...• Diagnosis of CD33 positive Acute Myeloid Leukaemia• Age ≥60 years (prior to the interim analyses performed after enrolment of 50 and 100 patients)• Genotype NPM1mut FLT3 ITDneg (FLT3- Tyrosine Kinase Domain mutation, TKD, is permitted) • Eastern Cooperative Oncology Group (ECOG) performance status 0-2 • Serum creatinine ≤ 1.5 x ULN (upper limit of normal)• Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 2.5 ULN and bilirubin ≤ 2 x ULN• Able to provide written informed consent• Considered fit for intensive chemotherapy with anthracyclines by treating physician...

...- AML with FLT3-ITD or FLT3-TKD mutations...

...Pazienti che hanno ricevuto una precedente diagnosi di leucemia mieloide acuta con mutazione di NPM1 con o senza concomitante mutazione di FLT3-TKD o FLT3-ITD3. ...

Eligible patients were R/R AML with FLT3-ITD...CRc was 76.5% with ORR of 82.4%. At a median follow-up of 10.3 months (IQR, 6.6-16.5), median duration of CRc was not reached (NR), overall survival was 18.1 months (95% CI, 12.2-NR) and event-free survival was 13.2 months (95% CI, 7.3-NR)....Sorafenib plus VAH regimen is well tolerated and highly active for R/R AML with FLT3-ITD.

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).

This multicenter, single-arm, phase 2 trial (NCT04752527) enrolled young pts (aged between 18 and 59) with ND AML...Pts with RUNX1 and FLT3-ITD mutations had higher CRc rates of 83.3% and 80%, respectively.

CONTRADICTING EVIDENCE: In this study, we aimed to evaluate the efficacy of VEN combined with hypomethylating agents (HMA) and identify the potentially predictive factors for response in R/R AML....Mutations in IDH1/2, NPM1 and ASXL1 predicted superior response to VEN-based therapy (CRc: 78.3%, 70.8% and 65.0%, respectively), while mutations in active signaling, such as FLT3-ITD, K/NRAS predicted inferior response (CRc: 29.0% and 28.6%).

CONTRADICTING EVIDENCE: With a median follow-up of 11.2 (95%CI, 7.2-14.8) months, 1- and 2-year overall survival were 46.9% (95% CI, 37.8%-58.1%) and 38.9% (95% CI, 28.7%-52.9%), respectively…Mutations in IDH1/2, NPM1, ASXL1 and chromatin-cohesin genes predicted superior response to VEN-based therapy, whereas mutations in active signaling genes such as FLT3-ITD and K/NRAS predicted inferior response...VEN combined with HMA was effective with R/R AML patients, and the response to treatment was associated with genetic characteristics.

CONTRADICTING EVIDENCE: 103 AML patients (median age 74 years, 67% male, 62% de novo) received upfront Ven + HMA....In univariate analysis, presence of ASXL1 mutation was associated with favorable response (CR/CRi 83% vs 53%, p=0.01), secondary AML (CR/CRi 49% vs 65%, p=0.09), adverse karyotype (49% vs 67%, p=0.11), presence of TP53 (32% vs 67%, p=0.002) and FLT3-ITD mutations (30% vs 61%; p=0.06) predicted inferior response.

CONTRADICTING EVIDENCE: Analysis of distinct molecular subgroups revealed that patients harboring FLT3-ITD mutation (16%, n = 9) had a significantly reduced median OS of 3.4 (1.9 - 8.0) months compared to 10.4 (0.8 - 24.3) months for those without an activating FLT3-ITD mutation (HR 3.59, 95% CI 0.94 - 13.72, p = 0.001).

Complete response (CR)+CR with partial hematologic recovery (CRh) rates in FLT3mut pts (Ven+Aza/Pbo+Aza) were 65% (95% CI:48%-79%)/18% (5%-40%)...Among pts with FLT3-ITD, CR+CRh rates (Ven+Aza/Pbo+Aza) were 61% (95% CI: 41%-79%)/23% (5%-54%)...CR+CRh rates in pts with FLT3-TKD were 69% (95% CI: 39%-91%)/20% (3%-56%) with mDoR 18.3 (95% CI: 3.0-NR)/NR (15.1-NR) mos.

This study compares two salvage therapies: gilteritinib or venetoclax and a hypomethylating agent (HMA; decitabine or azacitidine)....We retrospectively analyzed 129 patients with AML and mutated FLT3-ITD or FLT3-TKD….We compared patients treated with gilteritinib or venetoclax + HMA….The median overall survival in the gilteritinib cohort was 3.9 months — significantly shorter than 7.8 months for the venetoclax cohort (p = 0.048)....Venetoclax + HMA appears superior to gilteritinib for subsequent therapy after IC failure in FLT3mut AML, despite the gilteritinib cohort being significantly younger.

CONTRADICTED EVIDENCE: Treatment naïve NPM1 and IDH2 mutant AML blasts are highly sensitive to VEN alone and combination with cytarabine and anthracycline chemotherapy results in a high clinical response rate. TP53 and FLT3-ITD mutant cases were more resistant and outcomes were poor despite VEN combined with chemotherapy.

In another MV-4-11 xenograft study, the combination of 6.25mg/kg SM09419 with azacitidine (0.8 mg/kg QD) and/or venetoclax (25 mg/kg QD) induced significant TGI (95-98% vs. vehicle, p<0.001) with tumor regression at Day 26. Azacitidine + venetoclax induced 79% TGI (p<0.001), but no tumor regression was observed. The triple combination induced tumor regression in all mice and complete regressions in 4/6 mice (67%); it had a greater effect on slowing tumor regrowth after treatment discontinuation vs. a single agent or doublet.