B Acute Lymphoblastic Leukemia

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.

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.

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.

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

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.

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

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

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.

In this study, we infused allogeneic donor lymphocytes from haploidentical donors to patients with acute lymphoblastic leukemia who were receiving blinatumomab concurrently. Dose escalation of the T cell dose of the infused product was performed, while we monitored for unwanted effects from the T cell infusion. Starting doses were very small, 10e6 CD3+ cells/kg of recipient body weight, final doses were 100-fold larger, 10e8 CD3+/kg.

Non-responders to blinatumomab have poor outcomes (2-year RFS: 25%) but may be salvaged by ASCT. The relatively low rate of NGS MRD negativity with blinatumomab monotherapy (31% in Ph- B-ALL) highlights the need for combination therapies in B-ALL.

Myeloablative conditioning with cyclophosphamide and total body irradiation precede infusion of investigational Orca-T, which consists of infusions of HSPCs and Tregs on Day 0 and an infusion of T conventional (Tcon) cells on Day 2. Here, we report very promising initial feasibility, safety and efficacy of the combination of allogeneic CD19/CD22-CAR T cells with Orca-T in patients with high-risk B-ALL. This paradigm shifting combination of allogeneic CAR T and allo-HCT resulted in 100% MRD- CR with full donor chimerism but without GVHD or severe CAR-mediated toxicity. These data, which demonstrate antigen-specific anti-tumor benefit of allogeneic CAR T cells in combination with GVHD prophylaxis mediated by Tregs and tacrolimus, have potential implications that could benefit patients with other hematologic diseases.

Ten (77%) pts received blinatumomab as part of initial therapy...Among pts who completed the DLT period (n=11), 7 (64%) experienced transient grade (G) 1 cytokine release syndrome (CRS) that resolved with tocilizumab +/- corticosteroid... The use of CAR-T in older adults with B-ALL in CR1 appears safe with no observed ICANS or ≥G2 CRS. CAR T cells had a robust expansion in the blood and CSF despite the low antigen setting. We have observed preliminary durable remissions and pts maintained function and cognition on day 100 post CAR-T.

Eighty-four percent of responders to obe-cel for whom MRD by NGS could be analyzed achieved MRD <10–6 leukemic cells which was associated with more durable responses, and higher EFS and OS rates than those observed in pts with MRD ≥10–4 and between 10–4 and 10–6 leukemic cells. Pts who did not achieve MRD <10–6 had poorer outcomes.

Frontline therapy was hyper-CVAD-based ± immunotherapy (e.g. inotuzumab ozogamicin and/or blinatumomab) in 43% (n=69), mini-hyper-CVD-based ± immunotherapy in 28% (n=45), and chemotherapy-free in 29% (n=47, all of whom were Ph+). Early achievement of NGS MRD negativity identifies pts with excellent outcomes after frontline therapy. Importantly, no relapses were observed in pts with HR cytogenetic/molecular features who achieved early NGS MRD negativity, suggesting that early MRD dynamics should be included in ALL risk stratification systems. Pts with HR Ph- ALL who achieve deep MRD negativity within the first 6 months of frontline therapy do not appear to benefit from allogeneic SCT.

P=N/A, N=130, Recruiting, Peking University People's Hospital | Not yet recruiting --> Recruiting

P1/2, N=74, Active, not recruiting, ECOG-ACRIN Cancer Research Group | Recruiting --> Active, not recruiting

Indeed, with molecular docking and biochemical experiments, we identified EPZ-5676 as a YTHDC1 inhibitor, and combination of EPZ-5676 with Cytarabine (Ara-c) significantly improved the efficacy of chemotherapy in B-ALL mouse models using YTHDC1high primary and lined B-ALL cells. Collectively, YTHDC1 is required for DDR in B-ALL cells by upregulating DDR-related gene expression via stabilizing m6A-modified KMT2C mRNA, thereby leading to increased histone H3K4 methylation, and targeted inhibition of YTHDC1 is a potentially new therapeutic strategy against B-ALL, especially YTHDC1high B-ALL.

P1, N=133, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Jun 2040 --> Oct 2024

Drug-resistant B-ALL cell lines could be successfully established by exposing RS4;11 cell line to the ascending concentration of BCL-2 inhibitors, and the drug resistance mechanism may be related to the overexpression of EP300.

The application of FLAER in PNH-positive and PNH-negative reactive or malignant BM aspirates identified normally expected non-PNH FLAER-dim CD34-/CD117+/HLA-DR+/CD33+ myeloid precursors in all samples. A specific FLAER-associated maturation pattern was observed, which is proposed for further study within MRD and diagnostic protocols.

P2, N=300, Suspended, National Cancer Institute (NCI) | N=550 --> 300

Cytotoxic CARpos γδ-T cells expansion correlates with treatment efficacy validated in a cohort of B-ALL (n = 18) and diffuse large B cell lymphoma (DLBCL) patients (n = 58). Our data provide insights into the complexity of T cell responses following CAR-T cell therapy and suggest drivers of immunotherapy response.

P1, N=24, Recruiting, City of Hope Medical Center | Active, not recruiting --> Recruiting | Trial completion date: Aug 2025 --> Feb 2026 | Trial primary completion date: Aug 2025 --> Feb 2026

P1, N=48, Not yet recruiting, Beijing GoBroad Hospital | Initiation date: Sep 2024 --> Dec 2024

TIM-3 gene expression allowed for significant differentiation between patients with malignant B-ALL and non-malignant healthy controls, with an area under the curve (AUC) of 0.706. The current study addressed the potential of reduced levels of TIM-3 as a negative biomarker for B-ALL patients.

P1/2, N=196, Active, not recruiting, The First Affiliated Hospital of Soochow University | N=98 --> 196

Overall, our findings indicate the prevalence and impact of new ABL1 KD mutations in BCR::ABL1-positive ALL patients, highlighting the necessity for effective therapies targetingthese mutations.

P1/2, N=98, Active, not recruiting, The First Affiliated Hospital of Soochow University | Recruiting --> Active, not recruiting | N=50 --> 98 | Trial primary completion date: Dec 2024 --> Aug 2024

The SIRT7-Pax5 interplay was conserved in B cell acute lymphoblastic leukemia, where SIRT7 expression correlated with good prognosis. Our findings reveal a crucial mechanism for B lymphopoiesis and highlight the relevance of sirtuins in immune function.

However, challenges persist in developing safe and efficient delivery strategies to target miRNAs specifically, minimizing off-target effects and enhancing therapeutic outcomes. Future mechanistic pre-clinical and clinical research would contribute to overcoming these challenges.

P=N/A, N=50, Not yet recruiting, Rennes University Hospital

P1, N=24, Not yet recruiting, British Columbia Cancer Agency | Initiation date: Jul 2024 --> Nov 2024

However, our study demonstrates that of the majority the pathogenic variants in the TP53 gene are somatic (70.5%), and only 12.5% of patients with germline fulfilled the criteria of LFS. We also describe the first case of hypodiploid BCP-ALL with a mosaic pathogenic mutation in TP53 and the first case of the persistence of clonal hematopoiesis with the TР53 gene mutation in the child during 3-year minimal residual disease-negative remission, similar to what has been described in adults.

Two patients did not achieve remission even after two rounds of induction chemotherapy, with one achieving complete remission after treatment with blinatumomab immunotherapy...Five patients died, while two patients survived with sustained complete remission. TCF3-HLF-positive B-ALL is rare and has a high relapse rate and poor prognosis.

P1, N=28, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Jul 2025

P1/2, N=26, Recruiting, Vironexis Biotherapeutics Inc. | Not yet recruiting --> Recruiting

P2, N=28, Completed, Zhejiang University | Recruiting --> Completed | Phase classification: P1/2 --> P2 | N=50 --> 28 | Trial completion date: Mar 2025 --> Aug 2024 | Trial primary completion date: Mar 2024 --> Aug 2024

Furthermore, the exposure of mononuclear cells from patients with ALL in complete remission to the products of this organism reproduced genetic and cell phenotypes characteristic of ALL. These findings underscore the potential role of environmental factors in leukemogenesis and hint at novel avenues for therapeutic intervention and preventive strategies.

P1, N=24, Not yet recruiting, Chongqing Precision Biotech Co., Ltd

P2, N=171, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2027 --> Dec 2028 | Initiation date: Oct 2024 --> Jan 2025 | Trial primary completion date: Dec 2027 --> Dec 2028

The data indicate that circulating higher frequency of CD103+CD8+ T cells with lower expression of PD-1 and TIGIT are associated with favorable outcomes in patients with leukemia. This suggests a potential role of TRM cells in leukemia prognosis and provides a foundation for developing targeted immunotherapies.

No abstract available