...CR+CRi and OS by molecular subgroups, and event-free survival (EFS). Response rates in pts with DeNovo and secondary AML were 66%/30% and 67%/23% respectively. Other secondary endpoints are summarized in the Table.

...Newly diagnosed CD33-positive AML with NPM1 mutation according to WHO criteria 3....

...- NPM1 mutation...

...To determine the MRD response of patients with NPM1 mutated AML in the MRD failure stratum to their first-exposure to decision rule guided therapy with LDAC + Venetoclax....

...• 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...

...Newly diagnosed CD33-positive AML with NPM1 mutation according to WHO criteria3. ...

...Subject must have received previous diagnosis of NPM1mut AML with or without concomitant FLT3-TKD or FLT3-ITD3. ...

...Subject must have received previous diagnosis of NPM1mut AML with or without concomitant FLT3-TKD or FLT3-ITD 3....

...abnormal myeloid cells in bone marrow ≥ 0.1%, or NPM1 gene mutation and other fusion gene positive(RUNX 1-RUNX1T 1、CBFB-MYH11 and DEK-NUP214), the PCR quantification ≥1%....

VEN-based regimen can achieve a high response rate, especially in unfit AML with acceptable safety, and some patients can achieve MRD negative. It is also effective in NPM1-, IDH1/2-positive patients with long survival time.

A total of 89 AML cases registered in HLN from May 2021 to April 2023 were initially treated by VEN-based therapy....Furthermore, the ratio of CR or CRi was more than 80% in the patients with mutation of CEBPA-bZIP, DNMT3A, IDH1, IDH2, and NPM1 mutation-positive groups, respectively.

VEN in combination with intensive chemotherapy for NPM1(mut) AML pts ≥65 years resulted in rapid and deep responses (NPM1(mut) MRD-negativity) that are associated with prolonged remissions and OS.

We performed a retrospective analysis of the clinical outcomes and molecular features of 17 adult patients treated with VEN+HMA or VEN+LDAC for R/R NPM1mut AML… Median event-free and overall survival (EFS, OS) for the whole cohort were 11.8 and 11.9 months, respectively. A detrimental impact of FLT3-ITD mutation on CR rate, EFS, and OS was highlighted.

The median OS in the dose-intense chemotherapy group was 66.5 months, and 20.5 months in the HMA plus venetoclax group….NPM1-mutant AML patients treated with dose-intense chemotherapy had a favorable long-term outcome. Older/unfit patients treated with HMA plus venetoclax also showed impressive results. Due to the high sensitivity of NPM1 to venetoclax, there may be a role in incorporating venetoclax into dose-intense chemotherapy.

Adult patients (age ≥ 18 years) who received first-line (1L) VEN-based tx for AML and had available dosing information were included....Median OS for the population was 13.9 months (95% CI: 11.8, 16.6), and differed by mutation status (13.1 months for IDH1 positive patients, 42.0 months for IDH2 positive patients, not reached for FLT3-ITD positive patients, and 42.0 months for NPM1 positive patients).

The CAVEAT study enrolled pts aged ≥65 years with de novo or secondary/therapy-related AML (sAML) considered suitable for intensive chemotherapy....By intention-to-treat, the overall response (CR/CRi) rate was 73%. CR/CRi was 90% in de novo AML (vs 51% in sAML), 84% in intermediate karyotype (vs 69% in adverse), 76% and 83% in NPM1 and IDH2 mutant AML, respectively.

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%).

In this largest retrospective cohort study to date, HMA+Ven appeared to be effective and well-tolerated in this setting, with the potential for durable remissions and MRD negativity, especially in the presence of certain molecular aberrations such as NPM1 and IDH 1/2 mutations.

Patients were identified from real-world cohorts of AML treated with venetoclax and LDAC or hypomethylating agents (HMA)...In patients with In patients with NPM1 mutated AML attaining complete remission with venetoclax combination therapies AML attaining complete remission with venetoclax combination therapies...

In responding patients with a bone marrow sample evaluable for assessment of MRD by flow cytometry, 71/85 (84%) achieved MRD negativity while on study. Responses were preserved across ELN risk groups with the CRc (CR/CRi) rate of 95% (86%/9%), 95% (82%/14%), and 90% (73%/17%) for patients with ELN favorable, intermediate, and adverse risk, respectively. CRc rate for TP53 mutated disease was 88% (7/8, 86% MRD negative) and for NPM1 mutated disease was 96% (25/26, 100% MRD negative). Venetoclax added to CLAD/LDAC alternating with AZA is a highly effective, lower-intensity regimen which is well tolerated among older patients with newly diagnosed AML, producing high CRc and MRD negative remission rates and is effective in transitioning older adults to alloSCT. The rates of DFS and OS are encouraging.

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).

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.

A retrospective analysis was performed of all patients with AML or HR-MDS who received Ven combination therapy...The presence of NPM1 and IDH1/2 mutations were associated with high CR/CRi rates in both the frontline (85.7% and 84.6% respectively) and R/R groups (100% and 81.8%)...Notable responses were seen in patients with RUNX1 mutations in both settings (77.8% frontline, 66.6% R/R)...

After one cycle of treatment, 13 patients with IDH1/2 mutations and 4 that were TP53-positive all achieved CR/CRi. The CR/CRi rate of 18 patients with NPM1 mutations was 77.8%. Five patients with RUNX1-RUNX1T1 combined with KIT D816 mutation (two initial diagnoses and three recurrences) had no remission. Ven+ AZA was tolerable for AML patients...Ven+AZA has acceptable safety in previously untreated patients unfit for standard chemotherapy, patients with R/R AML can achieve a high response rate, and some patients can achieve MRD negativity.

In contrast, patients with NPM1, IDH1, or IDH2 mutations without co-occurring FLT3-ITD mutations showed an increased sensitivity to VEN-based therapy: 11.2 (5 - 24.3) months versus 5.0 (0.8 - 22.1), respectively (HR 0.53, 95% CI 0.23 – 1.21, p = 0.131).

40 patients received 41 ven-based treatments between November 2017 and July 2021…73% of patients that achieved a response to ven...The presence of NPM1 or IDH1/2 mutations was predictive of high response rates.

Analysis of a sub-group of patients with NPM1mt (n=18); 6 and 12 from Groups A and B, respectively revealed the median NPM1mt transcript level at study entry to be 8985 copies (IQR 826, 94,431). A molecular response was achieved in 14 (78%) patients, including 9 (50%) with complete molecular remission...

Pts received decitabine 20 mg/m2 on D1-10 until CR/CRi, followed by 5-day cycles. VEN dose was 400 mg daily but held on C1D21 if D21 bone marrow (BM) had ≤5% blasts….DEC10-VEN offered high rates of CR/CRi, negative MRD, favorable OS and RFS across several genomic subgroups of treatment-naïve AML including NPM1, FLT3, IDH1/2...

As in patients treated with VEN combinations at fist line, the NPM1 and IDH1/2 genotype was associated with better response and survival.

ELN-favorable patients (n = 11), with a high incidence of normal diploid karyotypes (11/11), NPM1 mutations (11/11) and IDH1/2 mutations (5/11), did particularly well, with no relapses observed so far within this group...Maintenance therapy with AZA-VEN is a feasible and tolerable strategy in AML patients who have achieved CR following both high- and low-intensity induction regimens.

The presence of mutated NPM1 and monoallelic CEBPA were the only two variables associated with increased CR/ CRiwith VEN in AML-RR.

CONTRADICTATING EVIDENCE...86 patients with RR-AML who were treated with venetoclax combinations...Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax...Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS.

Ven was given in combination with HMA, low dose cytarabine (LDAC), or IC in 35 (83.3%), 6 (14.3%), and 1 (2.4%) pt respectively....CR/CRi rates were higher for pts with FLT3 (p=.040) and NPM1 mutations (p=.04).

Ven was given in combination with HMA, low dose cytarabine (LDAC), or IC in 35 (83.3%), 6 (14.3%), and 1 (2.4%) pt respectively....CR/CRi rates were higher for pts with FLT3 (p=.040) and NPM1 mutations (p=.04).

All AML pts who received treatment with aza/ven, dec/ven or LDAC/ven as either initial induction or for RR disease...A total of 130 pts were treated with ven combo therapy with 18 pts (13.8% of all pts) receiving a subsequent alloSCT. While pts with DNMT3A, NPM1, IDH1/2 and FLT3 mutations had a high response rate to ven therapy...Only DNMT3A mutations were statistically significantly associated with a high response rate prior to alloSCT (ORR 100%, CR/CRi 63%, p=0.01).

At median 3.5-yr follow-up, VEN+LDAC resulted in median OS of 10 mo. At 2 yrs, 22% of study population remained alive; 32%, 36%, and 64% were alive with IDH1/2, de novo, or NPM1 mutant AML, respectively.

...Patients with baseline IDH1/2 and NPM1 mutations were more likely to achieve CR/CRi in ≤2 cycles as 67% (29/43) and 62% (16/26) with baseline IDH1/2 and NPM1 mutations achieved CR/CRi in ≤2 cycles of treatment respectively. Median duration of response was 21.2 months (95% CI: 14.1 – not estimable) for ≤2 cycle responders and 8.1 months (95% CI: 5.3 – 14.9) for >2 cycle responders.

In a phase 1/2 study, the potent BCL-2 inhibitor venetoclax (VEN)...Longer median OS was observed in pts who had mutations in NPM1 or IDH1/2 (not reached and 15.9 mo, respectively)…

DEC10-VEN is an effective regimen for AML. Addition of FLT3i to DEC10-VEN was safe and may improve upon responses in FLT3mut pts. Mutations in NPM1 and DNA methylation pathways were associated with more durable responses while mutations in ASXL1, RAS and TP53 were associated with refractory disease or relapse.

Responses in response-evaluable patients were most common in NPM1 mutant AML (100%; n=7), followed by RUNX1 (90%; n=11), RAS (90%; n=10) and IDH (89%; n=9)...To date, VEN up to 600mg in combination with 5+2 induction chemotherapy is tolerable in fit elderly patients with AML. Initial response rates >80% were observed in de novo AML, as well as NPM1, RUNX1, RAS and IDH mutant AML…

Patients with NPM1 mutations showed a CR + CRi rate of 91.5%, median duration of CR + CRi of NR (95% CI, 6.8 months-NR), and median OS of NR (95% CI, 11.0 months-NR); NPM1 mutation status was a statistically significant predictor of favorable outcome in both the univariate (P = .015) and multivariate (P = .049) analyses....Venetoclax plus decitabine or azacitidine showed tolerable safety and favorable overall response rate (CR + CRi rate: 67%) in elderly patients with AML.

The CR/CRi rates were 83.7% for pts with IDH1/IDH2 mutations, 84.6% for pts with NPM1 mutations, 59.5% for pts with TP53 mutations, and 53.3% for pts with FLT3 mutations (Table 2)….VEN + HMA or LDAC has efficacy across multiple molecular markers in AML

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.

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.