bluuebunny/crossref_metadata_2025 huggingface dataset:
The Association between Serum Ferritin and Survival Outcome in AML Patients: A Meta-Analysis
Authors: Tanariyakul Manasawee , Wannaphut Chalothorn , Fangsaard Panisara , Kanitthamniyom Chanakarn , Wattanachayakul Phuuwadith , Saowapa Sakditad
Published: December 2024

Background

Serum ferritin (SF), a test that measures body's iron stores and inflammation, has been established as a worthwhile prognostic impact indicator for myelodysplastic syndromes, including acute myeloid leukemia (AML). Thus, we sought to conduct a meta-analysis on the significance of SF in the prognosis of AML patients receiving treatment.

Methods

In May 2024, a PRISMA-compliant search for relevant studies until May 2024 was conducted. This search was based on PubMed, Web of Science, Scopus, and the Cochrane Library. Pooled Hazard Ratios of survival rates in AML patients based on their SF levels and 95% CIs were utilized as effect sizes. A Review Manager software was utilized for all data analyses.

Results

Five studies with an overall sample of 1237 clinically diagnosed AML patients, De novo or secondary AML, were pooled. Pooled results from the studies showed a poor prognostic association in terms of overall survival (OS) with high SF (> 800 µg/L) level, with a pooled Hazard Ratio of (HR: 2.01; 95% CI: 1.45 - 2.77). Moreover, four out of five studies compared survival rates for Progression Free Survival, Disease Free Survival (DFS), Recurrence Free Survival (RFS), and Event-Free Survival (EFS). Despite the significant heterogeneity, a pooled HR still showed a poorer prognostic association between high SF and AML (HR: 1.88; 95% CI: 1.29 - 2.75).

Conclusion

Elevated SF levels have been associated with adverse effects on the prognosis of AML patients.
Oral Decitabine/Cedazuridine in Patients with MDS and TP53 Mutations: A Propensity Score Matching Analysis from the Phase II and III Trials
Authors: Urrutia Samuel , Sasaki Koji , Bataller Alex , Kantarjian Hagop M. , Montalban-Bravo Guillermo , McCloskey James , Griffiths Elizabeth A. , Yee Karen , Zeidan Amer M. , Savona Michael R. , Oganesian Aram , Sano Yuri , Keer Harold N. , Garcia-Manero Guillermo
Published: December 2024

Patients with myelodysplastic syndrome harboring TP53 mutations have poor outcomes. Decitabine/cedazuridine has been suggested to have activity in TP53mut MDS. This study evaluates decitabine/cedazuridine in TP53mut MDS treated in the phase 2 and 3 studies that led to the FDA approval of these drugs. Using the WHO 2022 classification, we divided patients into three groups: TP53wt, TP53single-hit, and TP53multi-hit. A total of 180 patients were analyzed of which 73 (40.5%) had TP53 mutations, 23 with TP53multi-hit. Patients with TP53multi-hit were enriched for complex cytogenetics (69.5%), and had fewer median number of co-mutations (2.5, IQR 2-3) compared to TP53single-hit(3, IQR 1-5), or TP53wt (4, IQR 3-6) (p=0.002). Complete response rates were similar between these groups, but patients with TP53multi-hit had a relatively higher likelihood of lack of response with 39.1% vs 28%, and 27.1% for TP53single-hit, and TP53wt, respectively (p = 0.2). Patients with TP53multi-hit also received fewer courses of therapy due to progression, 5 vs 7.5 for TP53single-hit, and 9 for TP53wt (p =0.016). Patients with TP53mult-hit lost response earlier with 8.2 months, vs 13.2 months for TP53single-hit, and 15.1 months for TP53wt (p=0.1). Median overall survival (mOS) was 11.5 months (95% CI: 8.6 - 19.1) for TP53mult-hit, 22.1 months (95% CI: 14.6 - 35.9) for TP53single-hit, and 31.7 months (95% CI: 19.5 - 51.1) for TP53wt MDS (log-rank, p < 0.005). With a median follow-up time of 21.5 months, at a landmark analysis of 4 months, hematopoietic stem cell transplantation (HSCT) did not result in improved survival. A propensity score matched 47 patients treated with decitabine/cedazuridine and TP53mut were matched to 47 with MDS and TP53mut treated with single agent IV hypomethylating agent (HMA) using age, ECOG performance status, IPSS-R scores, and TP53 VAF as matching features. Median overall survival was 13.1 months (95% CI: 8.4 - 21.3) for decitabine/cedazuridine vs 8.0 months (95% CI: 5.2 - 13.0) for single agent IV HMA (log-rank, p=0.047). In patients with MDS harboring TP53mut, decitabine/cedazuridine may improve survival compared to conventional single-agent IV HMA.
Toxicities and Financial Costs Associated with CNS Prophylaxis in Diffuse Large B-Cell Lymphoma: A Retrospective Analysis in Nova Scotia, Canada
Authors: McGuire Maggie , Keating Mary-Margaret , Koto Prosper
Published: December 2024

Background: Central nervous system (CNS) prophylaxis with high-dose methotrexate (HD-MTX) is a treatment administered to patients with high-risk diffuse large B-cell lymphoma (DLBCL) in attempt to prevent relapse or progression of lymphoma in the CNS. The quality of evidence for this therapy is weak and clinicians are increasingly uncertain about the benefit versus risk of using CNS prophylaxis. In healthcare, maximizing patient outcome at the lowest cost is essential, therefore our study aimed to identify the toxicities and financial costs associated with this therapy at our local institution in Halifax, Nova Scotia. Methods: A chart review of 52 patients with DLBCL receiving HD-MTX for CNS prophylaxis from 2010-2019. Toxicities were assessed for up to 1 month after receiving HD-MTX. We conducted a cost-consequence analysis using real-world data from a third-party payer perspective, comparing 53 patients with DLBCL who received R-CHOP and HD-MTX prophylaxis (treatment group) to 28 DLBCL patients who received R-CHOP or similar (control group). Results: 42/52 (80.8%) patients experienced at least 1 toxicity from IV HD-MTX. Notable toxicities included: mucositis (11/52, 21.2%), renal injury (12/52, 23.1%) with half of these patients having no improvement in creatinine prior to next cycle of chemotherapy, anemia (27/52, 51.9%) with 66.7% of these patients having a hemoglobin less than 80 g/L or requiring a blood transfusion, severe neutropenia with absolute neutrophil count (ANC) less than 500 x 10^9/L (3/52, 5.7%) and a single patient (1/52, 1.9%) experienced methotrexate-related pneumonitis. Total costs in the treatment group were higher than in the control group, with a statistically significant cost difference of $31,892. Conclusion: Toxicities were frequent after HD-MTX administration and although the majority were mild in severity, some serious adverse events occurred, including Grade 3 renal toxicity and pneumonitis. Our cost analysis indicates there is a significant financial cost associated with the use of CNS prophylaxis. With recent large retrospective studies questioning the benefit of this therapy, our data further supports allocating resources away from this toxic and expensive treatment. With this evolving data, each health institution needs to carefully consider their local guidelines for CNS prophylaxis in DLBCL.
Ferritin Level As a Prognostic Marker for Non-Hodgkin Lymphoma: A Systematic Review and Meta-Analysis
Authors: Saowapa Sakditad , Polpichai Natchaya , Garcia Pleitez Hector , Bernal Diego Olavarria , Tanariyakul Manasawee , Wannaphut Chalothorn , McCullough Maireigh , Moreira Mariana , Kanitthamniyom Chanakarn , Siladech Pharit , Tijani Lukman
Published: December 2024

Background

Elevated serum ferritin (SF) has been associated with poor prognosis in several malignancies. However, little is known about the relationship between SF and survival outcomes of patients with non-Hodgin lymphoma (NHL). Therefore, the present meta-analysis has investigated the prognostic value of SF in NHL patients.

Methods

A systematic search for literature evaluating the prognostic effect of SF on NHL or its subtypes was conducted on PubMed, MEDLINE, Web of Science, and Google Scholar databases. The search was limited to records authored in English and published from inception until June 2024. A random-effects model was used in pooling hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS), of which the overall estimates were presented alongside their corresponding 95% confidence interval (CI). Moreover, data presented using Kaplan Meier (KM) curves, the survival probabilities, and time intervals were retrieved using WebPlotDigitizer, after which individual patient data (IPD) was reconstructed using IPDfromKM Shiny App.

Results

Ten studies with 1384 NHL patients were eligible for inclusion. The pooled data from these studies showed that high pretreatment SF was significantly associated with poor OS (HR: 2.68; 95% CI: 2.08 - 3.47, p<0.00001). Similarly, data pooled from six included studies showed a significant correlation between elevated SF levels and poor PFS (HR: 2.25; 95% CI: 1.79 - 2.83, p<0.00001). Furthermore, the subgroup analyses showed that elevated SF was a prognostic marker for poor OS and PFS regardless of the cut-off level and NHL subtypes. However, one study carried out in Africa did not find any considerable relationship between SF and OS 2.38 (1.01 - 5.60, p = 0.00001).

Conclusion

Overall, SF might help predict the survival outcomes of patients diagnosed with different NHL subtypes. However, further research in large-scale prospective studies is needed to validate this finding.
A Hepatic Impairment Index for Mortality Prediction in NK/T-Cell Lymphoma-Associated Hemophagocytic Lymphohistiocytosis
Authors: Yehua Yu , Shi Jun
Published: December 2024

Background: Hepatic impairment is a severe complication in natural killer/T cell lymphoma with hemophagocytic lymphohistiocytosis (NK/T-HLH). Abnormal levels of liver enzymes, bilirubin or albumin serve as features of hepatic impairment，but its critical indicators correlated with prognosis in NK/T-HLH remains unclear.

Patients and Methods: We conducted a retrospective study including 47 NK/T patients with and without HLH. Logistic regression and receiver-operating curve analyses were used to identify the most useful prognostic parameters of hepatic and to optimize laboratory cutoff values. Correlated factors of hepatic compromise was analyzed with Pearson's r-test.

Results: The incidence of patients experiencing hepatic impairment was 100% among 17 NK/T with HLH (NK/T-HLH), notably higher than the 50% incidence of 30 without HLH (NK/T-NHLH). Among hepatic features, gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), and direct bilirubin (DBIL) can serve as important predictive markers for mortality in NK/T patients. Integrating GGT, AST, and DBIL into a novel index that we termed the GSD index, which achieved an improved mortality predictive. The respective cut-off values for these three parameters were determined using ROC curves at GGT 181.8 U/L, AST 98.5 U/L, and DBIL 6.4 μmol/L. Moreover, patients with NK/T-HLH who fulfilled the GSD index criteria exhibited a significantly shorter median survival time compared to those who did not. Interferon-gamma (IFN-γ) is an important cytokine produced by immune cells that is often elevated in HLH patients. Our analysis revealed a significant and positive linear correlation between IFN-γ levels and the elevation of GGT, ALT, AST, and DBIL. Finally, we report two successful cases of NK/T-HLH patients with severe hepatic failure using a combination treatment of chemotherapy and emapalumab, a fully human anti-IFN-γ monoclonal antibody approved for treatment of patients with primary HLH.

Conclusion: The GSD index is critical for predicting poor outcomes in NK/T-HLH patients with hepatic impairment. Emapalumab combined with chemotherapy may be an effective treatment for those with severe liver damage.
Pomalidomide Induces Myeloma Cell Death Via GPX4-Mediated Ferroptosis
Authors: Wang Yin-Che , Teng Chieh-Lin Jerry , Liao Yu-Min
Published: December 2024

Pomalidomide is one of the immunomodulatory drugs (IMiDs) used for multiple myeloma (MM) treatment. However, the exact molecular mechanism of pomalidomide in MM therapy remains unclear. The current study demonstrated that pomalidomide treatment inhibited MM cell proliferation and induced cell death via ferroptosis. This phenomenon could be reversed by ferrostatin-1, a ferroptosis inhibitor. Additionally, pomalidomide induced ferroptosis by increasing lipid peroxidation, reactive oxygen species (ROS), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) expression. Furthermore, it blocked the conversion of GSH to GSSG and inhibited glutathione hydroperoxidase 4 (GPX4) expression. In vivo experiments demonstrated that pomalidomide significantly reduced the growth of subcutaneous MM tumors in mice, as evidenced by decreased tumor weight and volume. The molecular mechanisms observed in the mice model corroborated the findings from in vitro experiments. Collectively, these results enhance our understanding of the potential mechanisms of pomalidomide in MM therapy.
The Combination of Asciminib with ATP Competing Tyrosine Kinase Inhibitors Might Overcome the Negative Impact of ASXL1 Mutations on Molecular Response in Newly Diagnosed CML Patients
Authors: Ernst Thomas , Rinke Jenny , le Coutre Philipp , Crysandt Martina , Brummendorf Tim H. H. , Burchert Andreas , Lang Fabian , Saussele Susanne , Pfirrmann Markus , Lang Thomas , Fabisch Christian , Hochhaus Andreas
Published: December 2024

Clones characterized by gene mutations independent of BCR::ABL1 have been identified in approximately 20-30% of newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase with mutations in epigenetic modifier genes (e.g., ASXL1, TET2, DNMT3A) being the most common. We previously reported an inferior molecular response rate to nilotinib therapy in CML patients harboring ASXL1 mutations at diagnosis (TIGER study, NCT01657604, Schönfeld et al. Leukemia 2022;36:2242-9). Here, we sought to evaluate the clinical impact of these mutations in newly diagnosed CML patients treated with asciminib in combination with ATP competing tyrosine kinase inhibitors. The “Frontline asciminib in combination study” (FASCINATION, NCT03906292) is an ongoing multicenter, prospective, open-label, interventional phase II trial to evaluate efficacy and tolerability of asciminib in combination with conventional ATP-competing BCR::ABL1 inhibitors (imatinib, nilotinib, dasatinib). The primary endpoint was the rate of MR4 (BCR::ABL1 transcripts ≤0.01% on the International Scale, IS) at month 12. Between 2019 and 2022, 144 patients were recruited from 21 sites in Germany and 125 patients started the combination therapy with asciminib. Median age at diagnosis was 45.5 years (range, 19.0-89.0) and 66% were male. A total of 119 CML patients were investigated by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. Mutation status was correlated with the primary endpoint of the study. At diagnosis, 24/119 CML patients (20%) carried mutations in addition to BCR::ABL1 affecting the genes ASXL1, ATRX, BCOR, BCORL1, CBLB, CEBPA, CUX1, DNMT3A, ETV6, IKZF1, KDM6A, RAD21, STAG2, TET2, and ZRSR2. Five patients showed mutations in more than one gene. ASXL1 mutations were observed in 9 patients (8%, median age 45 years, range 32-65 years; ELTS low risk, n=5; intermediate risk, n=2; high risk, n=2). At month 12, 8/9 (89%) and 7/9 (78%) patients harboring ASXL1 mutations at diagnosis showed MMR and MR4, respectively. In comparison, patients with other mutations or no mutation had MR4 rates of 33% and 34%, respectively. In conclusion, mutations in addition to BCR::ABL1 are common at diagnosis of CML. The combination of asciminib with ATP competing drugs might be able to overcome the negative impact of ASXL1 mutations with regard to molecular response. However, the optimal therapy for CML patients with ASXL1 mutations needs to be defined within future studies.
Doxorubicin Synergizes Bortezomib-Induced Multiple Myeloma Cell Death By Inhibiting Aggresome Formation Leading to ER Stress and Apoptosis
Authors: Wang Yin-Che , Liao Yu-Min , Teng Chieh-Lin Jerry
Published: December 2024

Bortezomib is a proteasome inhibitor that eradicates multiple myeloma (MM) cells by accumulating toxic misfolded proteins. However, the emergence of bortezomib resistance remains a significant challenge in MM treatment. An aggresome is a subcellular structure enclosed by vimentin that forms when cells are treated with proteasome inhibitors. Aggresomes sequester misfolded proteins bound and transported by HDAC6 and dynein before they are degraded by autophagy, thereby potentially increasing the efficacy of bortezomib in MM treatment. To this end, we screened anticancer drugs for their potential to block aggresome formation and synergize bortezomib-induced MM cell death. The results showed that doxorubicin synergized bortezomib-mediated cytotoxicity and impaired bortezomib-induced aggresome formation in U266B1 cells. Mechanistic studies revealed that doxorubicin downregulated aggresome-promoting factors such as vimentin, HDAC6, and dynein, while enhancing pro-apoptotic pathways by inducing ER stress in bortezomib-treated U266B1 cells. Remarkably, doxorubicin did not potentiate cell death triggered by proteasome inhibitors that do not stimulate aggresome formation, and the combined treatment of bortezomib and doxorubicin failed to generate synergistic cell death in multiple myeloma cell lines lacking aggresome formation activity. These data demonstrate that doxorubicin synergizes bortezomib-induced cell death by blocking aggresome formation. Our studies suggest the therapeutic potential of combining bortezomib and doxorubicin in the treatment of MM.
Inhibition of PKM2 Promotes Chemosensitivity of DOX in ABC-DLBCL Via Imbalance of Gsh/ROS and Inhibition of the NF-ΚB Pathway
Authors: Yang Yutian , Zhan Minglang , Hanzhen Zhang , Wei Xiaolei , Wei Yongqiang , Feng Ru
Published: December 2024

Some patients with activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) remain resistant to the CHOP (cyclophosphamide, vincristine, doxorubicin [DOX], and prednisone) and rituximab (R)-CHOP treatment regimens. DOX induces reactive oxygen species (ROS) accumulation in ABC-DLBCL. Pyruvate kinase 2 (PKM2) is a crucial enzyme in glycolysis and plays metabolic and non-metabolic functions in tumor development. However, the role of PKM2 in modulating DOX sensitivity in ABC-DLBCL is unclear. In this study, PKM gene was highly expressed in common databases, and high PKM expression predicts poor prognosis. Inhibiting PKM2 increased DOX chemosensitivity and assisted DOX to induce cell apoptosis and cell cycle arrest. In the metabolic function of PKM2, inhibiting and knocking down PKM2 assisted DOX to inhibit glycolysis, disrupted the glutathione (GSH)/ROS balance, and activated oxidative stress-related pathways. Supplementation with GSH-MEE ameliorated ROS accumulation and apoptosis caused by DOX/PKM2i treatment. In the non-metabolic function of PKM2, inhibiting PKM2 caused DOX-induced NF-κB signaling pathway suppression. The histone acetyltransferases and deacetylases inhibitor chidamide functioned concurrently with DOX to inhibit cell viability and decreased PKM2 expression. In conclusion, this study revealed that enhanced DOX chemosensitivity can be achieved by inhibiting the metabolic and non-metabolic functions of PKM2 and partly elucidated the anti-tumor mechanism of chidamide.

Key Words:

DLBCL; PKM2; DOX; glycolysis; GSH/ROS; NF-κB; chidamide
Clinical and Genetic Profiles and Outcomes of Allogeneic HSCT in Secondary Myelodysplastic Syndrome Following Aplastic Anemia
Authors: Jia Li , Jiang Erlie , Feng Sizhou
Published: December 2024

Aplastic anemia (AA) often complicates due to clonal diseases like secondary myelodysplastic syndrome (sMDS). We retrospectively analyzed 25 sMDS patients post-AA, 337 patients with de novo MDS, and 285 AA patients without MDS progression who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), both before and after propensity score matching. Among sMDS patients, 80% had prior non-severe AA. Their median age at HSCT was 35 years, between de novo MDS (45 years, P=0.021) and non-progressing AA patients (24 years, P<0.001). Compared to de novo MDS, sMDS patients had lower pre-transplant platelet counts and frequently presented with early MDS status (2016 criteria: 44.0% vs 24.6%, P=0.033; 2022 criteria: 48.0% vs 21.4%, P=0.002). They exhibited higher rates of GATA2, PIGA mutations, and -7/del(7q) loss, while U2AF1 mutations were more common in de novo MDS. In sMDS, -7/del(7q) was often the sole chromosomal abnormality, significantly affecting the 1-year relapse incidence (25.0% vs 0.0%, P=0.045). Adjusted for baseline characteristics, sMDS survival was marginally better than de novo MDS. When AA severity was balanced, survival between sMDS and non-progressing AA showed no significant difference. Overall, post-AA sMDS patients exhibited unique clinical and genetic profiles, with -7/del(7q) holding distinctive significance, and allo-HSCT proved effective for these patients.
Incidence Trends for EBV-Associated Malignancies Extranodal NK/T-Cell Lymphoma and Nasopharyngeal Carcinoma in Taiwan
Authors: Su Yu-Chieh , Chiu Brian , Li Hung-Ju , Lin Sheng-Fung
Published: December 2024

Both nasopharyngeal carcinoma (NPC) and extranodal NK/T-cell lymphoma (ENKTL) are associated with the Epstein-Barr virus (EBV). The purpose of this study was to evaluate the incidence patterns of ENKTL and NPC in Taiwan during the previous 15-30 years. We conducted an epidemiological study using population-based registry data from the Taiwan Cancer Registry to assess the incidence of ENKTL from 2008 to 2021 and NPC from 1995 to 2021. The secular trends in the annual incidence rates were described as average annual percent change (AAPC). During the study period, 872 new ENKTL diagnoses and 39412 new NPC diagnoses were reported. The annual age-adjusted incidence rate of ENKTL and NPC both decreased significantly, with AAPC of -2.47 (p = 0.014) and -1.16 (p < 0.001), respectively. For NPC, the incidence rate decreased from 1995 to 2021 in the age groups of 20-44, 45-64, and 65+ years from 5.23 per 100,000 persons to 4.42 per 100,000 persons (AAPC of -0.45, p = 0.011), from 15.28 per 100,000 persons to 11.36 per 100,000 persons (AAPC of -1.21, p < 0.001), and from 10.48 per 100,000 persons to 7.24 per 100,000 persons (AAPC of -1.91 (p < 0.001), respectively. A substantial decrease in the age-specific incidence of ENKTL was seen in the 45-64 year age group, from 0.46 per 100,000 persons in 2008 to 0.32 per 100,000 persons in 2021 (AAPC of -3.37; p = 0.008). There was also a suggestive decrease in incidence between 2009 and 2021 in the 20-44 and 65+ age groups from 0.16 per 100,000 people to 0.11 per 100,000 people and from 0.87 per 100,000 people to 0.79 per 100,000 people, respectively. Interestingly, the EBV seroprevalence in Taiwan appears to remain stable from 1984 to 2007, with a seroprevalence of over 90% among persons Nonetheless, there appears to be a downward trend in seroprevalence in early childhood, with prevalence falling by approximately 20% in children aged 4 years and by nearly half in children younger than 2 years of age. This suggests that the downward trend of NPC/ENKTL may be affected by the decline in early EBV infection rates. In conclusion, our population-based data showed a decrease in incidence of NPC/ENKTL in the last 20 years in Taiwan. Given the EBV seroprevalence remained stable but early EBV infection declined during the same period in Taiwan, these findings suggest delayed EBV infection or factors other than EBV might be important in the downward trend of NPC/ENKTL in Taiwan and warrant further investigation.
Predictors of Mortality of Pediatric Cancer Patients Admitted to the Intensive Care Unit (ICU) in a Low Middle Income Country (LMIC)
Authors: Helmy Rana , Khedr Reham , Madany Youssef , Kamal Mohamed , Mostafa Ali , Kieran Mark W. , Elhaddad Alaa M.
Published: December 2024

BACKGROUND: Advances in cancer treatment have significantly improved survival rates for cancer patients, but this has also led to an increase in the number of pediatric cancer patients requiring ICU admission due to the severity of their illness and treatment complications. Understanding the predictors of mortality for this patient population is crucial for improving outcomes.

METHODS: A retrospective study including patients younger than or aged 18 years old at diagnosis of malignancy who were admitted to the medical ICU in The Children Cancer Hospital Egypt from January 1, 2019, to August 1, 2021. The primary objectives were to determine the mortality rate, identify the common causes of ICU admissions, and analyze the predictors of mortality among the pediatric cancer patients admitted to the ICU.

RESULTS: A total of 1,501 patients were included. The most common diagnoses were hematological malignancies, including acute lymphoblastic leukemia (24%) and acute myeloid leukemia (13%). The most common causes of admission were sepsis (39%) and respiratory failure (31%). 17% of patients were admitted to the ICU on presentation as new cases. The mortality rate for the whole cohort was 32%. The most common causes of death were sepsis (45%) and disease progression/relapse (28.6%). Multivariable analysis identified higher mortality for patients admitted with septic shock (OR= 6.01, 95%CI 3.97-9.23, P<0.001) and respiratory failure (OR= 6.35, 95%CI 4.13-9.97, P<0.001), patients with progressive disease (OR= 1.86, 95%CI 1.38-2.50, P<0.001), those transferred from inpatient wards (OR= 1.63, 95%CI 1.20-2.22, P= 0.002) and patients with longer ICU stay (OR= 1.04, 95%CI 1.04-1.06, P<0.001).

CONCLUSION: Pediatric cancer patients admitted to the ICU in LMICs have a high mortality rate, which confirms the need for targeted strategies to improve outcomes in this vulnerable population. Key approaches suggested by our research include early cancer diagnosis, optimized identification of early warning signs of critical illness, and decreasing sepsis-related mortalities by strict infection control, early diagnosis, and antimicrobial stewardship programs.

KEYWORDS: pediatric oncology, ICU admissions, mortality predictors, respiratory failure, septic shock, LMICs, hematological malignancies, acute lymphoblastic leukemia
BGB-11417-203, an Ongoing, Phase 2 Study of Sonrotoclax (BGB-11417), a Next-Generation BCL2 Inhibitor, in Patients With Waldenström Macroglobulinemia
Authors: Lee Hui-Peng , Opat Stephen S. , Hrom John , Kliman David , Marlton Paula , Liu Peng , Du Chenmu , Lussier Amber , Zhang Jun , Guo Haiyi , Treon Steven P.
Published: December 2024

Introduction: Bruton tyrosine kinase (BTK) inhibitors and anti-CD20 antibody-based systemic therapy are included within the preferred treatment algorithms for Waldenström macroglobulinemia (WM). However, to date, no treatments have been approved for patients with WM that are refractory to both BTK inhibitors and anti-CD20 therapy. Venetoclax, the first-generation BCL2 inhibitor, has demonstrated clinical activity in patients with relapsed/refractory (R/R) WM, but it has no regulatory approvals in WM. Sonrotoclax, a next generation BCL2 inhibitor, is more selective and a more pharmacologically potent inhibitor of BCL2 than venetoclax. In a phase 1 trial, sonrotoclax monotherapy was well tolerated at all dose levels tested up to 640 mg and showed promising evidence of antitumor activity in patients with R/R WM. Based on the data from these earlier studies, a phase 2 study of sonrotoclax monotherapy, and sonrotoclax in combination with zanubrutinib, in patients with WM has been initiated and is currently recruiting.

Methods: BGB-11417-203 (NCT05952037) is an open-label, international, phase 2 study among patients with histologically confirmed WM. Approximately 105 patients will be enrolled across 4 cohorts. Patients in Cohort 1 to 3 must have R/R disease with the following requirement: Cohort 1 enrolls patients R/R to both BTK inhibitor therapy and anti-CD20-based systemic therapy combined with chemotherapy or a proteasome inhibitor (PI); Cohort 2 enrolls patients R/R to anti-CD20-based systemic therapy combined with chemotherapy or a PI and who are intolerant to BTK inhibitor therapy; Cohort 3 enrolls patients R/R to a BTK inhibitor and who are unsuitable for chemoimmunotherapy. Patients in Cohorts 1 to 3 will receive sonrotoclax until disease progression, death, unacceptable toxicity, patient withdrawal, loss to follow-up, or study termination. Patients in Cohort 4 are previously untreated and will receive combination therapy with sonrotoclax plus zanubrutinib for up to 20 cycles. The primary endpoint of the study is major response rate (MRR; defined as partial response or better) in Cohort 1 per IWWM-11 criteria, as assessed by independent review committee (IRC). Secondary endpoints include MRR assessed by investigator (INV) in Cohorts 1 to 4, and by IRC in Cohorts 2 and 3; overall response rate and duration of response (INV, Cohorts 1 to 4; IRC, Cohorts 1 to 3); progression-free survival (IRC and INV, Cohorts 1 to 3); time to next treatment (INV, Cohort 4); overall survival (Cohorts 1 to 3); and safety and tolerability. Patient recruitment is ongoing, with approximately 72 study sites in Australia, China, Europe (Italy, Spain, France, Greece), the UK, Canada, and the US.
Real-World Retrospective Analysis of Immune Thrombocytopenia Patient Demographics and Treatment
Authors: Lee Sophia , Sherry Emily Grace , Auster Michael , Benkhadra Raed , Pandya Abhishek , Ocampo Miguel , Karnad Anand , Bowhay-Carnes Elizabeth
Published: December 2024

Background

Immune thrombocytopenia (ITP) is a serious immune-mediated phenomenon with an increasing incidence of 6.1 per 100,000 people. This incidence almost doubles in older adults 65 years or older, with an increased mortality risk found in fatal bleeding. Several treatment options are available, including corticosteroids, rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RA), immunosuppressives, and spleen tyrosine kinase inhibitors.

Aims

This retrospective study aims to investigate the ITP demographics and the preferred treatment modalities in a dataset from real-life clinic practice.

Methods

We conducted a retrospective chart review of adult patients diagnosed with ITP and treated in eit her inpatient or outpatient between January 2020 to January 2023. Data variables were collected and reviewed in descriptive analysis.

Results

Our study included 109 patients with ITP diagnosis. The most common ethnicity was White or Caucasian (52 patients, 48%) and Hispanic or Latino (42 patients, 39%). Many patients had primary ITP (82 patients, 75%), while 25% (27 patients) had secondary ITP with the most had concurrent active autoimmune disease (11 patients, 42%). 60% treated outpatient and 40% inpatient. At the time of diagnosis, 27 (25%) patients had bleeding episodes; and major bleeding occurred only in 4 (4%) patients. Initial treatments were steroid monotherapy (43 patients, 39.4%), observation only in 31 (28%) patients, and steroid and IVIG combination in 24 (22%) patients. Subsequently, 55 (50%) patients experienced refractory or relapsed disease, with Rituximab (17 patients, 31%) as the most common second-line treatment. The most common third-line treatment was Romiplostim (7 patients, 23%) and Rituximab (7 patients, 23%), whereas the fourth-line treatment was Eltrombopag (7 patients, 32%).

Conclusion(s)

This retrospective study provides the largest ITP analysis to our knowledge. Further research, including survival analysis, is needed to optimize the sequencing of subsequent ITP treatments and enhance patient outcomes in this challenging disease phenomenon.
Autosomal Recessive COPZ1 Mutations Cause Isolated Severe Neutropenia or Complex Syndrome with Severe Neutropenia
Authors: Borbaran Bravo Natalia Alejandra , Deordieva Ekaterina , Doll Larissa , Elgamacy Mohammad , Dannenmann Benjamin , Azevedo Joana , Iannuzzo Alberto , Delafontaine Selket , Lehners Moritz , Kolodziej Marius , Hernandez Alvarez Birte , Hellmuth Anna-Sophia , Ritter Malte Ulrich , Findik Betül , Zakharova Viktoria , Bräuning Sandro , Kandabarau Sergey , Lengerke Claudia , Feil Robert , Meyts Isabelle , Delon Jerome , Templin Markus , Sturm Marc , Rieß Olaf , Zeidler Cornelia , Welte Karl , Shcherbina Anna , Klimiankou Maksim , Skokowa Julia
Published: December 2024

We have identified new autosomal recessive mutations in the COPZ1 gene in three severe congenital neutropenia (CN) patients from two unrelated families. In one family, two siblings with a stop-codon COPZ1 mutation (NP_057141:p.Gln141Ter) suffered from CN, lymphopenia, anemia, thrombocytopenia, and syndromic organ involvement, including hepatosplenomegaly, atypical autism with mental retardation, varying degrees of bone defects, and dermatitis. An unrelated patient with a missense COPZ1 mutation (NP_057141:p.Gly132Arg) exhibited isolated CN and chilblains.

The COPZ1 gene encodes the zeta 1 subunit of the coatomer protein complex I (COPI), which is phylogenetically highly conserved, with two identified mutation positions in the conserved region. The protein structure of human COPZ1 is still unknown, and computational analysis using bovine COPZ1 and COPG1 proteins predicted that truncated COPZ1 exhibits substantial structural instability and reduced interaction with COPG1, whereas missense COPZ1 retains interaction with COPG1. Consistent with structural defects, truncated COPZ1 blocked retrograde protein transport from the Golgi to the ER in human fibroblasts, suggesting a detrimental effect on COPI complex functions.

We also found that truncated or missense COPZ1 mutations caused impaired granulocytic differentiation of human CD34+ cells in vitro with a more pronounced phenotype in COPZ1 truncated cells. In zebrafish embryos, truncated Copz1 also resulted in defective myelopoiesis. Intracellularly, truncated COPZ1 downregulated JAK-STAT-C/EBPE-G-CSFR signaling and hypoxia-responsive pathways while inducing interferon-stimulated genes (ISGs) and STING, stimulating oxidative phosphorylation activity, and increasing reactive oxygen species (ROS) levels in CD34+ cells. Missense COPZ1 protein also deregulated interferon signaling.

Therapeutically, by applying connectivity map analysis, we discovered that treatment with the HIF1α activator IOX2 successfully restored granulopoiesis in truncated Copz1 zebrafish embryos and human CD34+ cells. Furthermore, transduction with COPZ2 cDNA effectively corrected granulocytic differentiation defects in COPZ1-mutated CD34+ cells.

In summary, our findings elucidate the distinct pathogenic mechanisms and clinical presentations associated with truncated versus missense COPZ1 mutations and underscore the potential of HIF1α activation as a promising therapeutic approach for CN.
MLL1 Complex Is a Critical Regulator of Fetal Hemoglobin Repression
Authors: Han Yufen , Roy Kartik , Gudmundsson Kristbjorn , Gudmundsdottir Bjorg , Tisdale John , Du Yang
Published: December 2024

Increasing fetal-type hemoglobin (HbF) expression in adult erythroid cells represents a promising strategy for treating β-globinopathies including sickle cell disease and β-thalassemia. However, the mechanisms responsible for the repression of HbF expression in adult erythroid cells remain unclear. We have identified MLL1 complex as a critical regulator of HbF repression. Knockdowns of MEN1 and KMT2A encoding critical components of the complex by lentiviral shRNAs caused dramatic increases in γ- and ε-globin mRNA levels (up to 15- and 22-fold respectively) without causing major changes in β-globin expression in HUDEP-2 cells. Interestingly, we found that MEN1 and KMT2A knockdowns also induced a significant downregulation of BCL11A mRNA levels in these cells, suggesting that BCL11A may be a direct target of MLL1 complex. In supporting this notion, significant binding of MEN1 and KMT2A were readily detected at the promoter and a critical enhancer of BCL11A. We further tested these findings in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation in culture. Consistent with regulation of BCL11A transcription by MLL1 complex, both MEN1 and KMT2A were detected at high levels during early phase of differentiation and their expression declined gradually during terminal differentiation, in a similar pattern as the expression of BCL11A. MEN1 knockdowns in these cells also significantly increased γ- and ε-globin mRNA levels (up to 13- and 38-fold respectively) and γ-globin protein levels while decreasing BCL11A levels. Furthermore, MEN1 knockdowns did not block differentiation of the cells as enucleated red blood cells were readily detected and the number of F cells significantly increased in the knockdown cultures. Since MENIN inhibitors blocking the interaction between MEN1 and KMT2A showed mild side effects in clinical trials for acute myeloid leukemia (AML), we further tested MENIN inhibitor MI-3454 in inducing fetal and embryonic globin expression in human CD34+ HSPCs. Remarkably, treatment with MI-3454 significantly stimulated β- and ε-globin gene expression in these cells with γ-globin levels reaching over 30% of total β-globin levels. In summary, these results suggest that MLL1 complex is a critical regulator of fetal and embryonic globin expression and treatment with MENIN inhibitors could represent an effective therapeutic strategy for sickle cell disease and β-thalassemia.
Safety and Efficacy of Corvalimab in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Systematic Review and Single-Arm Meta-Analysis
Authors: Patel Zeel V , Saddique Muhammad Nabeel , Patel Shivani , Javaid Hammad , Gummalla Vaishnavi , Desai Bhavya Yauvanbhai , Bethineedi Deepak Lakshmi , Patel Kush Pareshkumar , Prajjwal Priyadarshi , Asfeen Ummul
Published: December 2024

Title: Safety And Efficacy of Crovalimab in Paroxysmal Nocturnal

Hemoglobinuria (PNH): A Systematic Review and Single-arm Meta-analysis

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is rare, genetic, life-threatening

haematological disease affecting 12-13 individuals per 1 million worldwide, caused by mutation

in PIGA gene. PNH is associated intravascular haemolysis, thrombosis and pancytopenia with up

to 35% 5-year mortality rates. Crovalimab, a novel FDA-approved C5 inhibitor, appeared to

promising therapy for C5 mutation patients with less effective outcomes on conventional

therapies.

Objective: To evaluate the safety and efficacy of Crovalimab in paroxysmal nocturnal

hemoglobinuria (PNH).

Methods: The PubMed, Embase, Scopus and Cochrane databases were systematically searched

using relevant keywords from inception until July 2024. A total of 3 studies fulfilling predefined

selection criteria were included. We performed meta-analysis of prevalence using MetaXL

Software (version 5.3). We pooled the prevalence rate presented as untransformed proportion

with the corresponding 95% confidence interval (CI) using the random effects model. The I2 and

X2 statistics were used to evaluate interstudy heterogeneity. A heterogeneity of I2 > 50% was

considered significant.

Results: We found the pooled prevalence of ≥1 any-grade adverse event (AE) of any cause 92%

(95% CI 0.76-1.00,I2=85%) and serious adverse event of any cause 15% (95% CI 0.05-0.29,

I2=75%). We found the pooled prevalence of ≥1 treatment-related any-grade AE 47% (95% CI

0.20-0.75, I2=91%) and serious AE 3% (95% CI 0.01-0.06, I2=0%).The pooled prevalence of the

patients with hemolysis control was 79% (95% CI 0.73-0.84, I2=0%), post-baseline transfusion

avoidance 59% (95% CI 0.50-0.68, I2=19%), stabilized hemoglobin 59% (95% CI 0.46-0.71,

I2=59%) and breakthrough hemoglobin 9% (95% CI 0.06-0.13, I2=0%)

Conclusion: We found that crovalimab showed less prevalence of both any-cause and treatment-

related adverse events, a high proportion of patients with controlled hemolysis, post-baselines

transfusion avoidance and stabilized hemoglobin in patients with PNH. Moreover, only a small

proportion of patients had breakthrough hemoglobin. More robust studies with larger sample

sizes are required to establish conclusive evidence.
Developing and Characterizing the Anti-Tumor Efficacy of a Tri-Specific CAR T Cell Targeting CD19, CD20 and CD22
Authors: Sheng Michael , Vick Logan , Collins Craig , Nielsen Ryan , Tuscano Joseph M , Orentas Rimas J , Xiong Ying , Murphy William
Published: December 2024

Chimeric antigen receptor (CAR) T cell therapy targeting proteins such as CD19 and BCMA has achieved considerable success in treating B cell cancers with several multicenter clinical trials reporting an overall response rate greater than 90%. However, relapse occurs in up to 50% of patients receiving treatment and remains a major limitation in part due to antigen downmodulation. To circumvent this, we have developed and generated CAR T cells using a bicistronic CAR vector (“DuoCAR”) simultaneously targeting 3 antigens: CD19, CD20, and CD22 and compared them to CD19-Targeted CAR (“CAR19”) T cells using in vitro and in vivo readouts. Purified CD3+ T cells were activated, transduced with either DuoCAR- or CAR19-encoding lentivirus, and expanded in rhIL2. Overall, DuoCAR T cells showed superior ex vivo expansion compared to regular CAR19 T cells. In our in vitro studies, DuoCAR T cells showed robust upregulation of T cell activation markers, such as CD25, Granzyme B, and HLA-DR, and potent target cell killing when co-cultured with the B cell lymphoma cell line, Raji, or CRISPR-derived Raji CD19 knockout (KO) cells while CAR19 T cells were capable of doing so only with parental Raji cells. Furthermore, when cultured with Raji CD19, CD20, or CD22 KO cell lines, DuoCAR T cells produced high levels of IFNg, IL2, and TNF. In vivo, we observed that DuoCAR T cells were capable of eradicating both Raji and Raji CD19 KO cells in tumor-bearing NSG mice within a week and displayed upregulation of T cell activation markers along with increased levels of serum cytokines. Furthermore, DuoCAR T cells displayed strong engraftment and persistence in both the bone marrow and spleen of treated mice several weeks after tumor clearance suggesting that they can potentially provide long-term immunity against relapse. Overall, our results demonstrate the feasibility of engineering tri-specific CAR T cells and their strong capabilities in eradicating both wild-type and antigen-loss tumor cells in vitro and in vivo, raising the likelihood of superior anti-tumor efficacy in B cell lymphoma treatment despite potential antigen downmodulation.
Optimal Timing and Impact of Allogeneic Peripheral Blood Stem Cell Transplantation in Adult T-Cell Lymphoblastic Lymphoma: Insights from a Large Cohort Multi-Center Real-World Study in Shanghai
Authors: Yu Fangfang , Niu Jiahua , Yang Jianmin , Hou Jian , Hao Siguo , Liang Aibin , Xiong Hong , Zhu Qi , Liu Ligen , Shi Jun , Du Juan , Chen Bobin , Wei Rong , Zhao Wenli , Sun Lihua , Hou Yunhua , Tao Rong , Song Xianmin
Published: December 2024

Consolidation therapy modalities for adult T-cell lymphoblastic lymphoma (T-LBL) are still debated. One-hundred and fifty-three adult T-LBL patients from sixteen centers in Shanghai were enrolled for a real-world study. Out of them, 103 (67.5%) patients achieved complete remission (CR), with early-T progenitor (ETP) immunophenotype significantly lowering the CR rate. The 2-year overall survival (OS) and progression-free survival (PFS) were 56.3% and 47.6%, respectively. Multivariate analysis revealed allogeneic peripheral blood stem cell transplantation (allo-PBSCT) was an independent prognostic factor for higher OS (HR 0.423, p= 0.027) and PFS (HR 0.362, p= 0.003). For patients in CR, allo-PBSCT significantly lowered the cumulative incidence of relapse (CIR) compared to autologous PBSCT (p= 0.043) and non-SCT (p= 0.001) and improved survival. Multivariate analysis for patients undergoing allo-PBSCT showed thatETP independently lowered OS (HR 3.943, p= 0.004) and PFS (HR 2.668, p= 0.025), and that non-complete remission (NCR) at transplantation (HR 2.643, p=0.023) also significantly lowered PFS (HR 2.643, p=0.023) and had a trend towards reducing OS (HR 2.316, p=0.068). For patients undergoing allo-PBSCT in CR, early (within four induction courses) and late CR (after four induction courses) had comparable 2-year OS (p= 0.590), PFS (p= 0.858), CIR (p= 0.500), and non-relapse mortality (NRM) (p= 0.11). Early and deferred allo-PBSCT for early CR patients yielded similar 2-year OS (p= 0.640) and PFS (p= 0.970). Our data revealed that allo-PBSCT could decrease the relapse risk and improve the survival of T-LBL patients, and it should be considered upon achieving CR.
Non-Invasive Monitoring of Multiple Myeloma in Patients Via Ultra-Sensitive Detection of Circulating Plasma Cells in Peripheral Blood
Authors: Xianling Chen , Li Nainong , Jing Wang
Published: December 2024

Circulating plasma cells (CPCs) in peripheral blood are robust and independent prognostic markers, but their detection is challenging due to their low abundance. Next-generation flow cytometry it requires expensive instruments, is costly, and time-consuming. This study introduces a straightforward surface-enhanced Raman spectroscopy (SERS) assay leveraging plasmonic nanoparticles functionalized with anti-CD138 and anti-CD38 antibodies for detecting CPCs in peripheral blood samples. A portable optical device was used for signal recording, enhancing the potential for point-of-care applications. The developed assay is highly sensitive and specific, capable of detecting as few as one or two cells. The application of machine learning algorithms to SERS signal analysis yielded area under the curve values ranging from 0.90 to 0.95, demonstrating excellent performance in differentiating multiple myeloma patients from healthy donors. This SERS method provides a more sensitive and more accessible way for CPC detection, showing significant potential for multiple myeloma diagnosis, treatment monitoring, and prognosis prediction.
Novel Fusion Gene PTPRC-Cyrib As a Drug Resistance Mechanism in T-ALL
Authors: Li Xindi , Yin Le , Wang Zhihua , Sheng Yue , Cheng Zhao , Peng Hongling
Published: December 2024

OBJECTIVE

To investigate the mechanisms of resistance conferred by the novel fusion gene PTPRC-CYRIB in T-cell acute lymphoblastic leukemia (T-ALL).

METHODS

Using next generation sequencing, we identified the novel fusion gene PTPRC-CYRIB in the bone marrow of a primary drug-resistant T-ALL patient, subsequently confirmed its presence by Sanger sequencing. Molecular cloning techniques were employed to construct a plasmid overexpressing the PTPRC-CYRIB gene. Stable overexpression of PTPRC-CYRIB in T-ALL cell lines was achieved via lentiviral transduction. The T-ALL cell line overexpressing PTPRC-CYRIB was designated as the overexpression (OE) group, while the control group (NC) consisted of cells transduced with empty vector. Polymerase chain reaction (PCR) and western blotting (WB) confirmed PTPRC-CYRIB gene expression in transduced cells. Growth curves were plotted to assess proliferation rates, colony formation assays were conducted to evaluate clonogenic potential, and cell counting Kit-8 (CCK8) assays were performed following treatment with Vincristine, Idarubicin, Cyclophosphamide, and Prednisone to determine drug resistance in the OE group compared to the NC group.

RESULTS

We successfully constructed stable T-ALL cell lines overexpressing PTPRC-CYRIB. PCR and WB analysis confirmed PTPRC-CYRIB overexpression in the OE group compared to the NC group. Growth curve analysis revealed significantly increased proliferation rates in the OE group. Colony formation assays demonstrated enhanced clonogenic potential in OE cells. Following drug intervention, CCK8 assays indicated significantly reduced inhibitory effects of Vincristine, Idarubicin, Cyclophosphamide, and Prednisone on proliferation in the OE group compared to the NC group, with statistical significance (P < 0.05).

CONCLUSION

Overexpression of the fusion gene PTPRC-CYRIB in T-ALL may contribute to the development of drug resistance.