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 [7]. 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 FLT3-mutant AML, in combination with daunorubicin and cytarabine induction and cytarabine consolidation. Nearly 25–30% and 5–10% of patients with AML harbor an FLT3-internal tandem duplication (ITD) and -tyrosine kinase domain (TKD) mutation, respectively [8]. Among the mutation locations, FLT3-ITD AML often presents hyperleukocytosis [9, 10] and is a known marker of adverse prognosis. However, the prognostic implication of FLT3-TKD mutation remains unclear [11]. Based on the RATIFY trial (randomized AML trial in FLT3-mutated adults younger than 60 years old) [12, 13], in which 717 patients were randomly assigned to chemo +/- midostaurin after screening approximately 3,300 patients, midostaurin was approved by the U.S. FDA after demonstrating a survival benefit in AML patients with mutated FLT3-ITD or TKD. This was the first FLT3 inhibitor approved in AML, breaking new ground for the trend of precision medicine in AML treatment.

Gilteritinib, for use as a single agent, was approved for relapsed or refractory (R/R) FLT3-ITD and/or FLT3-TKD mutant AML in November 2018. As mentioned earlier, nearly one-third of AML patients have an activating mutation in FLT3. Given that the FLT3 mutation is frequently observed and strongly associated with relapse and survival in AML, many novel agents have attempted to treat AML harboring the FLT3 mutation [8, 11, 12]. Gilteritinib, a second-generation FLT3 inhibitor, is characterized by highly specific and potent inhibition of FLT3, with narrower kinome profiles than first-generation FLT3 inhibitors such as midostaurin [14, 15]. The approval of this drug in AML was based on the phase 3 ADMIRAL trial [16], which demonstrated that gilteritinib significantly prolongs overall survival in FLT3 mutated relapsed/refractory AML when compared to comparative salvage chemotherapy arms.

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 CD33-positive AML. Additionally, the FDA approved GO in R/R CD33-positive AML in adults and pediatric patients at least two years of age. GO is a recombinant, humanized anti-CD-33 antibody conjugated to the intracellular toxin, calicheamicin [17]. In May 2000, this drug originally received accelerated approval for CD33-positive AML patients (60 yr or older) experiencing their first relapse, and in those not considered candidates for other cytotoxic chemotherapy [18]. Of note, Go combined with attenuated conventional chemotherapy was feasible in elderly patients with AML in Korea [19, 20]. Subsequently, in 2010, it was voluntarily withdrawn from the market due to failure to verify prior efficacy data, as well safety concerns, including a high number of early deaths and hepatic veno-occlusive disease (VOD). Interestingly, however, this drug has remained in the Japanese market based on an individual approach with Pfizer’s compassionate use program, which reflects the critical unmet need for novel agents in AML treatment. Indeed, GO with different dosing and different schedules remained of great interest among AML clinicians, resulting in independent investigators conducting investigator-initiated clinical trials, including ALFA-0701 (phase 3 study of GO with daunorubicin and cytarabine in 50–70 aged untreated AML) [21], AML-19 (phase 3 study of single-agent GO in newly diagnosed elderly AML) [22], and MyloFrance-1 (phase 2 open-label study of single-agent GO as induction therapy in relapsed AML) [23]. These studies formed the basis for the reapproval of GO, demonstrating an improved event-free survival (EFS), overall survival (OS), or relapse-free survival (RFS). The current approval has been granted for a lower dose “fractionated” schedule rather than the dose originally approved by the FDA (2 doses of 9 mg/m² each on days 1 and 8), aimed at a different target population. Currently, the widely accepted protocol of GO is 3 mg/m² on days 1, 3, and 5; this reduced and fractionated dose schedule seems to increase tolerance and decrease drug-related toxicity such as VOD [24, 25].

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 [28]. 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 (IDH2) mutation. In July 2018, ivosidenib was also approved as a single agent in IDH1-mutated R/R AML. Enasidenib [29-31] and ivosidenib [32-34] are small molecule inhibitors targeting IDH2 and IDH1, respectively. Isocitrate dehydrogenase (IDH) plays a key role in converting isocitrate to a-ketoglutarate (a-KG), demonstrating the three different isoforms of IDH1, 2 and 3. The IDH mutation results in a neomorphic enzyme, which can result in the abnormal accumulation of the oncometabolite R-2-hydroxyglutarate (R-2-HG) and promote leukemogenesis [35]. Notably, nearly 6–10% of AML patients bear a mutation in IDH1, and mutations in IDH2 are observed in 9–13% of AML patients [36-38]. However, reports on the prognostic potential of IDH1 and IDH2 mutations have been inconsistent. The approval of enasidenib in AML was based on a phase 1/2 study [31]. In this study, patients with IDH2 mutated R/R AML, treated with single-agent enasidenib, demonstrated a response rate of 40.3% [complete remission (CR) rate of 19.3%], and median OS of 9.3 months. Similarly, ivosidenib was approved based on a large phase 1 dose-escalation/dose-expansion trial [32]. In this study, IDH1 mutated R/R AML patients treated with single-agent ivosidenib demonstrated a response rate of 41.6% [composite CR (cCR) rate of 30.4%] and median OS of 8.8 months. As an adverse event of special interest, differentiation syndrome was observed in patients treated with enasidenib (7%) and ivosidenib (3.9%). Reportedly, the IDH-differentiation syndrome is manageable by interrupting medication and treatment with glucocorticoids, with or without hydroxyurea [39, 40].

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 (BCL2) [41]. The approval of this new agent was based on two open-label non-randomized trials of Study M14-358 (NCT02203773) [42] and Study M14-387 (NCT02287233) [43]. In M14-358 (Phase 1 dose-escalation study), venetoclax in combination with azacitidine or decitabine was evaluated in newly diagnosed elderly (≥65 yr), unfit AML patients, with venetoclax doses of 400, 800, or 1,200 mg daily. The median age of enrolled patients was 74 years, and the poor-risk cytogenetics comprised 49%. Promising results were observed with cCRs of 67% (all doses) and 73% (venetoclax 400 mg), the median duration of cCR was 11.3 months and the median OS was 17.5 months. Unexpectedly, the results demonstrated that patients with poor-risk cytogenetics and those at least 75 years of age reported cCR rates of 60% and 65%, respectively. Additionally, M14-387 (NCT02287233) was another notable study that contributed to the accelerated approval of venetoclax. This phase I/II study evaluated the safety and preliminary efficacy of venetoclax (600 mg) with low dose cytarabine (LDAC) in untreated elderly (≥60 yr) or unfit AML patients. The median age of enrolled patients was 74 years and the poor-risk cytogenetics comprised 32%. Nearly one-third of patients (29%) had received prior hypomethylating agents (HMA) treatment. In this difficult-to-treat population, 54% achieved cCR, median OS was 10.1 months, and the median response duration was 8.1 months. Based on the aforementioned trials [42, 43], the recommended venetoclax dose depends on the combination regimen: 400 mg daily in combination with HMA and 600 mg daily in combination with LDAC [7].

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 [46]. 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 [47]. 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, P=0.0004) and a higher CR rate (17.0% vs. 2.3%, P<0.05) in the glasdegib/LDAC combination arm.

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 [48]. 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 [7]. 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 [50].

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.