Acute myeloid leukemia (AML) is a devasting disease, which rapidly becomes fatal if left untreated. Anthracycline and cytarabine-based combination chemotherapy has been the mainstay of treatment since its introduction in the 1970s [1, 2].
Recent advances in genomic technologies have identified that AML is a heterogeneous group of diseases, and the long-term prognosis of AML is significantly different and largely dependent on its own cytogenetics and molecular aberrations [3, 4]. Consequently, there have been substantial changes in the classification and prognostication of AML over the last few decades [5, 6], which are now predicated on identifying genetic features of the individual disease. Concurrently, efforts to discover potential molecular targets have been ongoing.
At the 2017 American Society of Hematology meeting, it was announced that 2017 was a landmark year for the Food and Drug Administration (FDA)-approved therapies for AML, as the U.S. FDA had approved four new therapeutic options for the disease (midostaurin, enasidenib, CPX-351, and gemtuzumab ozogamicin). Subsequently, four additional drugs (gilteritinib, ivosidenib, venetoclax, and glasdegib) have received U.S. FDA approval for AML . Surprisingly, these advances have occurred only during the recent few years, and we are undoubtedly facing an “innovative era” in the treatment of AML.
In this review, we will focus on the recently approved new targeted agents for the treatment of AML.
Recently approved drugs for AML and their indication by disease status are listed in Table 1.
In April 2017, midostaurin was approved for treatment of naïve
Gilteritinib, for use as a single agent, was approved for relapsed or refractory (R/R)
In July 2017, gemtuzumab ozogamicin (GO), in combination with daunorubicin and cytarabine or as a single agent, was approved in adults for the treatment of newly diagnosed
In August 2017, CPX-351 was approved for newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). CPX-351 is a liposomal formulation that delivers a 5:1 fixed-molar ratio of daunorubicin and cytarabine [26, 27]. The approval was based on results of a phase 3 clinical trial in 309 patients with either t-AML or AML-MRC, which evaluated the efficacy and safety of CPX-351 compared to conventional cytarabine and daunorubicin induction . In this study, CPX-351 demonstrated an improvement in OS, with a median OS of 9.56 months for the CPX-351 arm versus 5.95 months for the conventional chemotherapy arm. Although the trial was conducted only in patients aged 60 to 75 years, the FDA approved CPX-351 for use in all adults with no age restrictions.
Enasidenib, for use as a single agent, was approved by the FDA in August 2017 for R/R AML with the isocitrate dehydrogenase-2 (
Venetoclax, in combination with azacitidine or decitabine or low dose cytarabine, received accelerated FDA approval in Nov 2018 for newly diagnosed AML (age 75≥yr or “unfit” patients). Venetoclax is an orally active, and potent small molecule inhibitor targeting B-cell lymphoma 2 (
Glasdegib, in combination with LDAC, was approved by the FDA in November 2018 for the frontline treatment of elderly (>75 yr) or unfit patients. Glasdegib is an oral inhibitor of the hedgehog signaling pathway [44, 45]. Recently, the aberrant activation of the hedgehog signaling pathway has been implicated in the maintenance and development of several malignancies including AML . Glasdegib received FDA approval based on a phase II, randomized, open-label, multicenter study (NCT01546038), in which 88 and 44 patients (older than 75 yr or older than 55 yr with significant comorbidities) were randomized to glasdegib/LDAC and LDAC, respectively . The results demonstrated that glasdegib/LDAC was superior to LDAC alone, indicating better survival (the median OS of 8.3 mo vs. 4.9 mo,
Over the years, there has been a gradual paradigm shift from traditional medicine to personalized or precision medicine owing to the explosive growth in available genetic data . Traditional or conventional medicine is characterized by empirical and mechanism-based treatments, targeting an entire population. On the contrary, precision medicine targets an individual patient based on the understanding of the unique molecular mechanisms of the patient [48, 49].
In the field of AML, there has been the growing understanding and discovery of leukemogenic pathways in the past years, and an innovative approach to AML treatment has “long” been expected. However, in the last 40 years, little has changed in the treatment of AML. Moreover, the majority of therapeutic advances in AML are associated with improved supportive care rather than the introduction of novel therapeutics.
Fortunately, with the introduction of numerous novel agents, we are now witnessing a new era in AML treatment . Notably, 2017 was a memorable year in the history of AML treatment, marking the success of biomedical research efforts over the last several decades. The one of future challenges will be to incorporate and use these new therapeutics where they have the greatest impact – use alone or combine targeted agents with each other or with conventional chemotherapy .
Lastly, in Korea, we still have a long way to go, with limited access to these novel agents in clinical practice. Although these are not all-around, I hope that these new FDA approvals are no longer ‘a pie in the sky’ for Korean patients as well in a near future.
No potential conflicts of interest relevant to this article were reported.