Thirty FLT3m AML patients with R/R disease, treated at Mayo Clinic with HMA+Ven (with/without gilteritinib [Gilt]) between 2019 and 2022, were analyzed….Univariate analysis for OS showed a significantly better OS with FLT3m ITD subtype (P<0.0001), FLT3 allelic ratio <0.5 (P=0.03), and TET2 mutation (P=0.007)….Hypomethylating agent plus Ven based combination seem to be effective as salvage therapy in patients with FLT3m AML.

Patients with TET2 (P=0.041), NPM1 (P=0.039), ASXL1 (P=0.044), FLT3-ITD/TKD (P=0.008), DNMT3A (P<0.001) or RAS (P=0.006) mutation or co-mutation of DNMT3A and FLT3 (P=0.020, DNMT3A and NPM1 (P=0.020) or DNMT3A and IDH/2 (P=0.016) acquired statistically higher rate of CR/CRi with VAH therapy as compared with VEN+HMA trerapy....AML1-ETO-positive AML patients poorly responded to VEN+HMA therapy (0/7), but responded much better to VAH treatment (5/7, P=0.005).

ASTX727 is administered daily on days 1‐5 of each cycle and ven on days 1‐28 of the first cycle after a dose ramp up of 100-200-400 mg over 3 days...Mutations of note in the frontline cohort were RUNX1 (33%), ASXL1 (33%), DNMT3A (7%), TET2 (40%) and TP53 (20%). The overall response rate (ORR) including complete response (CR), CR with incomplete count recovery (CRi) and morphological leukemia free state (MLFS) in the FL cohort is 61% (4 CR, 4 CRi, 1 MLFS and 3 non-responders)...Total oral therapy of ASTX727+ven is safe and feasible, particularly in the advanced elderly population, and demonstrates significant efficacy in pts unfit for chemotherapy both in the FL and R/R settings.

Of 26 newly diagnosed AML patients, the CR/CRi rate was 53.8%. The median DOR and OS were 6.9 months and not reached, respectively. Of 39 R/R AML patients, the CR/CRi rate was 38.5%. The median DOR and OS were both 8.1 months. Responders to HMA and venetoclax were enriched for TET2, IDH1, and IDH2 mutations, while nonresponders were associated with FLT3 and RAS mutations.

Venetoclax was combined with azacitidine in 45 (68%) patients, with decitabine in 12 (18%) patients and with low-dose cytarabine in the remaining 9 (14%) patients...The presence of a TP53 mutation was associated with a shorter survival (1.2 vs 6.7 months, OR=0.43, 95CI [0.13-1.44], p=0.049) while the presence of a TET2 mutation was associated with a higher response rate (67% vs 25%, p=0.02) without a significant impact on survival (11.3 vs 5.4 months, OR=1.56, 95CI [0.73-3.33], p=0.3). Venetoclax-based combinations are salvage regimens that allow correct response rates in AML and high-risk MDS.

...we observed that AML samples harboring PML-RARA translocations, WT1, and FLT3 with IDH1 mutations are more sensitive to venetoclax, and samples with TET2, KRAS, PTPN11 and SF3B1 mutations are more resistant.