) in Diffuse Large B Cell Lymphoma and Richter Transformation
Authors: Modi Dipenkumar , Yang Jay , Kim Seongho , Azmi Asfar , Tolksdorf Emily , Houde Christiane A. , Zonder Jeffrey A.
Published: December 2024

Background and Significance: Rituximab-containing chemoimmunotherapy remains standard front-line treatment for newly diagnosed diffuse large B cell lymphoma (DLBCL) including Richter transformation (RT). Approximately 70% of patients with DLBCL achieve durable remission with this approach. Patients with RT, however, frequently experience shorter remissions. Therefore, novel strategies are warranted to improve outcomes of these patients. Selinexor is a first in class, slowly reversible, potent and selective inhibitor of nuclear export (SINE) compound that specifically blocks exportin 1 (XPO1) and is approved for relapsed refractory DLBCL after ≥2 prior lines of therapy. We hypothesize that combination of Selinexor and RCHOP may improve outcomes of newly diagnosed DLBCL and RT.

Study Design and Methods: This was a phase I/II investigator-initiated dose escalation/dose-expansion study to evaluate the safety and tolerability of selinexor when combined with RCHOP. Phase I cohort included B-non-Hodgkin lymphoma and the RP2D of selinexor was determined to be 60 mg weekly (Seymour et al, 2021). Currently phase II expansion cohorts are enrolling. Key eligibility criteria for phase II expansion include patients ≥18 years of age with newly diagnosed advanced stage III-IV DLBCL (Group A) or RT (Group B), ECOG PS £1, and FDG avid measurable disease by PET. Patients with RT could receive prior non-anthracycline-based CLL treatment. All patients will receive selinexor orally on days 1, 8, 15 during each 21-day cycle for a total of 6 cycles along with standard dosing of RCHOP. Patients with response (partial or complete remission) at the end of 6 cycles will receive optional maintenance selinexor for 1 year. Maintenance selinexor will be given once a week on days 1, 8, 15, 22 in a 4-week cycle (1 cycle=28 days).

The primary objective of phase II expansion is to estimate 2-year progression-free survival (PFS) for group A, and overall response rate (ORR) for group B. Exploratory objective will evaluate association of baseline XPO-1 expression with response and outcomes after therapy. For group A, we expect to enroll 31 participants with DLBCL in the phase II expansion cohort. This design will provide 80% statistical power and a one-sided 5% type I error to assess a 2-year PFS greater than 55%. For group B, we will enroll 7 participants per the Simon's first stage of the study. If ³ 4 participants have an ORR by 12 weeks, an additional 13 participants will be enrolled for a total of 20. If at least 12 of 20 have an ORR by 12 weeks, it will be concluded that there is sufficient evidence of efficacy, that the ORR is at least 40%. The study is currently enrolling. The clinicalTrials.gov ID is NCT03147885.
Efficacy and Safety of Mesenchymal Stem Cells in Improving Thrombocytopenia after Chemotherapy in Malignant Tumors
Authors: Guo Bingling , Li Jieping , Liu Yao
Published: December 2024

INTRODUCTION

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of cytotoxic chemotherapy and targeted therapies, which always contributes to morbidity and poor overall survival. There are limited therapies to prevent or treat CIT. Mesenchymal stem cells (MSC) are immunogenic multipotent stem cells derived from the mesoderm with self-renewal and multi-directional differentiation potential. They have the ability of self-replication and multi-directional differentiation potential. They not only provide mechanical support for hematopoietic stem cells in the bone marrow, but also can secrete a variety of growth factors to support hematopoietic function. It has long-term hematopoietic support function. We have explored the application of MSC to patients with CIT to improve platelet levels and reduce bleeding-related complications.

METHODS

We screened out 25 patients who met the CIT criteria and whose platelet count was lower than 50×10^9/L. We recorded the age, gender, tumor type, stage, whether there was combined bone marrow invasion, the number and efficacy of previous treatment lines, the condition of bone marrow hyperplasia before chemotherapy, whether CIT occurred previously, and the lowest platelet count during previous chemotherapy.We conducted a therapy for CIT patients with mesenchymal stem cells to evaluate the efficacy and safety. Patients received therapies: mesenchymal stem cells（1×10^6/u, once a week, continuous for 4 weeks as a course）.

RESULTS

27 patients（F:M=13:14）with CIT had received MSC at least once, 18 of which were solid tumors, and 9 hematologic neoplasms. The median age of the patients was 58 years (24-80y). The lowest platelet level was 1×10^12/L. With MSC therapy, median treatment cycles were 1.75 cycles（7 times）. After MSC therapy, platelet levels increased in 23 patients（85%）, and the mean increase of platelet levels was 32×10^12/L. No treatment-relevant adverse reactions.

CONCLUSIONS

Our results show that MSC is a safe and effective method for CIT patients both in solid tumors and hematologic tumors. It indicates that the achieve efficient effectively improves the platelet level of patients with CIT, reduces the risk of bleeding and the frequency of blood transfusion, and without significantly increasing toxicity.
Patient Characteristics and Treatment Outcomes of TP53 Mutated Myeloid Neoplasms : A Single Cancer Center Experience from the MENA Region
Authors: Al-Rabi Kamal , Ma'Koseh Mohammad , Al-Batsh Tamer , Al Sawalha Karim , Zayed Anas , Yaseen Abeer , Ahmad Yazan Talab , Halahleh Khalid , Da'Na Waleed Kamel , Marei Lina , Barakat Farid , Alsmadi Osama , Abdel Rahman Zaid , Shahin Omar Ahmad , Abdel-Razeq Hikmat
Published: December 2024

Background and objectives: TP53 mutations occur in about 10% of myeloid malignancies and are linked to poor prognosis despite intensive treatments. This study aims to improve treatment outcomes by gaining a better understanding of the clinical features, cytogenetic profiles, molecular characteristics, and outcomes of TP53-mutated myeloid neoplasms.

Methods: Next Generation Sequencing (NGS) database at King Hussein Cancer Center was used to identify adult patients (≥ 18 years) with TP53 mutated myeloid neoplasms, diagnosed and treated at KHCC between 2014 and 2023. Baseline characteristics are summarized using descriptive statistics. The Kaplan-Meier method was used to compare overall survival between different cytogenetic and treatment groups.

Results: During the study period, 55 patients with TP53-mutated myeloid neoplasms were enrolled. Median age was 57 (22-84) years, and 35 (64%) were males. Myeloid neoplasms include AML (n=26, 47.2%), MDS (n=24, 43.6%), and MPN (5, 9.1%). Prior malignancies were present in 14 (25.5%) patients, and 12 (21.8%) had therapy-related neoplasms. Cytogenetic studies showed that 26 (55.3%) patients had complex karyotypes. The most common TP53 mutation was the missense mutation, found in 43 (78.2%) patients. Intensive chemotherapy was administered to 21 (38.2%) patients, while 19 (34.5%) received low-intensity regimens. Allogeneic stem cell transplantation (AlloSCT) was performed on 21 (38.2%) patients. After a median follow-up of 11 months, the median overall survival (OS) for the entire cohort was 9 months (95% CI, 6.8-11.2). Survival was worse in patients with complex karyotypes; 5 months (95% CI 1.3-8.7), compared to 12 months (95% CI, 8.2-15.9, p=0.005) in patients with other cytogenetics. There was no significant difference in survival between intensive and low-intensity therapy groups. However, AlloSCT improved OS rates in the entire cohort (12 months, 95% CI, 9.5-4.5 vs. 4.0 months, 95% CI, 0.0-9.71, p=0.006) and among those who received intensive chemotherapy (12 months, 95% CI, 10.3- 13.7 vs. 7 months, 95% CI, 0.0-14.9,p=0.007).

Conclusions: In this limited sample of patients with myeloid neoplasms, the presence of complex karyotype, in addition to TP53 mutation, is associated with poorer prognosis. AlloSCT can improve survival, but overall outcomes remain dismal compared to other genetic groups.