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.

Venclyxto monotherapy is indicated for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B cell receptor pathway inhibitor.

...- AML with any adverse cytogenetics, TP53 mutation, RUNX1 mutation, ASXL1, 11q23/KMT2 rearrangements...

...1.Primary hematologic disease was high-risk myelodysplastic syndrome or acute myeloid leukemia, with allogeneic HSCT indications; 2.High-risk MDS/AML includes the following conditions: (1)Compliance with the 2017 WHO classification MDS diagnostic criteria and has one of the following features: 1)Compliance with MDS-EB2 diagnosis; 2)With poor prognosis chromosomal karyotype; 3)IPSS-R score is extremely high risk; 4)Positive TP53 mutation in the first diagnosis. ...

...Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN1) or DNMT 3a or ASXL1 or RUNX1 3....

...Mutated TP53, del17p or monosomy 17 at diagnosis (stratum 1). ...

...AML or MDS diagnosed according to 2016 WHO criteria with TP53 mutation before enrollment; 2....

...TP53 mutant AML 3....

...- Patients with newly diagnosed AML with poor risk complex karyotype and/or TP53 deletions/mutations equal or younger than 60 year old...

...- Presence of a mutation in TP53...

CONTRADICTING EVIDENCE: The clinical data of 30 AML patients who received venetecla combined with azacitidine...After one course of trea- tment, CRc was 16 cases and ORR was 23/30. Patients with TP53 mutation had poor treatment response (P=0.009)...TP53 mutation is a predictor of poor response to veneclax in combination with azacitidine.

We retrospectively analyzed 35 patients with del17p or TP53mut AML treated with venetoclax + HMA or HMA alone....The composite complete remission (CCR) rate significantly favored the venetoclax arm at 40.0% (95% CI, 21.9 - 61.3), compared to 0% (95% CI, 0 - 27.8) in the monotherapy arm (p = 0.029). Furthermore, the median overall survival significantly favored the venetoclax cohort at 6.0 months compared to 3.4 months in the HMA cohort (p = 0.026)...in the venetoclax combination arm, we identified that a TP53mut VAF threshold of less than 35.0% predicted superior survival at 11.8 months compared to 2.8 months for VAF of greater than 35% (p = 0.035).

Patients received 1 or 2 cycles of VEN + DEC10 followed by additional cycles of VEN + 5-day decitabine (DEC5) per physician discretion….TP53-mutated AML had an ORR of 59% and a CRc of 50%. Median OS was 5.5 months in TP53-mutant AML...

CONTRADICTING EVIDENCE:...TP53 mutation (p=0.005) and complex karyotype (p=0.003) were the strongest predictors of venetoclax resistance, while IDH2 (p=0.006) and SRSF2 (p=0.007) mutations predicted favorable responses (FigureA).

CONTRADICTING EVIDENCE: Charts from 82 treatment-naïve AML patients from 7 french centers who received AZA-VEN 7+7 scheme from the 1st cycle were retrospectively analyzed...Univariate analysis revealed that complex karyotype, TP53 mutations (VAF≥10%) and adverse risk ELN-2022 were correlated with a worse ORR.

This multicenter, single-arm, phase 2 trial (NCT04752527) enrolled young pts (aged between 18 and 59) with ND AML...Pts harboring TP53 and ASXL1 mutations achieved encouraging CRc rates of 62.5% and 75%, respectively.

CONTRADICTING EVIDENCE: Patients with AML who received front-line Ven+HMA outside clinical trials at the Mayo Clinic between 2018 and 2020 were retrospectively recruited...The current study identifies presence of TP53 and K/NRAS mutations as predictors of inferior survival in patients with AML relapsed or refractory to front-line Ven+HMA.

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

CONTRADICTING EVIDENCE: Among 130 patients with AML, we identified with TP53 mutations….Among 3 patients treated with HMA plus Ven; 2 achieved a CR….Our analysis though small in numbers seems to confirm the poor response to intense cytotoxic chemotherapy in TP53 mutant AML...

We conducted a retrospective analysis of patients with TP53mut MDS/AML at our institution treated with 400 mg Ven...Overall response rate was 100%: 5/5 front-line patients had complete remissions (CR), and the R/R patient achieved a morphologic leukemia-free state....Weekly Ven with low-dose subQ Dec is well tolerated, yielding high response rates in TP53mut MDS/AML.

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.

We retrospectively analyzed 41 patients with AML treated with upfront venetoclax + HMAs from July 2017 to December 2020 at VCU Massey Cancer Center….Nine patients had TP53mut with a CRR of 33.3% and OS 12.6 months….Survival with venetoclax + HMA appears to numerically favor TP53mut AML when compared to more intensive strategies, consistent with prior literature reporting favorable responses to HMA monotherapy in this subset of disease.

CONTRADICTING EVIDENCE: CR, CR/CRi, and mOS were low across all treatments for patients with newly diagnosed, untreated TP53m AML….mOS was similarly low across the 3 treatments: IC, 6.5 months (N=155; 5.1, 8.5); VEN+HMA, 6.2 (N=73; 5.2, 7.2); HMA, 6.1 (N=34; 4.9, 7.2)….CR, CR/CRi, and mOS were low across all treatments for patients with newly diagnosed, untreated TP53m AML.

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.

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.

The overall response rate (ORR) was 100%: 4/4 frontline pts had complete remissions (CR), and the 1 R/R pt achieved morphologic leukemia-free state (MLFS). Median time to best response was 2.9 mo….Combination weekly Ven with subcutaneous low-dose Dec is well tolerated yielding high rates of clinical and molecular response in pts with TP53mut MDS/AML.

CONTRADICTING EVIDENCE: A phase 1b/2 study evaluating FLAG-IDA+VEN (Fig. 1A) in ND and relapsed/refractory (R/R) AML patients 18 years of age….Patients with TP53 mutations at diagnosis have significantly inferior OS (24 months vs. NR, p-value: 0.03) and EFS (median EFS 8 months vs. NR, p-value <0.001) compared to patients with wild-type TP53.

CONTRADICTING EVIDENCE: Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.

In this single-institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53mut AML and compared the clinical characteristics…Patients who received VEN-based regimens were older (aged >65 years: 81% vs 65%; P = .02) and had higher response rates (complete remission, 43% vs 32%; P = .06) than those who received non-VEN-based regimens.

CONTRADICTING 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.

CONTRADICTING EVIDENCE: 100% of patients with KMT2A rearrangements (N=7), and 50% of patients with extra-medullary AML (N=4) achieved a CRc. In R/R AML, mutations in tumor suppressor (TS) genes (TP53, WT1, PHF6) were more frequently identified in patients without response (66% vs. 19%, p-value: 0.014) while 100% of R/R patients with NPM1 mutated AML achieved CRc.

CONTRADICTING EVIDENCE: Pts with TP53mut had a lower rate of CR at 35% compared to 57% in pts with TP53WT (p=.026), lower rate of CR/CRi at 54% vs. 76% in pts with TP53WT (p=.015), and lower rate of MRD negativity by FCM in 19% compared to 52% in TP53WT AML….TP53mut is associated with inferior response with shorter response duration, higher MRD positivity and inferior survival outcomes in pts with AML receiving frontline therapy with VEN and DEC.

CONTRADICTING EVIDENCE: 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.

CONTRADICTING EVIDENCE: 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.

Sixty nine pts with TP53-mutated AML treated with VEN were identified...The overall response rate (ORR) was 47% & 24% in frontline and R/R pts, respectively….VEN based therapy was associated with similar ORR, but higher CR rates in TP53 mutated AML compared with HMAs alone.

Responses were observed in patients carrying the TP53 mutation, with CR + CRi rates of 47%, median duration of CR + CRi of 5.6 months (95% CI, 1.2-9.4 months), and median OS of 7.2 months (95% CI, 3.7 months-NR)….TP53 status was found to be a statistically significant predictor for CR + CRi...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.

CONTRADICTING 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.

CONTRADICTING EVIDENCE:...p53 KD OCI-AML3 and TP53 mutant Molm13 cells exhibited decreased sensitivity not only to VEN, but also to Mcl-1 inhibitor AZD5991 compared to OCI-AML3 vector control and Molm13 parental cells, respectively.