[Novel Strategies to Treat Acute Myeloid Leukemia]

by Selleckchem | Jul 23 2023

Background: While the "7+3" regimen of cytarabine + anthracycline has been the backbone of acute myeloid leukemia (AML) treatment for four decades, several novel drugs have been approved in the past five years. Despite these promising novel therapeutic options, treatment of AML remains challenging, given the biologically heterogenous character of the disease.

Aim: This review provides an update on novel treatment strategies for AML.

Material and methods: This article is based on the current European LeukemiaNet (ELN) recommendations and the DGHO «Onkopedia» guideline on AML treatment.

Results and conclusion: The treatment algorithm is based on patient-related and disease-specific factors, such as patient age and fitness as well as AML molecular profile. Younger patients considered fit for intensive chemotherapy receive 1-2 courses of induction therapy ("7+3" regimen, eg. cytarabine/daunorubicin, or CPX-351 for patients with myelodysplasia-related AML or therapy-related AML). For CD33+ patients or those with evidence of an FLT3 mutation "7+3" in combination with Gemtuzumab-Ozogamicin (GO) or Midostaurin is recommended, respectively. For consolidation, patients receive either high-dose chemotherapy (± GO/± Midostaurin) or undergo allogeneic hematopoietic cell transplantation (HCT), based on ELN risk stratification. In some cases, maintenance therapy with oral azacytidine or FLT3 inhibitor is indicated. Patients experiencing relapse should receive chemotherapy-based re-induction therapy or, in case of an FLT3 mutation, Gilteritinib and subsequently undergo allogeneic HCT. For older patients or those considered unfit for intensive therapy, azacytidine in combination with Venetoclax is a promising novel treatment strategy. Although not yet approved by the European Medical Agency (EMA), for patients with IDH1IDH1 or IDH2 mutations treatment with the IDH1 and IDH2 inhibitors Ivosidenib and Enasidenib should be considered.

Comments:

Introduction: Acute myeloid leukemia (AML) is a biologically heterogeneous disease, and despite the longstanding use of the "7+3" regimen of cytarabine and anthracycline as the backbone of treatment, the outcomes have remained challenging. In recent years, several novel therapeutic options have been approved, offering hope for improved outcomes. This review aims to provide an update on these novel treatment strategies for AML.

Methods: The information presented in this article is based on the current recommendations from the European LeukemiaNet (ELN) and the DGHO "Onkopedia" guideline on AML treatment. These guidelines are widely accepted and provide evidence-based recommendations for clinical practice.

Results and Recommendations: The treatment algorithm for AML is based on various factors, including patient age, fitness, and AML molecular profile.

1. Younger Patients Fit for Intensive Chemotherapy: Younger patients who are considered fit for intensive chemotherapy typically receive 1-2 courses of induction therapy. The standard "7+3" regimen of cytarabine and daunorubicin remains the recommended choice. However, for patients with myelodysplasia-related AML or therapy-related AML, a liposomal formulation of cytarabine and daunorubicin known as CPX-351 may be used.

Additionally, for patients who are CD33-positive or have evidence of an FLT3 mutation, the "7+3" regimen is combined with targeted therapies. Gemtuzumab ozogamicin (GO), an anti-CD33 antibody-drug conjugate, is recommended for CD33-positive patients. Midostaurin, a FLT3 inhibitor, is recommended for patients with FLT3 mutations.

For consolidation therapy, patients can either undergo high-dose chemotherapy with or without GO or Midostaurin or proceed to allogeneic hematopoietic cell transplantation (HCT) based on ELN risk stratification. In some cases, maintenance therapy with oral azacytidine or a FLT3 inhibitor may be indicated.

In the event of relapse, patients should receive chemotherapy-based re-induction therapy. For patients with FLT3 mutations, the FLT3 inhibitor gilteritinib can be used as salvage therapy. Subsequently, allogeneic HCT is recommended for eligible patients.

2. Older or Unfit Patients: For older patients or those considered unfit for intensive therapy, a promising novel treatment strategy involves the combination of azacytidine, a hypomethylating agent, and venetoclax, a BCL-2 inhibitor. This combination has shown improved efficacy and tolerability compared to azacytidine alone.

3. IDH1 and IDH2 Mutations: Although not yet approved by the European Medicines Agency (EMA), patients with IDH1 or IDH2 mutations may benefit from treatment with specific inhibitors. Ivosidenib and enasidenib are IDH1 and IDH2 inhibitors, respectively, and have shown promising results in clinical trials.

Conclusion: The treatment landscape for AML is evolving, with several novel therapeutic options available. Tailoring treatment based on patient-related and disease-specific factors, such as age, fitness, and molecular profile, is crucial for optimizing outcomes. The use of targeted therapies, consolidation with chemotherapy or HCT, and maintenance therapy further contribute to the management of AML. Ongoing research and clinical trials continue to explore and refine these novel treatment strategies, with the aim of improving outcomes for patients with AML.