Acute Myelogenous Leukemia

P3, N=700, Active, not recruiting, University of Birmingham | Recruiting --> Active, not recruiting

In multivariable analysis, patients who received azole AFP did not have improved survival (HR 1.29, 95% CI 1.10-1.53, P = .004) compared to patients who did not (median OS 10 months vs. 11 months), with similar lack of benefit across agents: voriconazole (HR 1.04, p = 0.75), fluconazole (HR 1.26, p = 0.039), isavuconazole (1.52, p = 0.048), and posaconazole (HR 1.62, p = 0.005). Routine azole AFP does not improve overall survival in patients receiving Ven/HMA, contrasting with proven benefits in intensive chemotherapy, likely due to lower fungal infection risk combined with the complexities of managing drug-drug interactions in routine practice, as evidenced by high rates of inadequate venetoclax dose adjustment in this cohort.

Functionally, MV4-11QR cells showed broad cross-resistance to clinically relevant agents, including midostaurin, venetoclax, and cytarabine. Importantly, pharmacological targeting of mutant p53 with eprenetapopt or MAPK signaling with trametinib restored sensitivity to quizartinib, inducing synergistic or additive cytotoxic effects and increased apoptosis. Together, these findings define a multilayered resistance program involving genetic, signaling, and metabolic adaptations and support rational combination strategies to overcome FLT3 inhibitor resistance in AML.

Multivariable and LASSO analyses identified independent risk factors: male gender (OR=3.28, p = 0.025), higher blast percentage (OR=1.03, p = 0.006), elevated baseline uric acid (OR=1.01, p = 0.011), IDH1/2 mutation (OR=4.86, p = 0.005), and a trend with venetoclax-based therapy (OR=7.52, p = 0.072)...Adequate urine output reduced TLS risk, while excessive positive fluid balance correlated with severe TLS (p = 0.046). Individualized fluid management and 72-hour intensive monitoring are critical for high-risk groups.

These findings support a role for seasonal triggers in ALL and warrant further investigation in larger, genetically stratified cohorts.

Notably, low-risk combinations increased CD107a degranulation by KIR3DL1+ NK cells against HLA class I-deficient targets in vitro, consistent with enhanced NK-cell education. These findings support KIR/HLA-based donor selection and underscore the role of antitumor NK cell immunity.

Key advancements include the integration of FLT3 inhibitors into intensive chemotherapy and the emergence of venetoclax...Innovations such as the liposomal formulation CPX-351 and oral formulations of CC-486 and oral decitabine/cedazuridine have further optimized treatment delivery and improved patient quality of life...Current research is actively exploring next-generation inhibitors, antibody-drug conjugates, and cellular immunotherapies such as BiTEs and CAR-T cells. This review summarizes the recent pharmacological evolution in AML and discusses how these emerging therapies bring us closer to the ultimate goal of achieving a definitive cure.

This study highlights potential metabolite signatures associated with in vitro SYK-targeted therapy in AML. These findings support future research to identify potential serum biomarkers, guiding personalized SYK inhibition strategies in AML.

This study reveals the mutational spectrum of BRCA1 in patients with acute myeloid leukemia, representing unique missense and novel pathogenic mutations that can be further targeted for designing diagnostic and therapeutic strategies for acute myeloid leukemia.

It underscores the importance of recognizing these atypical presentations to prevent misdiagnosis of infection and to ensure the timely initiation of immunosuppressive therapy. Clinicians should remain vigilant, as these variants may serve as a sentinel marker for underlying or relapsed leukemia.

Pharmacologic AC inhibition with the ceramide analog SACLAC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. Importantly, AC knockdown sensitized AML cells to venetoclax and induced NOXA protein accumulation, whereas NOXA knockdown protected against AC and BCL-2 cotargeting. Collectively, these findings demonstrate the efficacy of cotargeting AC and BCL-2, and rationalize targeting AC as a therapeutic approach for venetoclax-sensitive and -resistant AML.