Acute Lymphocytic Leukemia

These rhenium(I) tricarbonyl complexes also slightly increased ROS production and significantly decreased the mitochondrial membrane potential by 50 % (5eRe) and 45 % (6dRe) compared to untreated cells and cells treated with 5e and 6d. These results suggest that the cytotoxic effects of these compounds are mediated by their effects on mitochondrial membrane potential and the subsequent increase in ROS production.

Dexamethasone (DXM) was used in average-risk 2 (AR2) T-ALL and B-ALL during induction, 10 and 6 mg/m2/day, respectively. Leucovorin rescue was delayed to 42 h instead of 36 h after initiation of high-dose methotrexate, and a postconsolidation MRD time point was added to stratify patients...The HR was 2.15 (99% CI: 0.67-6.85) for very low-risk but 0.34 (99% CI: 0.13-0.89) for AR2. The particularly favorable results observed in the T-ALLs and AR2 subgroups suggest the benefit of using DXM in specific patient groups and highlight the importance of risk stratification.

These findings suggest that CD40 agonists are promising immunotherapeutic candidates for pediatric B-ALL, warranting further clinical investigations to improve patient outcomes in CD40-expressing B-ALL.

Our findings suggest that the CCCP genes may play a key role in the progression of ALL and can be used as potential therapeutic targets and diagnostic markers.

Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.

Importantly, various lines of experimentation reveal that BCL11B FR could fold into parallel G-quadruplex, triplex, and hairpin structures, which could act as a replication/transcription block, causing mutagenesis. Thus, our results suggest that AID binds to BCL11B exon 4 due to non-B DNA formation, causing U:G mismatches or replication blocks, which, when repaired erroneously, generates deleterious mutations, resulting in loss of functionality of BCL11B, and thus becomes the cause of T-ALL.

Our findings suggest that the NRAS p.Arg97Thr variant may disrupt the splicing machinery and functions of the protein, thus playing a vital role in leukemogenesis. In addition, the highly druggable pocket may possibly be studied for its therapeutic implications.

This study found that hypoploid B-ALL patients have distinct characteristics, such as lower S-phase cell percentages and specific immunophenotypic profiles, including higher HLA-DR expression and CD34/CD22 co-expression. These differences across DNA index-based prognostic categories warrant further research to explore their potential prognostic significance.

P=N/A, N=177, Completed, Ann & Robert H Lurie Children's Hospital of Chicago | Unknown status --> Completed

In this review, we emphasize the importance of distinct tissue-specific expression patterns, functional divergence, disease-specific considerations, and the necessity to minimize off-target effects that collectively underscore the significance of "individualized" targeting for Notch1 and Notch2. This comprehensive review sheds light on the receptor-specific characteristics of Notch1 and Notch2, providing insights into their roles in cellular processes and offering opportunities for developing tailored therapeutic interventions in the fields of biomedical research and clinical practice.

We report the first case of TCF3::ZNF384 mixed-phenotype leukemia presenting as isolated extramedullary disease in the mediastinum. Diagnosis using RNA-sequencing and whole genome sequencing on the primary issue is illustrated.

Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).

P1, N=19, Terminated, Beijing Boren Hospital | Recruiting --> Terminated; ethic commitee decision

P1, N=0, Withdrawn, Beijing Boren Hospital | N=18 --> 0 | Trial completion date: Jul 2024 --> Dec 2023 | Recruiting --> Withdrawn | Trial primary completion date: Jul 2024 --> Dec 2023

P1, N=16, Completed, Beijing Boren Hospital | Recruiting --> Completed

P3, N=5949, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2025

We demonstrated the capability of OGT's SureSeq Myeloid Fusion Complete NGS Workflow Solution V2 to achieve 100% accurate detection for novel and canonical translocations. By allowing concurrent detection of multiple known and novel rearrangements, NGS assays offer an economical and efficient alternative to routine cytogenetic approaches.

Six weeks later, while receiving the CD20-directed immunotherapies glofitamab and obinutuzumab, another bone marrow biopsy revealed eradication of the B-ALL and new involvement by pure erythroid leukemia (PEL). This patient's B-ALL lacked an IGH::BCL2 fusion resulting from t(14; 18), suggesting it did not arise through transformation of his prior FL/DLBCL. Instead, the B-ALL was likely caused by his extensive exposure to genotoxic chemotherapy drugs – including alkylating agents – for his preceding lymphomas. The shared cytogenetic and molecular features between this patient's B-ALL and PEL imply they are clonally related.

A linear relationship was found between reported and assigned values for all levels of the reference standards when tested across 3 different BCR-ABL RT-qPCR assays, enabling the calculation of an assay-specific CF to allow harmonized reporting on the International Scale (%IS). The BCR-ABL p210 Panel was validated for accuracy, precision, robustness, and traceability, and can be used as a WHO traceable reference standard to create assay-specific CF to enable standardized reporting on the International Scale (%IS).

P3, N=847, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

P2, N=59, Recruiting, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

P1, N=24, Suspended, Medical College of Wisconsin | Recruiting --> Suspended

P=N/A, N=51, Active, not recruiting, Roswell Park Cancer Institute | Recruiting --> Active, not recruiting | N=79 --> 51

P1, N=74, Recruiting, City of Hope Medical Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P=N/A, N=206, Not yet recruiting, Qilu Hospital of Shandong University; Qilu Hospital of Shandong University

P=N/A, N=94, Completed, The First Affiliated Hospital of Sun Yat-sen University; The First Affiliated Hospital of Sun Yat-sen University

P=N/A, N=1000, Recruiting, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Institute of Hematology

P=N/A, N=133, Completed, The First Hospital of Jilin University; The First Hospital of Jilin University

P4, N=200, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College.; Institute of Hematolog

P=N/A, N=283, Recruiting, Peking University People's Hospital | Not yet recruiting --> Recruiting | Initiation date: Jun 2024 --> Nov 2024

P=N/A, N=1000, Not yet recruiting, Nantes University Hospital

Global sensitivity analysis highlighted relative antigen expression, maximum killing rate constant, and CAR-T expansion rate constant as major determinants for observed exposure of dual-targeted CAR-T-cell therapy. This modeling framework could facilitate dose-optimization and construct refinement for dual-targeted bicistronic CAR-T-cell therapies, serving as a valuable tool for both forward and reverse translation in drug development.

This review examined the research progress of chimeric antigen receptor T-cell therapy in gliomas, medulloblastomas, and lymphohematopoietic tumors of the central nervous system, focusing on chimeric antigen receptor T-cells targeting antigens such as EGFRvIII, HER2, B7H3, GD2, and CD19 in preclinical and clinical studies. It synthesized current research findings to offer valuable insights for future chimeric antigen receptor T-cell therapeutic strategies for central nervous system tumors and advance the development and application of this therapeutic modality in this domain.

P2, N=39, Recruiting, SWOG Cancer Research Network | Trial completion date: Aug 2027 --> Aug 2032 | Trial primary completion date: Aug 2026 --> Aug 2028

To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent...ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL.

P1, N=22, Recruiting, University of Wisconsin, Madison | Suspended --> Recruiting | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

Stem reciprocity is predictive of disease state, BCR::ABL1 status and MRD status. Our findings highlight the potential of mechanistic learning in enhancing both the understanding and predictive accuracy of disease progression.

We recently demonstrated that INO can be added safely to a non-myeloablative conditioning of bendamustine, fludarabine, and rituximab in patients with indolent lymphoid malignancies who required an allogeneic hematopoietic transplantation (HCT) (Am J Hematol 2024)...Patients who received transplants from MUDs received an additional dose of methotrexate 5 mg/m2 on day +11 and 1 mg/kg of rabbit anti-thymocyte globulin IV on days -1 and -2 before HCT...The patient who was in CR2 at transplant had Ph+ ALL and was maintained on ponatinib after HCT. Key prior therapies in ALL patients included blinatumomab (n=5) and INO (n=5)... Our conclusions are limited by the small number of patients due to slow accrual. However, our data suggest that INO is safe when combined with a melphalan plus fludarabine HCT conditioning regimen. The survival outcomes are encouraging and need to be validated in a larger number of patients.

Blinatumomab was not used during consolidation therapy in the reported patients. Its incorporation in the routine therapy of newly diagnosed patients may increase the proportion of patients receiving AHCT in a MRD negative state and further improve outcomes in this historically poor risk patient population.

This analysis of 2,637 samples comprising a variety of molecular subtypes of ALL demonstrated that the F1H assay detects pathogenic genomic alterations with diagnostic, prognostic, and therapeutic significance. As both the treatment landscape and disease classification system in ALL have continued to evolve over time, CGP assays such as F1H can play a critical role in clinical decision making by simultaneously assessing the presence and absence of numerous actionable genomic alterations and biomarkers with a single assay.

"Introduction: Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL)...No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel... In a large real-world cohort of adults with R/R B-ALL infused with brexu cel, we identified practice variation regarding the use of consolidative HCT. Among brexu cel recipients who entered an MRD- CR, we identified ClonoSeq NGS MRD negativity as a novel predictive factor of favorable oncologic outcomes, even without a consolidative HCT. Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022)."

Because of the above, further research is needed to explore whether using upfront immunotherapy like inotuzumab ozogamicin or blinatumomab in the upfront setting, as well as administering allogeneic transplant early in the treatment course of muTP53-ALL would decrease the risk of relapse and improve long-term survival. The muTP53-ALL patients had similar CCR to first-line therapy to wtTP53-ALL. However, they had worse OS, likely because of relapses. The findings highlight the significant impact of TP53 mutation on outcomes in ALL.