bluuebunny/crossref_metadata_2025 huggingface dataset:
First Interim Results of the Real-Life Study Evaluating the Efficacy and Safety of Belinostat in Patients with R/R PTCL in Brazil (BELBRA)
Authors: De Moura Ricardo Pereira , Abdo Andre N.R. , Chiattone Carlos , Canutti Valnei , Fischer Thais , O'Connor Owen A.
Published: December 2024

Introduction: Belinostat (BEL) is a Pan-Histone Deacetylase Inhibitors (HDACi) that increases histone acetylation leading with anti-angiogenic and antitumor properties indicated in the treatment of in refractory or relapsed (R/R) Peripheral T-Cell Lymphoma (PTCL). BELBRA is the real-life observatory study initiated in Brazil with the participation of 90 lymphoma reference centers, with 97 patients to date.

Methods and Aims: To date, 97 R/R PTCL patients treated with Belinostat in Brazil have been identified. In this interim analysis, the demographic characteristics of the patients were analyzed. Furthermore, more detailed analyzes of 20 patients were carried out. Data collection and statistical analyzes continue to be conducted.

Results: The interim results of the BELBRA study, focus on the efficacy and safety of Belinostat (BEL) in treating R/R PTCL. The cohort demonstrated a diverse range of PTCL subtypes, with a majority being lymphoma NOS. Treatment primarily included CHOP or similar therapies, with Belinostat administered in later lines. The study reports a 45% overall response rate, stable disease in 10%, and disease progression in 45% of the detailed cohort, with treatments being well tolerated across an average of 5 cycles. No other AE´s than the Belief Study was observed.

Conclusion: These findings highlight Belinostat's potential as a favorable option for PTCL patients resistant to previous treatments, contributing as valuable real-world evidence to these challenging patients.
Therapeutic Potential of Roxadustat in Immune Thrombocytopenia: A Mendelian Randomization Analysis
Authors: Ma Jingyao , Wu Runhui
Published: December 2024

Background: Immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired megakaryocyte maturation. Hypoxia-inducible factor-1 alpha (HIF-1α), pivotal in the development of megakaryocytes and immune regulation, is downregulated in ITP, suggesting its role in disease pathogenesis. Given this relationship, roxadustat as an HIF-1α stabilizer, is a potential therapeutic agent in the treatment of ITP by augmenting HIF-1α mediated megakaryocyte development and immune system modulation.

Objectives: This study evaluates the safety profile of roxadustat and its therapeutic efficacy for ITP treatment using Mendelian randomization (MR) analysis.

Methods: We used expression Quantitative Trait Loci (eQTLseQTLs) data for roxadustat's target genes (EGLN1, EGLN2, EGLN3) and genetic associations with ITP, and adverse outcomes from the IEU OpenGWAS project. MR analysis included IVW, MR-Egger regression, weighted median, and MR-PRESSO methods to evaluate pleiotropy. Heterogeneity was assessed using Cochran's Q statistic and I² measure, with sensitivity analyses. A meta-analysis was performed to integrate effect sizes from multiple literature sources.

Results: MR analysis revealed a significant association between roxadustat and reduced ITP risk (OR 0.79, 95% CI 0.66-0.95, P=0.01) with no evidence of horizontal pleiotropy. Meta-analysis confirmed the protective effect of roxadustat on ITP risk. Utilizing eQTLs of roxadustat's target gene EGLN1 as instrumental variables, an MR analysis of 39 potential adverse reactions revealed no significant increase in risk, indicating a favorable safety profile for roxadustat.

Conclusion: Roxadustat demonstrates a potential protective effect against ITP without increasing the risk of adverse outcomes, suggesting its promise as a therapeutic option for ITP and warranting further investigation.
Comparisons between Haploidentical Hematopoietic Stem Cell Transplantation and Eltrombopag Adding to Standard Immunosuppression in Patients with Severe Aplastic Anemia
Authors: Fu Andie , Li Mengyuan , Peng Yizhou , Xu Bin , Li Li , Jia Jin-song , Yang Yan , Lin Shengyun , Wei Jia , Meng Fankai , Zhang Donghua , He Guangsheng
Published: December 2024

Background:

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) becomes an alternative choice for patients in the absence of a matched donor1. The use of eltrombopag (EPAG) combined with intensive immunosuppressive therapy (IST) as a front-line treatment has been shown to enhance both the rate and rapidity of hematologic response in SAA patients2. However, no studies have compared the outcomes of IST + EPAG and haplo-HSCT for the treatment of SAA.

Methods:

The study was performed among 111 patients with SAA from 5 medical centers, including 51 patients in the IST+EPAG group and 60 patients in the haplo-HSCT group. The overall survival (OS), failure-free survival (FFS), GVHD-free FFS (GFFS)/ survival with CR status (CROS), overall response rate (ORR) as well as complications were compared between the two groups.

Results:

At 6 months post treatment, 91.67% patients in the haplo-HSCT group and 19.67% patients in the IST+EPAG group achieved normal blood routine (P=0.000). It turned out that the OS was comparable (92.16% vs 91.67%, P=0.775), while the FFS and GFFS/CROS in the haplo-HSCT group was superior to that in the IST+EPAG group (88.33% vs 72.55%, P=0.045 and 78.33% vs 25.49%, P=0.000). Being diagnosed with non-VSAA was a favorable factor for FFS, and the choice of haplo-HSCT was a favorable factor for GFFS/CROS in multivariate analysis. None of the evaluated factors was recognized as an independent favorable factor of OS. Multivariate analysis showed that being diagnosed with non-VSAA, patients aged <40years, and receiving hematopoietic stem cell transplantation were significantly associated with good therapeutic outcomes. Using propensity score matching (PSM), a comparative analysis was conducted to assess the treatment outcomes between patients treated with haplo-HSCT (n=28) and patients who underwent IST+EPAG therapy (n=28). In the PSM cohort, OS and FFS who underwent haplo-HSCT were comparable to those of the IST+EPAG group (89.29% vs 96.43%, P=0.278 and 85.71% vs 82.14%, P=0.785); However, there was still a signiﬁcant difference between the 2 groups regarding GFFS/CROS (75.00 % vs 39.29%, P=0.024). The multivariate analysis showed that choosing haplo-HSCT was a favorable factor for GFFS/CROS, but did not affect FFS and OS in the PSM cohort。

Conclusions:

These results suggest that for the management of SAA patients, haplo-HSCT showed similar comparable long-term prognosis compared with IST+EPAG, whereas patients treated with haplo-HSCT could achieve faster hematopoietic reconstruction and higher CR rates.
Morin Promotes Cell Apoptosis By Suppressing Lxrα Expression and Transcription Activity in Imatinib-Resistant Chronic Myeloid Leukemia Cell
Authors: Nie Zi-Yuan
Published: December 2024

The abnormal activation of alternative signaling pathways plays an important role in Imatinib (IM) resistance chronic myeloid leukemia (CML). Therefore, there is an urgent need to determine the mechanism underlying IM resistance induced by abnormal signaling pathway activation and develop alternative treatment strategies. Here, we found that miR-188-5p expression was significantly upregulated while the protein level of PTEN was downregulated in IM-resistant CML cells. Notably, Morin could promote cell apoptosis and increase IM sensitivity by regulating the miR-188-5p/PTEN pathway. Furthermore, we found the overexpression of LXRα in IM-resistant CML cell. Knockdown of LXRα attenuated apoptosis in IM-resistant CML cells. Mechanistically, we revealed that LXRα bound to the parent gene of miR-188-5p promoter and positively regulated miR-188-5p expression at transcriptional level. Morin not only decreased LXRα expression but also reduced the transcriptional activation of LXRα in IM-resistant CML cells, thus blocking the miR-188-5p/PTEN axis. In conclusion, our findings provide the evidence that Morin can be used as a novel therapeutic approach for treating of IM-resistant CML by regulating the LXRα/miR-188-5p/PTEN pathway.
Efficacy and Safety Study of Chimeric Antigen Receptor-T Cell Therapy for People with Relapsed/Refractory Follicular Lymphoma
Authors: Xu Ting , Zeng Liangyu , Wu Depei , Li Caixia
Published: December 2024

Although follicular lymphoma (FL) is an indolent lymphoma, it is prone to multiple recurrences and has a poor prognosis for progression of disease within 24 months (POD24) patients. To improve outcomes for patients with relapsed/refractory follicular lymphoma (R/R FL), we evaluated the efficacy and safety of Chimeric Antigen Receptor-T (CAR-T) cell therapy in these patients.

This retrospective study included 12 patients with R/R FL receiving CAR-T cell therapy from January 2017 to December 2023 in the First Affiliated Hospital of Soochow University who have consented to be included in our two clinical trials of CAR-T therapy. These two trials were registered at ClinicalTrials.gov, NCT03196830, NCT04539444.

The median age of the 12 patients was 46 (range, 28-59) years. Eight (66.7%) patients were male and four (33.3%) were female. FLIPI≥3 was present in 6 (50%) patients, and there were 7 (58.3%) patients with POD24. All patients received at least two lines of prior therapy. Eight (66.7%) patients received CD19 single-targeted CAR-T cell infusion and four (33.3%) patients received CD19/CD22 dual-targeted CAR-T cell infusion.

At 1 month after CAR-T cell infusion, the overall response (OR) and complete response (CR) rates for R/R FL patients were 12/12 (100.0%) and 9/12 (75.0%), respectively. By the cut-off date on March 7, 2024, the median follow-up time was 21.9 (range, 6.6-59.8) months. No deaths occurred. 10 (83.3%) patients continued their responses. 2 (16.7%) patients had progressive disease after 9 and 5 months. The 2-year progression-free survival (PFS) and overall survival (OS) rates were 82.5% and 100.0%, respectively. In a subgroup analysis, the CR rate of patients in the POD24 group did not show a significant difference from that of the non-POD24 group (71.4% vs. 80.0%, p=0.735), and the estimated 2-year PFS rate of patients in the POD24 and non-POD24 groups did not show a significant difference (82.5% vs. 83.3%, p=0.964).

Only 2 (16.7%) patients had grade 3 cytokine release syndrome (CRS), which was resolved by glucocorticoid. No immune cellular-associated neurologic syndrome (ICANS) or treatment-related death occurred.

In conclusion, patients with R/R FL treated with CAR-T cell achieved durable response with favorable safety profile. The long-term efficacy and safety need to be confirmed in larger clinical trials and longer follow-up period.

Keywords: chimeric antigen receptor-T cell therapy, relapsed/refractory follicular lymphoma, outcome, progression of disease within 24 months
Targeting Proline Trna Biogenesis for Treatment of T Cell Acute
Authors: Ciaurro Valerio , Srivastava Priyanshu , Khalique Abdul , Brottem Jared , Payne N Connor , Mazitschek Ralph , Thandapani Palaniraja
Published: December 2024

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive blood cancer marked by the abnormal growth of immature thymocytes. While the survival rate in pediatric cases is around 80%, there remains a significant 20% of patients who succumb to the disease due to relapse or resistance to treatment. Moreover, adult survival rates are below 50% due to higher treatment-related toxicities. This highlights the critical need for new therapeutic approaches. At the molecular level, constitutive NOTCH1 signaling, resulting from activating mutations in NOTCH1 gene observed in over 60% of patients, is a major driver of the disease. In our recent work, we had identified an extensive oncogenic NOTCH1 dependent rewiring of global tRNA biogenesis in T-ALL and demonstrated that tRNA deregulation are critical contributors to the disease pathogenesis of T-ALL. In further underlining tRNA pathway as novel therapeutic targets in T-ALL, we report pharmacological inhibition of prolyl-tRNA synthetase (ProRS) domain, that charges proline tRNAs with the cognate proline amino acid, to decrease proliferation and induces cell death in pre-clinical models of T-ALL. Expression of the bifunctionl glutamyl-prolyl-tRNA synthetase (EPRS1) and proline tRNAs is significantly upregulated in primary T-ALL samples relative to thymocytes from healthy individuals. Moreover, CRISPR knockdown of EPRS1 and proline tRNAs in T-ALL cell lines leads to reduced cell fitness, underscoring the critical role of this pathway in tumor proliferation and survival. NCP26 is a new pyrazinamide-based drug that targets the ProRS domain of EPRS1 and its efficacy in treating multiple myeloma was thoroughly evaluated in a recent study. We show that NCP26 effectively inhibits proliferation and enhances apoptosis in T-ALL cell lines and PDX samples. In contrast, T cells from healthy donors show no signs of apoptosis and exhibit only minimal proliferation inhibition, confirming the lack of toxicity on normal T cells. Our findings identify upregulated proline tRNA biogenesis as a critical adaptation in T-ALL pathogenesis and provide a molecular basis to target ProRS in T-ALL.
Patient Journey Mapping Enhances Nursing Care in Patients with Hematologic Diseases
Authors: Kuang Zhexiang , Yu Xiao , Wang Anni , Xu Jing , Zhao Jingyu , Li Xinli , Wu Guibin , Yuan Weiping , Shi Jun , Xu Li , Xie Wenjun
Published: December 2024

Objective To assess nursing care using Patient Journey Mapping (PJM) approach in patients with hematological diseases.

Methods This study enrolled 268 patients with hematological diseases admitted to a grade-A tertiary hematological specialty hospital in Tianjin from January to December 2023. Nursing care based on PJM was integrated into standard healthcare, involving interventions across five stages: encounter, diagnosis, treatment, recovery, and outpatient follow-up, with a period of four weeks. At the time of patients' first admission and as they prepare for readmission, we evaluated their nutritional status, psychological well-being including anxiety and depression, sleep quality, and self-management abilities using Nutritional Risk Screening (NRS) 2002, Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Pittsburgh Sleep Quality Index (PSQI), and Self-Care Ability Scale (ESCA).

Results A total of 260 patients completed this study. There was a statistically significant difference in the NRS2002 scores pre and post intervention (P=0.008), with mean scores of (2.07±0.48) and (2.04±0.46), respectively. We observed statistically significant differences in psychological well-being, sleep quality and self-management abilities before and after intervention (P<0.001). Specifically, the HAMA scores were (8.30±4.43) and (7.78±3.67), the HAMD scores were (11.01±5.30) and (10.17±4.26), the PSQI scores were (8.47±2.47) and (6.97±2.05), the ESCA scores were (55.28±15.33) and (114.21±20.04), respectively.

Conclusion PJM can enhance the nutritional status, sleep quality and self-care abilities of patients, while also alleviating their negative emotions,thus effectively improving their overall healthcare experience.
Pharmacological and Pharmacokinetic Evaluation of AST-202, CD25-Targeted Aptamer Conjugated with Anti-Mitotic MMAE Warhead for the Treatment of Hematological Malignancies
Authors: Lee Daekyun , Kang Ju-Hyung , Song Inu
Published: December 2024

CD25 is an alpha subunit of IL-2 receptor that is overexpressed in various hematological malignant conditions. Evidences for meta-analysis and literatures indicate that the abnormal expression of CD25 is closely associated with poorer outcome and prognosis in lymphoma and leukemia patients. AST-202 is the novel micellar aptamer-drug conjugate (ApDC) composed of CD25-targeting aptamer precisely conjugated with 3 anti-mitotic MMAE warhead which is delivered to eliminate CD25-expressing leukemic/lymphoblastic cells.

Strong amphiphilic nature due to add 3 hydrophobic drugs at the end of an aptamer led AST-202 to self-assemble into a spherical micellar structure with hydrodynamic radius ~180nm (hydrophobic drug core and hydrophilic aptamer surface).

Interestingly, when the in vitro plasma stability of aptamer-MMAE linkage was monitored by measuring the released MMAE over a 4-day period, the amount of MMAE released was only less than 1% in AST-202 while the aptamer with a single MMAE lost 50~60% of its payload within 4 days, suggesting the significant improvement of the metabolic stability of AST-202. ). This improvement of stability was found to translate to improved PK profile relative to AST-202(1), resulting in the dramatic increase of AUC and half-life as well as the decreased CL.

Cytotoxicity evaluation against a panel of human lymphoma and leukemia cell lines with different CD25-expression level revealed the correlation of the expression level of the target and CD25-negative Daudi and H929 cells (derived from B-cell lymphoma and multiple myeloma, respectively) were not affected in the range of treatment up to 1uM.

Comparative in vivo study with subcutaneous xenografts of AST-202 and single MMAE-conjugated aptamer demonstrated CD25-specific tumor targeting and the superior anti-tumor efficacy of AST202 relative to ApDC with a single payload. The following study with a disseminated tumor model showed dramatic extensions of survival in all treatment groups compared with vehicle and non-binding ApDC controls and survival difference between AST-202(1) and AST-202(3) was not observed at the tested dose range.

Consequently, based on the improved in vitro stability, PK profile, and efficacy, AST-202(3) which is a novel micellar aptamer-drug conjugate could be a potential candidate for further preclinical development as a therapeutic candidate against hematological malignancies.
DNA Damage Activates Cgas-Sting Pathway Facilitating NK Cell Recognition and Clearance of T-Cell Acute Lymphoblastic Leukemia
Authors: Qing Yingjie , Hu Po
Published: December 2024

T-cell acute lymphoblastic leukemia (T-ALL) are tumors characterized by abnormal clones of T lymphocytes. Traditional chemotherapy and transplantation approaches continue to face risks of treatment failure and patient mortality. While immunotherapy has shown remarkable efficacy in solid tumors and B cell malignancies, T-ALL's lack of unique antigen targets and shared antigens with normal T cells present significant challenges for its immunotherapy. Inducing DNA damage to prompt T-ALL cells to active cGAS-STING pathway can enhance NK cell recognition of target cells, offering a novel adjunctive treatment method. Experimental results indicate that DNA damage-mediated activation of the cGAS-STING signaling pathway, and even promotes the expression of NK cell-stimulatory antigens in tumor cells, facilitating the clearance of T-ALL by NK cells. DNA damage therapy is ineffective in NOD/SCID mouse models of T-ALL, but DNA damage repair inhibitors can enhance the in vivo clearance of T-ALL in immunocompetent mice. Therefore, identifying methods to increase the immunogenicity of T-ALL, thus promoting their recognition and recruitment by the immune system, represents a new therapeutic strategy.
The Dark Horse: Introducing a Comparative Hematology Course into the Post-Clerkship Phase of Medical School
Authors: Kometas Marisa L. , Raman Ganesh , Adkins Brian , Rambally Siayareh , Hofmann Sandra L. , Aird William C. , Bavli Natalie
Published: December 2024

Introduction: Developing a deep understanding of pathophysiology is integral to training competent physicians. Although the basic sciences are taught primarily in preclinical curriculum, revisiting these concepts during the fourth year of medical school promotes integration into clinical medicine (Spencer et. al, 2008). Immersive comparative physiology courses increase trainee appreciation of physiology and its incorporation into patient care (Herzig et al, 2012). We introduced comparative physiology curriculum during a fourth-year medical student course at University of Texas Southwestern (UTSW) Medical School. Our course aimed to deepen students' understanding of human pathophysiology and its clinical applications by highlighting evolutionarily conserved and adaptive changes among diverse species.

Methods: We developed a one-week comparative physiology curriculum to present to fourth-year medical students in April 2024. The curriculum utilized the four stages of Kolb's Experiential Learning Theory through multimodal methodologies, including introductory lectures, case-based learning, laboratory experiments on human and animal blood with integrated case studies and group projects, and evolutionary biology group presentations at the Fort Worth Zoo. The UTSW Institutional Review Board approved the dissemination of pre- and post-course surveys. The surveys incorporated a 7-point Likert scale (1= strongly disagree, 2= disagree, 3= somewhat disagree, 4= neither agree nor disagree, 5= somewhat agree, 6= agree, 7= strongly agree). Anonymous six-digit identifiers tracked changes in individual perceptions. Scores were calculated by summing responses to series of questions evaluating perceptions of construct and knowledge. Paired samples t-tests through Microsoft Excel assessed the significance of differences between pre- and post-course mean perception of construct and confidence in knowledge scores.

Results: Fifteen fourth-year medical students enrolled, and 93% completed both surveys. Self-assessed confidence in knowledge significantly increased (p =1.02x10-5) in multiple concepts, including interpretation of the peripheral blood smear and of the complete blood count. In the post-course survey, 79% of respondents agreed or strongly agreed that comparative physiology models should be incorporated into medical education, 79% agreed or strongly agreed that the course increased their interest in hematology, and 100% strongly agreed to recommend the course.

Conclusion: Incorporating immersive comparative physiology curriculum into the post-clerkship phase of medical school can enhance understanding of core hematologic physiology principles and promote interest in hematology.
The Surface-Exposed Nuclear Speckle Protein SRRM2 Confers a Novel Target Molecule for the Immunotherapy of Acute Myeloid Leukemia
Authors: Zhang Wanqiu , Gao Zhimai , Gärtner Kathrin , Wang Huiping , Wu Fan , Guo Jinjing , Li Yingwei , Li Zijian , Li Lietao , Li Cong , Liang Xue , Xiao Hao , Zhai Zhimin
Published: December 2024

Acute myeloid leukemia (AML) is a serious, life-threatening and hardly curable hematological malignancy with a 5-year survival rate of only about 30%. CAR T-cell therapy has emerged as a highly effective option for the treatment of B-cell malignancies. Serine/arginine repetitive matrix 2 (SRRM2) is a nuclear speckle protein involved in RNA splicing that may contribute to survival of blast cells and drug resistance in AML. Interestingly, we recently identified SRRM2 on the surface of malignant cells, including AML blasts. Here, we investigated the specific level and characteristics of SRRM2 protein expression in AML patients and whether the protein can serve as a target antigen for AML treatment.

In this study, we detected and analyzed the expression and cellular localization of SRRM2 in AML cell lines and patients newly diagnosed/relapsed with AML using a proprietary SRRM2-specific antibody (EX02). Subsequently, a second-generation CAR-T cell targeting SRRM2 was constructed, and the efficacy and safety of SRRM2 CAR-T cells were assessed in vitro and in vivo using a NSG mouse model of AML.

Our results show that SRRM2 is exposed at the surface of most blast cells from various types of AML cell lines and patients with AML, and that the level of surface SRRM2 directly correlates to high risk, relapse and poor prognosis. Even more important, in normal hematopoietic stem cells and differentiated mature blood cells, as well as in normal tissues from lung etc., SRRM2 was only found to be located in the nucleus. Finally, SRRM2 CAR-T cells exhibited significantly elevated secretion of IFN-γ and TNF-α and enhanced cytotoxicity against AML cell lines. In the AML mouse model, SRRM2 CAR-T cells displayed significant suppression on AML and extended survival.

Collectively, we demonstrated that the ectopic exposure of the SRRM2 protein on the surface of AML cells constitutes an attractive target molecule for the development of targeted therapies against AML, like SRRM2-specific CAR-T cells.

The use of human material for these investigations was approved by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University (NO. YJ-YX2019-015).
The Role of Artificial Intelligence in Differential Diagnosis and Prognostic Significance of Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Authors: Tian Zizhu , Sheng Yue , Han Fangjian , Yu Li , Deng Zeyu , Jiang Yi , Peng Hongling
Published: December 2024

Objective To obtain quantitative pathological immunohistochemistry (IHC) data using artificial intelligence (AI) technology to investigate the differential diagnosis and prognostic significance of immunophenotypic expression in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Methods Retrospective collection of pathological sections from 52 cases diagnosed with MCL and 14 cases of CLL/SLL at our hospital between April 2017 and April 2022, together with the data of patients. The Kaplan-Meier method was used for survival function estimation. Results A diagnostic cut-off value of ≤35.02% for CD23 (AUC=0.904; P<0.0001) and >24.26% for Cyclin D1 (AUC=0.995; P<0.0001) was advocated for MCL. The model consisting of CD20, CD5, CD23, and Cyclin D1 achieved 100% accuracy in distinguishing MCL from CLL/SLL. Within the MCL cohort, the 3-year overall survival (OS) rates were (90.0±9.5) % and (60.2±11.8) % (P=0.027), and the 3-year progression-free survival (PFS）rates were (64.5±19.9) % and (23.6±12.7) % (P=0.026) in the Cyclin D1 low and high expression groups, respectively. SLL patients with high CD5 expression exhibit prolonged OS compared to the low expression group (64.7 months vs. 48.0 months, P=0.048). Conclusion The application of AI in IHC enhances the precision and efficiency of MCL and CLL/SLL identification. The identified risk factors hold promise for guiding improved treatment and prognosis for these conditions.
Optimizing Fresh Frozen Plasma Use: A Quality Improvement Initiative in a Community Healthcare Setting
Authors: Sanikommu Dhruvi Reddy , Nadeem Ahmed , Lussier Amanda , Mohamed Nida , Iannuccilli Jenna , Boyle Kerri
Published: December 2024

Introduction:

Blood products, including packed red blood cells, fresh frozen plasma (FFP), platelets, and cryoprecipitate, play a critical role in the clinical setting. However, there is a growing concern regarding the overuse of these products in community hospitals, often deviating from established transfusion guidelines. This practice not only increases the risk of transfusion-related reactions but also imposes a financial burden on the healthcare system. This study aims to assess the utilization of FFP and implement interventions to optimize the use of these essential blood products.

Methods:

A retrospective population study was conducted at Landmark Medical Center, Rhode Island. We identified patients who received FFP transfusions between 2021 and 2024 from blood bank records. Data were extracted from the EPIC electronic medical record (EMR) system, including the number of FFP units ordered and administered, pre-transfusion INR values, and the clinical indications recorded in the EMR. A proportional analysis was conducted to evaluate the concordance of FFP use with transfusion guidelines.

Results:

Among the 112 patients analyzed, 67.36% were above 65 years of age. The majority (81.42%) were White non-Hispanic, with a nearly equal gender distribution (57.52% male, 42.48% female). FFP transfusions were administered in accordance with EMR indications in 61.61% of cases, while 38.39% did not meet the documented indications. Notably, of the 69 patients (61.61%) who received FFP transfusions per EMR indications, 44 patients (63.77%) did not adhere to established transfusion criteria, suggesting these cases could have been managed without transfusion.

Conclusion:

This study identifies a significant discrepancy between the use of FFP and transfusion guidelines. Interventions, including provider education, enhanced oversight by the blood bank, and potential modifications to the EMR system, are being considered to improve guideline adherence and optimize the utilization of blood products. These measures are currently under discussion at our community hospital, and further evaluation will be necessary to assess their impact.
Severe Anemia and Neutropenia in a Patient with Gollop Wolfgang Syndrome: Implications of Malabsorption-Induced Micronutrient Deficiency. a Case Report
Authors: Olaosebikan Rasaq , Smink Gayle M
Published: December 2024

Introduction: Gollop-Wolfgang Complex syndrome is a rare congenital limb anomaly characterized by distal bifid femur and tibial agenesis. The etiology of this syndrome is unknown. Copper deficiency, an uncommon cause of severe anemia and cytopenia, results from malabsorption, issues with copper metabolism, or other nutritional deficiencies. Severe anemia and neutropenia due to copper deficiency have been documented in case reports and retrospective studies. Copper is vital for hematopoiesis, particularly in hemoglobin synthesis and red blood cell maturation. We present a case of Gollop-Wolfgang Complex presenting with severe copper deficiency.

Case Presentation: A 3-year-old female with Gollop-Wolfgang syndrome, spina bifida occulta, and a history of iron deficiency anemia who was being admitted for elective amputation of a bifid left femur presented with fatigue and chronic diarrhea. On admission, she exhibited significant anemia (Hb 2.3 g/dL), macrocytosis (MCV 100 fL), Neutropenia (500 K/µL), and an elevated Vitamin B12 (1,025 mcg). She was treated with blood transfusions and responded well. Comprehensive evaluation for viral infections, malabsorption, and inherited bone marrow failure syndromes was negative. Persistent severe anemia and neutropenia led to testing for micronutrient deficiencies, revealing undetectable copper, ceruloplasmin, and vitamin C, with normal zinc levels. Copper supplementation with IV Cupric Chloride improved anemia (Hb 9.5 g/dL), and neutrophil count (4,760 K/µL), and the patient became transfusion-independent. Genetic testing identified a homozygous variant of uncertain significance in the WDPCP gene associated with Bardet-Biedl Syndrome (BBS), though the patient's phenotype did not align with BBS.

Discussion: Gollop-Wolfgang syndrome, marked by tibial agenesis and bifurcated femur, has not been associated with hematologic abnormalities. Our patient had severe copper and vitamin C deficiency. Copper deficiency can lead to significant hematologic issues, including anemia and neutropenia. Our patient's chronic diarrhea suggested malabsorption despite normal endoscopic findings. Excessive cow's milk intake, known to interfere with copper absorption, was identified as a contributing factor. Copper deficiency should be considered in patients with unexplained severe anemia and neutropenia, especially when typical causes are ruled out.

Conclusion: Copper deficiency, though rare, should be evaluated in patients with severe anemia and neutropenia. Early recognition and supplementation can prevent severe hematologic complications. This case highlights the need for awareness and further research on copper deficiency, particularly in rare syndromes like Gollop-Wolfgang. A multidisciplinary approach is crucial for accurate diagnosis and management.
Haploidentical Peripheral Blood Stem Cell Transplantation Improves the Survival of Older Patients with Myeloid Malignancies Under Low-Dose Antithymocyte Globin (ATG)/Post-Cyclophosphamide (PTCy)-Based Regimen for Graft-Versus-Host Disease Prophylaxis
Authors: Jia Yannan , Xia Xinxin , Yang Jun , Cai Yu , Tong Yin , Huang Chongmei , Qiu Huiying , Zhou Kun , Zhang Ying , Shen Chang , Wan Liping , Song Xianmin
Published: December 2024

Our study delved into the clinical outcomes of haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) for older patients, utilizing a novel low-dose antithymocyte globin (ATG)/post-cyclophosphamide (PTCy)-based regimen to prevent graft-versus-host disease (GVHD). We juxtaposed these outcomes with transplants from matched unrelated/sibling donors (MUD/MSD) for elderly patients with myeloid malignancies from 2016 to 2023. The study encompassed 127 patients, with 40 undergoing MUD/MSD-PBSCT and 87 receiving haplo-PBSCT. The incidences of grades Ⅱ-Ⅳ and Ⅲ-Ⅳ acute GVHD were similar between the two groups, the haplo-PBSCT cohort displayed a promising trend toward reduced incidence of moderate to severe chronic GVHD compared to MUD/MSD-PBSCT (8.19% vs 23.40%, P=0.067). The 2-year disease-free survival (74.11% vs 59.67%, P=0.231) and overall survival (76.30% vs 64.00%, P=0.482) rates were comparable, while haplo-PBSCT exhibited higher graft-versus-host disease-free, relapse-free survival (GRFS) (68.85% vs 46.61%, P=0.041) and lower cumulative incidences of relapse (CIR) (11.16% vs 31.98%, P=0.010) compared to MUD/MSD-PBSCT. Our findings underscore the potential of haploidentical transplants with the low-dose ATG/PTCy-based regimen to yield improved GRFS and lower CIR for older patients with hematologic malignancies. Thus, haploidentical donors, especially when coupled with this specified GVHD prevention strategy, emerge as a viable and appealing graft source for elderly patients requiring allo-SCT.
Response of Thrombocytosis after Iron Replacement Therapy in Patients with Iron Deficiency Anemia
Authors: Bhatta Ghanshyam , Meseeha Marcelle , Khan Muneer , Richards Julie , Poulose Joyson , Talamo Giampaolo
Published: December 2024

ABSTRACT

Background: Iron deficiency anemia (IDA) is the most common cause of anemia worldwide. Patient with IDA often present thrombocytosis (defined as platelet count >450 x103/mL), but little is known about its degree and prevalence in this condition, and the response of platelet levels after iron replacement therapy.

Methods: We conducted a retrospective review of laboratory data of 24 consecutive patient with anemia secondary only to iron deficiency, both at baseline and at 3 months after either oral or intravenous iron replacement therapy.

Results: The mean age of the patients was 51 years (range, 24-83 years), and 17 of 24 (71%) patients were females. The causes of IDA were blood losses (n=12), poor gastrointestinal absorption (n=6), pregnancy (n=4), and unidentified (n=2). The iron replacement therapy consisted of oral FeSO4 (n=2), intravenous iron (n=9), or both (n=11). The mean Hb and ferritin levels at baseline and at 3 months after the iron replacement were 9.0 g/dL and 20.2 mg/dL, and 12.3 g/dL (p<0.001) and 176.2 mg/dL (p<0.001), respectively. Thrombocytosis at baseline was found in 5 of 24 (21%) patients, and after the iron administration it resolved in all patients (except one, who was found to have another condition causing thrombocytosis). The mean platelet level at baseline and at 3 months after the iron replacement was 380 and 288 x103/mL (p=0.002).

Conclusion: Thrombocytosis is found in about one fifth of patients with IDA, and it resolves within 3 months of adequate iron replacement therapy.
Dexamethasone Versus Prednisolone in Adults with Newly Diagnosed Immune Thrombocytopenia: A Systematic Review and Meta-Analysis
Authors: Srisurapanont Karan , Uawithya Ekdanai , Danpanichkul Pojsakorn , Worapongpaiboon Rinrada , Chai-Adisaksopha Chatree
Published: December 2024

Whether dexamethasone or prednisolone is the optimal first-line treatment in adults with newly diagnosed immune thrombocytopenia (ITP) remains controversial. We aimed to compare the efficacy and safety of dexamethasone and prednisolone in adults with newly diagnosed ITP. A systematic review and meta-analysis of randomized controlled trials (RCTs).

We searched Pubmed, Scopus, Cochrane Central Register of Controlled Trials, and Embase to identify relevant citations until May 16, 2024. RCTs comparing dexamethasone to prednisolone in adults with newly diagnosed ITP were included. The outcomes included early response (ER) at 1 week, initial response (IR) at 1 month, durable response (DR) at 6 months, persistent response (PR) at 12 months, and adverse events. The outcomes were pooled using the random-effect Mantel-Haenszel meta-analysis and reported as relative risks (RRs) alongside corresponding 95% confidence intervals (CIs). The certain of evidence of each outcome was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

We included 8 RCTs with 427 and 404 participants receiving dexamethasone and prednisolone, respectively. Dexamethasone yielded higher IR rates than prednisolone (RR 1.21, 95% CI 1.09-1.34). However, there was no improvement in terms of ER, DR, and PR. No significant difference was observed between 1-2 cycles and 3 cycles of dexamethasone in terms of IR (p=0.23), DR (p=0.64), and PR (p=0.88). Adverse events occurred more frequently in the prednisolone arm (141 events) than the dexamethasone arm (71 events), but the number of patients who discontinued the treatment was similar between both arms.

Very low certainty of evidence suggests that dexamethasone may be preferred compared to prednisolone in newly diagnosed adults with immune thrombocytopenia. Our findings suggested that one cycle of dexamethasone with a possible rescue course could be the optimal dosage.
Gene Mutation Profiles of Primary Pure Red Cell Aplasia and Large Granular Lymphocytic Leukemia Associated Pure Red Cell Aplasia
Authors: Zhang Yawen , Gong Yuemin , Liu Xiaoqing , He Guangsheng , Fan Lei , Li Jianyong
Published: December 2024

Acquired pure red cell aplasia (PRCA) is a kind of rare bone marrow failure disease characterized by destruction of erythrocyte by the immune system. However, the gene mutation profile of acquired PRCA remains obscure. Herein, we performed the targeted sequencing of 32 disease-related genes in 25 patients with primary PRCA and 32 patients with large granular lymphocytic leukemia (LGLL)-associated PRCA to reveal the mutational landscape of acquired PRCA, who were registered in Chinese Eastern Collaboration Group of Anemia (CECGA). Also, the T cell receptor (TCR) sequencing data of 8 patients with primary PRCA and 25 patients with LGLL-associated PRCA were collected to reveal the T cell clonotypes. The gene mutation was detected in 39.7% of acquired PRCA with a limited number of myeloid cancer candidate genes. The most frequent mutation is DNMT3A with 12.0% in PRCA, 12.5% in LGLL-PRCA. Mutations in RUNX1, ASXL1, BCOR, CBL, CEBPA, EZH2, IDH1 and SETBP1 were only found in patients with primary PRCA, and mutations in U2AF1 and MPL were only found in patients with LGLL-associated PRCA. Of note, except for the IDH2 mutation, the mutation sites of other genes were completely discordant in the PRCA and LGLL-PRCA groups. For LGLL-associated PRCA patients, TRBV6_TRBJ2, as a main clonotype was counted as a higher number during the disease period, as well as the number of clonotypes were relatively lower than that of the primary PRCA patients. The Hb levels were significantly higher in primary PRCA patients without mutation (P=0.0165). The ferritin level in patients with mutation was significantly higher (P=0.0217), in patients with LGLL-associated PRCA. This study describes and compares the mutation characteristics of primary PRCA and LGLL-associated PRCA.
Changes in Intensive Care Unit Mortality and Treatment Patterns in Acute Leukemia Patients over a 16-Year Period in China
Authors: Lu Linli , Cheng Qian , Li Xin
Published: December 2024

Background: Acute leukemia (AL) can lead to life-threatening complications and often requires treatment in the Intensive Care Unit (ICU). Our previous study found that patients with AL showed a poor prognosis after ICU admission. The aim of this study was to assess the prognostic changes of AL patients admitted to the intensive care unit in recent years, to analyze the basic characteristics of ICU patients, changes in treatment patterns, and to identify risk factors affecting patient prognosis, thereby providing further guidance for the clinical management of critically ill leukemia patients.

Methods: This was a single-center, retrospective study, including 126 patients diagnosed with AL and admitted to the ICU between 2008 and 2023, with the study period divided into four-year intervals.

Results: A total of 37 patients with acute lymphoblastic leukemia (ALL) and 89 patients with acute myeloid leukemia (AML) were included, with a median age of 40 years (14-81). The most common reason for ICU admission was respiratory failure (46%), followed by shock (17.5%). The average age of patients admitted to the ICU was similar during the study period, but there was a trend towards a decrease in criticality scores, including APACHE Ⅱ and SOFA scores, and a prolongation of the mean length of stay in the ICU at the time of ICU admission. The ICU mortality rate for the entire cohort of patients was 57.9%, ICU mortality decreasing from 72.7% in 2008-2011 to 46.5% in 2020-2023, and similarly, the 1-month mortality rate (90% to 46.5%) and the 6-month mortality rate (90% to 46.5%) have also decreased. The use of invasive ventilation and vasopressor drugs decreased (72.7% and 86.4% to 51.2% and 62.8%), while use of non-invasive ventilation (22.7% to 32.5%) and dialysis increased (0% to 20.9%). It should be emphasized that the detection rate of pathogens in infected patients rose from 36.4% to 74.4%, which were due to the application of bronchoalveolar lavage fluid and next-generation sequencing (NGS) in detecting the pathogens. Notably, despite the reduction in invasive ventilation, there was a significant increase in the mean duration of invasive ventilation. Multivariate analysis showed that the independent risk factor associated with ICU mortality was invasive ventilation treatment (OR=13.068), whereas ICU length of stay longer than 7 days (OR=0.18), direct admission to the ICU (OR=0.155), and disease remission status at ICU admission (OR=0.071) were protective factors.

Conclusion: In conclusion, ICU mortality and 6-month mortality for AL patients with ICU admission were decreased from 2008 to 2023. Concurrently, ICU treatment patterns changed, with prolonged stay in the ICU, increased use of non-invasive ventilation treatment, decreased use of invasive treatments, and a significant increase in pathogen detection rates in infected patients.
BEAT Chemofree Regimen for Relapsed/Refractory and De Novo T-ALL
Authors: Lin Jieping , Zhou Xuan , Wang Zhixiang , Lin Dainan , Zhan Yu , Li Zan , Huang Jiwei , Li Yonghua , Ma Xudong , Liu Qifa , Xuan Li , Xu Yang , Zhou Hongsheng
Published: December 2024

Background: Relapsed or refractory (R/R) and unfit T-cell acute lymphoblastic leukemia (T-ALL) have limited therapeutic options and a poor prognosis, with a 5-year overall survival rate of 20% and a complete response (CR) rate around 36%. Our previous study found that tucidinostat plus pediatric-inspired chemotherapy improves the survival of T-ALL. Venetoclax demonstrated high sensitivity in vitro and in vivo for T-ALL, particularly early T-cell precursor lymphoblastic leukemia (ETP-ALL), and exhibited synergistic therapeutic effects with l-asparaginase and dexamethasone. Therefore, we hypothesized that the BEAT chemofree regimen (Bcl-2 inhibitor, dExamethasone, Aaspargase, and Tucidinostat) would be safe and effective for R/R and de novo T-ALL.

Methods: BEAT chemofree regimen consists of bcl-2 inhibitor, dexamethasone, aspargase, and tucidinostat. Patients with R/R and de novo T-ALL were enrolled in this study and received BEAT chemofree regimen including venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14), tucidinostat and dexamethasone (10 mg on days 1-14) and pegaspargase (2000IU on day 3). This is a pilot study and we intend to conduct a multicenter randomized controlled trial in order to investigate and validate the efficacy and safety of the chemofree regimen in T-ALL.

Results: From January 2023 to June 2024, 6 patients with R/R T-ALL and 6 patients with de novo T-ALL were enrolled. For R/R T-ALL, the median age was 26 years (range 19-34 years), 67% were male, 100% were Asian, 4 had a diagnosis of ETP-ALL and 2 of Non ETP-ALL, 6 (100%) had received more than two lines of chemotherapy and 1 had received CD7 CAR-T therapy. For de novo T-ALL, the median age was 53 years (range 18-62 years), 73% were male, 100% were Asian, 4 had a diagnosis of ETP-ALL and 2 of Non ETP-ALL. Among the R/R T-ALL patients, 3 (50%) patients CR or CR with incomplete count recovery (CRi), including 2 (33%) patients achieved MRD <10-4. One (17%) patient achieved partial remission (PR). The overall response rate (ORR) for R/R T-ALL is 67%. Among the de novo patients, 6 (100%) achieved CR/CRi including 4 (67%) achieved MRD<10-4. The ORR for de novo T-ALL is 100%. The safety profile of BEAT regimen is well-tolerated in both R/R and de novo T-ALL. The most common grade 3-4 adverse events (AEs) of R/R T-ALL were neutropenia (67%), anemia (67%), thrombocytopenia (67%), febrile neutropenia (33%), lung infection (17%), septicemia (17%) and hypocalcemia (33%). The most common grade 3-4 AEs of de novo T-ALL were neutropenia (83%), anemia (67%), thrombocytopenia (34%), febrile neutropenia (17%), lung infection (17%) and ALT increased (17%). There were no gastrointestinal disorders of grade 3-4 or serious AEs of grade 5.

Conclusion: BEAT chemofree regimen is a promising and well-tolerated regimen in R/R and de novo T-ALL, with high CRc and ORR.
Transmembrane Thiol Isomerase TMX1 Inhibits Fibrin Formation By Down-Regulation of Platelet Phosphatidylserine Exposure
Authors: Zhao Zhenzhen , Lv Keyu , Cheng Yixin , Fang Chao , Wu Yi , Yang Aizhen
Published: December 2024

Objective: Membrane exposure of phosphatidylserine (PS) on platelets is critical for the binding of coagulation factors leading to coagulation activation, however, the mechanism controlling PS exposure remains largely unknown. Using genetically modified mouse models, we previously reported that a transmembrane disulfide isomerase TMX1 inhibited integrin αIIbβ3 outside-in signaling which is important for PS exposure on platelets. In this study, we investigated the role of TMX1 in PS exposure and coagulation.

Approach and Results: We found that the deficiency of TMX1 in platelets enhanced fibrin formation and PS exposure at the site of injury. In vitro, TMX1 inhibited thrombin generation mediated by activated platelets, and attenuated PS exposure on platelets, the effect of which was prevented when integrin αIIbβ3 outside-in signaling was blocked, suggesting that TMX1 inhibition of integrin αIIbβ3 outside-in signaling suppresses PS exposure. Moreover, TMX1 deficiency increased the free thiols of TMEM16F in platelets including Cys338, Cys349 and Cys352. In HEK293T cell overexpressing C338S-, C349S-mutated TMEM16F, the PS exposure was increased, suggesting that TMX1 oxidizes these disulfide bonds of TMEM16F, decreasing its activity to externalize PS on the membrane.

Conclusion: Together, our observations for the first time demonstrate that TMX1 inhibits PS exposure in platelets downregulating the procoagulant activity, by which TMX1 plays a critical role in maintaining vascular quiescence.