Acute Lymphocytic Leukemia

P2, N=10, Recruiting, Fred Hutchinson Cancer Center | Trial primary completion date: Dec 2024 --> Jun 2024

P2, N=20, Recruiting, The First Affiliated Hospital of Soochow University | Not yet recruiting --> Recruiting | Initiation date: Oct 2023 --> Apr 2024

P1/2, N=20, Completed, Celgene | Recruiting --> Completed | N=121 --> 20 | Trial completion date: Dec 2024 --> Jan 2024 | Trial primary completion date: Dec 2024 --> Jan 2024

This report provides novel insights into the leukemogenic potential of the KMT2A::CBL rearrangement and the correlation between gene rearrangements and clinical outcomes.

In conclusion, CSF3R mutations were found at a higher frequency in aCML patients than in previous studies, which might reflect ethnic differences. Additional studies are needed to confirm these findings and the relationship between CSF3R and CEBPA mutations.

We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.

The findings prompt reflection also on the broader role of epigenetics in decoupling of replication from lineage differentiation activation by the B cell lineage master transcription factor hub. Such oncogenesis and resistance mechanisms, being predictable and epigenetic, offer practical opportunities for intervention, potentially non-cross-resistant and safe vis-à-vis present cytotoxic and CAR-T treatments.

Our research proved shared genetic architecture between autoimmune disorders and B-ALL and shed light on the potential mechanism that might involve in.

P2, N=125, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2024 --> Dec 2026 | Trial primary completion date: Oct 2024 --> Dec 2026

P=N/A, N=60, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Our study shows enrichment of high-risk genetic variants in H/L B-ALL and raises consideration for novel therapeutic targets.

No abstract available

Our findings demonstrated that Mexican patients with B-ALL have a higher prevalence of genetic markers associated with poor outcomes. Incorporating genomic methodologies into the diagnostic process, a significant unmet need in low- and mid-income countries, will allow a comprehensive identification of relevant alterations, improving disease classification, treatment selection, and the general outcome.

In another validation cohort including 78 children with low-risk ETV6::RUNX1-negative B-cell ALL, high TIMD4 expression at diagnosis had an HR = 3.93 [1.31, 11.79] (p = 0.01). Our results suggest high TIMD4 expression at diagnosis in low-risk B-cell ALL in children might be associated with high risk for early relapse.

P3, N=310, Suspended, Alliance for Clinical Trials in Oncology | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

P=N/A, N=353, Recruiting, Beijing GoBroad Hospital | Not yet recruiting --> Recruiting

P2, N=59, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

Progress in the development of molecularly targeted therapies and immunotherapy presents exciting opportunities for potential improvement. This comprehensive review synthesizes the current literature on the epidemiology, clinical presentation, molecular genetics, and therapeutic approaches specific to ALL in the infant population.

Responses only occurred in Cohort B, with a partial response in one patient with Hodgkin's lymphoma and morphological complete remission in the bone marrow in one patient with blastic plasmacytoid dendritic cell neoplasm. In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies.

P2, N=112, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2023 --> Dec 2024

P1, N=130, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1

No abstract available

P2, N=50, Not yet recruiting, Shanghai Unicar-Therapy Bio-medicine Technology Co.,Ltd

P=N/A, N=100, Recruiting, University of Aarhus

According to the findings of this study, the mutant allele of the Methylene Tetra Hydro Folate Reductase C677T was detected and demonstrated varying degrees of significance. It was concluded that the MTHFR C677T gene mutation was associated with acute lymphoblastic leukemia in Sudanese patients.

Overall, these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.

P=N/A, N=150, Not yet recruiting, Roswell Park Cancer Institute | Trial completion date: Mar 2029 --> Jun 2029 | Initiation date: Mar 2024 --> Jun 2024 | Trial primary completion date: Mar 2029 --> Jun 2029

Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.

The introduction of rituximab has improved the outcomes in CD20 positive cases. Other monoclonal antibodies, such as tafasitamab (anti-CD19), obinutuzumab (anti-CD20) and epratuzumab (anti-CD22) have been tested in trials (NCT05366218, NCT04920968, NCT00098839)...In contrast to ATP site inhibitors such as dasatinib and ponatinib, the novel first-in-class selective allosteric ABL myristoyl pocket (STAMP) inhibitor asciminib did not significantly impact ADCC in our settings. Our results suggest that asciminib should be considered in clinical trials.

This trial was registered at www.clinicaltrials.gov as no. NCT01564784.

P1, N=21, Recruiting, Baylor College of Medicine | Trial completion date: May 2039 --> May 2040 | Trial primary completion date: May 2024 --> May 2025

P3, N=287, Recruiting, Amgen | Trial completion date: Sep 2031 --> Jan 2032 | Trial primary completion date: Dec 2026 --> Apr 2027

P=N/A, N=144, Recruiting, Rigshospitalet, Denmark | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2026 --> Dec 2025

P2, N=20, Recruiting, University of Florida | Not yet recruiting --> Recruiting

P3, N=81, Not yet recruiting, First Affiliated Hospital of Zhejiang University

P=N/A, N=158, Recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto | Not yet recruiting --> Recruiting

Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.

Utilizing high-throughput combination screening of 1971 FDA-approved and clinically advanced compounds, we identified BCL-xL/BCL-2 inhibitor navitoclax as the most promising idasanutlin combination partner. We demonstrate a preferential engagement of cell death over G1 cell cycle arrest, mechanistically implicating MCL-1-binding pro-apoptotic sensitizer NOXA. The proposed combination of two clinical-stage compounds independently under clinical evaluation for ALL is of high clinical relevance and warrants consideration for the treatment of patients with high-risk and relapsed ALL.

Since 2000, targeted therapy combined with chemotherapy, represented by the tyrosine kinase inhibitor Imatinib, has become the first-line treatment for PH + ALL...More recently, some innovative immune-targeted therapy greatly improved the prognosis of PH + ALL, such as Blinatumomab and Inotuzumab Ozogamicin...These new therapeutic interventions are changing the treatment landscape for PH + ALL. In summary, this review discusses the current advancements in targeted therapeutic agents shift in the treatment strategy of PH + ALL towards using more tolerable chemotherapy-free induction and consolidation regimens confers better disease outcomes and might obviate the need for HSCT.

Moreover, combination of dasatinib with BTK inhibitors (BTKi) (ibrutinib, acalabrutinib or zanubrutinib) significantly decreased E2A-PBX1+/preBCR+ human and murine cell proliferation, reduced PLCG2 and BTK phosphorylation and total protein levels and increased disease-free survival of mice in secondary transplantation assays, reducing particularly CNS-leukemic infiltration. Hence, dasatinib with ibrutinib reduced pPLCG2 and pBTK in primary ALL patient samples, including E2A-PBX1+ ALLs. In summary, genetic depletion and pharmacological inhibition of BTK increase dasatinib effects in human and mouse E2A-PBX1+/preBCR+ ALL in most of performed assays, and the combination of dasatinib and BTKi is very effective in reducing CNS-infiltration of E2A-PBX1+/preBCR+ ALL cells in vivo.

P1, N=55, Terminated, Fred Hutchinson Cancer Center | Active, not recruiting --> Terminated; Terminated due to slow enrollment and end of funding