Closing in on targeted therapy for acute myeloid leukaemia

Abstract

On Nov 28, 2018, the US Food and Drug Administration (FDA) approved the targeted agent, gilteritinib, as treatment for adult patients with relapsed or refractory acute myeloid leukaemia (AML) with a FLT3 mutation. 3 months later, the Japanese Ministry of Health, Labour, and Welfare allowed use of the same treatment in the same setting. Both decisions were based on the interim results from the currently unpublished phase 3 ADMIRAL trial. According to the US FDA, these findings showed that 21% of 138 patients achieved either complete remission or complete remission with partial haematological recovery, and that 31% of 106 patients who were transfusion-dependent before gilteritinib treatment became transfusion-free for a minimum time period of 56 days. With little change in the therapeutic landscape for the past three decades, these findings follow the recent promising phase 2 results of another small-molecule kinase inhibitor, midostaurin, used as monotherapy, and bring hope to patients who generally have a very poor prognosis. AML is a genetically heterogeneous disease, for which long-term survival rates can vary substantially, from a staggering 35–40% in adult patients younger than 60 years of age, to as low as 5–15% in older patients. Current conventional treatment options for patients remain heavily reliant on intensive chemotherapy-based induction and consolidation therapy, despite considerable research and clinical effort to develop therapeutic alternatives; these include targeting well characterised molecular genetic lesions, such as mutations in the receptor tyrosine kinase FLT3. There are two major classes of FLT3 mutations: point mutations in the tyrosine kinase domain and internal tandem duplications (ITDs), both leading to constitutive activation of FLT3 kinase activity and the downstream signalling pathways supporting the myeloproliferative phenotype. These mutations are present in up to 30% of patients with AML and are often associated with an aggressive disease course. Indeed, the path towards successful therapeutic development for these patients has been challenging. Early clinical studies using multitargeted tyrosine kinase inhibitors, sunitinib and lestaurtinib, either as a monotherapy, or in combination with chemotherapy-based regimens, or epigenetic therapy, yielded unimpressive and variable results. By contrast, following the initial promising findings for midostaurin, several clinical trials have further tested the efficacy of this drug in different settings. This led to the RATIFY phase 3 trial, which showed that midostaurin, combined with chemotherapy, significantly prolonged survival in patients with AML with a FLT3 mutation. This finding in turn led to the US FDA approval on Apr 28, 2017, of this combination therapy for newly diagnosed patients with AML with a FLT3 mutation. As the first targeted therapy approved for this patient population in the USA, the success of midostaurin represents a milestone in the treatment of AML. It is worth noting, however, that the approval was limited to the population of newly diagnosed patients, who tend to have a better prognosis than relapsed or refractory patients. 4 months after the FDA approval for midostaurin, a phase 1–2 trial reported that a second generation FLT3 inhibitor, gilteritinib, showed a favourable safety profile and consistent FLT3 inhibition in patients with relapsed or refractory AML, which paved the way for the phase 3 trial and led to the approval of the first FLT3-targeting therapy as a monotherapy in this patient population in the USA. The success of midostaurin and gilteritinib is encouraging, especially given the disappointing results that were seen with the earlier agents, and more second-generation FLT3 inhibitors are being tested in clinical studies. For instance, quizartinib as a single agent has showed higher efficacy (measured by composite complete remission) in FLT3-ITD-positive compared with FLT3-ITD-negative patients, and was generally tolerated in the setting of relapsed or refractory AML, as reported in a phase 2 study in May, 2018. Phase 3 studies are now underway. Furthermore, a pan-selective FLT3 inhibitor, crenolanib, is being tested in a phase 3 trial in a head-to-head comparison to midostaurin, whereas another phase 3 trial is comparing crenolanib, with or without chemotherapy, in the relapsed or refractory setting. The results of these studies are eagerly awaited, and will inform as to how far progress in managing AML through a targeted approach will improve the current dismal outlook for these patients. Until then, several questions remain, not least the issue of access and cost of these promising new agents. These considerations must be addressed if more than a handful of patients are to benefit. For more on the RATIFY phase 3 trial see https://www.nejm.org/doi/full/10.1056/NEJMoa1614359?query=recirc_curatedRelated_article For more on the RATIFY phase 3 trial see https://www.nejm.org/doi/full/10.1056/NEJMoa1614359?query=recirc_curatedRelated_article