Carfilzomib synergized with BCL2 family protein inhibitors (navitoclax or AZD5991), suggesting that drug combinations could be used to reduce the dose of each drug to minimize toxicity. Notably, thymic carcinomas differed from squamous cell carcinomas in other organs by higher levels of β5i (PSMB8) and constitutive proteasome β5 (PSMB5). We hypothesize that TC (and probably many TH) are uniquely suited for treatment with proteasome inhibitors alone or in combination with selective BH3 mimetics.

An intensification strategy guided by response and MRD deepened remissions in individuals with residual disease and spared early responders further treatment. This approach merits further study as an alternative to fixed-duration triplet therapy.

The combination of the B-cell lymphoma 2 inhibitor venetoclax with CIT has emerged as a new first-line benchmark with promising response rates and overall survival...Pirtobrutinib has demonstrated responses even in heavily pretreated patients...For R/R disease, novel BTK inhibitors, bispecific antibodies, and cellular therapies are demonstrating substantial efficacy. Ongoing trials investigating combinations of these agents are poised to further transform RT management.

P2, N=29, Recruiting, The First Affiliated Hospital of Soochow University

P1/2, N=145, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2026 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2026

Better responses were observed in patients treated with the venetoclax in combination with hypomethylating agent (VEN + HMA) regimen compared to those receiving the '3 + 7' regimens (composite complete remission [CRc], 53.8% vs. 30.2%; p = 0.018)...In conclusion, molecular factors matter in influencing the prognosis of TP53-mutant AML patients. Among them, TP53 mutation sites merit particular attention.

P=N/A, N=15, Completed, Fondazione IRCCS Policlinico San Matteo di Pavia

P=N/A, N=210, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting

P=N/A, N=14, Recruiting, Fondazione IRCCS Policlinico San Matteo di Pavia

While the patient failed high-risk T-LBLL induction therapy, blinatumomab followed by decitabine and venetoclax induced a morphologic remission. This case illustrated the importance of integrating MFC analysis with NGS data to provide individualized patient treatment. The authors have confirmed clinical trial registration is not needed for this submission.

Conventional treatments, including chemotherapy and hypomethylating agents +/- venetoclax, offer limited benefit, with high relapse rates and short remissions...Novel therapeutic approaches-ranging from p53 reactivation strategies to immunotherapy and targeted inhibition of specific signaling pathways-are under active investigation. Our review summarizes current knowledge on the molecular pathogenesis, prognostic implications, and therapeutic landscape of TP53-mutated MDS/AML and discusses ongoing challenges and opportunities for improving patient outcomes.

While targeted agents-such as LSD1 inhibitors, the BCL-2 inhibitor venetoclax, and IDH1 inhibitors-have provided clinical benefit, their efficacy is often limited by compensatory signaling and clonal evolution. This computational study supports the feasibility of a polypharmacology-based strategy for AML therapy by integrating epigenetic modulation, apoptotic reactivation, and metabolic correction within single molecular scaffolds. However, the identified compounds (Belumosudil, DB08512, and Elraglusib) have not yet demonstrated efficacy in AML models; further preclinical validation is warranted to substantiate these predictions and advance translational development.