Ushering in the era of precision medicine for AML
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Each year in the U.S., more than 20,000 patients are diagnosed with acute myeloid leukemia — an aggressive and often lethal malignancy — and more than half this number of patients die.
Although curable in some patients, the long-term survival rate is about 25% for the general population.
Outcomes are even more dismal among older patients (defined loosely as aged older than 55-65 years at diagnosis), with long-term survival rates of 10% or less. The median age at diagnosis of AML in the U.S. is 68 years, meaning that most patients belong to the “older AML” category with the worst outcomes.
Steady progress
On the therapeutic front, patients with AML generally belong to one of two main groups:
- those deemed fit enough to tolerate intensive chemotherapy, the most common version of which is an anthracycline and cytarabine combination often referred to as “7 + 3,” which has been in use since the 1970s; and
- those deemed unfit for intensive chemotherapy due to age, comorbidities and other factors.
Patients in the first group, often younger and healthier, achieve high rates of complete response (CR) with intensive chemotherapy, in the range of 70% to 80%, but often relapse within 3 years. Although around 40% of these patients can be cured, cure for many requires allogeneic hematopoietic stem cell transplantation.
Most patients with AML belong to the second group, for whom the goals of therapy are largely palliative, focusing on quality of life, minimizing sequalae of bone marrow failure and prolonging survival, if possible. Until 2017, therapy options for this group have been quite limited and included hypomethylating agents such as azacitidine and decitabine, low-dose cytarabine, or only best supportive care. In fact, population studies as recent as 2013 suggested that more than 40% of older patients with AML in the U.S. do not receive any active AML-directed therapy.
Despite these depressing statistics, progress has been steady and even accelerated in the last 2 decades.
Acute promyelocytic leukemia — a subtype of AML characterized by a 15;17 translocation leading to a chimeric PML/RARA fusion gene — can now be cured in most patients with a chemotherapy-free combination of all-trans retinoic acid and arsenic trioxide.
Precision medicine, in the sense of using cytogenetic markers to direct the use of allogeneic HSCT, has been employed for a long time. For example, patients with so-called core-binding factor (CBF)-translocated AML have better — or less worse, if you will — outcomes than those without CBF translocations, and about 50% of them could be cured with intensive chemotherapy without proceeding to allogeneic HSCT.
An increasing number of genetic mutations (eg, FLT3, NPM1, CEBPA, TP53, ASXL1, RUNX1, IDH1, IDH2 and others) have been associated with prognosis, especially for the 40% to 50% of patients with normal cytogenetics. Some of these genetic alternations were added to the commonly used prognostic and risk-based classification tools.
Therefore, testing panels to assess for the presence of the most common, recurrent, somatic genetic alternations are an integral part of the workup for patients with AML. A better understanding of the molecular landscape of AML and the disease biology also has allowed a quick transition from sole prognostic use of precision medicine to therapeutic targeting of specific molecular alternations.
FLT3 inhibitors
FMS-like tyrosine kinase 3 (FLT3) mutations, especially those in the internal tandem duplication domain, occur in about one-third of patients with AML and carry an adverse prognosis. Those patients generally cannot be cured without allogeneic HSCT, and many of them still relapse even after transplant.
In 2017, midostaurin (Rydapt, Novartis) became the first FLT3 inhibitor to be approved in U.S. based on the randomized phase 3 RATIFY study in the front-line setting, and the agent became a standard of care for this patient group. In combination with 7 + 3, midostaurin improved survival of patients with FLT3 mutations, with a 4-year OS rate (often meaning cure) of 51% compared with 44% with placebo.
It should be noted that many patients in the trial, which was limited to those aged younger than 60 years, still underwent allogeneic HSCT.
Subsequently, researchers confirmed benefits of this agent in older patients who were able to receive intensive chemotherapy.
In late 2018, gilteritinib (Xospata, Astellas), a more specific FLT3 inhibitor, received FDA approval for patients with refractory/relapsed FLT3-mutated AML based on interim analyses of the ADMIRAL phase 3 trial showing a CR rate of 21% and transfusion independence rate of 35%. This randomized trial of gilteritinib vs. physician’s choice of alternate therapy (with many patients receiving intensive chemotherapy) showed a statistically significant and clinically meaningful improvement in OS with gilteritinib, at a median 9.3 months compared with 5.6 months for the control group, further solidifying this oral agent as a standard-of-care option for these patients.
Several other FLT3 inhibitors are in advanced clinical trials, including phase 3 trials.
IDH inhibitors
Isocitrate dehydrogenase (IDH) 1 and 2 mutations — occurring in 15% to 20% of patients with AML — lead to neomorphic function of the corresponding enzymes, which have been implicated in leukemogenesis through different biologic mechanisms, some of which are mediated through the oncometabolite 2-hydroxyglutarte.
Data from a large phase 1 trial of the oral IDH2 inhibitor enasidenib (Idhifa; Celgene, Agios) among patients with IDH2-mutated relapsed/refractory AML showed a CR rate of 19%, an overall response rate of 40% and median OS of 9.3 months in this difficult-to-treat patient population, leading to FDA approval of the drug in 2017.
The FDA approved the IDH1 inhibitor ivosidenib (Tibsovo, Agios) in 2018 based on largely similar clinical results from a large phase 1 trial. The benefits of ivosidenib also were demonstrated as front-line monotherapy for older unfit patients with IDH1-mutated AML, and the drug was subsequently approved for this indication.
Other agents
Five other agents have received FDA approval for AML since 2017.
Gemtuzumab ozogamicin (Mylotarg, Pfizer) — an antibody-drug conjugate against CD33, which is expressed in more than 90% of patients with AML — was approved for CD33-positive AML as monotherapy for front-line management for older patients, as well as in the relapsed/refractory setting and in combination with 7 + 3 for fit patients.
Clinical benefit in combination with intensive chemotherapy is highest among patients with CBF-translocated AML, more modest in those with intermediate-risk AML, and absent in those with adverse-risk AML.
Randomized trials of different patient subpopulations have demonstrated improved survival with several therapies, including:
- liposomal cytarabine and daunorubicin, also known as CPX-351, (Vyxeos, Jazz Pharmaceuticals), a liposomal formulation of 7 + 3;
- the combination of the oral BCL-2 inhibitor venetoclax (Venclexta; AbbVie, Genentech) with azacitidine;
- the combination of the smoothened inhibitor glasdegib (Daurismo, Pfizer) with low-dose cytarabine; and
- an oral formulation of azacitidine (Onureg, Bristol Myers Squibb).
Additional agents are in advanced clinical testing, many of which are specifically targeted against important molecules/pathways in AML pathogenesis. Trials of various combinations of the above approved drugs, as well as novel agents, also are ongoing, including some using completely oral and chemotherapy-free combinations.
One area of specific unmet clinical need is TP53-mutated AML, which represents a subset of patients who often cannot be cured with intensive chemotherapy and exhibit extremely poor prognosis even after allogeneic HSCT. There are ongoing trials in this subtype of AML using novel approaches, including macrophage immune checkpoint inhibitors such as anti-CD47 antibodies or TP53-refolding agents.
Precision medicine has become a mainstay in the modern management of AML with complex and largely individualized clinical decision-making, which is dependent on extensive evaluation of cytogenetic and molecular alternations to recommend the best therapy for each patient.
References:
DiNardo CD, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1716984.
Perl AE, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1902688.
Roboz GJ, et al. Blood. 2020;doi:10.1182/blood.2019002140.
Shallis RM, et al. Blood Rev. 2019;doi:10.1016/j.blre.2019.04.005.
Stein EM, et al. Blood. 2017;doi:10.1182/blood-2017-04-779405.
Stone RM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1614359.
Zeidan AM, et al. Cancer. 2019;doi:10.1002/cncr.32439.
For more information:
To contribute to this column or suggest topics, email Wafik S. El-Deiry, MD, PhD, FACP, at wafik@brown.edu.
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