cytarabine

P2, N=30, Completed, The First Affiliated Hospital of Soochow University | Recruiting --> Completed | N=48 --> 30

More importantly, approval of the combination of the BCl-2 inhibitor, venetoclax, and hypomethylating agents or low dose cytarabine provided unprecedented breakthrough for the frontline treatment of older, unfit AML patients. Recent development of menin inhibitors targeting AML with KMT2A rearrangements or NPM1 mutations could represent a promising new horizon of treatment for patients within these subsets of AML. Our current review will focus on a summary and updates of recent developments of menin inhibitors in the treatment of AML, on the challenges ahead arising from drug resistance, as well as on the opportunities of novel combinations with menin inhibitors.

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

P2, N=68, Recruiting, The First Affiliated Hospital of Soochow University | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

Venetoclax was given for 21 days with each cycle of mini-hyper-CVD (cyclophosphamide, vincristine, dexamethasone alternating with methotrexate and cytarabine). In summary, for patients with newly diagnosed ALL, venetoclax plus mini-HCVD is well-tolerated with promising efficacy. NCT03319901.

As glucose metabolic symbiosis and the heterogeneous dependencies on aerobic glycolysis and cellular respiration tremendously impact chemosensitivity, the inhibition of GPR68 potentiated the tumoricidal effect of first-line chemotherapeutic agents, including BCL-2 inhibitors targeting OxPhos and cytarabine (AraC) targeting glycolysis...The overexpression of GPR68 drives a Ca2+/CaN pro-survival pathway and mediates glucose metabolic symbiosis in AML cells, suggesting the diagnostic and therapeutic potential of GPR68 in AML. (GPR68, G proton-coupled receptor 68; PLCβ, phospholipase C beta; CaN, Calcineurin; IDH, isocitrate dehydrogenase; HIF-1α, Hypoxia-inducible factor alpha subunit; GLUT1, Glucose transporter type 1; HK-1, Hexokinase 1).

Low-dose IL-21 treatment prolongs the survival of AML mice in syngeneic and xenograft experiments. Therefore, promoting IL-21/IL-21R signaling on LSCs may be an approach to reduce stemness and increase differentiation in AML.

To investigate cellular responses, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) was administered to the cells...The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells...BEZ235 significantly inhibits the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), mTOR, glycolytic metabolism, and Ara-C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara-C resistance in AML.

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

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

P2, N=40, Recruiting, The First Affiliated Hospital of Soochow University

P=N/A, N=83, Recruiting, Affiliated Hospital of Nantong University | Not yet recruiting --> Recruiting

P4, N=180, Not yet recruiting, Qilu Hospital of Shandong University; Qilu Hospital of Shandong University

P2, N=67, Recruiting, The First Affiliated Hospital, Zhejiang University School of Medicine; The First Affiliated Hospital, Zhejiang University School of Medicine

P3, N=414, Recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto | Trial primary completion date: Apr 2024 --> Apr 2025

P1/2, N=65, Active, not recruiting, Daiichi Sankyo | Recruiting --> Active, not recruiting

P=N/A, N=90, Recruiting, Ruijin Hospital | Not yet recruiting --> Recruiting | Initiation date: Jun 2024 --> Sep 2024 | Trial primary completion date: Sep 2025 --> Sep 2026

P3, N=158, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2024 --> Sep 2025

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.

We aimed to validate the prognostic value of the 2022 ELN classification (ELN22) evaluating 1,570 newly diagnosed AML patients (median age, 56 years) treated with cytarabine-based intensive chemotherapy regimens...In conclusion, the ELN22 risk stratification improves prognostic discrimination in a large cohort of intensively treated AML patients. Given the heterogeneous outcome in patients with MR gene alterations, ranging between those of intermediate and adverse risk patients, we suggest reevaluation of risk allocation in these patients.

In this interim analysis, gilteritinib 120 mg/day in combination with chemotherapy was well tolerated, with similar CRc rates to previous studies.

Induction with 3 cycles of bendamustine and rituximab followed by 3 cycles of cytarabine and rituximab (BR/CR) is associated with high complete metabolic response (CMR) and uMRD rates (Armand et al., BJH 2016; Merryman et al., Blood Adv 2020). Bruton’s tyrosine kinase inhibitors (BTKi) including ibrutinib and acalabrutinib (A) in combination with CIT are highly effective in MCL (Wang et al., EHA 2024, LBA 3439)... High PET/CT CMR uMRD rates were seen in all 3 arms. BR/CR can be considered as a standard induction in pts ≤ 70. Addition of acalabrutinib to the standard arm added toxicity without improvement in efficacy, suggesting acalabrutinib should be avoided during Ara-C cycles.

P1, N=3, Terminated, Institute of Hematology & Blood Diseases Hospital, China | N=18 --> 3 | Recruiting --> Terminated; It did not reach the expected results of clinical trial

P1, N=1, Terminated, Institute of Hematology & Blood Diseases Hospital, China | N=18 --> 1 | Recruiting --> Terminated; It did not reach the expected results of clinical trial

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.

P1/2, N=84, Ongoing, Fundación Pethema

P2, N=59, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

P3, N=430, Not yet recruiting, The First Affiliated Hospital of Soochow University

P1/2, N=37, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Dec 2026 --> Oct 2024 | Trial primary completion date: Dec 2026 --> Oct 2024

P1/2, N=35, Active, not recruiting, St. Jude Children's Research Hospital | N=98 --> 35 | Trial completion date: Jul 2029 --> Mar 2025 | Trial primary completion date: Aug 2025 --> Jun 2024

P2, N=80, Not yet recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto

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

In conclusion, our study reveals that CSE1L is a potential therapeutic target for overcoming Ara-c resistance in AML cells. Thus, we have gained new insights into the oncogenic process of CSE1L in AML cells and raised the prospect of knockdown of CSE1L in AML in combination with cytarabine-targeted therapy.

Its combination with HMA or low-dose cytarabine (LDAC) has been shown to enhance the response rates and prolong the survival outcomes of older or unfit patients with AML. Additionally, we examined the response rates and survival outcomes of CBF-AML when treated with a VEN-based regimen. Moving forward, it is imperative that risk stratification for LIT becomes more nuanced to better align with the requirements of personalized diagnosis and treatment strategies.

P2, N=110, Active, not recruiting, French Innovative Leukemia Organisation | Trial completion date: Sep 2024 --> Jul 2026

P1/2, N=55, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2024 --> Oct 2025 | Trial primary completion date: Aug 2024 --> Oct 2025

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

P2, N=52, Not yet recruiting, H. Lee Moffitt Cancer Center and Research Institute

miR-203 down regulated the protein level of Bcr/abl in K562 cells compared with plasmid control. In conclusion, Ara-C in combination with miR-203 has a synergistic effect of proliferation inhibition and apoptosis induction in chronic myelogenous leukemia K562 cells, which may be associated with miR-203 down regulating Bcr/abl, thereby inhibiting cell proliferation and promoting cell apoptosis.

Case presentation: Herein, we present the case of a 23-month-old girl with high-risk B-ALL who experienced very early isolated medullary relapse; following the failure of conventional chemotherapy according to the ALL-IC REL 2016 protocol, she went on to receive the bispecific T-cell engager (BiTE) blinatumomab and subsequently, due to refractory disease, the combination of fludarabine, cytarabine, and the proteasome inhibitor bortezomib without achieving remission. The minimal residual disease (MRD) was 0.08% on day 28, and InO was continued, thus achieving MRD negativity; the patient successfully underwent an allogeneic stem cell transplantation from a matched family donor. Our case highlights the efficacy and safety of InO as a salvage treatment in the setting of relapsed B-ALL refractory not only to conventional chemotherapy but also to novel treatments, such as blinatumomab and bortezomib.

Although many patients achieve complete remission with standard induction therapy, a combination of cytarabine and anthracycline, ~40% of patients have induction failure...Moreover, A20 prevents necroptosis in AML by targeting the necroptosis effector RIPK1, and anthracycline-induced necroptosis is abrogated in A20High AML. These findings suggest that NF-κB-driven A20 overexpression plays a role in failed chemotherapy induction and highlights the potential of targeting an alternative cell death pathway in AML.

The "7+3 regimen", which consists of 7 days of cytarabine in combination with daunorubicin during the first 3 days, is a widely used therapy protocol. These simulations are in line with the clinical finding that G-CSF priming can improve the treatment outcome. Furthermore, our model suggests that a decline of HSC counts during remission might serve as an indication for salvage therapy in patients lacking MRD (minimal residual disease) markers.