P2, N=39, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

Adding venetoclax might not improve CR/CRi of IA. A well-designed prospective randomized controlled study is now warranted.

The incidence of bone marrow suppression and pneumonia in the decitabine group was higher compared with that in the azacitidine group. Continuous and regular use of appropriate doses of hypomethylating agents may benefit MDS patients to the greatest extent if it is tolerated.

Clonal hematopoiesis of DNMT3A may have a crucial role in the coexistence of MM and AML and Venetoclax-based regimens reveal favorable treatment responses. However, drug resistance still needs to be considered, and further research is required to elucidate the underlying mechanisms and treatment strategies.

P=N/A, N=75, Active, not recruiting, Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori | Recruiting --> Active, not recruiting | Trial completion date: Dec 2021 --> Dec 2025 | Trial primary completion date: Dec 2021 --> Dec 2024

The combination of BCL-2 inhibitors and HMAs had good efficacy and safety in AML patients who were unfit for high-dose chemotherapy, which may improve the immune microenvironment and enhance anti-leukemia immune response.

P2, N=45, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=40, Recruiting, University of Colorado, Denver | Not yet recruiting --> Recruiting | Initiation date: Dec 2024 --> Feb 2024

P2, N=127, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.

Consistently, the ubiquitination inhibitor, TAK-243, and the SUMOylation inhibitor, TAK-981, show synergistic effects with HMAs through DNMT1 stabilization. Our study provides a novel HMA-based therapeutic strategy that interferes with the resolution of DNA-DNMT1 crosslinks.

P2, N=39, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2024 --> Oct 2024

P2, N=4, Terminated, Case Comprehensive Cancer Center | N=25 --> 4 | Recruiting --> Terminated; Slow Accrual

P1, N=11, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Apr 2025 --> Aug 2024 | Trial primary completion date: Apr 2025 --> Aug 2024

P2, N=37, Recruiting, H. Lee Moffitt Cancer Center and Research Institute

P1, N=9, Not yet recruiting, Medical College of Wisconsin

Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).

P3, N=48, Not yet recruiting, Institut de Recherches Internationales Servier

P1, N=11, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=20 --> 11

Notably, high-fat-diet or hypomethylating agent decitabine treatment boosts the immunosuppressive potential of AML cells by hijacking CD36-dependent innate immune signaling, leading to a dampened therapeutic effect. This work is of translational interest because lipid restriction by US Food and Drug Administration (FDA)-approved lipid-lowering statin drugs improves the efficacy of decitabine therapy by weakening leukemic CD36-mediated immunosuppression.

Recently, the treatment based on Venetoclax (VEN), a specific B-cell lymphoma 2 (BCL-2) inhibitor, in combination with hypomethylating agents (HMAs) or low-dose cytarabine, has emerged as a promising clinical strategy in AML. Indeed, the reduction of cytokine-secreting non-suppressive Tregs, the increased TIM-3 expression on CD8+ T cells, and the reduced co-expression of PD-1 and TIM-3 on both CD4+ and CD8+ T cells are all VEN-specific. Collectively, our study shed light on immune modulation induced by VEN treatment, providing the rationale for a novel therapeutic combination of VEN and IC inhibitors in AML patients.

P2, N=20, Recruiting, Brian Jonas | Trial completion date: Apr 2025 --> Dec 2025 | Trial primary completion date: Apr 2024 --> May 2025

HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML.

P2, N=39, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=90 --> 39

P2, N=77, Recruiting, The First Affiliated Hospital of Soochow University | Trial primary completion date: May 2024 --> Dec 2024

No abstract available

VEN combined with HMA had a high response rate in patients with HR-MDS, both at initial treatment and with HMA failure. ALP ≥ 90 U/L, TP53 mutation, and U2AF1 mutation were independent risk factors for non-response to treatment.

P2, N=53, Recruiting, Joshua Zeidner | Not yet recruiting --> Recruiting

P2, N=90, Recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2025 --> Jun 2024 | Trial primary completion date: Jan 2024 --> Sep 2023

P2, N=77, Recruiting, The First Affiliated Hospital of Soochow University

P1/2, N=15, Terminated, Shanghai Antengene Corporation Limited | N=59 --> 15 | Trial completion date: Mar 2024 --> Sep 2023 | Active, not recruiting --> Terminated; The study was stopped early because the sponsor decided to change the study-drug development strategy

Multifactor analysis revealed that IPSS-R score and response to treatment were independent prognostic factors for OS; the presence of SETBP1 gene mutations was associated with a longer hospital stay (51.5 days vs 27 days, P=0.017) . There is clinical benefit of venetoclax in combination with hypomethylated agents in patients with higher-risk MDS, but adverse events such as severe hypocytopenia during treatment should be avoided.

The OS benefit of HMA + VEN in secondary ontogeny was similar in those with vs. without splicing mutations (P = 0.92). Secondary ontogeny AML highlights a group of patients whose disease is selectively responsive to VEN added to HMA and that the addition of VEN has no clinical benefit in TP53-mutated AML.

P1, N=28, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1 | Trial completion date: Jun 2023 --> Mar 2025

Newly diagnosed AML patients with AML1/ETO fusion had a poor response to frontline VEN/HMA treatment. When determining induction therapy for patients with AML1/ETO-positive AML, IC should be preferred over VEN/HM.

P1, N=38, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

These data support the efficacy of this combination in the alloHCT relapse setting where we report responses among nearly half of patients, with possibly greater benefit for NPM1 and IDH 1/2-mutated cases. These responses can be durable and profound as evidenced by conversion to MRD negativity.

No abstract available

In this study, we employed routine diagnostic techniques, such as immunohistochemistry and flow cytometry, to investigate the expression of CD70 in bone marrow samples from treatment-naïve and relapsed AML patients after hypomethylating agents (HMA). Also, we evaluated the impact of HMA on CD70 expression and examined CD70 expression in various leukemic cell subsets and normal hematopoietic progenitors.

In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

Our study first identify vulnerability to ferroptosis by regulating MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway. Combined treatment with HMAs and FINs provides a potential therapeutic choice for AML patients, especially for R/R-AML.

P2, N=40, Not yet recruiting, University of Colorado, Denver