Acute Myeloid Leukemia (Age ≥18 years): IDH1 of IDH2 mutation or FLT3 mutation…Venetoclax-based therapy with azacitidine noted as category 1 and preferred...

431 patients with confirmed AML who were previously untreated and ineligible for intensive therapy were randomly assigned 2:1 to Aza plus either Ven (286 patients) or Pbo (145 patients)....For patients in the IDH1/2 mutant subgroup, median OS was reached at final analysis, at 19.9 mo (95% CI, 12.2-27.7) in the Ven+Aza group and 6.2 mo (95% CI, 2.3-12.7) in the Pbo+Aza group (HR, 0.314; 95% CI, 0.189 to 0.522; P<0.001)...

Composite complete remission (CRc, complete remission [CR]+CR with incomplete hematologic recovery [CRi]) rates (venetoclax+azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. Patients with IDH1/2mut who receive venetoclax+azacitidine had high response rates, durable remissions and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut.

Ven+Aza compared to Aza monotherapy resulted in higher response rates, longer DoR, and mOS among treatment-naïve pts with IDH1/2mut ineligible for intensive chemotherapy.

IDH1/2 mut pts achieved higher CR+CRh rates with Ven+Aza treatment as compared to pts with IDH not detected (72%/60%)....Ven+Aza compared to Aza monotherapy resulted in higher response rates, longer DoR, and mOS among treatment-naïve pts with IDH1/2 mut ineligible for intensive chemotherapy.

...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....Among treatment-naïve predominantly elderly pts with AML ineligible for intensive therapy, the combination regimen of AZA+VEN led to statistically significant and clinically meaningful improvement in response rates and OS as compared to AZA, with a manageable safety profile.

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.

These findings provide evidence suggestive of the comparable efficacy of VEN+HMA and IC in older adults with IDHmut AML. Both treatment strategies appear to offer significantly prolonged survival relative to HMA monotherapy.

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.

The CR/CRi rate was 76% (n=38; 30% CR, n=15; 46% CRi, n=23) for ND patients and 52% (n=23; 32% CR, n=14; 20% CRi, n=9) for R/R patients....In a single-center retrospective setting, HMA/Ven is efficacious in achieving CR/CRi in ND and R/R IDH-mutant AML.

Assess outcomes in IDH1/2mut AML treated with “triplet regimen” of 10-day decitabine, venetoclax, and IDHi (DAC+VEN+IDHi)….One patient had PR after cycle 1. Best responses to DAC+VEN+IDHi were unchanged after cycle 1. Five patients were alive at last follow-up (median of 409 days from cycle 1, day 1 of DAC+VEN+IDHi); 4 were in CR and 1 in PR.

The median RFS was 9.2 months (95% CI: 0–20.8), median OS 16 months (95% CI:7.9–19.5), 12- and 24-month OS was 55% and 39%, respectively. The ORR (CR+CRi+MLFS) was 81%. CR, CRi, and MLFS rates were 63%, 11% and 7%, respectively….ACTIVE regimen demonstrated high antileukemic efficacy in R/R IDHm AML.

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).

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.

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 the unfit subgroup, VEN pts received VEN-AZA (77.6%) or VEN-DEC (22.4%) and 55.2% of CON pts received high intensity regimens...Among pts with IDH1/2 mutations, CRc was significantly higher in overall VEN versus CON (87.9% vs. 54.2%; p<0.01) and in the unfit subgroup (85.7% vs. 52.9%; p<0.05)...Pts with ND AML receiving VEN-HMA had significantly higher rates of CRc than matched pts on non-VEN-based regimens in the overall population...

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.

We retrospectively analyzed 47 patients with AML...A Cox proportional hazards model was used to investigate the effects of commonly mutated genes (NPM1, ASXL1, FLT3, IDH1/2, RAS, TP53, TET2) on OS in venetoclax-based re-induction, and identified IDH1/2 mutations as having a favorable impact in the relapsed/refractory setting (HR 0.01, 95% CI 0.0001-0.7214)....Although limited by sample size, IDH1/2 mutations may convey a better prognosis in the relapsed/refractory setting when treated with venetoclax + HMAs.

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)...

This retrospective study included consecutive patients treated with VEN-AZA for R/R AML and ND AML....ASXL1, IDH1/2 and SRSF2 mutations were associated with a trend in a higher response rate in the R/R group.

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.

To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML)....Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months....In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months....Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut.

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.

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...

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.

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

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.

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.

Included are data from two open-label trials of Ven, at label recommended doses, in combination with Aza, Dec (NCT02203773; phase 1b), or low-dose cytarabine (NCT02287233; phase 1/2) in newly diagnosed patients with AML....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)…At median follow-up of 3.5 yr, VEN plus LDAC Tx resulted in median OS of 10 mo.

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…

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

...Of these, 5 patients achieved a CR/CRi as a best objective response (3/5 patients had IDH1/2 mutation and none had FLT3-ITD mutation)...Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features.

IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199...