bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Immunosuppression Intensified Conditioning Regimen for Patients with Strong Positive Pre-Transplantation Donor Specific Anti-HLA Antibodies (DSAs) Undergoing Haploidentical Hematopoietic Stem Cell Transplantation
Authors: Liu Huixia , Wei Daolin , Shao Shan , Jiang Ying , Li Su , Zhu JUN , Wang Chun , Zhao Chuxian
Published: December 2023

Objective: Immunosuppression intensified conditioning regimen has been applied for 10 patients with strong positive pre-transplantation Donor specific Anti-HLA Antibodies (DSAs) undergoing Haploidentical Hematopoietic Stem Cell Transplantation (HSCT), its effects on engraftment of hematopoietic stem cell were examined.

Methods: Characteristics of 10 consecutive patients with strong positive pre-transplantation DSAs were retrospectively analyzed, including gender, age, diagnosis, disease status pre-transplantation, presence of DSA, conditioning regimens, engraftment, graft versus host disease (GVHD) incidence and survival.

Results: Ten patients [3 males vs 7 females, median age 53.5(36-64)] received immunosuppression intensified conditioning regimen: Fludarabine plus busulfan (FluBu) combining total body irradiation and cyclophosphamide (TBI-Cy). DSA levels gradually decreased in all patients after preparative conditioning, and the mean fluorescence intensity (MFI) values dropped significantly (P＜0.003). The average MFI values dropped 40% at day 7 post-HSCT, 8 cases acquired hematopoietic reconstitution, the median time of neutrophil engraftment was 15.6(10-16) days, and 19(13-22) days for platelet engraftment. One case had primary graft failure and another one had poor graft function. After a median follow-up of 12.5(1.5-27) months, 7 cases remained in disease remission state with negative DSA assay, including 2 cases with MFI values higher than 20000 pre-transplantation.

Conclusions：Immunosuppression intensified conditioning regimen can efficiently decrease the Donor specific Anti-HLA Antibodies (DSA) level, which leads to lowered chances of primary graft failure.
A Feasibility Study Evaluating Von Willebrand Factor in Patients with Gastrointestinal Angiodysplasia
Authors: Chornenki Nicholas L.J. , Grabell Julie , Bowman Mackenzie L , Good David , Hookey Lawrence , James Paula
Published: December 2023

Background: Abnormalities of von Willebrand Factor (VWF), such as those found in von Willebrand Disease (VWD) are associated with the development of abnormal blood vessels known as angiodysplasia. Angiodysplasia occurs primarily in the gastrointestinal (GI) tract, particularly the small bowel. Among patients with VWD, angiodysplasia is significantly overrepresented as a cause of GI bleeding and occurs in all VWD subtypes although it is reported more frequently in those with loss of the high molecular weight multimer of VWF. Recent studies have demonstrated more than a third of patients with VWD and GI bleeding have angiodysplasia when systematically assessed with Video Capsule Endoscopy (VCE) to examine the small bowel. Given the relationship between angiodysplasia and VWD our objective was to assess the feasibility of evaluating patients with GI angiodysplasia for abnormalities of VWF.

Methods: We undertook a prospective single center pilot study to assess patients over the age of 18 with GI angiodysplasia for underlying abnormalities of VWF. Patients were identified based on angiodysplasia being present on a VCE study. Patients who consented to enrollment completed a self-administered bleeding assessment tool (BAT) as well as baseline demographic data. VWF testing included VWF antigen (VWF:Ag), VWF functional assay (VWF:GPIbM), Factor VIII coagulant activity (FVIII:C), and VWF pro-peptide (VWFpp) levels.

Results: After reviewing 190 consecutive VCE studies performed at our institution between April 2021 and April 2023, we identified 50 patients who had capsule endoscopies demonstrating angiodysplasia of the GI tract. Thirteen of these patients consented to enrollment in the study. The bleeding histories of included patients are detailed in Table 1 along with their baseline clinical, laboratory, and demographic data. Two patients endorsed lifelong bleeding symptoms and three reported a significant family history of bleeding - all in a female relative. ISTH-BAT scores ranged from 0 to 18 with a median score of 2. Since our population is older than other studies that report on bleeding scores, we considered an abnormal bleeding score to be >6 as recent evidence indicates normal BAT scores increase over time. Five patients (38.6%) in our study had an ISTH-BAT abnormal bleeding score. VWF levels were assessed (Table 1) and one patient aged 88 years old with a significant family and lifelong history of bleeding received a new diagnosis of Type 2A VWD. Severe iron deficiency anemia requiring ongoing IV iron was diagnosed in two patients.

Conclusion: In our feasibility study, we demonstrated a feasible protocol for recruitment of patients with GI angiodysplasia for clinical and laboratory testing of VWF. A significant proportion of our patients (38.6%) had abnormal bleeding scores and one patient had an underlying Type 2A VWD diagnosis.
A Conditioning Regimen of Bendamustine and Melphalan for Autologous Stem Cell Transplantation in Multiple Myeloma: A Phase 2, Single-Arm, Prospective Study
Authors: Zeng Qiang , Li Jian , Dong Tian , Chen Xinchuan , Kuang Pu , Niu Ting , Ji Jie , Liu Zhigang , Liu Ting
Published: December 2023

Aim: A registered study to investigate the efficacy and safety of bendamustine plus melphalan conditioning for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) (ChiCTR2100047782).

Method: Bendamustine and melphalan were given to patients at the dose of 150 mg/m 2 on Days -5 and -4 and 70 mg/m 2 on Days -3 and -2, respectively. Progression-free survival (PFS) and overall survival (OS) were used to assess the efficacy and adverse events were used to assess the safety of the conditioning regimen.

Results: A total of 80 patients were included in our study. Of them, 45 patients achieved complete response (CR); 7 patients achieved very good partial response (VGPR), and 28 patients achieved partial response (PR) before ASCT. With a median follow-up period of 16 months, the overall PFS rate was 91%, and the overall OS rate was 95%. Patients with CR pre-transplantation were all in CR until the last follow-up; two patients with VGPR pre-transplantation relapsed and one of them died; four patients with PR pre-transplantation relapsed and one of them died. The median time to neutrophile and platelet engraftment were 11 (9-13) and 13 (10-18) days. Three patients experienced sepsis during ASCT. Vomiting occurred in 45 (57.2%) patients; diarrhea occurred in 27 (34.2%) patients, transaminase elevation was observed in 18 (22.3%) patients; mucositis was found in 16 (18.8%) patients. All these adverse events were grade 1-2, and no grade 3-4 adverse events were observed.

Conclusion: Bendamustine plus melphalan regimen is promising for ASCT in MM patients, and the long-term efficacy and safety remain to be investigated.
Time to Resolution of Iron Deficiency: A 10-Year Single State Retrospective Review
Authors: Cogan Jacob C , Meyer Julia D , Jiang Ziou
Published: December 2023

Introduction: Iron deficiency can have clinical consequences even without anemia, including fatigue, exercise intolerance and mood disorders. The time from laboratory diagnosis to resolution of iron deficiency has not been previously evaluated.

Methods: In a retrospective review of electronic medical record (EMR) data from a single state health system, we identified patients meeting laboratory criteria for iron deficiency (defined as a ferritin level < 25 ng/mL). Patients with at least one follow-up ferritin level of any value within 3 years were included in the final cohort. Patients with a follow-up ferritin > 50 ng/mL at any time point within 3 years were classified as having resolved iron deficiency. Diagnoses of interest included iron deficiency anemia (IDA), as well as other conditions where iron deficiency is routinely assessed and treated irrespective of anemia, namely heart failure (HF) and restless leg syndrome (RLS). Descriptive statistics and time to event analyses (via Cox proportional hazards regression) were performed to determine time to resolution of iron deficiency in the cohort and characteristics predictive of achieving resolution.

Results: We identified 13,084 patients with iron deficiency detected between 2010 to 2020. The majority of patients were female (86.6%) and White (79.3%); 57.3% had an EMR diagnosis of IDA (Table 1). We found that 5,485 (41.9%) had resolution of iron deficiency within 3 years of diagnosis, while 7,599 (58.1%) had unresolved iron deficiency. Among those with resolved iron deficiency, the median time to resolution was 1.9 years (IQR 0.8, 3.9 years). Factors associated with resolution of iron deficiency included increasing age (aHR 1.42 [95% CI 1.31 - 1.54], p < 0.001 for age > 60), male gender (1.49 [1.39 - 1.59], p < 0.001) and a diagnosis of HF (1.23 [1.11 - 1.36], p < 0.001) (Table 2). Black race (0.75 [0.68 - 0.83], p < 0.001) and absence of an EMR diagnosis of IDA, HF or RLS (0.75 [0.71 - 0.81], p < 0.001) were associated with a lower likelihood of iron deficiency resolution.

Conclusion: Prolonged and unresolved iron deficiency were prevalent in this cohort, with young age, female gender and Black race increasing risk of non-resolution. Interventions are needed to raise awareness of the clinical consequences of non-anemic iron deficiency and of diagnostic ferritin thresholds.
TRIM28 Regulates DHCR7-Mediated Cholesterol Biosynthesis to Promote Survival in B Cell Lymphoma
Authors: Zhang Jiawei , Xin Dijia , Fan Yili , Wang Luyao , Chen Boxiao , Xu Yang
Published: December 2023

Background: TRIM28, a member of the tripartite motif-containing (TRIM) protein family, is a critical regulator of gene expression, DNA damage response and protein degradation, but little is known about its role in lipid metabolism. Dysregulation of cholesterol metabolism has been implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL). However, the role of TRIM28 in lymphomagenesis and its clinical relevance remain unclear.

Methods: We searched public databases to characterize the gene expression pattern, clinical parameters, and survival data of TRIM28 in B-cell lymphoma, and immunohistochemistry (IHC) was used to confirm TRIM28 expression. Then, we knocked down TRIM28 by lentiviral shRNA transduction in several B-cell lymphoma lines to determine the effect of TRIM28-KD on cell proliferation, cell cycle progression, apoptosis and drug resistance. In addition, a lymphoma xenograft mouse model was established to test whether TRIM28-KD inhibits lymphoma growth in vivo. Using RNA-seq, we aim to identify novel transcriptional targets and elucidate the mechanisms by which TRIM28 promotes survival in B-cell lymphoma.

Results: Analysis of bioinformatic datasets and clinical samples indicated that TRIM28 expression was significantly upregulated in B-cell lymphoma compared to normal tissues, and high expression of TRIM28 was closely associated with disease progression and poor prognosis in patients with B-cell lymphoma. Knockdown of TRIM28 inhibited lymphoma cell proliferation, induced cell cycle arrest at G0/G1, increased cell apoptosis, and enhanced the sensitivity of lymphoma cells to chemotherapeutic agents. Moreover, TRIM28-KD significantly suppressed lymphoma and prolonged mouse survival in DLBCL xenograft models. The RNA-seq with TRIM28-KD vs. control revealed differentially expressed genes, many of which were enriched in lipid metabolism-related pathways. DHCR7, a critical terminal enzyme in cholesterol biosynthesis, was identified as a potential transcriptional target of TRIM28. TRIM28-KD inhibited DHCR7 expression, which was associated with reduced total cholesterol levels. DHCR7-KD impaired cell proliferation, whereas overexpression of DHCR7 rescued the phenotypes of TRIM28-KD in lymphoma cells.

Conclusions: TRIM28 drives lymphomagenesis through upregulating DHCR7-mediated cholesterol biosynthesis, which may serve as a novel therapeutic target for B-cell lymphoma.
E3 Ubiquitin Ligase TRIM21 Enhances Macrophage-Mediated Bortezomib Resistance By Inducing M2 Polarization in Multiple Myeloma
Authors: Cao Wen , Chen Jing , Zhang Enfan , Cai Zhen
Published: December 2023

Background: Multiple myeloma (MM) is a malignant plasma cell hematologic tumor with an increasing incidence and has become the second most common hematologic malignancy after non-Hodgkin lymphoma. Macrophage is an abundant component of the MM bone marrow microenvironment and contributes to the enhancement of MM drug resistance. Our previous study found that the expression of the E3 ubiquitin ligase TRIM21 was reduced in MM cells, and MM cells with low expression of TRIM21 showed reduced sensitivity to Bortezomib (Bort). This study aims to investigate the role and mechanism of TRIM21 in macrophage-mediated MM Bort resistance.

Objective ：Explore the effect and mechanism of TRIM21 in mediating multiple myeloma Bortezomib resistance.

Methods ：1. Immunofluorescence to analyze the expression of TRIM21 on macrophages in bone marrow biopsy specimens from patients with MM; 2. QPCR, western blot (WB) and flow cytometry (FCM) to detect the level of macrophage polarization markers after constructing overexpression or knockdown of TRIM21; 3. WB and FCM to detect the sensitivity of MM cells to Bort after co-culture of MM cells and macrophage; 4. Transcriptome sequencing to identify TRIM21-mediated pathway changes in macrophage; 5. QPCR and WB to verify the effect of TRIM21 on macrophage polarization after treatment with pathway inhibitors.

Results:1. Immunofluorescence analysis showed increased expression of TRIM21 in macrophage from relapsed and refractory MM (RRMM) patients compared to newly diagnosed multiple myeloma (NDMM) patients;2. QPCR, WB and FCM results showed that overexpression of TRIM21 in macrophage led to decreased polarization markers of M1 phenotype and increased the polarization markers of M2 phenotype. In contrast, knockdown of TRIM21 increased M1 polarization and decreased M2 polarization; 3. WB and FCM results demonstrated that co-culture of MM cells with TRIM21-overexpressing macrophages significantly enhanced MM cell tolerance to Bortezomib and decreased MM cell apoptosis; 4. Transcriptome sequencing revealed activation of the JAK-STAT3 pathway in macrophages after TRIM21 overexpression; 5. QPCR and WB results showed that the macrophage polarization effect induced by TRIM21 overexpression was reversed after treatment with the STAT3 inhibitor C188-9.

Conclusions: Our study shows that TRIM21 is overexpressed in macrophages in patients with relapsed and refractory MM. In addition, TRIM21 induces M2 polarization by activating the JAK-STAT3 pathway, thereby enhancing the protective effect of macrophage on MM cells. These findings provide a new insight into the role of TRIM21 in MM drug resistance and lay an important theoretical foundation for targeting macrophages in MM.

Key words: TRIM21, Macrophage, Bortezomib, JAK-STAT3
Efficacy and Safety of Human Umbilical Cord-Derived Mesenchymal Stem Cells in the Treatment of Immune Thrombocytopenia: A Prospective, Single Centre, Single Arm, Phase I Trial
Authors: Chen Yunfei , Yanmei Xu , Gao Yuchen , Chi Ying , Sun Ting , Dou Xueqing , Han Zhibo , Xue Feng , Li Huiyuan , Liu Wei , Liu Xiaofan , Dong Huan , Fu Rongfeng , Ju Mankai , Dai Xinyue , Wang Wentian , Ma Yueshen , Song Zhen , Gu Jundong , Gong Wei , Yang Renchi , Zhang Lei
Published: December 2023

Background Patients with refractory immune thrombocytopenia (ITP) often suffer severe bleeding events and have poor responses to various treatments. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have been used to treat multiple autoimmune diseases due to their low immunogenicity and strong immunomodulatory potential. To explore the safety and efficacy of UC-MSCs in treating refractory ITP, we conducted this phase Ⅰ clinical trial.

Methods Patients diagnosed with refractory ITP were screened for the study. The major inclusion criteria included age 18 to 60 years, ITP duration lasting for more than six months, platelet count < 30 × 10 9/L and concomitant bleeding manifestations at enrolment. The study consisted of two parts: a dose-escalation phase for exploring the safety and efficacy of three different dosage groups according to the traditional 3+3 protocol and a dose-expansion phase for further verifying the optimal UC-MSC dosage. UC-MSCs were administered at doses of 0.5×10 6 cells/kg, 1.0×10 6 cells/kg, and 2.0×10 6 cells/kg per week four times in the dose-escalation phase and 2.0×10 6 cells/kg per week four times in the dose-expansion phase. The adverse events, platelet counts, and bleeding symptoms were evaluated and recorded during the administration and follow-up period. The study protocol was approved by the Ethics Committees of the Institute of Hematology and Blood Diseases Hospital, and informed consent was obtained from each participant according to the Declaration of Helsinki (ClinicalTrials.gov ID: NCT04014166).

Results Between November 2019 and August 2022, 18 refractory ITP patients hospitalized in our centre were successfully screened and enrolled in the study. Twelve patients were enrolled in the dose-escalation phase (three additional patients were added in the 2.0×10 6 cells/kg group due to the dose-limiting toxicity), and six patients were included in the dose-expansion phase. Thirteen patients (13/18, 72.2%) had one or more TEAEs. SAEs occurred in four patients (4/18, 22.2%), including gastrointestinal haemorrhage (2/4), profuse menstruation (1/4), and acute myocardial infarction (1/4). There were 0.0% (0/3), 66.7% (2/3), and 50.0% (6/12) patients in the 0.5×10 6, 1.0×10 6 and 2.0×10 6 cells/kg cohorts who achieved a response after treatment, respectively. The overall response rate was 44.4% (8/18) in all patients who received UC-MSCs.

Conclusion UC-MSC infusion achieved a 44.4% overall response rate in patients with refractory ITP and mild adverse events.
Long Term Disease Free Survival and Survival of Patients with Relapsed Hodgkin's Lymphoma Treated with Autologous Stem Cell Transplantation
Authors: Abedrabo Sabree , Rodriguez Tulio E. , Klein Leonard M. , Bitran Jacob
Published: December 2023

CONCLUSION

Autologous Stem Cell Transplantation (ABMT) is a standard treatment approach for patients with relapsed Hodgkin's Lymphoma (HL). We wish to report long term (>10 year) outcomes for patient's with HL treated with ABMT at our institution. We treated 35 patients over a 30 year time period (1992-2022) Of these 35 patients, there were 19 males and 16 females with a median age of 41 years (range 21-70 years) and a median performance status of 1 (0-1). The preparative regimen was carmustine, etoposide, and melphalan (CEM,1992-2005) and BCNU, etoposide, cytarabine, and melphalan (BEAM, 2006 to present). Brentuximab was added was added to BEAM in 2018 as post-transplant consolidation therapy in 13 patients. All patients underwent mobilized peripheral blood stem cell collections with high dose filgrastim and since 2008 filgrastim and plexiform. The required stem cell product was at a minimum 2 million CD34+ cells per kilogram of body weight.

Fifteen patients received CEM and 9/15 (60%) achieved a complete response (CR). Twenty patients received BEAM and 16/20 (80%) achieved a CR, p=0.27 (Fisher's exact test). The median time to hematologic recovery was 12 days (range 8-21). Treatment related complications included: S. Epidermis sepsis (3 patients), E. coli sepsis (3 patients) and esophageal perforation that lead to death (1 patient). With a median follow up of 13 years (range 1-23 years).The actual 10 year disease free survival (DFS) is 52% and overall survival (OS) is 64%. The actuarial DFS and OS at 15 years are 52% and 64% respectively. Six patients are in continuous CR for greater than 20 years. Long term complications at greater than 15 years include: cardiomyopathy (5 patients), breast cancer (1 patient), liposarcoma (1patient).

Patients with relapsed HL can achieve long term curative outcomes when treated with ABMT. The most frequent long term complication is cardiomyopathy.
Number Needed to Treat Analyses of Zanubrutinib in Relapsed/Refractory Chronic Lymphocytic Leukaemia
Authors: Chanan-Khan Asher Alban , Hanna Kirollos S. , Xue Mei , Massoudi Marjan , Balk Mark , ZivariPiran Hossein , Duan Cecilia , Yang Keri
Published: December 2023

Introduction: Chronic lymphocytic leukaemia (CLL) is the most common leukaemia type. In 2020, there were an estimated 207,463 people living with CLL, with an annual incidence of approximately 4.9 per 100,000 in the United States (US). Zanubrutinib is a Bruton tyrosine kinase inhibitor that is FDA-approved and an NCCN preferred and recommended treatment of CLL. In the phase 3 ALPINE trial (NCT03734016), zanubrutinib elicited a significantly higher overall response rate and significantly longer progression-free survival (PFS) than ibrutinib. This study aimed to compare zanubrutinib versus ibrutinib in Relapsed/Refractory (R/R) CLL by calculating the number needed to treat (NNT) to avoid one progression or death and associated incremental costs.

Methods:A health-economic model was developed to evaluate the number of R/R CLL patients needed to be treated to avoid a progression or death from the US payer perspective. Payer blend was assumed with 40% Commercial and 60% Medicare payer mix. Clinical efficacy data were extracted from the ALPINE trial. Final analysis result of 24-month PFS (79.5% for zanubrutinib and 67.3% for ibrutinib) was used for the base-case analysis in the model. Treatment, adverse event management, other medical resource use, and subsequent treatment costs were considered in the model. The NNT, incremental cost per treated patient, and incremental cost per additional patient with progression or death were captured. Deterministic sensitivity analyses were conducted to assess parameter uncertainties and explore key model drivers. Scenario analyses were conducted to test the impact of different PFS estimates.

Results: The base-case results fromthe NNT model showed that for every 8 patients treated with zanubrutinib, 1 event of progression or death would be avoided compared to using ibrutinib. The total costs per patient treated with zanubrutinib and ibrutinib are $370,558 and $430,150, respectively, with a cost savings of $59,593 associated with using zanubrutinib (Table). Drug costs and PFS have the greatest impact on the incremental cost per patient. Varying the PFS scenarios, including adjustment with drug interruption, COVID death, or treatment discontinuation, change the NNT from 8 to 12, and are associated with cost savings of $58,179 to $67,153 per zanubrutinib-treated patient in a 24-month time frame. Applying the model result to a hypothetical scenario of a clinical practice of 100 patients treated with zanubrutinib versus ibrutinib suggest that approximately 13 patients will avoid disease progression events or death.

Conclusions: The NNT model suggests thatusing zanubrutinib to treat R/R CLL patients, compared to ibrutinib, will result in more favorable clinical and economic outcomes in the US.
Systematic Literature Review to Identify Influencing Factors of Efficacy and Safety Outcomes of Chimeric Antigen Receptor T-Cell Therapies in Large B-Cell Lymphoma
Authors: Heger Jan-Michel , Jost Jonas , Riou Sybille , Walzer Stefan , Mahlich Joerg , Borchmann Peter
Published: December 2023

Background:

The interpretation of clinical data involving chimeric antigen receptor T-cell therapies (CAR-T's) in Large B-Cell Lymphoma (LBCL) requires a thorough understanding of factors that influence efficacy and safety outcomes.

Materials & Methods:

To identify relevant influencing factors of efficacy and safety outcomes, we conducted a systematic literature review for CAR-T cell therapies. Articles were searched on PubMed from 06.2018 till 06.2023. Data for progression free survival (PFS), overall survival (OS), complete response (CR), objective response rate (ORR), duration of response (DOR), and safety (i.e. Immune Effector Cell-Associated Neurotoxicity Syndrome [ICANS], and Cytokine Release Syndrome [CRS]) were extracted in accordance with the PRISMA guidelines.

Results:

A total of 236 articles were identified and narrowed to 44 publications for full text screening. 13 articles were included in the final analysis. The main reasons for exclusion were other indications, missing data, and lack of significance.

Factors affecting OS that were identified in more than one publication were Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) ≥ 2, presence of bulky disease, and high lactate dehydrogenase (LDH) values. For PFS it was presence of bridging therapy before CAR-T infusion, and LDH values as well. Table 1 presents the full list of identified variables. For DOR no influencing factor was observed.

Influencing factors for safety outcomes are summarized in table 2. Evidence is less compelling here because all identified variables were supported by one publication only.

Conclusion:

This review provides a set of factors that influences efficacy and safety outcomes of CAR-T therapies in LBCL. It can be used to assess comparability of different treatment arms in randomized controlled studies or to make careful adjustments when performing indirect treatment comparisons in order to better understand the true value of innovative treatments.
A Phase I/II Trial to Evaluate the Safety, Pharmacokinetics, and Efficacy of Glofitamab As Monotherapy and in Combination with R-ICE Chemoimmunotherapy in Children and Young Adults with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (iMATRIX-GLO)
Authors: Burkhardt Birgit , Rossato Gianluca , Dixon Mark , Carlile David John , Dmytrasz Steven , Wulff Jade , Negricea Raluca , Wulff Beate
Published: December 2023

Background: Although rare,relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) in children, adolescents, and young adults is an area of high unmet need, with 1-year overall survival rates of <30% and complete remission (CR) rates of 27% after treatment with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemoimmunotherapy (Burke et al. Leukemia 2020). New treatment regimens are urgently needed (Woessmann et al. Blood 2020; Burkhardt et al. Cancers (Basel) 2021). T-cell engagers have been identified as medicinal products with the greatest probability of being beneficial for the pediatric population (Pearson et al. Eur J Cancer 2019).

Glofitamab is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate B cells and is currently under investigation as monotherapy and in combination with chemoimmunotherapy for the treatment of adults with R/R B-NHL, with encouraging clinical activity and a manageable safety profile. Known risks associated with glofitamab are cytokine release syndrome (CRS), febrile neutropenia, tumor flare, tumor lysis syndrome, pyrexia, and infections. The safety profile of glofitamab in children is expected to be similar to that seen in adults.

Study Design and Methods: iMATRIX-GLO (NCT05533775) is a Phase I/II, open-label, single-arm, two-part trial to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of glofitamab as monotherapy in children 6 months to <18 years of age with second and higher R/R B-NHL (i.e. relapse after 2 or more lines of treatment), or in combination with R-ICE in children and young adults ≤30 years of age with first R/R disease (i.e. relapse after the first line of treatment). Patients with a histologically confirmed diagnosis of CD20-positive R/R B-NHL are eligible. Study treatment is administered with a single dose of obinutuzumab pretreatment followed by glofitamab step doses and repeated glofitamab full doses every 21 days as monotherapy or in combination with R-ICE.

Primary objectives and endpoints are the achievement of CR after up to three cycles of combination therapy (glofitamab plus R-ICE) as determined by the investigator according to the International Pediatric NHL Response Criteria for pediatric participants and Lugano Classification for young adult participants, evaluation of glofitamab safety (CRS by ASTCT 2019 criteria, otherwise by NCI CTCAE v5.0 criteria), tolerability, and PK as monotherapy and as combination therapy. The first patient was enrolled in November 2022 and the study is ongoing. The study is planned at 23 sites in 9 countries (Europe, Australia, North America, South Korea, and China).
Provisional Prognostic Score for Mast Cell Leukemia
Authors: Haddad Philip A , Chennapragada Suma Sri
Published: December 2023

Background

Mast cell leukemia (MstCL) is a rare but aggressive variant of systemic mastocytosis (SM), defined by the presence of >20% atypical mast cells in the bone marrow. It is further classified into leukemic and aleukemic variants based on the presence or absence of >10% atypical mast cells in the peripheral blood, respectively. There is a wide variation in treatment regimens used to treat MstCL. Despite this, prognosis remains poor. While MstCL often follows an aggressive course, its outcomes vary considerably. We conducted this study to develop a provisional MstCL prognostic score (MCLPS) for this rare disease.

Methods

We used our constructed MstCL database, which contains retrospective data on 144 cases. Such data included demographics such as sex, age, and race. It also included disease presentation symptoms, duration of symptoms before diagnosis, site(s) of the disease, blood counts, coexisting comorbidities, disease immunohistochemical and molecular phenotype, types of treatment, and survival outcomes. Of the 144 cases, only 104 had complete survival and outcomes data, the sample chosen for this study. Cox proportional-hazards model and Log-rank tests were used to assess the influence of clinicopathologic factors on overall survival (OS). We included factors that statistically impacted OS and scored them by the impact of their hazard ratios.

Results

The median OS of the cohort was 9 months. The following dichotomous variables were identified as impactful prognostic factors in this cohort: Age<55 (6 vs. 15 months), Hgb<10g/dl (3 vs. 29 months), Platelets<100K (3 vs. 23 months), leukemic phase (7 vs. 18 months), and complex cytogenetics (2.3 vs. 23 months). A prognostic model was devised using these variables to identify different levels of risk. Each variable was assigned a score of 1 when present for a maximum score of 5. In this exploratory cohort, low risk was assigned a score of 0, intermediate risk a score of 1-2, and high risk a score of 3-5. This prognostic score system led to our cohort's most optimal risk discriminatory model, where low, intermediate, and high risk had a median OS of 29, 8, and 2.4 months, respectively (p=0.0006).

Conclusion

This MCLPS is a promising new tool for risk-stratifying patients with MstCL. However, it still requires prospective validation.
PET Radiomics Score Generated By Cross-Combination Approach for Treatment Response and Prognosis Prediction in Primary Gastrointestinal Diffuse Large B-Cell Lymphoma Patients
Authors: Zhao Jincheng , Rong Jian , Teng Yue , Chen Man , Chen Bing , Jiang Chong , Chen Jianxin , Xu Jingyan
Published: December 2023

Background: Current risk stratification for primary gastrointestinal diffuse large B-cell lymphoma（PGI-DLBCL） relies on mainly on clinical factors. Radiomics score (RadScore) associated with survival outcomes have been developed for other cancer types, however few studies have thus far examined the role of radiomics in PGI-DLBCL.

Objective: In this study, we investigated the value of PET RadScore constructed using a machine learning cross-combination approach in predicting the early treatment response and prognosis of patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) treated with the R-CHOP-like regimen.

Methods: A retrospective analysis was conducted on 108 PGI-DLBCL patients diagnosed through histopathological examination at two independent medical centers from March 2011 to March 2023, with 86 patients in the training cohort and 22 patients in the validation cohort. Seven different machine learning models were used to generate 49 feature selection-classification candidates, and the optimal candidate was selected based on the area under curve of ROC to establish RadScore. Risk factors were identified through logistic regression, and a radiomics nomogram was constructed by combining RadScore with the selected risk factors. The model was evaluated through calibration curves and decision curve analysis (DCA) using the training cohort and validation cohort.

Results：A total of 111 radiomics features were extracted, and 19 features with strong predictive performance were selected to generate RadScore. The results suggest that RadScore can stratify patient prognosis.The logistic regression analysis results in the training cohort showed that elevated lactate dehydrogenase (LDH) level (OR=3.53, 95%CI: 1.21-10.31, p=0.021), intestinal involvement (OR=3.04, 95%CI: 1.04-8.88, p=0.042), and total lesion glycolysis (TLG) (OR=6.73, 95%CI: 2.23-20.29, p＜0.001) were independent risk factors for predicting early treatment response. A multi-parameter model incorporating clinical risk factors, metabolic factors, and RadScore was constructed (training cohort AUC: 0.834; validation cohort AUC: 0.902), and the performance of the model was evaluated.

Conclusion：The RadScore, constructed based on a cross-combination approach using machine learning, can predict the survival of PGI-DLBCL patients. When RadScore is combined with clinical risk factors and metabolic factors, it forms a combinatorial model suitable for predicting early treatment response to R-CHOP-like chemotherapy regimens. Larger studies will be needed to validate these results.

Keywords ： Primary gastrointestinal diffuse large B-cell lymphoma · [18F]FDG PET/CT · Early treatment response · Prognosis · Machine learning
Efficacy and Safety of Chidamide Combined with BEAM Conditioning Regimen in Autologous Transplantation for T-Cell Lymphoma
Authors: Shen Yige , Zheng Zhong , Ji Mengmeng , Tang Wei , Zhao Wei Li
Published: December 2023

Background:

T cell lymphoma (TCL) is a group of highly heterogeneous aggressive non-Hodgkin lymphomas with different pathogenesis and clinical prognosis. Despite the survival benefits of anthracycline-based chemotherapy bridging autologous stem cell transplantation (ASCT), 40% to 50% of TCL patients fail to respond to treatment and relapse or die within a short period of time. Chidamide is an oral selective histone deacetylase inhibitor (HDACi), interferes with epigenetic regulation by deacetylating nuclear transcription factors, affects proliferation and differentiation of tumor cells, and regulates cytokines in the tumor microenvironment. Chidamide combined with chemotherapy has promising clinical applications in ASCT.

Aims:

This prospective Phase II trial aims to evaluate the efficacy and safety of chidamide in combination with carmustine, etoposide, cytarabine, and melphalan (Chi-BEAM) conditioning regimen in ASCT of TCL patients received CR/PR to first-line chemotherapy.

Method:

In this study, eligible patients with TCL (except IPI 0-1 ALK+ anaplastic large cell lymphoma) aged 18-65 years were enrolled. All patients received Chi-BEAM conditioning regimen before ASCT. 30mg of chidamide was administered twice a week for at least 2 years after ASCT.The primary end point was 2-year progression-free survival (PFS) rate, and the secondary end points were 2-year overall survival (OS) rate and safety evaluation.

Results:

At the time of data cut off, a total of 18 patients were enrolled, with a median age of 48 (15-65) years. The 1-year PFS rate and OS rate after ASCT were 90.0% and 100.0%, respectively. The median implantation time of neutrophils was 10 days (9-13 days), and the median implantation time of platelets was 17 days (11-25 days). Most of the adverse reactions (AEs) were tolerable, including controlled grain deficiency with fever, electrolyte disturbance, and abnormal liver function.

Conclusion:

Chidamide combined with BEAM as a conditioning regimen for ASCT can significantly improve PFS and OS in TCL patients, and the AEs are controllable. The study is ongoing and further results will be continuously released.
Orelabrutinib Plus R-CHOP Regimen in Treatment-Naïve Patients with TP53-Mutated Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Xiao Yi , Wu Jiaying , Zhou Mi , Shang Zhen , Zhu Ming
Published: December 2023

Background: TP53-mutated DLBCL may be refractory to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The A53 subtype was reported to be sensitive to Bruton's tyrosine kinase inhibitors (BTKi). Orelabrutinib (O), a novel BTKi with high selectivity for B-cell lymphomas, combined with R could produce higher anti-tumor effects. O plus R-CHOP-like regimens have shown an encouraging efficacy and acceptable safety in the first-line therapy of DLBCL.

Methods: This study retrospectively collected data on the efficacy and safety of patients (pts) with TP53-mutated DLBCL who received OR-CHOP-based regimens as the first-line therapy between Mar 2021 and Mar 2023. The primary endpoint was complete response (CR) rate at the end of treatment (EOT).

Results: Seven pts (4 males; median age, 56.0 years) were included. Key baseline characteristics included 71.4% IPI score 2-5, 57.1% Ann Arbor stage III-IV, 57.1% non-GCB, 28.6% ECOG PS 2-3, 42.9% MYD88&CD79B co-mutations, 57.1% extranodal lesions, 14.3% HBV and 0% EBV. Two pts had transformed DLBCL from follicular lymphoma. Of 7 pts, 5 pts received OR-CHOP, 2 OR-CHOP plus lenalidomide. With a median follow-up of 9.1 months (range, 3.5-11.8 months), 4 pts completed first-line therapy and 1 died due to progressive disease after 2.5-month discontinuation of medication for economic reasons. Of these 5 pts, 4 (80.0%) achieved a CR at the EOT. During the whole therapy, 4 of 7 (57.1%) pts had a CR as best response; 2 (28.6%) pts with a PR remained on treatment (Table 1 and Figure 1). As cut-off date (March 26, 2023), median progression-free survival and overall survival were not reached, with 12-month PFS rate of 80.0% and 12-month OS rate of 75.0%. Most common adverse events (AEs) of any grade were erythropenia (6 [85.7%]), infection (5 [71.4%]), fever (4 [57.1%]), and anemia (4 [57.1%]), with 71.4% grades 3-4. AEs associated with BTKi off-target activities such as atrial fibrillation, hypertension, and hemorrhage were not reported.

Conclusions: These data supported that OR-CHOP-based regimens had favorable anti-tumor activity and manageable safety profile in pts with TP53-mutated DLBCL. BTKi related off-target AEs were rarely observed. More prospective studies are warranted to validate our findings.
The Variable Heavy Chain Antibody Syn-VWFA1 Inhibits the Interaction of Platelets to Von Willebrand Factor in Solution but Not to Immobilized Von Willebrand Factor Thereby Inhibiting 3-Dimensional but Not 2-Dimensional Thrombus Formation
Authors: Huskens Dana , Van Der Vorm Lisa Nynke , Konings Joke , Arce Nicholas , Roest Mark , De Groot Philip G. , Li Renhao , Remijn Jasper A. , De Laat Bas
Published: December 2023

Neutralizing the interaction between GP1bα and von Willebrand Factor (VWF) is an attractive strategy for treatment and prevention of platelet-VWF agglutinate formation in von Willebrand disease type 2B and thrombotic thrombocytopenic purpura.

The aim of this study was to characterize a llama-derived variable heavy chain antibody (VHH) targeting the A1 domain of active VWF (Syn-VWFA1), in terms of its interference with platelet VWF interaction.

Syn-VWFA1 (1.5 µM) abolished platelet binding to ristocetin-activated VWF (native and Haemate® P VWF) and R1306W VWF (VWF type 2B) in a flow-cytometric platelet function assay (Figure 1). Moreover, Syn-VWFA1 dose-dependently inhibited ristocetin-activated VWF and R1306W VWF platelet agglutination, but not collagen- and ADP-induced platelet aggregation. Under flow conditions, Syn-VWFA1 (1.8 µM) did not affect adhesion of platelets to collagen at high shear. In the shear- and collagen-dependent PFA-200, Syn-VWFA1 prolonged the closure time, but only at high concentrations (>3 µM), while GPIba binding to immobilized VWF remained unaffected by Syn-VWFA1. Syn-VWFA1 increased the cleavage of VWF multimers by ADAMTS13. Furthermore, by applying deuterium exchange, we found a small region in the β1 to α1 loop (1288-1293) in the A1 domain of VWF, which is likely to constitute the nanobody binding site (Figure 2) and binding of Syn-VWFA1 to the A1 domain results in a conformational change exposing regions in the α2 and α3 helices.

In conclusion, Syn-VWFA1 dose-dependently blocks platelet-binding to activated VWF in solution, but not to (collagen-) immobilized active VWF. This implies that immobilization of VWF to collagen affects VWF conformation in such a way (1) that access of Syn-VWFA1 to its epitope in the A1 domain is hindered or (2) that conformational changes following Syn-VWFA1 binding are blocked, while allowing platelet binding. This implies that Syn-VWFA1 has potential treatment opportunities for patients with increased circulating active VWF, to prevent 3-dimensional thrombus formation (pathological platelet-VWF aggregate formation) but not 2-dimensional thrombus formation (leaving physiological hemostasis at sites of vascular injury intact).
Impact of COVID-19 Epidemics on Paediatric and Adult Patients with Haemophilia Treated in a Haemophilia Therapeutic Centre
Authors: Zhang Shuxia , Li Xiaofan , Yang Feng'e
Published: December 2023

Abstract

Introduction: The pandemic of coronavirus disease 2019 (COVID-19) has posed an unprecedented health crisis for all humans, including people with haemophilia.

Aim: To investigate the impacts of COVID-19 pandemic on the infection, symptoms, drug use, and social intercourses of patients with haemophilia.

Methods: 265 adults or children with haemophilia followed up in the Haemophilia Diagnosis and Treatment Center of Fujian Medical University Union Hospital during the COVID-19 pandemic were collected and analyzed between January 2022 and January 2023.

Results: A total of 265 patients participated in this survey, 30.2% were children and 69.8% were adults. During the COVID-19 pandemic, coagulation factors were not associated with the type and severity of haemophilia, residence, or infection. Compared with adult patients, more children reduced social intercourses and outdoor activities due to the fear of COVID-19 (85.0% vs 66.5%; p = 0.002). The bleeding events were also significantly lower in children than in adult patients (61.2% vs 81.1%; p = 0.001). The SARS-CoV-2 infection rate was significantly higher in patients living in urban areas than in rural areas (74.3% vs 53.6%; p < 0.001). The lasting time of symptoms after infection was not significantly associated with hemorrhage, type and classification of haemophilia, presence of inhibitors, complications, and vaccination.

Conclusions: The accompaniment of COVID-19 did not significantly influence the symptoms and treatments in patients with haemophilia. Compared with adults, the number of pediatric patients with bleeding events was significantly lower .

Keyword: COVID-19, haemophilia, hemorrhage, infection, symptoms
Cardiotoxicity Related Mortality Among Children with Acute Myeloid Leukemia in Low Middle Income Countries: Is It Treatment or Sepsis Related?
Authors: Khedr Reham , Gaber Parween , Selim Zeinab salah , Elkhaiat Samah
Published: December 2023

Background: Heart disease and cancer are two major causes of morbidity and mortality worldwide, accounting for at least 70% of the medical reasons for mortality across the globe. Modern treatment strategies led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Over the last few decades, cooperative oncology group trials for pediatric acute myeloid leukemia (AML) have improved overall survival (OS) to nearly 65% by combining intensive chemotherapy with improved supportive care. Despite their efficacy, anthracyclines are linked to an increased risk of cardiotoxicity. Objectives:The study aimed to describe the incidence of cardiotoxicity among pediatric patients with acute myeloid leukemia, assess the effect of cardiotoxicity on treatment outcome in terms of overall survival (OS) and event free survival (EFS) and to determine the different risk factors (Age, gender, body mass index, cumulative doses of anthracyclines and sepsis) that may contribute to cardiotoxicity. Patient and Methods: A retrospective study, conducted at the National Cancer Institute (NCI), Cairo University, Egypt.,that included all pediatric patients ≤ 18 years old diagnosed and treated as Acute Myeloid Leukemia (AML) during the period from the first of January 2015 to the end of December 2019. Retrospective analysis of the different features of cardiotoxicity associated with the treatment of AML. Results : The study included 142 patients with a median age of 8.5 years old and M/F ratio 1.2:1.Out of the total study population, Eighty four patients (59.2%) developed cardiotoixicity in which 59.5% were acute onset cardiotoxicity and 40.5 % were chronic early cardiotoxicity and there was no detected cases of chronic late cardiotoxicity.Cardiac dysfunction was detected in 65/142 (45.8%) patients at time of death in association with sepsis. The cumulative incidence of cardiotoxicity was higher in the presence of blood stream infection with p value (p<0.001).55/84 (65.5%) patients with cardiotoxicity showed progressive cardiac dysfunction and they all died due to sepsis that was associated with cardiac dysfunction. At the end of the study the OS and EFS were 16.2 % and the median survival time was 1.9 month.The cumulative OS,EFS and the median survival time were reduced in the presence of acute cardiotoxicity with statistical significant p-value (p<0.001). Conclusion: The incidence of cardiotoxicity is high among pediatric AML patients and the most important risk factor for cardiotoxcity is blood stream infection. The Cumulative OS, EFS and median survival time are reduced in patients with acute cardiotoxicity which represents a major challenge that warrants more attention to the field of cardio-oncology.