bluuebunny/crossref_metadata_2025 huggingface dataset:
Revealing Morphometric Differences between Hematopoietic and Leukemic Stem Cells in Acute Myeloid Leukemia: AI-Based Analysis of Imaging Flow Cytometry Data
Authors: Engelbrecht Hybel Trine , Jensen Sofie Hesselberg , Rodrigues Matthew A. , Hybel Thomas Engelbrecht , Qvick Signe Håkansson , Enemark Marie Hairing , Bill Marie , Rosenberg Carina Agerbo , Ludvigsen Maja
Published: December 2024

Acute myeloid leukemia (AML) is a heterogenous blood cancer originating from genetic transformation of hematopoietic stem cells (HSCs) into aberrant leukemic stem cells (LSCs), causing accumulation of immature leukemic blasts and suppression of healthy hematopoiesis in the bone marrow (BM). The frequency of LSCs holds strong prognostic value in AML, and LSC surveillance during treatment improves minimal residual disease monitoring. However, LSC detection and differentiation from healthy HSCs remain challenging due to substantial heterogeneity in immunophenotypes. Therefore, new techniques are warranted for HSC-LSC discrimination. In this regard, imaging flow cytometry (IFC) combined with artificial intelligence has proven a novel tool for morphometric cell characterization. Recently, we have described the application of deep learning on IFC data to classify stem cells as either CLEC12A+ aberrant AML LSCs or CLEC12A- healthy HSCs, achieving up to 93% accuracy using brightfield (BF), side scatter (SSC), and DNA imagery (Hybel et al. 2024). In the present study, we have analyzed the image data to identify the discriminative cellular features that may have contributed to the previously observed results. Using the IDEAS software, a total of 85 morphometric feature values, including 31 BF, 36 SSC, and 18 DNA features, were generated for 44,277 CLEC12A+ LSCs and 8,817 CLEC12A- HSCs acquired by IFC from five AML BM samples and ten healthy donor BM samples, respectively. A logistic regression model was trained for HSC-LSC differentiation and revealed significant differences in 17 BF features (e.g., cellular area, compactness, and contrast), 22 SSC features (e.g., intensity, gradient root mean square, and perimeter), and 15 DNA features (e.g., nuclear area, circularity, and lobe count). Following class balancing by oversampling, an overall accuracy of 78%, sensitivity of 76%, and specificity of 81% were achieved. Moreover, unsupervised principal component analysis was performed on LSCs and HSCs, both separately and combined. However, HSCs and LSCs were not segregated into distinct groups. The analyses revealed subtle differences in LSC morphometry between different AML patients, whereas HSCs from healthy donors displayed morphometric similarity. Our results support the use of IFC as a technique for characterizing pathological changes within stem cells in AML. The morphometric differences described between HSCs and LSCs may facilitate future development of innovative methodologies for monitoring minimal residual disease within AML.
Association between Provoked and Unprovoked Venous Thromboembolism and Malignancy: A Cross-Sectional Retrospective Cohort Study
Authors: Naqvi Syeda Hira , Cheekati Mahija , Saad Firas , Caulfield Joseph , Farber Charles M. , Pillai Anjana
Published: December 2024

Introduction:

A strong association exists between incidences of deep venous thrombosis (DVT), pulmonary embolism (PE), or venous thromboembolism (VTE) in cancer patients. Evidence for subsequent incidence of new malignancy in patients with VTE is poor and controversial. There is even less evidence to demonstrate an association between malignancy and provoked and unprovoked VTE. Despite this, extensive invasive and non-invasive diagnostic investigations are often performed during hospitalizations for VTE to rule out malignancy in patients. Through our study, we sought to further investigate the association of incidences of malignancy between provoked and unprovoked VTE patients.

Methods:

A retrospective search was first conducted to identify adult hospitalizations for VTE at a single tertiary care center for 2019. Through manual chart review for inciting risk factors, these patients were categorized as provoked and unprovoked. The two cohorts were longitudinally followed over a subsequent 5-year period (2020-2024). for the incidence of new malignancies. Patients with known malignancy and those who were lost to follow-up over the 5 years were excluded from the final analysis pool. Final data was analyzed using StataBE18 software to perform the Chi-squared test and Risk Ratio.

Results:

We identified 221 VTE hospitalizations in the year 2019, of which 155 were categorized as provoked and 66 as unprovoked. After excluding patients lost to follow-up and patients with active malignancy (75 provoked and 12 unprovoked), the final analysis included 80 provoked and 54 unprovoked VTE cases. Of the 54 unprovoked VTE patients, 5 (9.26%) were diagnosed with new malignancy during the follow-up period. Of the 80 provoked patients, 7 (8.75%) patients were diagnosed with new malignancy. We performed a Pearson's Chi-squared test to evaluate statistically significant differences in incidences of new cancer between each of the cohorts and found that the incidences were similar (chi2=0.0103; p-value 0.919) with a risk ratio of 1.03 and a 95% Confidence Interval between 0.51-2.10.

Conclusions:

Our analysis indicates that there is no statistically significant relationship between unprovoked or provoked VTE and the diagnosis of new malignancy. The incidence rates were almost similar in both cohorts. Therefore, patients with either provoked or unprovoked VTE should not require additional aggressive testing for malignancy. They should be expected to undergo age-appropriate screening as otherwise indicated. Excessive testing can lead to anxiety, prolonged hospitalization, misallocation of resources, and increased healthcare spending. Our study limitations include a small sample size and single-center analysis. Future larger studies comparing outcomes at different centers can provide further clarity to streamline our findings, given historically conflicting reports.
Evaluation of the Individual Components of the International Metabolic Prognostic Index (IMPI) in the Context of CAR T-Cell Treatment of Lymphoma
Authors: Winkelmann Michael , Rejeski Kai , Blumenberg Viktoria , Sheikh Gabriel , Buecklein Veit L. , Brendel Matthias , Von Bergwelt Michael , Subklewe Marion , Kunz Wolfgang G
Published: December 2024

CD19 specific chimeric antigen receptor (CAR) T-cell therapy with patient-derived T cells has emerged as novel and effective treatment for relapsed or refractory (r/r) lymphoma. Imaging biomarkers are becoming increasingly important in risk assessment. Recently, the International Prognostic Metabolic Index (IMPI) consisting of metabolic tumor volume (MTV), patient age and Ann Arbor stage was introduced for prognostic assessment in NHL. Since higher patient age is a favorable prognostic factor and a high MTV is a negative prognostic factor in the context of CART, we compared the predictive value of the individual components of the IMPI for progression-free survival (PFS) and overall survival (OS).

Consecutive r/r NHL patients treated with CD19 CAR T-cell therapy and 18F FDG-PET/CT imaging at baseline less than 2 weeks before lymphodepletion and infusion of CAR T cells were included. Patient age was calculated at the time of lymphodepletion. Ann Arbor stages were determined at the baseline PET/CT. MTV was also quantified on the same PET/CT scan before CART and quantified with LIFEx software using semi-automated segmentation with an absolute SUV cutoff of 4 defining metabolic active lymphoma. Survival analysis of PFS and OS was analyzed and plotted with Kaplan-Meier curves.

Out of all examined patients 43 patients were included (37% female, 63% male) with a median age of 66 years and a median baseline MTV of 276 mL. The Ann Arbor stage was I in 4 patients, II in 11 patients, III in 8 patients and IV in 4 patients. The distribution of patients in to two different groups by median IMPI showed minor, non-significant differences in median PFS (97 vs 364 days; p=0.198) and OS (657 days vs not reached; p=0.718). Dichotomization by median MTV alone showed a larger, statistically significant difference (p=0.037) in median PFS (87 vs 659 days) and a larger, non-significant difference in OS (p=0.300). Patients with older age had slightly longer PFS (153 vs 97 days) and a comparable OS (686 vs 657 days), but these findings were not statistically significant (both p>0.05). In addition, there were no relevant differences when the patients were divided into subgroups according to their Ann Arbor stages.

For r/r NHL patients on CART, the IMPI is a promising tool. However, in our study, the MTV alone was superior in estimating prognosis. Future studies with a larger cohort should investigate the best combination of the individual components. The integration of multiple diagnostic modalities as in IMPI offers a promising method to clinically assess patient risk in CART treated lymphoma patients and should be further investigated.
The Procoagulant Effect of Plasma-Derived Preparations of Apo H (b2-glycoprotein I) on Thrombin Generation Is Mediated By FXIa Contaminant
Authors: Liang Yideng , Tarandovskiy Ivan , Yang Hailing , Wang Yonggang , Eller Nancy , Surov Stepan , Parunov Leonid , Scott Dorothy E , Sauna Zuben E. , Ovanesov Mikhail
Published: December 2024

Background. Apolipoprotein-H (APOH), also known as b2-Glycoprotein I (b2GPI), is a plasma protein that was found in immune globulin product lots associated with thrombotic complications. Previously, APOH demonstrated anticoagulant activity, on the contrary, Lackner et al reported that APOH has procoagulant function. In the present study, we show that plasma derived APOH (pdAPOH) can be contaminated with activated coagulation factor XI (FXIa).

Methods. In-house modified simultaneous thrombin and fibrin generation assay (TGA) along with FXIa activity chromogenic assay (FXIa:C) were used to detect FXIa function. In parallel, high-performance liquid chromatography (HPLC) was used to demonstrate presence of FXIa in the procoagulant APOH.

Results. Functional FXIa activity was detected in plasma derived APOH (pdAPOH-FIT). This activity was comparable to that measured in purified FXIa and procoagulant immune globulin product (IGIV) batches known to contain FXIa. Anti-FXIa antibody blocked procoagulant activity of pdAPOH-FIT in the TGA. An APOH sample from another source pdAPOH-2 and recombinant APOH did not show any activity in the TGA. Presence of FXIa in pdAPOH-FIT was confirmed using the chromogenic assay. Using HPLC, we show that peaks for pdAPOH-FIT and pdAPOH-2 differed. However, procoagulant pdAPOH-FIT demonstrated peaks similar to pdAPOH-2 when spiked with FXIa.

Conclusions. APOH does not demonstrate procoagulant activity in TG assay in plasma. plasma derived APOH products may contain procoagulant FXIa contaminant in the amounts sufficient to impact TG which may be misinterpreted as procoagulant activity of APOH.
BTK Inhibitors and Chidamide-Combined Therapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma with MYC+
Authors: Zhou Lili , Ye Shiguang , Li Ping , Li Bing , Lu Yan , Li Shaoguang , Liang Aibin
Published: December 2024

Background:

Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) shows poor clinical outcomes, particularly in patients with MYC rearrangement or mutations. Monotherapy Bruton tyrosine kinase inhibitors (BTKi) have established modest antitumor effect in R/R DLBCL by targeting B-cell receptor signaling, with median progression-free survival (PFS) and overall survival (OS) of 1.64-2.8 months and 6.4-8.4 months, respectively. Chidamide is a selective oral histone deacetylase inhibitors (HDACi) that shows promising treatment for DLBCL and may overcome BTKi resistance. So, we evaluated the efficacy and safety of BTKis and chidamide-combined therapy in R/R DLBCL with MYC+ .

Methods:

This retrospective study consists of 12 R/R DLBCL who received combination therapy of chidamide and BTK inhibitors between January 2023 and July 2024. Chidamide was orally administered at a dose of 20 mg twice a week, while the BTK inhibitor was administered daily. Patient clinical characteristics were collected upon patient enrollment. Efficacy outcomes included overall response rate (ORR), PFS and OS, whereas safety outcomes included incidence of adverse events.

Results:

12 R/R DLBCL patients were enrolled. Median age was 63 years (range, 39-73), and 83.33% of the patients had non-germinal center B-cell-like (non-GCB) DLBCL, two had transformed DLBCL. The median number of previous treatment lines was 3 (range, 1-8). 10 patients (83.33%) received treatment with BTK inhibitors before. The best ORR was 66.67%, with 8 of 12 patients acquired objective disease remission after 1-2 cycles. Among them, 6 patients (50%) achieved complete response, and 2 patients (16.67%) achieved partial remission. With a median follow-up of 6.5 months, the median PFS and median OS was not yet reached. In terms of adverse events, the most common hematologic toxicities observed were neutropenia (50%, 6/12) and anemia (66.67%, 8/12). This study was registered as ChiCTR2300073233.

Conclusion:

This study revealed promising results. Chidamide combined with BTK inhibitors showed high efficacy and manageable tolerability in R/R DLBCL patients with MYC+. Although the majority of patients were treated with BTK inhibitors and experienced relapse and resistance, the addition of chidamide brought patients back into remission, suggesting that chidamide can enhance the efficacy of BTK inhibitors and overcome acquired resistance.

Keywords: BTK inhibitors, Chidamide, R/R DLBCL, MYC，efficacy and safety
Identification of Amino Acid Residues in Protein S LG Domains Responsible for Binding to and Inhibiting Factor IXa
Authors: Yasmin Rafika , Kumar Narender , Vandana  , Satish Vijaya Pilli , Majumder Rinku
Published: December 2024

Protein S (PS) is a key negative regulator of blood coagulation. Protein S deficiency and dysfunction cause life-threatening thrombotic conditions such as neonatal purpura fulminans, deep vein thrombosis, arterial thrombosis, and pulmonary embolism. Protein S has long been described as a cofactor for both Activated Protein C and Tissue Factor Pathway Inhibitor. However, we discovered that PS has an important regulatory function in the coagulation cascade, namely, direct inhibition of activated Factor IX (FIXa). This function is performed by binding between the laminin G (LG) domains of PS and the heparin-binding exosite of FIXa.

Our goal in this study was to identify the amino acid residues of PS involved in binding FIXa. In silico interaction studies predicted candidate FIXa interaction sites within PS LG domains. These sites were mutated to obtain single amino acid substitutions D345A, T372A, S394A, E435A, and E437A and a double mutant E453A/E437A, all successfully expressed in E.coli. The purity of these proteins was confirmed by SDS-PAGE followed by silver staining and immunoblotting. Using fluorescence-based interaction methods, we identified the amino acid residues that are vital for PS-FIXa interaction. The double mutant E453A/E437A had the lowest binding affinity of the mutants. The mutants were further analyzed by in vitro biochemical assays to measure their ability to inhibit FIXa's activity of converting FX to activated FXa. Interestingly, both the E453A/E437A double mutant and the single mutants E453A and E437A showed minimal inhibition of FIXa. These data suggested that the glutamic acid (E) residues at positions 453 and 437 of PS are important both for binding FIXa and for inhibiting FIXa activity.

In summary, we identified two amino acid residues in the PS LG domain required for binding FIXa and inhibition of FIXa enzymatic activity. Our results explain the structure-function relation between PS and FIXa in hemostasis. Further measurement of effects these mutants in vivo will provide a comprehensive understanding of the PS function in the coagulation pathway and potentially identify targets for therapeutic interventions to manage coagulation disorders.
Clinical and Molecular Differences in Diffuse Large B-Cell Lymphoma with and without Testicular Involvement: A Cbioportal Analysis
Authors: Bahar Furkan , Khaddour Karam
Published: December 2024

Background: Diffuse Large B-Cell Lymphoma (DLBCL) exhibits diverse clinical behaviors. Testicular DLBCL can have distinct clinical presentation and genetic landscape compared to non-testicular DLBCL. This study aims to characterize these differences to improve diagnostic precision and therapeutic strategies.

Methods: By using cBioPortal (1), we detected 1,658 DLBCL cases from six studies that were previously published, focusing on 722 cases with recorded testicular involvement status. We compared demographic data, survival, tumor mutational burden (TMB), and gene alteration profiles between groups with and without testicular involvement in DLBCL.

Results: Among the 722 cases, 80 (11.1%) had testicular tumor infiltration. Patients with testicular DLBCL presented at a significantly younger age (mean is 60.82 years, 95% CI: 59.49-61.87) compared to those without testicular involvement (mean is 67.56 years, 95% CI: 65.05-70.07). Moreover, testicular involvement was associated with a higher incidence of pleural and intraabdominal lesions (p=2.11E-3 and p=1.53E-4, respectively). Both groups had statistically similar overall survival. Consistent with previous small cohort studies, mutational analysis revealed that, MYD88 gene, a critical mediator in the NF-kB signaling pathway which influences B-cell survival and proliferation, showed significant mutation enrichment in the testicular group (45.88% vs. 15.8% in the non-testicular group, p=1.42E-9). Other mutations such as PIM1(p=2.694E-4), CDKN2A(p=1.844E-3), and ARID1A(p=6.845E-3) were also significantly higher in the testicular group despite similar TMB in both groups, suggesting a distinct pathogenic mechanism in these lymphomas.

Conclusions: Patients with testicular DLBCL present at a younger age compared to the patients with non-testicular DLBCL. The high prevalence of MYD88 mutations in the testicular subgroup suggests potential therapeutic targets and warrants further investigation into tailored treatment protocols for this population. In addition, non-testicular DLBCL patients with MYD88 mutations might benefit from regular testicular examination with ultrasound for early detection.
Impact of Daratumumab in Transplant Eligible/Ineligible Patients with Newly Diagnosed Multiple Myeloma: An Updated Meta-Analysis of Phase-III Trials
Authors: Fernandes Bolivia Crocete Aloysia , Shah Vedant , Ali Muhammad Ashar , Shah Abhi , Madine Makarand , Gottumukkala Mounika , Pandeti Sucharitha , Syed Safa , Nookala Vinod
Published: December 2024

Introduction: With the recent advancement in multiple myeloma, Daratumumab a monoclonal antibody against CD38 has been shown promising results especially in those with who were refractory to other treatments. In this meta-analysis, we aimed to analyze the efficacy of daratumumab in newly diagnosed patients with multiple myeloma who were or were not eligible for transplant therapy.

Methods: A thorough search was conducted in PubMed, Cochrane, and Clinicaltrials.gov using the MeSH terms “daratumumab” or “Darzalex” and “multiple myeloma” covering the period from 2000 to 2024. Studies that compared daratumumab combined with other therapies versus combination therapy alone were included. The Mantel-Haenzel formula was employed to calculate the pooled risk ratio (RR), and the Generic Inverse Variance method was used to determine the pooled hazard ratio for disease progression, using RevMan version 5.4 with a 95% confidence interval (CI). A P value of less than 0.05 was deemed significant.

Results: A total of 6 phase-III RCTs 3664 patients were analyzed. The use of daratumumab was associated with 39% fewer events of progression of disease or deaths in TE group (RR= 0.61; 95% CI= 0.39 to 0.93; p=0.02) and 29% lower in TIE group (RR= 0.71; 95% CI= 0.53 to 0.94; p=0.02). The hazard ratio for progression or death with daratumumab group versus control in both transplant eligible (TE) (HR= 0.44; 95% CI= 0.35 to 0.57; p<0.00001) or transplant ineligible (TIE) (HR= 0.47; 95% CI= 0.38 to 0.59; p<0.00001) group was significantly lower. Daratumumab significantly increased overall response rate (ORR) (RR= 1.20; 95% CI= 1.11 to 1.30 ; p<0.00001) and complete response (CR) (RR= 1.34; 95% CI= 1.02 to 1.76; p=0.04) in the TIE group only. Interestingly, the rate of minimal residual disease (MRD)-negative was increased only in the TIE group (RR= 4.09; 95% CI= 2.81 to 5.94; p<0.00001) with the use of daratumumab compared to the TE group.

Conclusion: Use of daratumumab showed benefits in both TE and TIE patients with newly diagnosed multiple myeloma (NDMM). It significantly reduced the risk for disease progression or deaths and improved clinical outcomes in terms of ORR and CR. The most notable improvements were observed in the TIE-NDMM group, suggesting an effective treatment option in these patient groups.
Allogeneic Haematopoietic Stem Cell Transplantation Is Safe and Effective for Myeloid Neoplasms with Germline DDX41 Mutation
Authors: Nelles Ricky , Butler Jason , Curley Cameron , Henden Andrea S , Hunt Stewart , Morton James , Subramoniapillai Elango , Stewart Caroline , Tey Siok-Keen , Kennedy Glen A , Scott Ashleigh P
Published: December 2024

Aim:

Germline DDX41 mutations define specific myeloid neoplasm subtypes including AML and MDS. Whilst DDX41-mutated patients often undergo allogeneic haematopoietic stem cell transplant (HSCT), recent retrospective analyses have reported higher severe acute and chronic graft vs host disease (GVHD)1 and inferior survival2 compared to non-DDX41 mutated patients. We aimed to review the outcomes of patients transplanted at our center for myeloid neoplasms with germline DDX41 (MN-DDX41).

Method:

We conducted a retrospective analysis of all patients treated at our institution for MN-DDX41 between January 2019 to January 2024. Data collected included disease characteristics, genomic data, treatment details, response outcomes and survival. The primary endpoint was overall survival (OS), with secondary endpoints including treatment-related mortality (TRM), relapse, and GVHD incidence.

Results:

22 patients with MN-DDX41 were identified (8 AML, 14 MDS). Median age at diagnosis was 64 (range 59-75 years), with 18 (87%) male. Donor source was matched sibling (1; 7%), matched unrelated (11; 79%) or mismatched unrelated (2; 14%); conditioning was reduced-intensity or non-myeloablative in 13 and 1 respectively; GVHD prophylaxis was CsA/MTX in 8 (57%) and PTCy/tacrolimus/MMF in 6 (43%). After median follow-up of 27 months (range 6-64mo), 17 (77%) are alive; 4 patients not receiving HSCT died from progressive/refractory disease, and 1 HSCT recipient died from infection soon after engraftment. For HSCT recipients, after median follow-up 18 months post-HSCT (range 1-45mo), 13 (93%) remain alive in remission. The cumulative incidences of acute (grade II-IV) and moderate-severe chronic GVHD are 35% and 50% respectively. OS following original diagnosis showed a non-significant trend for HSCT recipients vs non-recipients (2-yr OS 90% vs 65%; p=0.19).

Conclusion:

Despite adverse risk factors our early single-centre experience suggests that allogeneic HSCT is acceptably safe and efficacious for patients with MN-DDX41, and supports its use compared to non-HSCT alternatives. Confirmation in larger, multicentre studies with longer follow-up is warranted.

References: Saygin C, Roloff G, Hahn CN, Chhetri R, Gill S, Elmariah H, et al. Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies. Blood Adv. 2023 Feb 17;7(4):549-54. Baranwal A, Nanaa A, Viswanatha D, He R, Foran J, Badar T, et al. Outcomes of allogeneic transplant in patients with DDX41 mutated myelodysplastic syndrome and acute myeloid leukemia. Bone Marrow Transplant. 2022 Nov;57(11):1716-8.
Influence of Intestinal Flora Metabolism on Aplastic Anemia and Its Mechanism
Authors: Meng Xiaorui , Fu Rong
Published: December 2024

Aplastic anemia (AA) is an autoimmune disease mediated by T-lymphocyte hyperfunction and targeting the hematopoietic system. Recent studies have shown that gut flora metabolism has an important role in the human immune system, which in turn affects a number of immune system diseases. Our previous study found that flora metabolites and intestinal microbial species were significantly different in both AA patients and healthy individuals, with increased levels of isobutyric acid in plasma and bone marrow supernatants, and decreased levels of Citrobacter, among others, in the feces of AA patients. In this study, we conducted an animal model to further explore the mechanism. through mouse experiments, we found that the intestinal mucosa of AA model mice was thinner, less mucus, and fewer cup cells in comparison with healthy mice. transplantation of intestinal flora from normal mice in AA mice resulted in a significant improvement in the survival rate compared with that of the non-transplanted AA mice, and the analysis revealed that the proportion of CD4+ T cells in peripheral blood, spleen, and bone marrow was elevated in relation to absolute value and CD8+ T cells decreased in proportion and absolute value, and pathologic analysis showed improved myeloproliferation. In addition, isobutyric acid, in normal mice, resulted in an increase in the proportion of CD8+ T cells, a trend identical to that of AA, with a tendency to exacerbate the condition in AA mice. This suggests that intestinal flora may affect immune cells by influencing the intestinal mucosal barrier and thus AA disease progression.再生障碍性贫血(AA)是一种由t淋巴细胞功能亢进介导的以造血系统为靶点的自身免疫性疾病。最近的研究表明，肠道菌群代谢在人体免疫系统中具有重要作用，进而影响许多免疫系统疾病。我们前期研究发现AA患者与健康个体的菌群代谢物和肠道微生物种类存在显著差异，AA患者血浆和骨髓上清液中异丁酸水平升高，粪便中柠檬酸杆菌(Citrobacter)水平降低。在本研究中，我们通过动物模型来进一步探讨其机制。通过小鼠实验，我们发现AA模型小鼠的肠黏膜较健康小鼠更薄，粘液更少，杯状细胞更少。正常小鼠肠道菌群移植AA小鼠的存活率较未移植AA小鼠明显提高，外周血、脾、骨髓中CD4 T细胞比例绝对值升高，CD8 T细胞比例绝对值降低，病理分析显示骨髓增生改善。此外，异丁酸在正常小鼠中导致CD8 T细胞比例增加，与AA相同，并有加重AA小鼠病情的趋势。这表明肠道菌群可能通过影响肠黏膜屏障从而影响免疫细胞，从而影响AA疾病的进展。
CXCL-9 and IL-18: Potential Biomarkers for Efficacy Evaluation in Refractory Hemophagocytic Lymphohistiocytosis Treated with RED (Ruxolitinib, Emapalumab and Dexamethasone)
Authors: Lan Xuan , Wang Zhao
Published: December 2024

Hemophagocytic lymphohistiocytosis (HLH) is a severe disorder characterized by excessive inflammation of cytokines. More than 30% refractory to frontline therapy. Unfortunately, there is no standard second-line regimen for HLH, and around 30% patients showed no responses to current salvage treatments. However, little study reported the alternative therapy and the changing time point for refractory patients. This study retrospectively analyzed the efficacy and safety of the RED (Ruxolitinib Emapalumab, and dexamethasone) regimen in 15 refractory HLH patients who failed to respond to at least twice salvage therapies. Overall, eight (53.3%) patients achieved better remission after RED regimen, of which four patients received HSCT. The level of CXCL-9 and IL-18 before RED treatment showed a significant difference between PR and PD patients, which suggested patients with high level of CXCL-9 and IL-18 may benefit from RED. By analysis of 8 PR HLH, we also found that except white blood cell, Hb and Fbg, the level of AST, CXCL-9 and Ca2+ remission after two weeks of RED treatment. We didn't observe grade 3 or higher adverse effects related to the RED regimen. This is the first comprehensive research of RED in HLH, represents a viable and safe alternative treatment for salvaging R HLH.
Use of Dihydroartemisinin-Piperaquine for the Treatment of Malaria in HIV+ Pregnant Women: Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Younas Ayesha , Nashwan Abdulqadir , Pottabathini Rahul , Ayoobkhan Fathima Shehnaz
Published: December 2024

.Background The use of dihydroartemisinin-piperaquine for the prevention of malaria in HIV-positive pregnant women was not investigated yet. Hence, we conducted systematic review and meta-analysis to discover the effectiveness of dihydroartemisinin-piperaquine for the prevention of malaria in HIV-positive pregnant women. Methodology A comprehensive search on PubMed, Google scholar, Cochrane library was conducted from inception till July 2024 and only randomized controlled trials were searched. Rev Man 5.4.1 was used to pool risk ratios of dichotomous outcomes under Random Effects models. Our primary outcome includes incidence of any malaria infection at pregnancy or during delivery diagnosed by any test. While secondary outcomes include composite birth outcome and prevalence of maternal anemia at pregnancy or during delivery. Results Statistical analysis shows that dihydroartemisinin-piperaquine significantly reduced the risk of any malaria infection at pregnancy or during delivery (RR=0.46. CI=0.33-0.64, I2=0). However, the prevalence of maternal anemia at pregnancy or during delivery (0.94, CI=0.84-1.05, I2=21%) and adverse pregnancy outcome (RR=0.95, CI=0.66-1.36, I2=32%) did not differ significantly between the two groups. Conclusion Hence, we conclude that addition of dihydroartemisinin-piperaquine to daily cotrimoxazole reduce the incidence of any malarial infection in HIV-positive pregnant women, however incidence of maternal anemia at pregnancy or during delivery and adverse pregnancy outcome did not differ between the two-treatment groups.
Ixazomib, Pomalidomide and Dexamethasone (IxaPD) Pan-Oral Regimen in the Treatment of Refractory and Relapsed Multiple Myeloma
Authors: Chen Miao , Yu Hong , Liu Aijun , Wang Wei , Qin Xiaoqi , Li Ziping , Ma Yanping , Chen Wenming , Fu Rong , Zhuang Junling
Published: December 2024

Aim To analyze the efficacy and safety of Ixazomib, pomalidomide and dexamethasone (IxaPD) regimen in patients with refractory and relapsed multiple myeloma（RRMM）.

Methods Clinical data of RRMM patients were prospectively collected from 5 centers in north China from Mar 2021 to Nov 2023 who were treated by IxaPD regimen for at least two courses. Overall response rate (ORR), time to next treatment (TTNT) and overall survival (OS) were analyzed as end points.

Results A total of 50 patients were enrolled, including 30 in multicenter real-world study and 20 in investigator initiated IxaPD trial (NCT04989140) who were naïve to ixazomib or pomalidomide with previous treatment of 1 to 3 lines. There were 28 males and 22 females with the median age 65.5 (range 41-82) years old. The median duration from diagnosis to enrollment was 30 months (range 1-170), including 26/50 (52.0%) patients were in first relapse. Twenty-three in 41 (56.1%) patients had high-risk cytogenetic abnormalities. Regarding previous history, 15.2% presented renal insufficiency, 4 cases (8.0%) had extramedullary diseases, and 7 case (14.0%) received autologous hematopoietic stem cell transplantation (ASCT). After median 8.5 courses (range 2-23) of IxaPD regimen, the ORR was 70.0%, with 54.0% VGPR or better. The median time to achieve the best response was 2 months (range 1-9). After a median follow-up of 18 months (range 3-47), 62.0% of patients progressed and the median TTNT was 9.5 months (range 2-31). The mortality rate was 24.0%, and the median OS was not reached. In the multivariate analysis, age, first relapse, R-ISS, high-risk cytogenetics abnormalities, and renal insufficiency and response to first-line induction therapy did not significantly affect TTNT. Neither did those factors also have significant impact on OS. Most of the adverse effects (AEs) were grade 1-2, mainly skin rash, peripheral neuropathy, constipation, diarrhea, edema, arthralgia, herpes zoster, and shortness of breath. There were only two grade 3 AEs, one for pulmonary infection and one for severe myelosuppression.

Conclusion The pan-oral IxaPD regimen showed anticipated effect and good tolerance for RRMM patients. More patients are being enrolled and update data will be reported.

【Key words】 Multiple myeloma; refractory and relapse; pan-oral regimen; ixazomib; pomalidomide
Anemia in Patients Undergoing Therapeutic Phlebotomy for Polycythemia Secondary to COPD and OSA
Authors: Draviam Anna , Soundar Esther
Published: December 2024

Background:

Therapeutic phlebotomy is performed to relieve symptoms of secondary polycythemia in chronic hypoxic lung diseases such as chronic obstructive pulmonary disorder (COPD) and obstructive sleep apnea (OSA). Excessive phlebotomy may cause iron deficiency anemia, leading to hypoxemia and resulting in vicious cycle of further erythropoiesis and hyper viscosity. Also, anemia of chronic disease is prevalent both in COPD and OSA patients due to the underlying systemic inflammation. Our aim is to find if adult patients develop anemia while undergoing prolonged therapeutic phlebotomy treatments.

Methods:

We retrospectively reviewed all outpatients that have undergone therapeutic phlebotomy from September 2018 to July 2024 in our ambulatory outpatient clinic for demographic and relevant clinical and laboratory data including hematologic indices. Cumulative incidence that represents the cumulative probabilities of anemia was computed from the life table using the Kaplan Meier method. Continuous variables with non-normal distribution are presented as median (interquartile range [IQR]).

Results:

The cohort had 19 patients among which 74% are males. Fifty eight percent were diagnosed with OSA and the remaining with COPD. The majority (68%) of patients belong to White race. The age of patients at their first therapeutic phlebotomy at our institution is 62 (IQR, 55-74) years and the median body mass index (BMI) is 31.9 (28.6 -36.6) kg/m2. The baseline hemoglobin is 18 (17-19) g/dL. The total number of therapeutic phlebotomy procedures done is 8 (4-12). The duration between the first therapeutic phlebotomy at our institution and the last one reviewed is 210 days (121-385). The cumulative incidence of anemia after 10 procedures is 37%.

Conclusions:

The incidence of anemia is high in patients undergoing therapeutic phlebotomy for mitigating symptoms of secondary polycythemia. Careful and regular monitoring is necessary to prevent anemia in this at-risk population.
The Safety and Efficacy of Inotuzumab Treatment for Elderly Unfit r/r B ALL
Authors: Lin Yuehui , Liu Dan , Xia Yu , Wu Tong , Tong Chunrong
Published: December 2024

Introduction：B cell acute lymphoblastic leukemia(B ALL) is highly prevalent in children and has a good prognosis with a 5-year survival rate of 80-90%. However, the prognosis of elderly ALL is extremely poor, mainly due to its poor prognosis and poor tolerance to treatment. Therefore, for elderly unfit ALL patients, a safe and effective treatment is urgently needed. In recent years, immune therapies have developed rapidly, and these treatment have high efficacy and safety for relapsed and refractory(r/r) B ALL or MRD+ALL. Our aims to observe safety and efficacy of CD22 antibody inotuzumab ozogamicin conjugated with calicheamicin toxin (Ino.) treatment for elderly unfit r/r B ALL

Methods：A total of 9 elderly unfit r/r B ALL pts who received Ino. treatment from August, 2023 to July , 2024 were included. All patients expressed CD22 antige before treatment. 1 pts received three dose Ino.,other pts received Ino.1mg/W 1～2 times.

Results：9pts:5 females and 4 males with a median age of 59 years (56～72 years old),1 pts CML AP，6 pts Ph+ALL，2pts Ph-ALL.All patients were treated with chemotherapy and all Ph+ALL patients were treated with TKI. Among them, 2 patients had relapse after allogeneic hematopoietic stem cell transplantation(allo-HSCT): 1 patient had relapse after HSCT and CD19 CAR-T treatment,1 patient had relapse after HSCT and CD19 antibody blinatumomab(BITE) with COVID-19 infection;7 pts did not undergo HSCT：1 pt experienced recurrent/ineffective treatment after BITE, CD19 CAR-T, CD22 CAR-T,1 pt experienced recurrence after CD19 CAR-T twice and CD22 CAR-T twice、1 pt who was CML-AP experienced recurrence after BITE、CD19 CAR-T with renal dysfunction，1 pt relapsed after BITE accompanied by pulmonary mucormycosis infection，3 pts did not receive any immunotherapybefore：1 pt has been cured of lung cancer.Before INO.,1 pts MRD+,8 pts have hematological recurrence.All patients have safely completed the INO. treatment and after treatment:5 pts(100%) with hematological recurrence achieved CR (3 pts FG-，1 pts FCM-MRD-、FG-MRD+，1pts morphological CR with FCM/FG+），1pts MRD+;In addition, there are 3 pts who cannot evaluate the efficacy of INO: 2 pts achieved the opportunity to collect lymphocytes for CAR-T therapy, and 1 pt died due to subsequent sepsis.

Conclusions：

For elderly unfit r/r B ALL pts even including those after treatment with both CD19 and CD22 CAR-T cells or HSCT, ino. treatment is safe and effective and so ino. can be the first treatment recommendation.
The Combination of Isatuximab with Pomalidomide and Dexamethasone in Second Line Relapse and Refractory Multiple Myeloma
Authors: Bobin Arthur , Soufyane Ennebet , Guidez Stephanie , Chacon Aurelia , Gardeney Helene , Basle Caroline , Dindinaud Elodie , Douma Soukaina , Roul Christophe , Corby Anne , Motard Carine , Olivier Gaelle , Denis Guillaume , Vinson Camille , Tomowiak Cecile , Gruchet Cecile , Moya Niels , Mocquot Pauline , Dessane Berangere , Boscagli Annick , Perrot Aurore , Leleu Xavier
Published: December 2024

Introduction: The most impressive data obtained from CD38 targeting immunotherapies-based regimens were observed when used as early as possible in the MM disease course, in second line if not offered in line 1. CD38 targeting immunotherapies, Isatuximab and Daratumumab, are approved in the relapse-refractory Multiple Myeloma (RRMM) setting in triplet-based combinations with pomalidomide (P) and dexamethasone (IsaPd and DPd), however with very limited data in line 2 with IsaPd.

Methods: We conducted a multicenter review study of the patients with second line RRMM treated with CD38 targeting immunotherapies-based regimens with pomalidomide and dexamethasone backbone, IsaPd. Eligible patients were to be adult RRMM in second line, refractory to lenalidomide upfront, naïve to pomalidomide, not refractory to CD38 immunotherapy upfront. The primary endpoint of the study was median PFS. All patients received isatuximab + pomalidomide + dexamethasone until progression as per the approved regimen according to the EU approval.

Results: We recruited 35 patients,median age 72 years old (IQ 67;76), 10 (28%) ISS3, 18 (62%) RISS2-3, 8 (22%) had plasmacytomas', 5 (14%) had PCL features, 4 (11%) HR according to IMS new definition (del17 at the threshold of 50%), 6 (16%) had ASCT upfront. The patients received a median of 12 (IQ 5;20) cycles of IsaPd. At 35.4 (CI95% 35;39.5) months median follow-up, 19 (51%) relapsed and 13 (35%) died. The median PFS was 22.4 (CI95% 13.8-nr). The median OS was nr, projected 40 months was 64% from start of IsaPd. All pre-specified HR definitions had a shorted PFS median time.The median relative dose intensity in IsaPd was >90%, similar to either drug. The safety profile is consistent with the approved IsaPd in ICARIA study.

Conclusions: IsaPd reported prolonged PFS median in second line in lenalidomide refractory RRMM.This study confirms IsaPd as a standard of care for second line RRMM patients.
Male Sex Had an Adverse Impact on Outcomes of Pediatric B-Lineage Acute Lymphoblastic Leukemia
Authors: LI Zhiheng , Wang Lingzhen , Cai Jiaoyang , Guo Ailian , Gao Ju , Jie Yu , Zhu Xiaofan , Li Chi Kong , Jiang Hua , Ju Xiuli , Zhai Xiaowen , Wang Ningling , Jiang Hui , Yang Liangchun , Hu Qun , Jin Runming , Pan Kaili , Fang Yongjun , Wu Xuedong , Liang Changda , Cheng Cheng , Shen Shuhong , Sun Lirong , Hu Shaoyan
Published: December 2024

Purpose

Despite the improved overall survival of childhood B-lineage acute lymphoblastic leukemia (B-ALL) under contemporary risk-directed therapy, ~15% patients still experience relapse which calls for additional prognosis predicting factors. We aim to investigate the impact of sex on clinical outcomes in childhood B-ALL.

Patients and Methods

Between January 2, 2015, and December 31, 2019, 6916 pediatric patients with newly diagnosed B-ALL were enrolled in the Chinese Children's Cancer Group ALL-2015 clinical trial (CCCG-ALL-2015, ChiCTR-IPR-14005706).

Results

Among the 6916 cases pediatric B-ALL, the ratio of males to females was 1:0.74 (males 3982, 57.6%; females 2934, 42.4%). An inferior 5-year EFS was observed in males compared with females (79.7%; 95%CI, 78.5-81.0 vs 83.5%; 95%CI, 82.1-84.9; P< .001). Male sex was identified as an independent poor EFS predictor by a multivariant cox model (HR, 1.19; 95%CI, 1.05-1.35; P= .006). Incidence of relapse was the major difference between the two groups. Males had increased relapse risk compared with females, with a 16.4% (95%CI: 15.2-17.6) 5-year cumulative incidence of relapse (females: 12.2%; 95%CI, 11.0-13.4; P< .001) and a 2.9% (95%CI: 2.4-3.5) 5-year cumulative incidence of central nervous system leukemia relapse (females: 1.6%; 95%CI, 1.2-2.2; P< .001). Although the sex impacted the EFS and CIR, males and females achieved a comparable 5-year OS (93.2%; 95%CI, 92.3-94.2 vs 93.2%; 95%CI, 92.4-94.0; P= .800), indicative of the successful salvage therapy for males. Compared with females, males more often had BCR::ABL1 fusion (5.83%, 232/3982 vs 3.31%, 97/2934; P< .001), but no sex-associated difference in the incidence of ETV6::RUNX1, KMT2A-rearranged or TCF3::PBX1 subtypes were noted. Males with BCR::ABL1 fusion or ETV6::RUNX1 fusion exhibited higher relapse rates than females in the same subtype (BCR::ABL1: 38.4%, 89/232 vs 26.8%, 26/97; P= .045; ETV6::RUNX1: 11.9%, 100/838 vs 4.9%, 30/615; P< .001). Such difference was not seen in KMT2A-rearranged or TCF3::PBX1 subtypes. BCR::ABL1 was identified as a male-specific relapse predictor using the multivariate competing risks model.

Conclusions

Sex impacts the prognosis of childhood B-ALL. Males has an inferior EFS and is identified as a relapse predictor in B-ALL which warrants the development of male-adapted regimen to prevent disease reoccurrence. The mechanism underlying the sex impact needs further investigation.
Bortezomib-Based Triplet Therapy As First Line Treatment in Newly Diagnosed Multiple Myeloma Patients in Perú
Authors: Vasquez Jule F , López Córdova Naty , Castillo Claudia , Saavedra Alexandra , Calle Cindy , Lopez Chavez Lourdes Isabel , Alcarraz Cindy Elizabeth , Lovato Rios Pedro Eduardo , La Torre Matuk Alejandra , Laboriano Jorge , Vilcarano Abner , Tokumura Carmen , Quintana Shirley , Samanez-Figari Cesar , Vidaurre Tatiana
Published: December 2024

Introduction

Standard treatment in multiple myeloma is based on triplet and more recently in quadruplet therapy, with lenalidomide being the preferred immunomodulatory drug, however in low-and middle-income countries novel therapies are not readily available. Bortezomib-based triplet is the standard treatment in Peru. We aimed to determine the outcomes with the different combinations of bortezomib.

Methods

We retrospectively reviewed medical records of patients with newly diagnosed multiple myeloma (MM) treated at 5 institutions from Perú including the National Cancer Institute (public institution) and Oncosalud-AUNA (private institution). Patients with MM who received bortezomib-based triplet therapy from 2017 to 2023 were included for the analysis. Smoldering MM and plasma cell leukemia were excluded. Baseline characteristics were evaluated, and overall survival was analyzed using STATA program.

Results

During the period of study 164 patients were included. The median age was 59 (range 30-83). Most were male (60%). Ig G subtype was seen in 61% of cases, followed by Ig A (24%) and light chain myeloma (14%). Non-secretor myeloma accounts for 1% of cases. According to ISS classification ISS I, ISS II, ISS III and unknown were 34%, 21%, 40% and 5%, respectively. 75% were eligible for transplant. However, only 46% of the entire cohort underwent autologous transplantation, all patients with VRd received transplant. 91% (149) received VTd, 8% (14%) VRd and only 1% VCd. 150 patients had evaluation of the treatment response, the overall response rate (ORR) was 83%, complete response + strict complete response was obtained in 43%, followed by very good partial response in 30% of and partial response in 13%. Cytogenetics risk stratification was not available due to the lack of FISH. The median follow-up was 23 months (range 1 -122m). The median overall survival for the entire cohort was not reached (IQR 80-NR). The 5-y OS was 79.5% (95 IC, 71.2-85.6). The 5y OS for the VTd group was 77% and 100% for the VRd group.

Conclusion

Bortezomib-based triplet therapy is highly effective in patients with newly diagnosed multiple myeloma more than the published in international reports. Most patients used VTd as first line treatment. Three-quarters of patients were eligible for transplant. However less than half actually received transplant. Overall survival is good being 100% at 5 years for the VRd group compared to 77% for the VTd group, although seems that the benefit is due to the transplant for the VRd group. The lack of the availability FISH test is very important to stratify our patient to give a better treatment.
Clearance of Sickle Hemoglobin By Hepatic Endothelial Cells Is Critical to Protect Against Hemolysis Induced Organ Damage in Sickle Cell Anemia
Authors: Kaminski Tomasz , Katoch Omika , Li Ziming , Sundd Prithu , Pradhan-Sundd Tirthadipa
Published: December 2024

Sickle cell disease (SCD) is a homozygous recessive genetic disorder caused by a single nucleotide point mutation in the β-globin gene. Hemolysis and accumulatio of cell free hemoglobin is a predominant pathophysiology associated with multi organ damage including liver damage in SCD. The mononuclear phagocytic system plays a critical role in sickle hemoglobin (HbS) clearance. However, the role of liver sinusoidal endothelial cells (LSEC) in HbS clearance and liver injury in SCD was not previously established. Using real-time intravital (in vivo) imaging in mice liver as well as flow cytometric analysis, confocal imaging and biochemical analysis of primary human LSEC, we show that liver injury in SCD is associated with accumulation of HbS in the LSEC, leading to senescence of these cells. Hepatic monocytes were observed to attenuate LSEC senescence by accelerating HbS clearance in the liver of SCD mice; however, this protection was impaired in P-selectin-deficient SCD mice secondary to reduced monocyte recruitment in the liver. These findings are the first to suggest that LSEC contribute to HbS clearance and HbS-induced LSEC senescence promotes progressive liver injury in SCD mice. Our results provide a novel insight into the pathogenesis of hemolysis-induced chronic liver injury in SCD caused by LSEC senescence. Identifying the regulators of LSEC-mediated HbS clearance may lead to new therapies to prevent the progression of liver injury in SCD.