Acute Myeloid Leukemia (AML) is one of the most frequent acute leukemias in adults and second most prevalent among children and infants. Due to an aging population, increasing use of chemotherapy and exposure to chemical products, the forecasts assume a steady rise in AML cases. Furthermore, it is one of the most aggressive types of cancer. Without treatment AML normally leads to death in just a few months or even weeks. To make matters worse, AML is an extremely heterogenous disease. So finding novel clinically relevant remedies represents a formidable challenge.
Despite intensive research, the treatment options have changed only slightly in the last few decades with cytarabine and anthracyclines as cornerstones. Modifications in dose and schedule and improvement in supportive care have led to a rise in favourable outcomes, but the overall survival rate is still unsatisfactory, especially in elderly, patients with certain mutations and patients with relapsed AML. Therefore, the demand for novel agents is correspondingly high. In the past, many seemingly promising substances could not measure up to their high expectations. At the moment most of the clinical trials with AML are in Phase 1 or 2. So it is good to see that the industry including nearly all global pharmaceutical key players and a large number of niche players has new substances or therapeutic approaches in the pipeline.
According to ClinicalTrials.gov there are currently over 800 ongoing and prospective clinical trials regarding AML worldwide, most of them in North America followed by Europe. Over 80 of them are not recruiting patients yet and more than 750 are currently recruiting patients or are still ongoing. Graphic 1 shows a short overview of the selected substances and their targets.
Graphic 1: Selected substances and targets for AML
The majority of the trials not recruiting patients yet, as of April 2019, are Phase 1 and 2 and roughly half of them are planned to happen in the future. One focus of interest is CPX-351 (Vyxeos; Jazz Pharmaceuticals), a liposomal formulation of daunorubicin and cytarabine in a fixed, synergistic ratio. A novel anti-AML substance is pevonedistat (TAK924/MLN4924; Takeda), a first-in-class NEDD8-activating enzyme inhibitor. Other emphases are the CD33 antibody gemtuzumab ozogamicin (Mylotarg; Pfizer), FLT3 inhibitors like midostaurin (Rydapt; Novartis) and gilteritinib (Xospata; Astellas), the Bcl-2 protein inhibitor venetoclax (Venclexta; AbbVie/Roche) and enasidenib (Idhifa; Agios and Celgene), an inhibitor of mutated IDH2.
The area of ongoing studies is dominated by FLT3 inhibitors (e.g. midostaurin, gilteritinib, quizartinib), venetoclax, gemtuzumab ozogamicin and two DNA hypomethylating agents, azacitidine (Vidaza; Celgene) and decitabine (Dacogen; Otsuka). Other substances against AML under current investigation are nivolumab (Opdivo; Bristol-Myers Squibb), an anti-PD-1 antibody that works as a checkpoint inhibitor, and the IDH1 inhibitor ivosidenib (Tibsovo; Agios). Table 1 provides an overview of the substances and some more in-depth information.
Ongoing studies also encompass combined therapies of e.g. FLT3 inhibitors with hypomethlylating agents to provide additional strategies especially for the treatment of patients with adverse genetics or elder patients.
Taken together, the approval of several new substances in 2017 and 2018 such as midostaurin and gemtuzumab broadened the therapeutic options for different AML-subtypes and patient groups. The multitude of studies underway focusing on different targets may add even more choices to the therapeutic spectrum for this heterogenous disease.