Leukemia (2015) 29, 760–769 © 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15 www.nature.com/leu REVIEW Novel drugs for older patients with acute myeloid leukemia G Montalban-Bravo1,2,3 and G Garcia-Manero1,3 Acute myeloid leukemia (AML) is the second most common form of leukemia and the most frequent cause of leukemia-related deaths in the United States. The incidence of AML increases with advancing age and the prognosis for patients with AML worsens substantially with increasing age. Many older patients are ineligible for intensive treatment and require other therapeutic approaches to optimize clinical outcome. To address this treatment gap, novel agents with varying mechanisms of action targeting different cellular processes are currently in development. Hypomethylating agents (azacitidine, decitabine, SGI-110), histone deacetylase inhibitors (vorinostat, pracinostat, panobinostat), FMS-like tyrosine kinase receptor-3 inhibitors (quizartinib, sorafenib, midostaurin, crenolanib), cytotoxic agents (clofarabine, sapacitabine, vosaroxin), cell cycle inhibitors (barasertib, volasertib, rigosertib) and monoclonal antibodies (gentuzumab ozogamicin, lintuzumab-Ac225) represent some of these promising new treatments. This review provides an overview of novel agents that have either completed or are currently in ongoing phase III trials in patients with previously untreated AML for whom intensive treatment is not an option. Other potential drugs in earlier stages of development will also be addressed in this review. Leukemia (2015) 29, 760–769; doi:10.1038/leu.2014.244 INTRODUCTION still lacking. In the current review we will focus on the novel Acute myeloid leukemia (AML) is a heterogeneous disease agents under development for older patients not eligible for characterized by uncontrolled clonal expansion of hematopoietic intensive treatment. progenitor cells. As the second most common form of leukemia and the most frequent cause of leukemia-related deaths in the NOVEL AGENTS CURRENTLY IN PHASE III DEVELOPMENT FOR United States, predictions for 2014 estimate that there will be up THE TREATMENT OF AML to 18 860 new diagnoses of AML, resulting in ∼ 10 460 related deaths.1 The incidence of AML increases with advancing age, with Table 1 lists the novel agents for which phase III trials are ongoing 54% of all cases diagnosed in adults aged ⩾ 65 years and or have been completed in previously untreated patients with approximately one-third of cases over 75 years of age.2 AML who are older, or for whom intensive therapy is not an 12–14 In the past decades, there have been important advances in the option. elucidation of the different molecular mechanisms involved in 3 AML pathogenesis including mutational events affecting cell Hypomethylating agents cycle regulators and kinases (TP53, NPM1, NRAS/KRAS, FLT3-ITD),4 4 DNA methylation regulates gene expression in normal and tumor transcription factors (RUNX1, CEBPA), epigenetic regulators (TET2, fi 15 5 6 cells through the modi cation of cytosines. Aberrant promoter IDH 1/2, ASXL1, DNMT3A) and microenvironment alterations. DNA methylation in cancer cells has been associated with the Despite this progressively growing understanding of the disease, silencing of tumor suppressor genes.15 Methylation status has there have only been small advances in treatment strategies in been shown to be prognostic in AML and myelodysplastic AML. Molecular data have mostly had an impact in better syndrome (MDS), with hypermethylation exerting a negative determining response to treatment, risk of relapse and overall effect on the outcome of induction treatment.16,17 Hypomethylat- 7 survival (OS), hence allowing us to better determine which ing agents (HMAs) currently used to treat AML and MDS include patients may benefit from allogeneic hematopoietic stem cell azacitidine, a ribonucleoside, and decitabine, a deoxyribonucleo- 8–10 transplantation in first remission. Prognosis of AML remains side. Both are incorporated into DNA as decitabine triphosphate- poor even when allogeneic hematopoietic stem cell transplanta- depleting DNA methyltransferases as cells replicate, resulting in tion in younger patients is possible, with even worse outcomes in hypomethylation of DNA, differentiation and subsequent p53- patients older than 65 years in whom the median survival is independent apoptosis.18,19 Azacitidine can also be incorporated 7.4 months with a 5-year OS of 10%11 and treatment options are into RNA throughout the cell cycle, leading to direct inhibition very limited. Many efforts are being made in order to develop of protein synthesis, reducing cell viability.18 Azacitidine and specific drugs targeting many of the biological hallmarks of the decitabine are approved in the United States for the treatment of disease (Figure 1). Unfortunately, despite the increasing array of MDS; with decitabine also approved in the European Union for new potential therapeutic agents under development, availability patients with newly diagnosed de novo or secondary AML aged of new treatments in the clinical setting outside of clinical trials is 465 years, and for those who are not eligible for standard 1Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA and 2Department of Hematology, University Hospital La Paz, Madrid, Spain. Correspondence: Dr G Garcia-Manero, Department of Leukemia, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA. E-mail: [email protected] 3These authors contributed equally to this work. Received 30 April 2014; revised 30 July 2014; accepted 4 August 2014; accepted article preview online 21 August 2014; advance online publication, 12 September 2014 Novel agents for patients with AML G Montalban-Bravo 761 Figure 1. The mechanisms of action of novel agents currently in development. DNMT, DNA methyltransferase; FLT3, FMS-like tyrosine kinase receptor-3; FT, farnesyltransferase; GO, gemtuzumab ozogamicin; HDAC, histone deacetylase; LDAC, low-dose cytosine arabinoside. induction therapy. In addition, azacitidine and decitabine are time in hospital compared with those treated with CCR.25 recommended low-intensity treatment options for patients with Preliminary results from an ongoing phase III study of azacitidine intermediate-2/high-risk MDS by the National Comprehensive versus CCR in patients with AML aged ⩾ 65 years with 430% Cancer Network (NCCN).20 Because of the achievement of blasts (NCT01074047/AML-001) were recently presented.26 A total cytogenetic responses in both MDS and AML caused by a p53- of 488 patients were randomized to azacitidine (n = 241) or CCR independent clonal suppression,21 DNA methyltransferase inhibi- (n = 247 including best supportive care (BSC), low-dose cytosine tors represent an interesting treatment option in patients with arabinoside (LDAC) and intensive chemotherapy). Median OS, the complex cytogenetics and TP53 mutations in whom response primary end point, was not significantly different between the two rates to conventional chemotherapy remain very low,22 and in arms: 10.4 months in the azacitidine group compared with whom responses to azacitidine appear to be independent of TP53 6.5 months in the CCR arm (stratified hazard ratio (HR) = 0.85 status.23 This is especially the case if toxicities derived from a more (0.69–1.03); P = 0.1009). However, a prespecified sensitivity analysis intensive treatment approach are also taken into account. Both for OS with patients censored at the start of subsequent AML azacitidine and decitabine are category 1 recommendations. The therapy showed a significant benefit with azacitidine: median OS only alternative low-intensity treatment option is enrollment into was 12.1 (9.2–14.2) vs 6.9 (5.1–9.6) months (stratified HR = 0.76 a clinical trial (category 2A recommendation).20 (0.60–0.96), P = 0.019). The 1-year survival was 47% in the azacitidine arm compared with 34% in patients treated with Azacitidine. In a phase III, randomized trial investigating azaciti- CCR. Grade 3–4 anemia, neutropenia, febrile neutropenia and dine versus conventional care regimens (CCRs) in patients with thrombocytopenia were higher in the azacitidine group compared intermediate-2 and high-risk MDS, azacitidine was associated with with BSC, but similar to LDAC and intensive chemotherapy. No a significant OS benefit.24 Approximately one-third of the patients difference in 30- and 60-day mortality was found between the enrolled into this trial were classified as having AML under World different treatment groups. Health Organization (WHO) criteria (20–30% blasts), and an analysis of this older AML subgroup demonstrated a survival Decitabine. In a phase III trial of decitabine versus supportive care benefit of azacitidine compared with CCR.25 Median OS for or LDAC in older (⩾65 years) patients with newly diagnosed AML azacitidine-treated patients was 24.5 months compared with and poor‐ or intermediate-risk cytogenetics, decitabine treatment 16.0 months for conventional care-treated patients (P = 0.005). resulted in improved rates of complete response (CR) and CR Azacitidine was also well tolerated with patients who received without platelet recovery (CRp) compared with treatment choice azacitidine, requiring fewer hospital admissions and spending less (17.8% vs 7.8%; odds ratio, 2.5; 95% confidence interval (CI), © 2015 Macmillan Publishers Limited Leukemia (2015) 760 – 769 Novel agents for patients with AML G Montalban-Bravo 762 Table 1. Novel agents at phase III development