B Acute Lymphoblastic Leukemia

P2, N=30, Not yet recruiting, University of Washington

Upon ruxolitinib withdrawal, TSLPRCART functionality recovered in vivo with clearance of subsequent ALL rechallenge. These translational studies demonstrate an effective two-pronged therapeutic strategy that mitigates acute CART-induced hyperinflammation and provides potential anti-leukemia 'maintenance' relapse prevention for CRLF2-rearranged Ph-like and DS-ALL.

These findings highlight significant differences in ID1 and ID3 expression levels and their impact on TIME populations, particularly neutrophil-related pathways. The results suggest a potential role for ID1 and ID3 in immune evasion in adult B-ALL, mediated through neutrophil activation and immune regulation.

P1/2, N=80, Recruiting, Wuhan Union Hospital, China

P1, N=10, Recruiting, Institute of Hematology and Blood Transfusion, Czech Republic | Trial completion date: Jun 2025 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

Starting from the initiation of blinatumomab treatment, with a median follow-up of 12 months, all patients remained in complete remission. Our study was the first to demonstrate that blinatumomab could further eradicate ddPCR MRD after patients achieve MFC-MRD undetectable status in B-ALL patients.

Not available.

Therapeutically relevant doses of CD19/CD22 CAR-T cells can be successfully manufactured from whole blood. On average, 80 mL of whole blood yields enough CAR-T cells to create a single dose for a pediatric patient (50 kg) at a dosage of 1 × 106 CAR-T cells/kg. For larger patients, scaling up is straightforward by collecting a larger blood volume. This method also demonstrates a cost-effective approach to T cell activation and expansion which, alongside a more straightforward collection of whole blood, makes it more widely accessible especially for middle- and low-income countries. By reducing costs and labor, this strategy has the potential to significantly expand global access to CAR-T cell therapy.

Here we report the case of a child with DS who was diagnosed with a second relapse of BCP-ALL and has maintained complete remission through regular single-agent InO therapy. Single-agent maintenance using InO can be a good option to avoid subsequent relapse in patients with relapsed or refractory BCP-ALL who cannot proceed to allo-HCT and require less-toxic treatments.

Incorporation of blinatumomab and/or inotuzumab in CR1 may mitigate the negative prognostic significance of MRD, however it is unclear if intensity of standard post-remission therapy can be safely reduced without compromising outcomes...We designed a phase I clinical trial to determine safety and tolerability of UCD19 CAR-T cell therapy for adults with B-ALL in MRD+ CR1 who are at high risk for relapse.Methods : Eligible patients include adults (≥18yo) with B-ALL in CR1 after induction therapy, with MRD positivity by either flow cytometry or NGS (Clonoseq)...Longer follow-up is needed to determine if remissions remain durable, and to determine the relationship between functional persistence (as measured by B-cell aplasia) and remission durability. Enrollment is ongoing at DL2.

Translation of our findings to the human system showed that high expression of LY6E on tumour cells impaired their physical interaction with NK cells and led to worse prognosis in leukaemia patients. Our results demonstrate that tumour cells are actively edited by NK cells during the equilibrium phase and use different avenues to escape NK cell-mediated eradication.

P=N/A, N=60, Not yet recruiting, National Research Center for Hematology, Russia

CD10, CD20, and CD200 were valuable in distinguishing MRD-positive cases from MRD-negative cases. Moreover, the MRD "lite" panel had 100% concordance between the two observers, suggesting simplicity in assessment and, hence, wider applicability.

P2, N=81, Terminated, Beijing Boren Hospital | Active, not recruiting --> Terminated; ethic commitee decision

P2, N=20, Not yet recruiting, Ruijin Hospital

P3, N=488, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Mar 2025

Further, despite adding a second antigen, antigen-negative relapses have not yet been eliminated. This review will summarise the state-of-the-art with dual targeting CAR-T cells for B-cell ALL and B-NHL, challenges encountered, and possible next steps to overcome them.

P1, N=71, Active, not recruiting, City of Hope Medical Center | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

P2, N=53, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

P1/2, N=60, Recruiting, National Research Center for Hematology, Russia | Not yet recruiting --> Recruiting

P1/2, N=30, Recruiting, Chinese PLA General Hospital | Trial completion date: Jul 2027 --> Feb 2028 | Initiation date: Jul 2024 --> Feb 2025 | Trial primary completion date: Jul 2026 --> Feb 2027

P=N/A, N=50, Not yet recruiting, University of Washington

In our study, the in vitro and in vivo experiments confirmed that chidamide and venetoclax synergistically inhibited the expression of MYCN and increased the expression of DKK3 by inhibiting the activity of HDAC and BCL2, inhibiting the Wnt/β-catenin signaling pathway and B-ALL cell proliferation. These findings indicate that the HDACi chidamide and the BCL2 inhibitor venetoclax can be used in combination to treat B-ALL, providing a new method and strategy for treating B-ALL.

Although it is uncertain whether the complex karyotype and somatic mutations observed in case 1 and KMT2A rearrangement and variants identified in case 2 may have either independently or cooperatively conferred a poor prognosis, we contend that additional comprehensive studies are needed to further understand the pathophysiology and prognosis of BRAF mutations in AML. We further posit whether patients with BRAF V600E-mutant AML may benefit from the combined use of BRAF inhibitors and/or RAS-pathway-targeting regimens, which are currently FDA-approved for the treatment of BRAF V600-mutant solid tumors and BRAF-mutant histiocytic neoplasms.

This study also revealed FLAER differences in other acute leukemias and even between different precursors (myeloid and lymphoid) from healthy controls. However, the reason for FLAER's non-binding to the malignant precursors of these leukemias remains unknown, and future studies should explore the possible relation with an immune escape phenomenon in these leukemias.

In summary, the PAX5::ZCCHC7 is a recurrent genetic aberration in B-ALL and seems to act as an additional genetic abnormality of subtype-defining aberration. Whether the PAX5::ZCCHC7 could act as a leukemia-initiating event or not needs further investigation.

P1/2, N=60, Not yet recruiting, National Research Center for Hematology, Russia

Given the rarity of NUTM1 fusion-positive B-ALL in adults, this case contributes to the growing evidence that such cases may present with a more aggressive clinical course compared to the pediatric population. Our findings suggest the need for a re-evaluation of therapeutic strategies in adult patients with this subtype of B-ALL.

P1/2, N=120, Recruiting, AstraZeneca | Trial completion date: Feb 2027 --> Jun 2027 | Trial primary completion date: Jan 2026 --> Jun 2026

A total of seven major clones of NRAS [five] and NT5C2 [two] were noted in six out of 14 (43%) relapse patients, accounting for 44% of early relapses. In addition, 10 minor clones (PMS2 [two], NRAS [four], NT5C2 [three], and TP53 [one]) were noted in five out of 14 (36%) patients. In the 56 sequential therapy samples, six major clones were noted (NRAS [five], KRAS [one]) in four out of 14 (28.5%) patients, with two increasing in size in maintenance samples, leading to subsequent relapse in both cases. In addition, therapy-acquired minor clones in NT5C2 [four] and PMS2 [one] were seen to emerge in maintenance samples in four out of 14 (28.5%) patients, with concordant detection of such major and minor clones in unpaired relapse samples, indicating the need for their active surveillance during therapy. Overall, digital PCR validated NRAS and NT5C2 major clones in one-third (10 out of 27; 37%) of cases, driving nearly half of early relapses.

P1/2, N=24, Not yet recruiting, Ann & Robert H Lurie Children's Hospital of Chicago

Together, our findings suggested that BLACE gene specifically expressed in B-cell ALL could serve as a new therapeutic target. Further investigations are required to get a comprehensive understanding of the BLACE gene mechanism.

P3, N=440, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

Human data confirm that IGF1 and fibronectin staining in trephine biopsies are correlated. Our studies suggest that fibrinolysis-mediated ECM remodeling and subsequent growth factor release influence B-ALL progression and inhibition of this process by EACA may be beneficial as adjunct therapy.

The identification of the SPINK1 c.194 + 2T>C variant, which is recognized as pathogenic, provides valuable information for understanding the heightened risk of AAP in our pediatric ALL patient. Our case underscores the potential role of genetic predisposition in the development of AAP and highlights the importance of considering genetic screening prior to asparaginase therapy in pediatric ALL patients to identify those at increased risk.

P1, N=18, Recruiting, The First Affiliated Hospital of Soochow University

We also evaluated the therapeutic potential of targeting these proteins with AZD0466, a novel drug-dendrimer conjugate of the BCL2/-XL inhibitor AZD4320, and with BCL2 inhibitor venetoclax (ABT-199). Our findings therefore suggest that the novel dual BCL2/-XL inhibitor AZD0466 outperforms single BCL2 inhibition by venetoclax in T-ALL. These findings facilitate the translation of dual BCL2/-XL inhibitors into ALL clinical trials, either alone or in combination with standard- of- care chemotherapy and immune therapies.

P2, N=30, Recruiting, The First Affiliated Hospital of Soochow University | Not yet recruiting --> Recruiting

P=N/A, N=36, Recruiting, The First Affiliated Hospital of Soochow University | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

The subgroup analysis based on the CDKN2A, CDKN2A/b and different ALL subtypes further strengthen the validity of the findings. Our meta-analysis revealed that CDKN gene deletions (including CDKN 2A/B, CDKN 2A) serve as adverse prognostic indicators for T-ALL/B-ALL patients.

No abstract available

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.