Recently approved drugs are rapidly changing the treatment of patients with acute myeloid leukemia (AML), with newer options including less toxic front-line therapies and several targeted drugs. These new drug combinations and targeted therapies may offer a brighter future – especially among older patients who may be more frail or are managing co-morbidities
Physician-scientists at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine surveyed the field. The results from their study were published in the August 8, 2024 edition of the Journal of the American Medical Association Oncology (JAMA Oncology).[1]
“It’s been an exciting time in the treatment of AML,” said Mikkael A. Sekeres, M.D., M.S., Chief of the Division of Hematology at Sylvester, and senior author on the article.
“The time was ripe for an update on the biology of AML and the treatment approaches that we’ve adopted since the approval of these drugs,” Sekeres added.
Incidence of AML
In the United States, about 20,800 people are diagnosed with AML annually, with a median age of onset of 69. Only about a third of patients live five years or longer, according to data from the National Cancer Institute data from 2014-2020. [2]
Historically, a substantial fraction of patients were unable to tolerate the first-line, harsh combination of chemotherapy drugs. Many frailer, typically older patients or patients diagnosed with specific comorbidities often did not receive any active therapy.
Less ‘harsh’
However, over the last 10 years major advances in the molecular profiling of AML characterized have resulted in a deeper understanding of disease pathobiology and therapeutic vulnerabilities. This improved understanding has resulted in that treatment options for newly diagnosed patients with AML is no longer based on the straightforward belief that intensive chemotherapy would only be an optimal choice for ‘younger’ patients and patients without comorbidities who ate ‘fit’ enough to receive these ‘harsh’ treatment options. Instead, the approval of newer, less intensive, therapy options places the choice of frontline AML therapy more on so-called disease-specific features, including cytogenetics and mutational profile.[3]
The approval of the drug venetoclax (Venclexta®; AbbVie/Genentech) in 2020, and similar drugs after that, enabled physicians to offer such patients a less harsh option. Venetoclax targets a molecule involved in cell death, promoting cell apoptosis. It is typically combined with the older chemotherapy drug azacitidine (Vidaza®; Bristol Myers Squibb/Celgene).
Patients generally better tolerate the azacitidine-venetoclax combination than traditional chemotherapy and often stay on it for the rest of their lives.
“Since we’ve introduced this combination, more patients are getting treated, [and] more patients are getting treated as outpatients closer to their homes, and the people who are being treated are living longer,” Sekeres said.
Other therapies
Patients have also benefitted from targeted therapies that aim to target different mutations often found in AML, including in a gene called fms-like tyrosine kinase 3 (FLT3) gene, and the isocitrate dehydrogenase (IDH) genes, IDH1 and IDH2.
FLT3
The first molecularly targeted drug, midostaurin (Rydapt®, Novartis), was approved in 2017 to treat patients with newly diagnosed AML who are FLT3 mutation-positive (FLT3+), as detected by an FDA-approved test.* Since then, several others have been added to the mix.
Midostaurin and another FLT3 inhibitor, quizartinib (Vanflyta®; Daiichi Sankyo), are used as part of initial, front-line treatment in eligible patients, typically combined with conventional chemotherapy agents, including cytarabine and daunorubicin induction and cytarabine consolidation.
IDH1 or IDH2.
Approximately 20% all cases of newly diagnosed AML harbors a mutation in IDH1 or IDH2. leading to the production of the oncometabolite 2-hydroxyglutarate, which promotes leukemogenesis through a block in normal myeloid differentiation.
Since this discovery, selective oral inhibitors of mutant IDH1 and IDH2 have been developed and are now approved, including ivosidenib (Tibsovo®; formerly AG-120; Servier Pharmaceuticals), a first-in-class, selective and orally available mutant IDH1 inhibitor and enasidenib (Idhifa®, formerly AG-221; Celgene Corporation, a Bristol Myers Squibb company, licensed from Servier Pharmaceuticals) a first-in-class, selective and orally available mutant IDH2 inhibitor.
Other, newer, drugs are approved for patients who do not respond to first-line therapy or become resistant to it, including several drugs that target IDH1 and IDH2.
“The future is bright for targeted therapies,” concluded Sylvester physician-researcher, Sangeetha Venugopal, M.D., M.S., the article’s first author.
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Note: * The US Foof and Drug Administration (FDA) has approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay (developed by Invivoscribe Technologies), for use with midostaurin to test patients with AML for the FLT3 mutation.
Highlights of Prescribing Information
Venetoclax (Venclexta®; AbbVie/Genentech) [Prescribing Information]
Azacitidine (Vidaza®; Bristol Myers Squibb/Celgene) [Prescribing Information]
Midostaurin (Rydapt®, Novartis) [Prescribing Information]
Quizartinib (Vanflyta®; Daiichi Sankyo) [Prescribing Information]
Ivosidenib (Tibsovo®; Servier Pharmaceuticals) [Prescribing Information]
Enasidenib (Idhifa®, Bristol Myers Squibb) [Prescribing Information]
Reference
[1] Venugopal SSekeres MA. Contemporary Management of Acute Myeloid Leukemia: A Review. JAMA Oncol. Published online August 08, 2024. doi:10.1001/jamaoncol.2024.2662
[2] Cancer Stat Facts: Leukemia — Acute Myeloid Leukemia (AML) National Cancer Institute (NCI) Online. Last accesses on August 9, 2024
[3] Chen EC, Garcia JS. Does patient fitness play a role in determining first-line treatment of acute myeloid leukemia? Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):41-50. doi: 10.1182/hematology.2020000087. PMID: 33275683; PMCID: PMC7727557.
Featured image courtesy Getty-images/Unsplash. Used with permission.
DOI:10.14229/onco.2024.08.09.001
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