# Hypomethylating Agents and Venetoclax Based Triplets Targeting FLT3, IDH and KMT2A in Acute Myeloid Leukemia: Current Studies and Challenges of a Tailored Approach

## TL;DR

This paper reviews new triple drug combinations for treating acute myeloid leukemia, focusing on their effectiveness and challenges.

## Contribution

The paper provides a comprehensive review of emerging triplet therapies combining hypomethylating agents, venetoclax, and novel inhibitors targeting FLT3, IDH, and KMT2A.

## Key findings

- Triplets like azacytidine/venetoclax/gilteritinib show high complete remission rates in treatment-naïve patients.
- Some patients initially considered too frail for intensive chemotherapy can undergo stem cell transplantation after achieving remission.
- Orally administered triplet regimens are being tested in advanced clinical trials.

## Abstract

The outcome of acute myeloid leukemia patients ineligible for intensive chemotherapy has dramatically improved by the implementation of the hypomethylating agent/venetoclax doublet. The therapeutic landscape is rapidly evolving, in both relapse/refractory and newly diagnosed settings. Driven by disease-specific features, personalised treatment strategies are developing through the incorporation of novel agents into the doublet backbone. This review aims to present and summarise the main data from recent clinical trials investigating these arising triplets, and, above all, addresses their main challenges and limitations based on currently available evidence. Given the broad spectrum of targets, triplets addressing FLT3, IDH, and KMT2A are chosen exemplarily.

Recent implementations with novel target drugs of the hypomethylating agent/venetoclax doublet challenge our treatment approach in acute myeloid leukemia patients ineligible for intensive chemotherapy. Given the doublets’ efficacy, associations of agents based on the disease’s biology to the doublet backbone are leading to novel triplet (or more) combinations. In the present review mainly FLT3, IDH and KMT2A are discussed as possible targets in this context. These triplets do not only have efficacy in relapsed/refractory patients but also in treatment-naïve patients. Results from concluded and ongoing clinical trials, as well as real-world experiences, report high efficacies competing with intensive chemotherapy. For instance, the azacytidine/venetoclax/gilteritinib triplet as first-line is reported to induce a complete remission rate with and without incomplete recovery (CR/CRi) of 96%, with 90% of responders achieving minimal residual negativity. Once a stable CR was obtained, 47% of patients who were initially considered too frail for intensive chemotherapy were able to undergo allogeneic stem cell transplantation. However, there are still open questions and challenges regarding toxicity, post-remission therapy, and overall treatment duration. The present review will not only present the specific potency of these arising triplets, but also discuss their challenges and limitations, based on currently available data. Besides regimens containing approved inhibitors, triplets with next-generation inhibitors, including completely orally administered triplet regimens, are also summarized. Their promising results are leading to advanced phase clinical studies by international consortia and collaborative groups, aiming to further refine their clinical management.