FLT3 mutation + NPM1 mutation

Thus, FLT-3 inhibitors may be viable treatment options in this setting. Here, we report three patients with FLT3 and NPM1 mutated AML who relapsed early after allo-HSCT and were treated with gilteritinib (associated with donor lymphocyte Infusion in two patients) to achieve long-term remission without a second transplantation.

Thus, early CH-associated mutations that precede malignant transformation subsequently shape the evolutionary trajectories of AML through diagnosis, therapy, and relapse. DNMT3A , TET2 and ASXL1 mutations persist through AML-directed therapy Distinct CH-related mutations shape the evolutionary trajectories of AML from diagnosis through relapse.

The study highlights the presenting age is lower than global figures. The median time for initial diagnosis and the start of treatment is within the acceptable norms. Normal karyotype and NPM1 and FLT3 mutations were common in adult AML patients, whereas AML-ETO was more common in the pediatric cohort. These findings will help plan prospective studies and see the correlation with treatment outcomes. The laboratory workup practice currently complies with the standard guidelines at our center.

Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit.

In AML patients with FLT3 ITDand wild-type NPM1, we noticed a significant decrease over time in the CIR and improvement of LFS and OS, likely reflecting the efficacy of FLT-3 inhibitors, including when used as post-transplant maintenance, in this high-risk setting. On the contrary, no significant change over time was noticed in outcomes of patients harboring a FLT3 and NPM1 mutation.

56 pts received allopurinol ≥72 hours prior to starting ven, 21 received ≥2L of IV fluid per day starting at least the day prior to ven, and 56 had TLS labs measured every 8-12 hours during the first 3 days following ven initiation...We defined significant TLS as pts who required hospitalization (if started treatment outpatient) or ICU transfer, received rasburicase, developed AKI, or had treatment held due to TLS...Of the pts who developed significant TLS, a majority had spontaneous TLS; only 5 pts had significant TLS occur after starting ven. We also found that the Howard criteria for TLS better identify pts who will have adverse outcomes from TLS and may be a more clinically meaningful set of criteria to use in future studies.

Entospletinib (ENTO) and lanraplenib (LANRA) are inhibitors of spleen tyrosine kinase (SYK); the latter is a next-generation SYK inhibitor and is currently being evaluated in combination with gilteritinib (GILT) in patients with relapsed or refractory FLT3-mutated AML (NCT05028751)...Two different AML patient cohorts were assessed by ex vivo treatment with ENTO, LANRA and combinations of LANRA (trametinib, gilteritinib (GILT), aPD-1) over a range of time points (2h, 4h, 3d and 9d) and readouts for cellular phenotype (e.g., differentiation state, immune cell populations) and functional readouts (pSYK, viability) for each cohort were analyzed by HP-FC and sc-MI and associated with available mutation information (bulk gene and single cell RNA sequencing)...These support studies investigating the use of pSYK inhibitors in combination with other therapies to reduce tumor burden, and as an improved line of treatment for AML. Acknowledgements: We are appreciative of the patients and families for their time and participation.

In the ongoing phase 1 trial, RVU120 shows clinical activity in both AML and HR-MDS, inducing RBC transfusion independence and blast reduction with a tolerable safety profile. Clearance of BM blasts including a formal CR were observed in patients treated at different dose levels. Relevant target inhibition is achieved from 110 mg onwards with expected higher pSTAT 5 inhibition with further dose escalation.

In an orthotopic mouse model of FLT3-mutant AML, tuspetinib exhibited greater antitumor activity than gilteritinib, entospletinib, venetoclax (VEN), and azacitidine (AZA) and combined favorably with VEN and AZA individually. Tuspetinib was well-tolerated and delivered single agent clinical responses across four dose levels among diverse AML genotypes; with a RP2D of 80 mg chosen for future single agent studies. Although early, the VEN/TUS combination has been well tolerated with preliminary objective responses noted.

These results demonstrate the success of this approach in producing a virtual dataset that perfectly mimics the original and that, from a "privacy by design" perspective, minimizes the risk of re-identification of patients. Mirroring an AML population treated with a conventional chemotherapeutic approach, synthAML1310 is suitable to represent the control group when testing novel innovative treatments, most likely in an in-silico randomizedtrial, but also in other settings like propensity score matching analyses in observational studies. Shifting to an in- silico trial would overcome the challenges of randomized trials and it would be beneficial also for patients.

A preliminary model based on the targeted metabolomics approach was developed for the prediction of mutation status of NPM1 and FLT3 proteins in AML patients. Proposed model has a high fit value, validity, and strong predictive power. The reliability and validity of the model can be further increased by future multicenter studies.