IDH1/2,   FLT3

August 2019 | Druggable mutations in AML

Targeted therapies in acute myeloid leukemia (AML) focus on druggable mutations, such as IDH1/2 and FLT3. These drugs have limited activity as monotherapy, and are therefore often used in combination with chemotherapy or hypomethylating agents (HMAs).

Currently, new treatment paradigms for patients with AML are emerging, where targeted therapies increasingly complement the use of more conventional, chemotherapy-based approaches according to the molecular profile. Although targeted therapies have advanced the treatment for patients with AML, they also come with specific side effects. This month, the AML Global Portal (AGP) is focusing on providing educational content surrounding druggable mutations, and how targeted therapies can be used as effective treatment regimens for AML.

Here are some of the highlights of content the AML Global Portal has recently covered on the topic:

What is the clinical value of new drugs in AML?

At EHA 2019, Prof. Ossenkoppele stated these are exciting times for hematologists working in the AML field. Novel drugs, gilteritinib and quizartinib, were highlighted as potential options to meet an urgent medial of relapsed/refractory (R/R) AML, as was venetoclax, which was described by Prof. Ossenkoppele as "a game changer" in AML.

FLT3 inhibitors

Why does FLT3 testing need to be performed? [video]

At EHA 2019, Jorge Sierra described how FLT3 mutations are one of the most common molecular abnormalities in AML. He stressed the importance of testing patients for FLT3 mutations because there are FLT3-targeting agents available, such as midostaurin, and because the presence of FLT3 internal tandem duplication (FLT3-ITD) confers an adverse prognosis.

Effect of gilteritinib in patients with FLT3-mutated R/R AML with common AML co-mutations or a high FLT3-ITD allelic ratio

 FLT3 mutations occur in approximately 30% of patients with AML and are often associated with poor survival. Gilteritinib was recently approved by the US Food & Drug Administration (FDA) for the treatment of patients with R/R AML based on interim data from the randomized phase III ADMIRAL study (NCT02421939). This showed that the oral FLT3 inhibitor, gilteritinib provides superior response and overall survival (OS) compared with salvage chemotherapy (SC) in patients with FLT3 mut+ R/R AML.

Sorafenib associated with improved outcomes for patients with FLT3-ITD AML

Approximately 25% of patients with AML have FLT3-ITD mutations and survival is often inferior due to high relapse rates and short remission periods. Since the standard therapy is challenging for patients with FLT3-ITD AML who relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), sorafenib, as monotherapy or in combination, has recently been suggested to be an option for SC.

What effect does gilteritinib have on FLT3 mutated R/R AML? 

At the 24th Congress of the European Hematology Association (EHA), Alexander Perl from the University of Pennsylvania, US, presented the data from the ADMIRAL phase III trial of gilteritinib, a selective FLT3 inhibitor, for R/R AML. Patients were randomized 2:1 to receive either gilteritinib or one of four standard SC treatments. The favorable outcomes of gilteritinib observed in this trial (increased complete response rate (CRR) and overall survival (OS)) led to its FDA approval for R/R AML.

Impact of genetic mutations in gilteritinib treated patients with FLT3 mutated R/R AML 

At the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, US, Mark J. Levis, Johns Hopkins University, Baltimore, US discussed an abstract based on the impact of co-mutations and FLT-3 allelic burden on the outcome of patients treated with gilteritinib in the randomized ADMIRAL study (NCT02421939). Dr. Levis explained that in this follow-up study, the FLT3 inhibitor, gilteritinib, showed superior response and overall survival (OS) compared with SC in patients with FLT3 mut+ R/R AML. Dr. Levis analyzed the impact of baseline co-mutations and FLT3-ITD allelic ratio (AR) on response and OS.

QuANTUM-R trial of quizartinib versus salvage chemotherapy in FLT3-ITD mutated AML

The presence of FLT3-ITD in AML is a marker of poor prognosis, and when patient relapse with FLT3-ITD AML, there is a high unmet need for effective therapies. Quizartinib monotherapy in comparison with SC, was studied in a phase III trial. Researchers observed that quizartinib was well tolerated and prolonged OS compared with SC.

Quizartinib rejected by the FDA for FLT-ITD AML

The FDA decided not to grant approval to quizartinib for the treatment of patients with FLT3-ITD-+ R/R AML, as results of a trial failed to show that the benefits of the treatment outweigh the risks. A final decision is set to be made by the FDA this month, before August 25 2019.

IDH inhibitors

Inhibitors of IDH1 and IDH2 for targeted therapy in AML

Whilst IDH mutations are not the most commonly occurring aberrations in AML, approximately 20% of patients have mutant IDH (mIDH) genes with approximately 8% affecting IDH1 and 12% in IDH2. These mutations are early events, with 20% of IDH1 and 35% of IDH2 occurring at diagnosis. However, these can also be acquired during progression from myelodysplastic syndrome or myeloproliferative neoplasms to AML in 10–15% and 20–25% of cases, respectively.

Ivosidenib approved as first-line treatment for AML with IDH1 mutation

An open-label, multicenter study has led to the approval of ivosidenib for the treatment of newly diagnosed AML with a susceptible IDH1 mutation. Despite patients undergoing side effects, 42.9% achieved complete remission (CR), or CR with partial hematologic recovery.

Enasidenib found to induce molecular remissions in IDH2-mutated, relapse/refractory AML

This phase I/II trial evaluated enasidenib in adults with IDH2-mutated AML that had relapsed after allo-HSCT. Due to the results of the study, the IDH inhibitor is now being studied in a phase III trial of older patients with late-stage, IDH2-mutated, R/R AML.

BCL-2 inhibitors

BCL-2 as a universal target in AML [video]

Dr. Konopleva explains how BCL-2 has become a very important target in AML, specifically using the example of venetoclax, in combination with HMAs, which was approved by the FDA prior to the completion of the phase III trial and became the standard of care in the US for the treatment of unfit elderly patients.

Activity of venetoclax-based therapy in TP53-mutated AML

Guillermo Garcia-Manero, MD Anderson Cancer Center, talks to the AGP at ASCO 2019, Chicago, US, about the use of venetoclax in combination with HMAs; FLAG-Ida, low-dose Ara-C or CPX-351 for TP53-mutated AML.

Optimizing the dose of venetoclax with less intensive therapies for elderly patients with newly diagnosed AML

Venetoclax was recently approved by the FDA for the treatment of elderly patients with newly diagnosed AML, or for patients who have comorbidities, in combination with HMAs or low-dose cytarabine (LDAC). First indicated for the treatment of patients with chronic lymphocytic leukemia (CLL), it is a potent, selective B-cell lymphoma-2 (BCL-2) inhibitor.

Venetoclax and other BH3 mimetics in AML

This article highlights the clinical impact of venetoclax in potential therapy combinations, discussed possible mechanisms of resistance and ways to overcome them, as well as the future of ventoclax and other BH3 mimetics in AML.

Watch out for more content surrounding the use of druggable mutations in AML on the AML Global Portal, or via our social channels on Facebook, Twitter and LinkedIn.

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