...• 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...

...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. ...

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

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).

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%).

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: 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.

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.

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.