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Publications

Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML


DiNardo CD, Tiong IS, Quaglieri A, MacRaild S, Loghavi S, Brown FC, Thijssen R, Pomilio G, Ivey A, Salmon JM, Glytsou C, Fleming SA, Zhang Q, Ma H, Patel KP, Kornblau SM, Xu Z, Chua CC, Chen X, Blombery P, Flensburg C, Cummings N, Aifantis I, Kantarjian H, Huang DCS, Roberts AW, Majewski IJ, Konopleva M, Wei AH.
Blood Mar 2020
Abstract

The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance), or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations, with prolonged molecular remissions prevalent for NPM1 mutations. Primary and adaptive resistance to venetoclax-based combinations was most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS or biallelically perturbing TP53. Single-cell studies highlighted the polyclonal nature of intratumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes divergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3 internal tandem duplication gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies.

VIEW

Area

Heme

Institution Type

Academia

Indication / Modality

Acute Myleoid Leukemia (AML)

Goal of Study

MRD, Therapeutic Resistance, Disease Progression, Retrospective, Longitudinal

Key Genes

NPM1, IDH2, FLT3, RAS, TP53

PAD Project

No

Analytes Assessed

SNV, InDels

Sample Storage

Fresh Frozen

Sample Prep

Whole Cells

Sample Type

Patient Material

Tissue / Organ

Bone Marrow Aspirates

Species

Human

Panel Used

Catalog AML Panel

Proof Point Demonstrated

Clonality, Co-occurrence, Sensitivity
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