StemCell Therapy

Over the last two decades, few drugs have been approved for the treatment of AML, however increased understanding of the leukemic genome has allowed the development of targeted therapeutic agents.2,3 Between April 2017 and November 2018, eight new drugs in various different classes were approved, including: enasidenib, ivosidenib, midostaurin, glasdegib, venetoclax, and gilteritinib.4 An overview of mutations that can be targeted in AML is available on the AML Global Portal (AGP).

Some of these targeted agents are being investigated in novel combination therapies, as different lines of AML treatment, and some as monotherapy compared to standard chemotherapy. This article provides a summary of AGP content relating to novel agent-containing combinations to date and introduces the new editorial theme of Novel combination therapies using targeted agents.

The AGP were pleased to speak to Andrew Wei during the European School of Haematology (ESH) Translational Research Conference on AML, 2019, about how targeted therapies will be used in the future treatment of AML. In this interview, available below, Andrew Wei discusses whether these targeted agents should be used in combination or sequentially.

During the American Society of Clinical Oncology (ASCO) meeting in 2018, the AGP spoke to Uma Borate about how targeted therapies will impact the treatment of AML. Uma Borate discussed targeted agents, such as venetoclax, azacitidine, ivosidenib, and enasidenib.

Precision medicine may have a particular role in the treatment of older patients, since this population are often unable to receive allo-HSCT or intensive chemotherapy regimens. During the 61st American Society of Hematology (ASH) meeting, the AGP spoke to John Byrd about how precision medicine may be used to improve the outcomes of older patients with AML.

The AGP interviewed Courtney DiNardo about the treatment of elderly or frail patients with AML at the 1st National Cancer Research Institute (NCRI) AML Academy Meeting. Watch Courtney DiNardo discuss how the treatment approach for this patient group has changed in recent years with the advent of combination therapies below.

Studies have shown that epigenetic dysregulation can promote a preleukemic state that precedes leukemic transformation. Drugs targeting epigenetic dysregulation have been developed and include: azacitidine and decitabine, which are hypothesized to reverse DNA hypermethylation and reactivate repressed tumor suppressor genes; ivosidenib and enasidenib, which target IDH1 and IDH2 mutations thought to be involved in aberrant DNA hypermethylation.2 Combining these agents may improve patient outcome compared to azacitidine monotherapy.

Ivosidenib/enasidenib plus azacitidine: phase I/II study: AG221-AML-005 (NCT02677922)5,6,7

Patients with newly diagnosed AML, with either IDH1 mutations (mIDH1) or IDH2 mutations (mIDH2), were treated with azacitidine plus ivosidenib (for mIDH1) or enasidenib (for mIDH2).

Ivosidenib/enasidenib plus standard chemotherapy8

A phase III study, HOVON 150/AMLSG 29-18, is comparing enasidenib or ivosidenib (by mIDH status) plus chemotherapy (7+3) versus placebo.9 An overview of IDH inhibitors, including further information on the data from trials involving these combination therapies, is available here.

Other new targets for AML therapies are the FLT3 pathways. FLT3 is a transmembrane tyrosine kinase with two mutational subtypes: an internal tandem duplication (ITD) or point mutations in the tyrosine kinase domain (TKD).4 A third of patients with de novo AML have mutations in the FLT3 gene and patients with FLT3-ITD AML have a poor prognosis. FLT3 is therefore an attractive target for therapeutic agents, with several FLT3 inhibitors in clinical development, such as sorafenib, midostaurin, quizartinib, crenolanib, and gilteritinib.2,4

Examples of combination therapies involving FLT3 inhibitors are shown in Table 1 below. One example of a trial involving a FLT3 inhibitor is the RATIFY (NCT00651261) trial. The RATIFY trial assessed whether the addition of midostaurin to standard chemotherapy could prolong survival in newly diagnosed adult patients with FLT3-ITD AML compared to placebo + chemotherapy. The results showed midostaurin prolonged median OS and event-free survival (EFS) compared to placebo10:

However, the authors questioned if more specific FLT3 inhibitors could further improve outcomes.10

Table 1. Examples of combination therapies containing FLT3 inhibitors4,11,12

Targeted agent

In combination with/versus

Patient population

Trial name/NCT reference

Midostaurin

Induction chemo

ND AML with FLT3-ITD or TKD mutations

RATIFY

NCT00651261

Quizartinib

Induction chemo

ND AML with FLT3-ITD mutations

QuANTUM-First

NCT02668653

Crenolanib

vs midostaurin, in combination with induction chemo

ND AML with FLT3-ITD mutations

NCT03258931

Gilteritinib

Induction chemo

ND AML

NCT02310321

Sorafenib

Induction chemo

ND AML <60 years old

SORAML

NCT00893373

Learn more about FLT3 inhibitors in AML here.

During the 2019 EHA meeting, the AGP spoke to Alexander Perl about gilteritinib for the treatment of relapsed/refractory (R/R) AML.

Another example of a targeted agent for the treatment of AML is venetoclax, which is a Bcl-2 inhibitor. Venetoclax is approved by the U.S. Food & Drug Administration (FDA) for the treatment of newly diagnosed patients with AML who are not eligible for intensive induction chemotherapy, in combination with azacitidine, decitabine, or low dose cytarabine.13

Results from a phase Ib study (NCT02203773) investigating venetoclax with decitabine or azacitidine showed that these combination therapies led to a 61% complete remission or complete remission with incomplete marrow recovery rate in newly diagnosed patients with AML aged 65 and over.14 A phase III study (NCT02993523) comparing venetoclax plus azacitidine to azacitidine alone in patients with treatment-nave AML is ongoing.15

During the Acute Leukemias XVII Biology and Treatment Strategies biennial symposium, Andrew Wei gave a presentation on novel therapeutic combinations containing venetoclax for the treatment of AML.

There are a number of ongoing studies of venetoclax in combination therapies and examples of these include4:

During the 2018 ASCO meeting, the AGP spoke to Courtney DiNardo about the combination of venetoclax with hypomethylating agents (HMAs).

Subsequently, during the Society of Hematologic Oncology (SOHO) meeting in 2019, the AGP spoke to Jeffrey Lancet about the potential of venetoclax + HMAs to replace induction chemotherapy.

The AGP spoke to Marina Konopleva at the 2019 EHA meeting about Bcl-2 as a universal target in AML.

The development of targeted therapies and novel combinations holds promise for the treatment of AML, especially when compared to currently approved options. In some cases, these combinations may be more efficacious than intensive induction chemotherapy. In addition, some patients have been able to undergo allo-HSCT following treatment with a novel combination, which may indicate that the future of AML treatment will be in novel combinations and involve less chemotherapy. Additionally, these combinations appear tolerable to date.

Despite the promising results seen so far, not all patients respond equally. In order to maximize response to these therapies, it will be important to identify the right patient subgroups, with specific mutations, and may require particular combinations of agents to be used.2

Read this article:
An introduction to novel combination therapies using targeted agents in AML - AML Global Portal

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