FLT3-ITD mutation

P1, N=15, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Aug 2026 --> Dec 2026 | Trial primary completion date: Aug 2026 --> Dec 2026

This study identifies WNK1 as a key oncogenic driver in AML and establishes WNK1 inhibition as a promising therapeutic strategy that not only suppresses AML progression but also sensitizes leukemia cells to venetoclax. These findings provide a rationale for novel combination regimens to overcome drug resistance in AML.

Notably, the combination of 6k and the FLT3 inhibitor quizartinib showed significant synergistic antiproliferative effects both in vitro and in vivo. Mechanistic studies showed that this combined strategy could simultaneously inhibit glycolysis and OXPHOS by blocking the PI3K/AKT signaling pathway, ultimately exerting antitumor activity. In summary, this study highlights 6k as a potential metabolic regulator and provides a promising therapeutic strategy for AML.

P1, N=9, Not yet recruiting, Fred Hutchinson Cancer Center

P1, N=38, Recruiting, National Cancer Institute (NCI) | N=28 --> 38

After six cycles of azacitidine, she achieved remission of MDS but rapidly progressed to AML and ultimately died. This case provides a key clinical lesson: persistent cytopenias during ibrutinib therapy were attributable to MDS progression rather than SWM, underscoring the importance of re-evaluation. Furthermore, it completely documents clonal evolution from 2.5% blasts (MDS with low blasts) to 6% blasts (MDS with increased blasts-1) and ultimately to AML (66% blasts), and it introduces the emergence of an FLT3-ITD mutation that rapidly drove the disease into AML even after the patient had achieved MDS remission. We also review the rare coexistence of WM and MDS/AML, and MGUS with MDS.

In this large multicenter cohort, KIT and FLT3-ITD mutations did not adversely affect the prognosis of pediatric CBF-AML treated according to the C-HUANAN-AML-15 protocol. MRD after induction was the most powerful predictor of relapse and survival, underscoring its importance for risk stratification in future pediatric AML trials.

P1/2, N=20, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

And post-HCT FLT3 inhibitor maintenance independently improved RFS (p = 0.003), with greatest benefit observed in MRD-positive patients. These findings support PCR-NGS-based molecular MRD assessment to refine risk stratification and guide individualized transplant strategies in FLT3-ITD-mutated AML.

Moreover, Compound 14 demonstrated an impressive pharmacokinetic profile and exerted significant antitumor efficacy in the FLT3-ITD-positive AML xenograft mouse model (approximately 80% decrease in tumor mass). Also, biochemical blood analysis and histopathological studies revealed that Compound 14 demonstrated a good safety profile.

P1/2, N=58, Recruiting, Hellenic Society Of Hematology | Not yet recruiting --> Recruiting

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.