Pretransplant treatment was intentionally limited to 2-3 cycles: three cycles of Aza in Case 1, intensive induction chemotherapy followed by one cycle of Aza in Case 2, and two cycles of venetoclax plus Aza in Case 3. In addition, for patients with FISH-detectable TP53 abnormalities, serial FISH may provide a practical adjunct for pretransplant decision-making in routine practice. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

Here, we define a clinically actionable strategy that functionally targets PLK1 by combining inhibition of the AAA+ ATPase p97/valosin-containing protein (VCP) with the hypomethylating agent decitabine (DAC). In vivo, CB-5339/DAC is well tolerated, significantly prolongs survival, reduces leukemic burden, and suppresses PLK1 in bone marrow blasts. Together, these data establish p97 inhibition as a rational means to exploit replication and proteotoxic stress in AML and provide strong rationale for clinical evaluation of CB-5339 plus DAC in high-risk disease.

P1, N=33, Active, not recruiting, City of Hope Medical Center | Trial completion date: May 2026 --> Apr 2027 | Trial primary completion date: May 2026 --> Apr 2027

The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.

P2, N=60, Recruiting, Shirley Ryan AbilityLab | Not yet recruiting --> Recruiting

Gene expression and DNA methylation data from DAC-treated and untreated T-47D (Luminal-A) and JIMT-1 (HER2-amplified, trastuzumab-resistant with a TNBC-like phenotype) breast cancer cell lines were obtained from a published dataset. Survival analysis identified 114 DAC-responsive genes associated with overall survival in ER/PR-positive BC and 8 in the JIMT-1-derived gene set. DAC induces subtype-dependent epigenomic and transcriptional remodeling, selectively disrupts age-associated regulatory programs, and underscores the need for subtype-stratified evaluation of epigenetic therapies in breast cancer.

P1, N=55, Active, not recruiting, University of Southern California | Trial completion date: Jul 2026 --> Dec 2026

Before conditioning, 20 patients received intensive induction chemotherapy, 1 received decitabine plus venetoclax, and 3 proceeded directly to transplant. In conclusion, our results suggest that achieving remission before alloHSCT in BP-MF is associated with favorable outcomes. The adverse impact of TP53 or EZH2 mutations supports early post-transplant strategies to prevent relapse.

Furthermore, HELLS deficiency enhanced myeloid differentiation and apoptosis in HL-60 cells when treated with chemotherapy drugs, including 5-azacytidine, cytarabine, and doxorubicin. Ex vivo validation in AML patient-derived LSPCs demonstrated that HELLS deficiency reduces leukemic marker burden (CD123 and TIM-3) and increases apoptosis. Overall, we show HELLS upregulation drives leukemogenesis with poor outcomes, highlighting its potential as a prognostic marker and therapeutic target in AML.

P2, N=80, Recruiting, Shirley Ryan AbilityLab | Not yet recruiting --> Recruiting

P2, N=62, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

Both genotype and DNA methylation subclassification have been integrated into clinical decision-making, incorporating pretransplant azacitidine, watch-and-wait approaches for favorable-risk patients, and emerging targeted therapies including MEK inhibitors. This review synthesizes recent advances in understanding JMML as a bona fide RASopathy; provides a diagnostic algorithm, molecular landscapes, and prognostic models; and highlights opportunities for molecularly targeted therapeutic intervention.