T Acute Lymphoblastic Leukemia

P1, N=18, Not yet recruiting, M.D. Anderson Cancer Center

We illustrate four use cases of ASHOP: (1) stratification of DUX4-rearranged B-cell leukemias into Early/Multipotent and Committed subgroups with distinct outcomes, (2) characterization of HOXA/HOXB expression patterns in acute myeloid leukemias, (3) correlating mutational burden with mismatch repair deficiency and mutational signatures, (4) investigation of TP53 alteration landscape. ASHOP is an open-access resource to inform genomic and transcriptomic data interpretation for hematologic malignancies, and will expand to support additional diseases and data modalities from the ASH community.

Here, we analyzed the sensitivity of T-ALL to inhibitors of BCL-2 (venetoclax), BCL-XL (A1331852), MCL-1 (AZD5991) and dual inhibition of BCL-2/BCL-XL (AZD4320) and evaluated their combination effects with natural killer (NK) cells. Importantly, NK cell-mediated killing could be further enhanced by combining NK cells with AZD4320, proposing this combination as a potential effective treatment. Taken together, we demonstrated promising potential of BH3-mimetics and NK cells for the treatment of T-ALL alone and in combination, warranting further preclinical and potential clinical evaluation.

P2, N=350, Active, not recruiting, Actuate Therapeutics Inc. | Trial completion date: Jan 2026 --> Jun 2026 | Trial primary completion date: Jan 2025 --> Jun 2026

Lastly, MYC induces Usp10 expression, and pharmacologic inhibition of USP10 delays MYC-driven leukemogenesis in a mouse leukemia model. Our results thus identify USP10 as coordinator of developmental signals and oncogenic processes in thymocytes, and implicate USP10 as a potential target for T-ALL therapy.

In T-ALL, aside from MRD, validated molecular markers for risk-group stratification remain limited. Our data suggest that molecular metrics analogous to those in T-LBL may help refining risk stratification in T-ALL as well.

In Jurkat xenograft models, SAp-CD28 demonstrated potent antitumor activity, and its combination with cytarabine resulted in near-complete tumor suppression, highlighting its potential for T-ALL treatment. This work introduces a CD28-targeted, enzyme-activated nanotherapeutic strategy that synergizes biochemical and mechanical mechanisms to selectively eliminate T-ALL cells. This multi-mechanistic tumor-killing strategy can also be extended to inspire therapeutic approaches for other diseases.

Importantly, pharmacological targeting of NUDT21 with ouabain octahydrate induces robust apoptosis in T-ALL cells by promoting NUDT21 protein degradation and concomitant suppression of UBE2D3 and MYC. Collectively, our findings establish NUDT21 as a multimodal oncogenic regulator and a promising therapeutic target in T-ALL.

The 11q23 rearrangement ALL with non-KMT2A::AFF1 transcript is mainly KMT2A::MLLT1, T-ALL is more common, and the rate of chromosomal karyotype detection is relatively low. Persistent positive KMT2A-r is unfavorable for patient survival, and allo-HSCT during the CR1 period may improve patient survival.

PDGFRB-rearranged ALL in children is uncommon, is most often detected in B-ALL, and presents at a relatively older age. Fusion partners are diverse and frequently co-occur with additional gene mutations. Despite high initial remission, MRD negativity and molecular clearance rates remain suboptimal, and allogeneic hematopoietic stem cell transplantation may improve prognosis.

P1, N=30, Suspended, University of Chicago | Recruiting --> Suspended

Collectively, our results indicate that PAMD-Ch17 has anti-leukemic effects against T-ALL cells but not healthy cells, likely mediated through a CXCR4 independent, mitochondrial based mechanism. These findings support further development of PAMDs as potential therapeutics for patients with T-ALL.