bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted Next Generation Sequencing Is Comparable with Metagenomic Next Generation Sequencing in Hematological Malignancies with Suspected Pneumonia for Pathogenic Microorganism Detection
Authors: Tang Yishu , Yulian Xiao , He Rong , Li Xin
Published: December 2024

Pulmonary infections are commonly observed in hematologic malignancy (HM) patients.For HM patients with low immune functionality and high susceptibility to pulmonary infections, timely identification of pathogens and administration of correct medications can greatly improve patient outcomes[1, 2].The next generation sequencing can achieve an early diagnosis of respiratory infection.To date, the systematic evaluation of the clinical use of mNGS and tNGS for pneumonia in HM patients has been insufficient.

A retrospective analysis was conducted on HM patients with suspected pneumonia admitted to the Hematology Department of The Third Xiangya Hospital between April 2019 and April 2024.A total of 234 patients were identified for analysis,including 126 patients used mNGS to detect bronchoalveolar lavage fluid(BALF）and 108 patients used mNGS to detect BALF.The purpose was to compare the diagnostic efficacy of mNGS and tNGS in pulmonary infection pathogens.

The overall microbial detection rate of mNGS and tNGS were 88.9% (112/126) and 93.5% (101/108), respectively. And there was no significant difference between them ( p = 0.217).Viruses,bacteria and fungi accounted for 42.2%(117/277), 33.9% (94/277) and 23.8% (66/277) among the microorganisms detected in mNGS, respectively. Meanwhile,Viruses,bacteria and fungi accounted for 61.0%(147/241), 21.2% (51/241) and 17.8% (43/241) among the microorganisms detected in mNGS.In order to compare the diagnostic and concordance between mNGS and tNGS.We used the final clinical diagnosis as the “gold standard”.The sensitivity, specificity, positive predictive value and accuracy of mNGS were 92.7%,37.5%,91.1% and 85.7%, respectively, compared with 97.9%,45.5%,94.1% and 92.6% for tNGS.Further more,we compared the clinical impact of mNGS and tNGS on antibiotic usage.The mNGS results led to adjustments in antibiotic usage for 63 out of the 126 patients(56.3%). Following these alterations, 56 patients (88.9%) reported significant improvements.In tNGS,there are 59 out of the 108 patients(58.4%%) adjustmented in antibiotic usage and 56 patients(94.9%) reported significant improvements.The total death of mNGS and tNGS were 9.8%(11/126) and 4.0%（4/108), respectively. There were no significant differences between the two groups (P ＞0.05).Compared to the microbial range detected by tNGS, mNGS detected an additional 14 pathogenic microorganisms, in which had a very low proportion of pathogenic microorganisms (3.6%,4/112), which did not have any adverse effects on the clinical outcomes of patients.

Collectively,we found that tNGS is comparable with mNGS in HM patients with suspected pneumonia for pathogenic microorganism detection.What's more,the ability of tNGS in guiding treatment was consistent with those of mNGS.
Humanized Anti-CD25 Monoclonal Antibody for Graft-Versus-Host Disease Prophylaxis in Older Patients Receiving Haploidentical Hematopoietic Stem Cell Transplantation
Authors: Zhang Xiaoyu , Zhai Weihua , MA Qiaoling , Feng Sizhou , He Yi , Han Mingzhe , Jiang Erlie
Published: December 2024

Introduction

Allogeneic stem cell transplantation (SCT) for elderly patients presents difficulties due to graft-versus-host disease (GVHD) and elevated non-relapse mortality (NRM). Advancing age correlates with a higher comorbidity index, diminished performance status, and an inherently increased risk of disease, all of which negatively affect survival rates. We conducted a prospective pilot study that the addition of humanized anti-CD25 monoclonal antibody as GVHD prophylaxis for older patients with hematologic malignancies undergoing haplo-identical donor transplantation.

Method

We prospectively reported and analyzed the data of 9 patients (>50 years old) with hematologic malignancies who received haplo-HSCT from Augst 2023 to April 2024. The enrolled patients were administrated with a combination of cyclosporine (CsA) or tacrolimus, mycophenolate mofetil (MMF), anti-human thymocyte immunoglobulin (ATG), MTX (15mg, +1d, 10mg, +3d, +6d,+11d), and humanized anti-CD25 monoclonal antibody (Xenopax, 1mg/kg, +1d, +4d) . This study is registered with the clinicaltrial.gov (NCT05923814).

Result

All patients achieved neutrophil and platelet engraftment (neutrophil: 14 days (11-20); platelet: 19 days (11-33). Two patient developed intestine involved grade II and III aGVHD, respectively. Of note, the two aGVHD cases resolved following treatment with a median time of 21 (14 - 28) days and no recipients died of aGVHD or associated complications. No cGVHD cases were diagnosed. No severe bacterial/fungus occurred. At a median follow-up of 271 days (range, 73 - 359), only one patient died of RSV pneumonia.

Conclusions

The humanized anti-CD25 monoclonal antibody is a promising GVHD prophylaxis for older patients receiving haplo-HSCT.
The Efficacy and Safety of the Addition of Mitoxantrone Hydrochloride Liposome in Conditioning Regimen for High-Risk Acute Myeloid Leukemia: The Short-TERM Analysis
Authors: Zhang Xiaoyu , Zhai Weihua , MA Qiaoling , Han Mingzhe , Feng Sizhou , He Yi , Jiang Erlie
Published: December 2024

Background:

Mitoxantrone, a synthetic anthracycline agent, has demonstrated superior anti-leukemic efficacy in acute myelogenous leukemia (AML). Mitoxantrone hydrochloride liposome (Lipo-MIT) represents a novel nano-drug, showcasing promising pharmacokinetics and extending survival in animal studies when compared to standard mitoxantrone. Several studies have validated the anti-tumor effects and safety of Lipo-MIT. We review our experience with Lipo-MIT as a conditioning regimen in high-risk acute myelogenous leukemia (AML) who underwent allo-HSCT.

Method

Between October 2022 and April 2024, high-risk AML patients, achieving CR1 or CR2, applied for allo-HSCT were retrospectively enrolled in this study at Institute of Hematology and Blood Diseases Hospital, CAMS and PUMC. Patients with HSCT were conditioned on the basis of Bu/Cy. Lipo-MIT was added at beginning of conditioning regimen (30mg/m2).

Result

This study included a total 17 high-risk AML patients achieving CR1 or CR2, with median age 42 years (ranged 18-60 years), received allo-HSCT (MSD-HSCT n=9, HID-HSCT n=7, MUD n=1). Five patients (5/17) had a diagnosis of extramedullary disease. Mucositis was the main reported regimen-related toxicity (10/17), most were well tolerated and only two were evaluated severe. No graft failure occurred. It is inspiring that all patients achieved hematology complete remission (CR) (100%) and 14/17 achieved MRD clearance on reconstitution day. The incidence of acute GVHD was 29.41% (5/17), and no severe aGVHD documented. With a median follow-up of 218（89-657）days, no relapse or deaths occurred among the patients.

Conclusion

The preliminary data demonstrated the efficacy and acceptable toxicity of Lipo-MIT containing regimen for high-risk AML patients.
Safety and Efficacy of R-PAD Regimen in Patients with Severe Multiple Center Idiopathic Castleman Disease: A Retrospective Case Series
Authors: Lu Yingting , Ying Chunrong , Liu Ligen , Zhao Limin , Jiang Xuewei , Zhang Tinghua , Zhang Zhizhi , Zhou Xiang , Chang Li , Zhu Xinying , Du Chao , Yang Li
Published: December 2024

To report the efficacy and safety of R-PAD regimen in four cases of patients with idiopathic multiple center Castleman disease (iMCD).

The clinical data of the four cases of patients met the diagnostic criteria of severe iMCD were collected, the efficacy and safety of R-PAD regimen were analyzed. The detail of R-PAD regimen is as follow: Rituximab 375mg/m2 day 1; Bortezomib 1.3mg/m2 day 1, 8, 15; Liposomal adriamycin 15mg/m2 day 1; Dexamethasone 20mg day 1-4, 9-12, 17-20. Four weeks as a course, total 4-6 courses were administered. And then, thalidomide and predinisone or dexamethasone were administered as maintenance.

Total 4 cases were enrolled, 3 female and 1 male. The median age was 45 years-old. One case was with TAFRO，1 case idiopathic plasmacytic lymphadenopathy, 1 case NOS and 1 NOS with hemophagocytic lymphohistiocytosis. The complete remission rate were 100%，and no 3 grade above adverse events were found.

R-PAD regimen might be a useful protocol as an induction regimen for patients with severe iMCD.
Circumventing the Platelet Storage Lesion By Relieving Platelet Inhibition Using a Novel Bi-Specific Antibody
Authors: Moroi Alyssa , Newman Peter J.
Published: December 2024

Human platelets undergo a series of structural and functional deteriorations that begin at the time of collection, and continue during both room temperature and/or cold storage conditions awaiting transfusion into human subjects. The so-called “platelet storage lesion” is characterized by altered cellular metabolism, increased apoptosis, changes in platelet morphology, and a decline in membrane integrity, all of which contribute to reduced platelet viability and function, Upon transfusion, platelets affected by storage lesions exhibit impaired aggregation, reduced ability to form stable clots, and decreased circulating lifespan, together reducing their efficacy in controlling bleeding. To improve the reactivity of stored platelets, we have adopted the tactic of restraining the function of a naturally occurring inhibitor of platelet function, the cell adhesion and signaling molecule, Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1). PECAM-1 is a 130kDa member of the immunoglobulin gene superfamily expressed on platelets, endothelial cells, and certain leukocyte subsets. In monolayer cells like the vascular endothelium, PECAM-1 functions as a cell adhesion receptor that helps maintain cell-cell junctions that control the permeability barrier. In circulating cells, PECAM-1 functions primarily as an inhibitor of cellular activation - a function that is mediated by tyrosine residues in its cytoplasmic domain Immunoreceptor Tyrosine-based Inhibitory Motifs (ITIMs), which become phosphorylated and recruit the SH2 domain-containing non-receptor protein tyrosine phosphatases, SHP-1 and SHP-2. To prevent this biochemical inhibitory reaction from occurring, we co-opted the ability of the transmembrane protein tyrosine phosphatase, CD148, to dephosphorylate phosphorylated tyrosine residues in PECAM-1. To promote cis-ligation of the phosphatase activity of CD148 with PECAM-1 cytoplasmic domain ITIMs to direct their dephosphorylation, we designed a novel bi-specific tandem single-chain antibody fragment (scFv) comprised of the variable region of an antibody specific for CD148 linked to the variable region of an antibody specific for PECAM-1. When added to human platelets, this engineered bi-specific scFv enhanced platelet secretion, and potentiated platelet aggregation and activation induced by weak platelet agonists, especially in stored platelets. Finally, tandem CD148/PECAM-1 scFv treatment also improved whole blood thrombus formation on collagen-coated surfaces under conditions of flow. Taken together, these results suggest that ITIM receptor inhibition through enforced phosphatase recruitment may be a useful strategy for increasing the functionality of donor-derived stored platelets.
A Systematic Review on Efficacy and Safety Profile of Blinatumomab in Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (R/R BCP-ALL) in Children and Young Adults
Authors: Ibrahim Ahmed , Yousaf Muhammad Abdullah , Gull Nayab , Khalid Saba , Khalid Huma , Rehman Mohammad Ebad Ur , Alliende Anna Maria Akhtar , Shafqat Aiza Binte , Malik Mustafa Nadeem , Rafae Abdul
Published: December 2024

Introduction:

Chemotherapy for relapsed or refractory B-cell precursor Acute Lymphoblastic Leukemia (R/R BCP-ALL) is associated with a high-grade toxicity profile and in a few cases subsequent relapse in children and adolescents. However, the bispecific T cell-binding antibody blinatumomab (target CD19/CD3) has been used successfully for the treatment of R/R BCP-ALL in pediatric populations with a favorable adverse effect profile and early bridging to Hematopoietic Stem Cell Transplant (HSCT). In this study, we report a systematic review of published literature on the efficacy and toxicity profile of blinatumomab in children, including data from the real world.

Materials and Methods:

Following PRISMA guidelines, an electronic search was performed on PubMed, Embase, Cochrane Library, Web of Science, and Clinicaltrials.gov, from inception to June 2024. Eligible patients were older than 28 days and younger than 18 years with an Eastern Cooperative Oncology Group score of 2 or less. Children included in this study were required to have B-cell precursor ALL, either refractory to induction or salvage chemotherapy treatments, or with relapsed disease after chemo and/ or hematopoietic stem cell transplantation. Initially, 347 articles were identified, and we finalized 12 studies with single-agent use of blinatumomab for inclusion in our review after a thorough screening. MeSH terms were “Precursor B-Cell Lymphoblastic Leukemia-Lymphoma,” “refractory”, “relapsed”, “safety”, “efficacy”, AND “blinatumomab”.

Results:

According to the reported data, the median age (mAge) was 8.6 years. Number of patients achieving Complete Remission or Complete Remission with incomplete hematologic recovery (CR/CRh) was 322 out of 555 (58%). The pooled Minimal Residual Disease (MRD) response was observed in patients 66.5% and 70.8% of patients were able to undergo HSCT. Blinatumomab treatment showed a median Overall Survival (mOS) of 10.35 months and a median Relapse-Free Survival (mRFS) of 12.7 months. The most frequently reported greater than grade 2 adverse events (AEs) were neutropenic fever (NF), cytokine release syndrome (CRS), and neurological events like headache, altered sensorium encephalopathy, etc.

Conclusion:

The current data reinforces that single-agent immunotherapy with blinatumomab is more effective in treating R/R BCP-ALL children facilitating early transplantation, and is safer, compared to standard-of-care chemotherapy. The toxicity with blinatumomab is majorly limited to cytokine release syndrome and neurologic events but is controllable and low in number. Prospective studies with longer follow-ups and bigger sample sizes, need to be conducted, to help us better understand blinatumomab.
A Single-Center Study of Long-Term Efficacy and Discontinuation Patterns of Thrombopoietin Receptor Agonists in Chronic Immune Thrombocytopenia
Authors: Stafylidis Christos , Diamantopoulos Panagiotis T , Vlachopoulou Dimitra , Antoniadou Vasiliki , Syriopoulou Stavroula , Patsialos Iraklis , Mantzourani Marina
Published: December 2024

Introduction

Thrombopoietin receptor agonists (TPO-RAs) have shown promising efficacy in the management of persistent or chronic immune thrombocytopenia (ITP), as second-line treatment, whereas sustained responses after TPO-RA discontinuation have also been reported. We present real-world data of TPO-RA-treated chronic ITP patients in a single center.

Methods

This retrospective study was conducted at the Hematology Unit of the First Department of Internal Medicine of the National and Kapodistrian University of Athens, Laikon General Hospital in Athens, Greece. Data were obtained from consecutive adult patients with chronic/refractory primary ITP treated with TPO-RAs from January 2010 to June 2024. Complete response (CR), defined as platelet count ≥ 100 × 109/L and absence of bleeding as well as durable response, defined as platelet count ≥ 30 x 109/L and at least doubling of the baseline count, were evaluated in these patients after initiation of TPO-RA treatment.

Results

A total of 52 patients were included. The median age was 52 (19-72) years and 70% were female. Patients had been previously treated with corticosteroids (100%), intravenous immunoglobulin (54%), immunosuppressants (21%), rituximab (8%), or splenectomy (17%). The majority of the patients (65%) received eltrombopag as initial TPO-RA treatment, while 35% were treated with romiplostim. The median time from diagnosis to TPO-RA treatment initiation was four years. The median duration of TPO-RA treatment was 48 months. CR was achieved in 52% of patients with TPO-RA treatment, whereas 23% of patients yielded durable responses. The median time to CR was 24 months. Ten patients (19%) who did not initially respond to eltrombopag, switched to another TPO-RA (90% avatrombopag), with 70% of them achieving CR and 20% yielding a durable response. The median time to CR after switching to a different TPO-RA was 16 months. Among all patients who achieved durable responses, a reduction in TPO-RA dose was achieved in 71%. Treatment discontinuation was observed in 58% of patients, due to either CR (90%) or poor response (10%). The median treatment-free period was 11 months, while treatment reinitiation due to loss of CR was noted in 11%.

Conclusion

TPO-RAs are highly effective in treating chronic ITP patients who are refractory to or relapse after first-line treatments. Furthermore, these agents can lead to sustained responses, thus allowing for treatment discontinuation and ultimately contributing to life quality improvement. Finally, switching to another TPO-RA may be beneficial for patients who do not initially respond.
Clinical Outcomes for Black Patients Following Hematopoietic Stem Cell Transplant: An Analysis of the National Inpatient Sample
Authors: Thor Danielle C , Elias Tony , Polineni Vineet , Brik Ben
Published: December 2024

Background: As hematopoietic stem cell transplant (HSCT) grows in accessibility and utility, it remains imperative to understand outcomes for its recipients. Limited data is available on the race-based correlations for this steadily increasing patient population. We sought to examine the National Inpatient Sample (NIS) database to describe in-hospital outcomes among the black population who have received a HSCT.

Methods: Data were extracted from the NIS Database from 2019 and 2020. The NIS was searched for hospitalizations of all patients greater than 18 years old who had previously received a HSCT and were hospitalized thereafter. We then analyzed the outcomes of patients who were identified as black. Multivariate logistic regression analysis was used to adjust for confounders; SPSS software was used for statistical analysis. The primary outcome was inpatient mortality and secondary outcomes are listed below.

Results: This study included 8,302 patients who had received a HSCT, of which 1070 (12.9%) were identified as black. Black recipients of a HSCT had a higher prevalence of obesity (8.6% versus 7.0%, p<0.001), hypertension (32.4% versus 23.7%, p<0.001), and chronic kidney disease (28.1% versus 21.3%, p<0.001), as well as a lower prevalence of smoking (17.1% versus 20.5%, p<0.001). Multivariate regression demonstrated that black recipients of a HSCT had higher inpatient mortality (OR 1.130, CI 1.087-1.174, p<0.001). On secondary analysis, black HSCT recipients were found to be more likely to have non-alcoholic fatty liver disease (OR 1.092, CI 1.039-1.147, p<0.001), thrombocytopenia (OR 1.133, CI 1.112-1.155, p<0.001), peripheral artery disease (OR 1.113, CI 1.067-1.161, p<0.001), hypertension (OR 1.215, CI 1.190-1.240, p<0.001), acute kidney failure (OR 1.162, CI 1.141-1.183, p<0.001), all-cause arrhythmias (OR 1.152, CI 1.120-1.186, p<0.001), all-cause shock (OR 1.173, CI 1.104-1.246, p<0.001), all-cause heart block (OR 1.089, CI 1.048-1.132, p<0.001), pericarditis (OR 1.186, CI 1.119-1.258, p<0.001), sepsis (OR 1.136, CI 1.119-1.153, p<0.001), hematuria (OR 1.128, CI 1.078-1.180, p<0.001), esophagitis (OR 1.138, CI 1.119-1.157, p<0.001), coagulopathies (OR 1.150, CI 1.108-1.193, p<0.001), chronic pulmonary disease (OR 1.120, CI 1.094-1.146, p<0.001), pulmonary hypertension (OR 1.178, CI 1.118-1.240, p<0.001), severe liver disease (OR 1.096, CI 1.061-1.132), acute heart failure (OR 1.188, CI 1.161-1.216, p<0.001), and myocardial infarction (OR 1.113, CI 1.081-1.147, p<0.001).

Conclusion: In this nationally-representative, population-based retrospective cohort study, black patients who have received a HSCT and were subsequently hospitalized were associated with higher mortality and worse outcomes.
LARP1 Regulates Leukemogenesis of AML By Altering Cell Metabolism and mRNA Translation
Authors: Nahotko Dominik A. , Baran Aneta H. , Fischietti Mariafausta , Small Sara H. , Beauchamp Elspeth M. , Platanias Leonidas C.
Published: December 2024

The mammalian target of rapamycin (mTOR) plays a crucial role in the pathophysiology of various tumors. However, attempts to target mTOR for cancer treatment have often been met with limited success, potentially due to overlapping signaling pathways, including the recently identified CDK9 mTOR-like (CTORC) complexes. La-related protein 1 (LARP1) is a common interactor of both mTORC1 and CTORC2 and is known to regulate ribosome production by managing the translation of 5‘ terminal oligopyrimidine tract (5‘ TOP) mRNAs, which typically encode ribosomal proteins and translation factors. In this study, we confirm LARP1 as a target shared by mTORC1 and CTORC2, and we explore the molecular mechanisms through which it drives the progression of acute myeloid leukemia (AML). Using CRISPR/CAS9 technology, we generated LARP1 knockout (KO) AML cell lines. The loss of LARP1 expression significantly reduced the proliferation and leukemic progenitor potential of these AML cell lines both in vitro and in vivo AML xenografts. Furthermore, we observed that LARP1 KO cell lines showed increased sensitivity to conventional chemotherapy drugs such as Azacitidine, Cytarabine, and Venetoclax. Polysome profiling followed by RNA-seq was employed to compare global translation levels between LARP1 KO and control U937 cells treated with mTOR, CDK9 inhibitors, combination of both or vehicle control. Our results indicate that loss of LARP1 expression had similar effects to treatment of U937 AML cells with mTOR and CDK9 inhibitors on translation. Finally, we performed global metabolomics analysis by LC-MS of U937 cells treated with either mTOR, CDK9 inhibitors or their combination as well as LARP1 KO cells. The results reveal that loss of LARP1 as well as inhibition of mTOR and CDK9 by small molecule antagonists diminish levels of some important oncometabolites. Altogether our findings suggest that LARP1 could be a potential therapeutic target for AML and warrants future drug discovery efforts to create LARP1 targeting small molecules.
Developing Novel Nanobodies Against the 5-Methylcytosine Dioxygenases TET2
Authors: Cai Xiaoli , Liu Xiaoxuan , He Lian , Liu Siyao , Fang Shaohai , Ma Guolin , Wang Rui , Zhou Yubin , Huang Yun Nancy
Published: December 2024

The Ten-eleven Translocation (TET) family of dioxygenases mediate DNA demethylation by oxidating 5-methylcytosine in the mammalian genome. Among the three TET family members, TET2 is frequently mutated in hematological disorders, including age-related clonal hematopoiesis and hematological malignancies. Previous reports suggest that loss-of-function mutations of TET2 lead to increased self-renewal and myeloid bias of hematopoietic stem and progenitor cells (HSPCs) in both mouse and human studies, suggesting its tumor-suppressive role. On the other hand, TET2 depletion in myeloid or lymphoid cells enhances their immune function in the tumor microenvironment and remarkably augments the efficacy of anti-tumor immunotherapy. Indeed, loss of TET2 enables antigen-independent CAR-T cell clonal expansion and improves tumor infiltration. Therefore, there remains a clinical need to harness TET2 in the hematopoietic system in a tunable manner to enhance anti-cancer immunity and suppress tumor cell growth while limiting the risk of uncontrolled proliferation.

Developing nanobodies as therapeutics has emerged as a promising avenue, offering minimal toxicity and facile delivery. A nanobody is about one-tenth of the size of a full-size antibody (~15 kDa), ranking it among the smallest known antigen-binding modules. The unique structures of complementarity determining regions (CDRs), along with their smaller molecular size, allow nanobodies to penetrate deeper and more rapidly into target cells or tissues. Additionally, the high homology of nanobodies to the human family III heavy chain domain results in low immunogenicity and high tolerance, making them ideal candidates for translational therapeutic development.

In this study, we developed a set of nanobodies against human TET2. We validate the specific recognition of nanobodies to human TET2 based on cell-based imaging and biochemical immunoprecipitation approaches. Randomized mutagenesis was performed in CDRs to further improve the binding affinity between nanobodies and TET2. The specific recognition between optimized nanobodies and TET2 were further evaluated using GST-tagged recombinant protein. We then further fused the nanobodies with modular domains derived from the proteasomal degradation machinery to enable specific degradation of TET2 protein in both HEK293T and Jurkat T cell lines. We will apply this nanobody-based degradation tool in human CD19 CAR-T cells to explore its potential to increase CAR-T efficacy and enhance tumor killing. In summary, the development of nanobodies against TET2 provides a novel approach to modulate endogenous TET2 protein level and activity, setting the stage for precise epigenetic regulation in both HSPCs and immune cells to benefit cell-based therapies.
Generation of Functional iPSC-Derived CAR-T Cells for Cancer Immunotherapy Via G9a/GLP Inhibition
Authors: Jing Ran , Falchetti Marcelo , Han Tianxiao , Najia Mohamad , Hensch Luca , Meader Eleanor , Kononov Martin , Wang Stephanie , Kubaczka Caroline , Lummertz Da Rocha Edroaldo , Rowe Robert Grant , Schlaeger Thorsten M. , Maus Marcela , North Trista E. , Zon Leonard I. , Daley George Q.
Published: December 2024

Cancer immunotherapy using patient-derived T cells modified with chimeric antigen receptors (CAR) has shown exceptional success against lymphoid malignancies. However, these autologous cell therapies involve complex and labor-intensive cell processing. Utilizing human induced Pluripotent Stem Cells (iPSCs) to produce CAR T cells offers significant potential for developing allogeneic, off-the-shelf cancer immunotherapies. The main challenge is generating fully mature T cells from iPSCs, as iPSC-derived T cells often display characteristics of innate-like gamma-delta T cells, lacking the robust functionality of mature alpha-beta T cells derived from peripheral blood. Previously, we developed a stroma-free culture system for differentiating iPSCs into T cells that entailed genetic knockdown of the EZH1 histone methyltransferase, which functions as an epigenetic barrier to hematopoietic maturation (Jing et al, Cell Stem Cell, 2022). To facilitate cell manufacture for clinical translation, we conducted small molecule screens to identify compounds that phenocopy EZH1 deficiency in affecting lymphoid development. We discovered that inhibiting G9a/GLP similarly promotes the generation of mature T cells from iPSC-derived hemogenic endothelial cells (HECs). ATAC-seq and RNA-seq analyses revealed that G9a/GLP inhibition regulates chromatin accessibility and gene expression patterns associated with lymphoid differentiation, and influences the fate choice between myeloid and lymphoid lineages. We also showed that inhibiting G9a/GLP enhances lymphopoiesis in zebrafish, demonstrating the evolutionary conservation of G9a/GLP's role in T cell development. Most importantly, chemically-induced epigenetic reprogramming via G9a/GLP inhibition enables the generation of highly functional iPSC-derived T cells with a molecular profile similar to that of mature alpha-beta T cells from peripheral blood. Single-cell RNA-seq analysis further revealed that iPSC-derived T cells give rise to both effector and memory-like T cell subpopulations upon activation. When these epigenetically reprogrammed iPSC-derived T cells were engineered to express an anti-CD19 CAR, they showed potent effector responses and antitumor activity in vitro and in a xenograft lymphoma mouse model. We also demonstrated that mice treated with epigenetically modulated iPSC-CAR-T cells were resistant to tumor cell rechallenge, further demonstrating that iPSC-CAR-T cells derived through G9a/GLP inhibition can persist and induce sustained remission. These findings support the efficient production of clinically relevant iPSC-derived T cells for adoptive cell therapies.
Epidemiological Analysis and Overall Survival of Leukemia in the Pediatric Population in a Developing Middle Eastern Country over 18 Years
Authors: Abdulelah Ahmed A , Abdulelah Zaid A , Al-Bitar Farah , AlQirem Lina , Al-Husni Dua' , Alhajahjeh Abdulrahman , Abdel-Razeq Hikmat , Haddadin Michael
Published: December 2024

Introduction: Leukemia in the pediatric age group is widely regarded as the third most common malignancy and contributes to significant burden due to the resultant morbidity and mortality. Accordingly, it is undoubtedly warranted to thoroughly evaluate and consequently establish the epidemiological characteristics in developing middle eastern countries with scarce resources, such as Jordan, to achieve effective risk stratification and introduction of appropriate measures.

Methods: Extensive and comprehensive data on a cohort consisting of 2038 pediatric males and females of different nationalities residing in Jordan who were diagnosed with leukemia during the timespan of 2000-2018 was obtained from the official cancer reporting body in Jordan, the Jordan Cancer Registry. Epidemiological features and characteristics, including overall survival and crude incidence, of leukemia in the pediatric age group were evaluated through statistical analysis.

Results: A total of 2038 pediatric patient with a mean age of 7.86 ± 5.36 years old and a male predominance of 59.2% were included in the analysis. Acute lymphocytic leukemia was the most commonly encountered malignancy as reported in 68.2% of the study population, followed by acute myeloid leukemia which was reported in 21.6%. The overall survival was 94.7%, 92.5%, 92.2%, 92.1%, and 92.0% at 1-year, 2-year, 3-year, 4-year, and 5-year interval, respectively. Furthermore, a statistically significant decline in the crude incidence of pediatric leukemia in Jordan over 18 years was identified with a crude incidence estimated effect of -0.059.

Conclusion: Over a span of 18 years, leukemia in the pediatric age group in Jordan demonstrated a significant decline of approximately 5.9% in the crude incidence along with a generally comparable overall survival to the witnessed rates in the international reports.
Electron Spatially Fractionated Radiation Therapy for Mycosis Fungoides
Authors: Liu Melody , Zhang Hualin , Xu ZhengZheng , Yaghmour George , Lukas Lauren
Published: December 2024

Introduction: The tumor microenvironment of mycosis fungoides is involved in disease progression and immune evasion. The presence of regulatory T-cells and progressive lack of cytotoxic T-cells fosters an immunosuppressive environment contributing to proliferation and resistance to immunotherapy. Understanding the mechanisms behind immune cell dysfunction in mycosis fungoides is vital for developing therapies that can restore immune responses and synergize with immunotherapy. Photon based spatially fractionated radiation therapy (SFRT) has been shown to have immunomodulatory effects on the tumor microenvironment, but there is a need to develop radiation strategies for cutaneous tumors. Electron radiation therapy is widely utilized for the palliative treatment of mycosis fungoides. Currently there are no clinical studies of electron SFRT (eSFRT) or evaluation of the immunomodulatory effects of eSFRT in mycosis fungoides to potentially synergize with immunotherapy. The first step is to assess the feasibility and dosimetry of GRID collimators designed for eSFRT delivery.Methods: The 3 mm and 1.5 mm lead GRID collimators were placed on a solid water phantom and the percentage depth doses (PDD) and lateral dose profiles were measured for 6, 9 and 12 MeV electron beams with Gafchromic EBT3 films. At the lateral dose profile, the peak to valley dose ratios (PVDR) and output factors were evaluated.Results: The dmax values with the 3 mm thick lead GRID collimator at 6, 9, and 12 MeV were 1.3, 2.1, and 2.9 cm, respectively. The output factors at dmax for 6, 9, and 12 MeV using a 10x10 cm field size were 0.815, 0.723, and 0.700, respectively. The PVDRs for 6 MeV at dmax and d90 for the 1.5 mm thick lead GRID collimator were 8.9 and 3.0, respectively.Conclusions: It is feasible for a lead GRID collimator to deliver a dose distribution amenable for eSFRT. Further research is warranted to evaluate preclinical models of eSFRT for mycosis fungoides to assess tumor microenvironment immune effects alone and in combination with immunotherapy.
Retrospective Study Evaluating Outcomes of Patients Treated with HIDAC123 Regimen with No Growth Factor Support Post Remission AML Treatment
Authors: Kamau James , Dadeboyina Chandrakala , Ghafari Ghazal , Straining Rachael , Hua Gwen
Published: December 2024

Introduction: High-dose cytarabine (HiDAC) is a widely used post-remission consolidation therapy for patients with acute myeloid leukemia (AML). However, the optimal regimen for HiDAC administration remains unclear, with studies on the use of granulocyte colony-stimulating factor (G-CSF) yielding mixed results. This study aims to evaluate the safety and efficacy of the HiDAC-123 regimen without routine G-CSF support in patients who achieved first complete remission (CR) after a single cycle of induction chemotherapy.

Methods: This retrospective analysis included adult patients (≥18 years) diagnosed with AML between June 1, 2013, and June 1, 2023. All patients achieved CR or CR with incomplete hematological recovery (CRi) after one cycle of intensive induction chemotherapy. The standard HiDAC dosing was 3 g/m², with dose adjustments based on age and renal function. A total of 24 patients received 48 cycles of HiDAC-123 with G-CSF, while 51 patients received 110 cycles of HiDAC-123 without G-CSF. Primary endpoints were relapse and overall survival rates. Secondary endpoints included time to marrow recovery, incidence of documented infections, and need for platelet transfusions within the 28-day consolidation cycle.

Results: The mean age was 57.9 years in the HiDAC-123 with G-CSF group and 51.7 years in the HiDAC-123 without G-CSF group (p=0.0285). The relapse incidence was higher in the G-CSF group 54.2% versus 41.2% (p=0.292), with the average time to disease recurrence of 240 versus 343 days (p=0.0730). Overall survival rates were 41.7% versus 54.9%, respectively (p=0.285). Time to marrow recovery (WBC > 1.0 and ANC > 500) was faster in patients receiving G-CSF (4.00 days versus 6.85 days, p=0.000667). The incidence of infections was lower in the G-CSF group (22.9% versus 26.4%, p=0.372). The average number of platelet transfusions required was similar between the two cohorts (1.56 versus 1.6, p=0.855).

Conclusions: The HiDAC-123 regimen with G-CSF support resulted in faster marrow recovery and fewer infections but did not significantly impact relapse or overall survival rates. The study's limitations include its small sample size and retrospective design. Further prospective trials are necessary to evaluate the effects of G-CSF on the safety and efficacy of the HiDAC-123 regimen.
High-Risk TP53-Mutated Acute Myeloid Leukemia in Puerto Rico: Elevated Variant Allele Frequency and Clinical Implications
Authors: Crespo Orta Ian , Marrero Leon William , Cintron-Colon Hector R , Sanchez Paredes Dominic , Rodriguez-Arocho Cristian I. , Caceres William , Cruz-Chacon Alexis M.
Published: December 2024

Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy with poor prognosis, particularly in patients with TP53 mutations. TP53 mutations disrupt tumor suppressor gene function, causing genomic instability, chemoresistance, and adverse clinical outcomes. Variant allele frequency (VAF) of TP53 mutations carries prognostic significance, with higher VAF (>40%) being linked to worse outcomes. Despite extensive research on TP53 mutations in AML, there is a lack of knowledge regarding their prevalence and specific characteristics in the Puerto Rican community.

Methods: This is a retrospective study of newly diagnosed AML patients with TP53 mutations detected via next-generation sequencing (NGS) at San Juan City Hospital, a primary referral center for AML in Puerto Rico. We analyzed patient demographics, cytogenetics, molecular markers, and VAF of TP53 mutations. This study is compliant with the Declaration of Helsinki for Studies.

Results: Among the 184 newly diagnosed AML patients identified during the study period (2020-2024), 14% (N = 25) exhibited TP53 mutations. Within this subset, 64% were male, with a median age of 66 years. The average TP53 VAF was 47%, higher than reported in previous studies, with 65% of cases exhibiting a VAF >40%. We identified complex cytogenetics in 72% of cases, with 36% having co-occurring RUNX1 mutations and 40% having 5q deletions. Additionally, 57% of the cohort had biallelic TP53 mutations. Outcome data showed only 4 patients surviving, with 2 having undergone allogeneic stem cell transplant and the other 2 currently receiving treatment.

Conclusion: This study is the first to describe TP53 mutated AML in patients from Puerto Rico. There is an elevated prevalence of TP53 VAF, biallelic mutations, and concurrent RUNX1 and 5q deletions compared to the general population. These findings suggest that Puerto Rican patients with TP53 mutated AML form a high-risk subgroup burdened by TP53 mutations. Further investigations are required to understand the reasons behind the elevated VAF in this community, considering the unique sociostructural factors influencing health on the island and existing health inequalities. Additionally, our findings highlight the necessity for targeted treatments and personalized therapeutic strategies for this high-risk group due to their connection with chemoresistance and poor prognosis. Tackling these challenges through appropriate and fair healthcare interventions is essential for improving outcomes for this vulnerable population.
Trends in Mortality Due to Hematologic Malignancies Among Patients Aged 25 and Older in the United States: Racial and Ethnic Disparities, Insights from the CDC Wonder Database
Authors: Durugu Satya R , Ahmed Faizan , Ali Hassan , Sinha Shrishti , Iqbal Sabah , Rojulpote Krishna V , Abboud Brian , Thirumaran Rajesh
Published: December 2024

Introduction

Hematologic malignancies significantly impact mortality among adults aged 25 and older in the United States. This study investigates racial and ethnic disparities in mortality rates from 1999 to 2020.

Methods

Data from the CDC WONDER database (1999-2020) were retrospectively analyzed to calculate age-adjusted mortality rates (AAMRs) per 100,000 persons. Trends were assessed using Average Annual Percentage Change (AAPC) and Annual Percent Change (APC), stratified by race/ethnicity.

Results

Between 1999 and 2020, hematologic malignancies caused 1,463,046 deaths among adults aged 25 and older. White and Black populations had the highest AAMRs, followed by Hispanics, American Indians and Alaska Natives, as well as Asian, Asian American and Pacific Islanders. White populations saw a significant decrease in AAMR from 1999 to 2018 (APC: -1.5114; 95% CI: -1.6751 to -1.3964; p < 0.001), followed by a slight non-significant increase from 2018 to 2020 (APC: 1.3750; 95% CI: -0.9371 to 2.3460; p = 0.1382). Similarly, Black populations experienced a significant decline in AAMR from 1999 to 2018 (APC: -1.5083; 95% CI: -1.7281 to -1.3535; p < 0.001), with a non-significant increase from 2018 to 2020 (APC: 2.5566; 95% CI: -0.3603 to 4.1183; p = 0.0853). Hispanics saw a significant decrease in AAMR from 1999 to 2018 (APC -1.33; 95% CI: -3.46 to 2.68; P= 0.080), followed by slight non-significant increase in AAMR from 2018-2020 (APC 2.18; 95% CI: -1.38 TO 4.50; P=0.560). American Indian or Alaska Native saw decline in AAMR from 1999 - 2020 (APC -1.17; 95% CI -1.91 to -0.29; P=0.0099) while Asian or Pacific Islanders saw significant decline in AAMR from 1999-2020 (AAPC -1.52; 95% CI -1.69 to -1.24); P<0.001.

Conclusion

This study highlights significant racial and ethnic disparities in mortality rates due to hematologic malignancies among adults aged 25 and older in the U.S. Despite overall declines, there remains a persistently higher mortality rate among White and Black populations compared to Hispanic, American Indian and Alaska Native, as well as Asian, Asian American, and Pacific Islander populations. These findings indicate that race and ethnicity impact survival across multiple hematologic malignancies, necessitating further investigation into the factors driving these differences. The relationship between environmental exposures and disparities in incidence and clinical presentation should be explored in future studies to develop multilevel explanatory models, investigate interventional trials, and create preventive strategies.
Clinical Analysis and Gene Mapping of 12 Children with Therapy-Related Myelodysplastic Syndrome/Acute Leukemia
Authors: Chen Xia , Zhu Xiaofan
Published: December 2024

Objective Retrospectively analyze the clinical characteristics, regimen, prognosis and genetic profiles of the largest single-center therapy-related myelodysplastic syndrome/acute leukemia (t-MDS/AL) in China.

Methods clinical data of all pediatric patients diagnosed with t-MDS/AL since January 1,2018, were retrospectively collected and analyzed.

Results

(1) 12 pediatric t-MDS/AL patients were involved including 5 boys and 7 girls. The median age of primary and secondary tumors were 8 years old (range: 1-13 years) and 11 years old (range: 4-15 years). All patients received chemotherapy/radiotherapy after primary tumor diagnosis, and developed hematologic malignancies 6-71 months later, including 5 cases of t-MDS, 6 cases of t-AML and 1 case of t-ALL among them. Then 3 in 5 cases of t-MDS developed AML in late stage.

(2) All patients fellow up to July 1,2024. one patient received partial remission (PR) after EA induction regimen, but relapsed soon later, then gave up. 2 cases were treated with decitabine chemotherapy all with non-remission (NR). One case was treated with HAD induction regimen and NR. One case was treated with HAG regimen, NR. One case was treated with Decitabine + CAG regimen, NR. One case was treated with HAG + cladribine regimen and achieved complete remission (CR). 1 case was treated with VIA protocol, CR. One case of t-ALL was treated with induction chemotherapy (NR) in CCCG-ALL-2015 regimen. In the transplantation group, there were 6 cases, including 2 cases of direct transplantation without treatment, 3 cases of rescue transplantation with NR status and 1 case of transplantation with CR status, one patient relapsed 6 months after transplantation, and one patient relapsed 2 months after transplantation. In the non-transplantation group, there were 4 cases, 1 case of disease-free survival, 1 case of persistent NR status and 2 cases of death.

(3) The fusion gene of acute leukemia was detected in 10 patients. There were WT1 gene in 6 cases, P2RY8-CRLF2 fusion gene in 1 case, AML1-ETO fusion gene in 2 cases, MLL-AF9 fusion gene in 1 case, FLT3-ITD in 1 case and FLT3-TKD in 1 case.

(4) In the cytogenetics, only 2 cases had normal karyotype, 1 case had complex karyotype with recurrent genetic abnormalities such as t(8; 21), t(9; 11) and other chromosomal abnormalities such as 45, x,-y, etc. Another common abnormal karyotype was -17.

(5) the second-generation sequencing showed that there were 2 mutations in TP53, 2 mutations in KMT2D, 2 mutations in RUNX1,2 mutations in NRAS and 2 mutations in FLT3.

Conclusion Therapy-related hematologic malignancy is a rare disease which is caused by lots of factors. The remission rate of traditional chemotherapy is low and the mortality is high. Reducing the overlap of chemotherapy drugs, choosing new drugs, or performing transplantation directly and as soon as possible may improve the prognosis.
Management of Acquired Hemophilia a in the Backdrop of Coronavirus Disease 19 and Multiple Myeloma
Authors: Cai Zhen , Dong Mengmeng , Zhang Jinna , Wang Jiasheng
Published: December 2024

Background Acquired hemophilia A (AHA) is an autoimmune disorder characterized by unexpected bleeding that is likely caused by the development of clotting factor VIII inhibitors. Both virus infections and hematologic malignancies are among the possible underlying conditions for AHA because of their potential to cause immune dysfunction. Currently, the main treatments for AHA focus on achieving hemostasis and removing inhibitors, as well as managing the underlying pathology.

Case presentation Herein we present a patient who was diagnosed with AHA complicated with an emergency of osteofascial compartment syndrome. The patient experienced acute subcutaneous bleeding in his left calf during his recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Notably, the patient also had multiple myeloma (MM) and was undergoing maintenance treatment. Cases of coronavirus disease 19 (COVID-19) or MM-associated AHA are rare, and there have been no reported AHA cases with both underlying conditions. To determine the potential causes of AHA, a comprehensive analysis was conducted. Hemostatic and immunosuppressive treatments were administered based on the underlying etiology and relevant examination findings, ultimately resulting in a successful cure for AHA.

ConclusionThis clinical case highlights the occurrence of severe bleeding in an MM patient who was undergoing maintenance therapy and contracted SARS-CoV-2 infection. The patient was subsequently diagnosed with AHA. Given the presence of multiple immune disorder factors, clinicians should carefully analyze the potential contributing factors to guide treatment decisions and prevent future recurrences.