Talha Badar: Venetoclax and Azacitidine for elderly AML ineligible for intensive Induction
Talha Badar shared on X:
“Brief overview of venetoclax+azacitidine for elderly AML ineligible for intensive induction:
1. Long term outcome from VIALE-A trial
2. Common toxicities and duration of therapy (7 vs 14 vs 28 days)
3. Differential outcome based on molecular signature
4. Venetoclax resistance and outcome post Ven failure
At 43.2 mo median follow-up, median OS was 14.7vs 9.6 months
2 yrs OS 37.5% vs 16.9%
Median OS for patients with IDH1/2 mutation 19.9 vs 6.2 mo
Median OS with MRD < 0.01 by flow: 34.2 vs 18.7 mo
Authors: Keith W. Pratz et al.
Toxicity and duration of therapy (7 vs 14 vs 28 days)
Myelosuppression most common, followed by infection and GI toxicities
a) VIALE-A trial recommends AZA for seven days combined with VEN for 28 days for every 28 days However in RWD it is associated with significant myelosuppression, especially high TRM in elderly pts.
Authors: Yasmin Abaza et al.
b) Christophe Willekens from France evaluated 82 AML pts with 7+7 regimen: ASH22
median age 75y, 29% meets exclusion criteria of VIALE-A 56% sAML, 70% adverse risk, 37% PS 2-4
CR/CRi 41.5% after C1, 53.9% after C2.
EFS 7.5 &OS 12.8 m
c) Our data from Mayo Cancer Care on 301 pts 28 days of Ven not better than 21/14 days.
14D may be suitable for favorable and 21D for adverse risk AML
G3 or higher drop in ANC & Plt; 45%/48%, 39%/38, 42%/41%, among pts receiving Ven for 14, 21, & 28 D; p NS
CR/CRi were comparable between 3 gp
Authors: Omer Karraret al.
Molecular signature predicting outcome
Outcome with Ven+HMA is variable based on molecular aberrations.
TP53m AML do the worse, while NPM1/IDH/DDX41m tends to have best outcome
Mayo risk model and VIALE-A response predictors
Authors: Naseema Gangat et al.
Authors: Hartmut Döhner et al.
a) Outcome of patients progressing after VEN+HMA is extremely poor with median survival 3-6 months
Authors: Jan Philipp Bewersdorf et al.
b) Mechanism of VEN resistance: MCL1 over-expression, acquired mutations in BCL-2 BAX mutation, FLT3 mutations( FLT3 F691), RAS mutations, TP53 Mutations and PTPN11 mutations
The path to venetoclax resistance is paved with mutations, metabolism, and more
Authors: Graeme P. Sullivan et al.
c) Outcome remains dismal with intensive or targeted therapies.
Authors: Jan Philipp Bewersdorf et al.
d) Possible strategies to overcome resistance; Ven +BH3 mimetics, limited duration of Ven? prevent emergence of resistance, upfront Flt3i/RASi triplets.”
Dr. Talha Badar, MD, is a specialist in Hematology Oncology based in Mayo Clinic, Jacksonville, Florida. His primary areas of expertise include Leukemia, particularly Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Acute Lymphoblastic Leukemia (ALL), and Bone Marrow Transplantation. Over his career, he has actively contributed to clinical research and clinical trials.
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