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 Acute myeloid leukemia (AML) is a heterogeneous disease characterized by uncontrolled clonal expansion of hematopoietic progenitor cells. As the second most common form of leukemia and the most frequent cause of leukemia-related deaths in the United States, predictions for 2014 estimate that there will be up to 18 860 new diagnoses of AML, resulting in ∼ 10 460 related deaths.1 The incidence of AML increases with advancing age, with 54% of all cases diagnosed in adults aged ⩾ 65 years and approximately one-third of cases over 75 years of age.2 In the past decades, there have been important advances in the elucidation of the different molecular mechanisms involved in AML pathogenesis including mutational events3 affecting cell cycle regulators and kinases (TP53, NPM1, NRAS/KRAS, FLT3-ITD),4 transcription factors (RUNX1, CEBPA),4 epigenetic regulators (TET2, IDH 1/2, ASXL1, DNMT3A)5 and microenvironment alterations.6 Despite this progressively growing understanding of the disease, there have only been small advances in treatment strategies in AML. Molecular data have mostly had an impact in better determining response to treatment, risk of relapse and overall survival (OS),7 hence allowing us to better determine which patients may benefit from allogeneic hematopoietic stem cell transplantation in first remission.8–10 Prognosis of AML remains poor even when allogeneic hematopoietic stem cell transplantation in younger patients is possible, with even worse outcomes in patients older than 65 years in whom the median survival is 7.4 months with a 5-year OS of 10%11 and treatment options are very limited. Many efforts are being made in order to develop specific drugs targeting many of the biological hallmarks of the disease (Figure 1). Unfortunately, despite the increasing array of new potential therapeutic agents under development, availability of new treatments in the clinical setting outside of clinical trials is

still lacking. In the current review we will focus on the novel agents under development for older patients not eligible for intensive treatment. NOVEL AGENTS CURRENTLY IN PHASE III DEVELOPMENT FOR THE TREATMENT OF AML Table 1 lists the novel agents for which phase III trials are ongoing or have been completed in previously untreated patients with AML who are older, or for whom intensive therapy is not an option.12–14 Hypomethylating agents DNA methylation regulates gene expression in normal and tumor cells through the modification of cytosines.15 Aberrant promoter DNA methylation in cancer cells has been associated with the silencing of tumor suppressor genes.15 Methylation status has been shown to be prognostic in AML and myelodysplastic syndrome (MDS), with hypermethylation exerting a negative effect on the outcome of induction treatment.16,17 Hypomethylating agents (HMAs) currently used to treat AML and MDS include azacitidine, a ribonucleoside, and decitabine, a deoxyribonucleoside. Both are incorporated into DNA as decitabine triphosphatedepleting DNA methyltransferases as cells replicate, resulting in hypomethylation of DNA, differentiation and subsequent p53independent apoptosis.18,19 Azacitidine can also be incorporated into RNA throughout the cell cycle, leading to direct inhibition of protein synthesis, reducing cell viability.18 Azacitidine and decitabine are approved in the United States for the treatment of MDS; with decitabine also approved in the European Union for patients with newly diagnosed de novo or secondary AML aged 465 years, and for those who are not eligible for standard

1 Department 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] 3 These 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

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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 recommended low-intensity treatment options for patients with intermediate-2/high-risk MDS by the National Comprehensive Cancer Network (NCCN).20 Because of the achievement of cytogenetic responses in both MDS and AML caused by a p53independent clonal suppression,21 DNA methyltransferase inhibitors represent an interesting treatment option in patients with complex cytogenetics and TP53 mutations in whom response rates to conventional chemotherapy remain very low,22 and in whom responses to azacitidine appear to be independent of TP53 status.23 This is especially the case if toxicities derived from a more intensive treatment approach are also taken into account. Both azacitidine and decitabine are category 1 recommendations. The only alternative low-intensity treatment option is enrollment into a clinical trial (category 2A recommendation).20 Azacitidine. In a phase III, randomized trial investigating azacitidine versus conventional care regimens (CCRs) in patients with intermediate-2 and high-risk MDS, azacitidine was associated with a significant OS benefit.24 Approximately one-third of the patients enrolled into this trial were classified as having AML under World Health Organization (WHO) criteria (20–30% blasts), and an analysis of this older AML subgroup demonstrated a survival benefit of azacitidine compared with CCR.25 Median OS for azacitidine-treated patients was 24.5 months compared with 16.0 months for conventional care-treated patients (P = 0.005). Azacitidine was also well tolerated with patients who received azacitidine, requiring fewer hospital admissions and spending less © 2015 Macmillan Publishers Limited

time in hospital compared with those treated with CCR.25 Preliminary results from an ongoing phase III study of azacitidine versus CCR in patients with AML aged ⩾ 65 years with 430% blasts (NCT01074047/AML-001) were recently presented.26 A total of 488 patients were randomized to azacitidine (n = 241) or CCR (n = 247 including best supportive care (BSC), low-dose cytosine arabinoside (LDAC) and intensive chemotherapy). Median OS, the primary end point, was not significantly different between the two arms: 10.4 months in the azacitidine group compared with 6.5 months in the CCR arm (stratified hazard ratio (HR) = 0.85 (0.69–1.03); P = 0.1009). However, a prespecified sensitivity analysis for OS with patients censored at the start of subsequent AML therapy showed a significant benefit with azacitidine: median OS was 12.1 (9.2–14.2) vs 6.9 (5.1–9.6) months (stratified HR = 0.76 (0.60–0.96), P = 0.019). The 1-year survival was 47% in the azacitidine arm compared with 34% in patients treated with CCR. Grade 3–4 anemia, neutropenia, febrile neutropenia and thrombocytopenia were higher in the azacitidine group compared with BSC, but similar to LDAC and intensive chemotherapy. No difference in 30- and 60-day mortality was found between the different treatment groups. Decitabine. In a phase III trial of decitabine versus supportive care or LDAC in older (⩾65 years) patients with newly diagnosed AML and poor‐ or intermediate-risk cytogenetics, decitabine treatment resulted in improved rates of complete response (CR) and CR without platelet recovery (CRp) compared with treatment choice (17.8% vs 7.8%; odds ratio, 2.5; 95% confidence interval (CI), Leukemia (2015) 760 – 769

Novel agents for patients with AML G Montalban-Bravo

762 Table 1.

Novel agents at phase III development stage

Novel agent

Regimen (Clinical Trials number)

Patient characteristics

Results (if trial completed)/key outcome measures (if trial is ongoing)

HMAs Azacitidine

Azacitidine versus CCR (NCT01074047)

Older patients with newly diagnosed AML (aged ⩾ 65 years) with 430% blasts (N = 480 planned) Older patients with AML (aged ⩾ 60 years; N = 46 planned)

Primary outcome measure: OS

Decitabine

Cytotoxic LDAC

Clofarabine

Decitabine alone (NCT01633099)

LDAC versus hydroxyurea (BSC) with or without ATRA (NCT00005823)

Clofarabine versus LDAC (NCT00454480)

Sapacitabine Sapacitabine administered in alternating cycles with decitabine versus decitabine alone (NCT01303796)

Cell cycle kinase Barasertib Barasertib alone and in combination with LDAC in comparison with LDAC alone (NCT00952588) Volasertib Volasertib in combination with subcutaneous low-dose cytarabine versus placebo plus low-dose cytarabine (NCT01721876; POLO-AML-2) Other Tipifarnib

CPX-351

GO

Tipifarnib versus BSC (NCT00093990)

CPX-351 versus cytarabine and daunorubicin (7+3 regimen; NCT01696084) GO monotherapy versus standard supportive care (NCT00091234)

Primary outcome measures: CR, OS, EFS, RFS

217 Older patients (aged ⩾ 60 years) with AML or high-risk MDS ineligible for intensive therapy

Improved CR rate of 18% with LDAC compared with 1% for hydroxyurea (P = 0.00006); OS was superior with LDAC compared with hydroxyurea (OR, 0.60; 95% CI, 0.44–0.81; P = 0.0009). ATRA had no effect16 406 Older patients (aged ⩾ 60 years; median age 74 ORR was significantly improved with clofarabine years) with AML or high-risk MDS treatment (38 vs 19% with LDAC; HR = 0.41 (0.26–0.62); P o 0.0001). No improvement in OS with clofarabine treatment17 Patients aged ⩾ 70 years with newly diagnosed AML Primary outcome measures: OS Secondary outcome measures: CR, CRi, PR (all with for whom standard intensive treatment is not duration), hematologic improvement, stable recommended, or the patient has decided not to disease with duration, 1-year survival receive standard intensive treatment (N = 485 planned) Patients aged ⩾ 60 years with newly diagnosed AML Primary outcome measures: CR, CRi (N = 417 planned) Secondary outcome measures: OS, DOR, DFS, time to CR Patients aged ⩾ 65 years with previously untreated Primary outcome measures: CR, CRi Secondary outcome measures: OS, EFR, RFS AML, ineligible for intensive remission induction therapy (N = 660 planned)

457 Patients with previously untreated AML ineligible for intensive chemotherapy (age ⩾ 70 years; median age 76 years) Previously untreated high-risk (secondary) AML (aged 60–75 years; N = 300 planned)

Improved OS end point not met; 18 (8%) patients achieved CR with tipifarnib treatment18 Primary outcome measure: OS

Previously untreated AML ineligible for intensive chemotherapy (aged ⩾ 61 years; N = 279 planned)

Primary outcome measure: OS Secondary outcome measure: rate of complete remission (CR+CRp), DFS, PFS

Abbreviations: AML, acute myeloid leukemia; ATRA, all-trans retinoic acid; BSC, best supportive care; CI, confidence interval; CR, complete remission; CCR, conventional care regimens; CRi, complete response with incomplete platelet recover; CRp, CR without platelet recovery; DFS, disease-free survival; DOR, duration of response; EFS, event-free survival; GO, gemtuzumab ozogamicin; HMA, hypomethylating agent; HR, hazard ratio; LDAC, low-dose cytosine arabinoside; MDS, myelodysplastic syndrome; OR, odds ratio; OS, overall survival; ORR, overall response rate; PR, partial response; RFS, relapsed-free survival.

1.4–4.8; P = 0.001).27 According to the per-protocol specified analysis, there was no significant OS benefit with decitabine treatment despite improved CR/CRp rate (7.7 vs 5.0 months; P = 0.108).27 An unplanned analysis using mature survival data demonstrated that the survival benefit with decitabine treatment was significant (P = 0.037).27 However, in 2012, the Food and Drug Administration (FDA) rejected the supplemental new drug application for decitabine to treat older patients (⩾65 years old) ineligible for induction therapy, based on a review of the data from this trial, as the risk–benefit profile was deemed unfavorable.28 Cytotoxic agents LDAC. Cytarabine administered at a low dose provides a lowintensity treatment option included in the NCCN guidelines.29 The mechanism of action of LDAC is not completely understood, but it is believed to be cytotoxic or to induce apoptosis through induction of differentiation.30,31 A prospective randomized trial of first-line LDAC versus hydroxyurea (BSC), with or without all-trans retinoic acid, was conducted in older patients with AML who were ineligible for intensive therapy and patients with high-risk MDS.12 Treatment with LDAC was associated with improved CR rate and Leukemia (2015) 760 – 769

OS compared with hydroxyurea, with no significant differences in toxicity or supportive care requirements. There was no apparent benefit to treatment with LDAC for patients with adverse cytogenetics. LDAC therapy has henceforth been used as a benchmark to compare new therapies, and as combination with new therapies in older patients with AML.12 Clofarabine. Clofarabine is a purine nucleoside analog prodrug that, when phosphorylated by deoxycytidine kinase, acts to impair the synthesis and repair of DNA. Clofarabine also causes the disruption of mitochondrial membranes resulting in activation of apoptotic pathways.32 A randomized trial has compared singleagent clofarabine with LDAC in 406 untreated older patients with AML or high-risk MDS. Clofarabine treatment resulted in a CR rate of 22% that was significantly superior to the CR rate of 12% achieved with LDAC (HR = 0.47 (0.28–0.79); P = 0.005). The overall response rate (ORR) was significantly improved with clofarabine treatment (38%) compared with LDAC treatment (19%; HR = 0.41 (0.26–0.62); P o 0.0001). However, this did not translate into an improvement in OS with clofarabine treatment, and the authors noted that this was because of superior survival of the patients treated with LDAC who failed to enter CR or who relapsed from CR compared with the clofarabine-treated patients.13 Patients treated © 2015 Macmillan Publishers Limited

Novel agents for patients with AML G Montalban-Bravo

763 with clofarabine reported significantly more grade 3–4 gastrointestinal and hepatic toxicity, and clofarabine treatment was more myelosuppressive, leading to greater supportive care requirements, days in hospital and days on antibiotics.13 Furthermore, in a phase II trial, single‐agent clofarabine was found to be well tolerated and active in older adults (aged ⩾ 60 years) with untreated AML with at least one unfavorable baseline prognostic factor (age ⩾ 70 years; antecedent hematologic disorder; an Eastern Cooperative Oncology Group (ECOG) performance status of 2; or unfavorable cytogenetics).33 Of the 112 patients analyzed from 20 sites in the United States, the median age was 71 years, the ORR was 46%, including 38% CR, and the all-cause 30-day mortality was 9.8%. This resulted in a median OS of 41 weeks (95% CI, 28–53).33 Phase II data are available for clofarabine in combination with LDAC versus clofarabine alone in older patients with AML or MDS, the majority of whom were newly diagnosed with AML.34 Treatment with clofarabine plus LDAC gave superior ORR versus treatment with clofarabine alone (67% vs 31%; P = 0.012); however, the median OS was not significantly improved (11.4 vs 5.8 months; P = 0.10).34 More patients treated with clofarabine plus LDAC experienced prolonged myelosuppression; however, induction mortality (deaths occurring within the first treatment cycle) was not significantly different between the two arms.34 Sapacitabine. Sapacitabine is an oral, nucleoside analog prodrug. Its active major metabolite, CNDAC (1-(2-C-cyano-2-deoxy-β-Darabino-pentofuranosyl) cytosine), interferes with DNA synthesis, causing double-strand breaks and resulting in cell death; CNDAC also causes an arrest of the cell cycle, resulting in apoptosis.35,36 Repair of sapacitabine‐induced double-strand breaks is dependent on the homologous recombination DNA repair pathway that in AML is known to contain defects.37 In a randomized, phase II study investigating three schedules of oral sapacitabine in 105 older patients with AML who were either treatment naive or at first relapse, sapacitabine was well tolerated and associated with 1‐year OS of up to 35%; with median OS ranging from 102 to 213 days for the three schedules. The 30- and 60-day mortality rates were 13% and 26%, respectively. The most common grade 3–4 adverse events (AEs) were anemia, neutropenia, thrombocytopenia, febrile neutropenia and pneumonia. The authors recommended that future investigations should combine sapacitabine with other low‐intensity regimens in older patients with AML.38 In a pooled analysis, 46 older patients with untreated AML who were not candidates for standard induction chemotherapy received sapacitabine and decitabine, administered in alternating cycles in a phase I/II trial, and in the lead‐in phase of a phase III study. The authors indicated that this treatment combination had an acceptable safety profile and evidence of efficacy in this patient group; 17 patients (37%) responded, including 10 CRs, the median OS was 238 days and the 60-day mortality rate was 13%.39 Consequently, sapacitabine is currently being investigated in a phase III, randomized trial in older patients with newly diagnosed AML who are not candidates for standard intensive chemotherapy. The trial compares sapacitabine administered in alternating cycles with decitabine or decitabine alone (SEAMLESS; NCT01303796). Cell cycle kinase inhibitors Barasertib. Barasertib is a prodrug that rapidly undergoes phosphatase-mediated cleavage in serum, and the resulting barasertib-hydroxy-quinazoline pyrazole anilide is a reversible, selective, ATP-competitive inhibitor of Aurora B kinase.40 Aurora B kinase is a serine/threonine kinase involved in the regulation of the spindle assembly checkpoint in mitosis,41 and increased expression of Aurora B kinase has been demonstrated in AML cell lines and patient samples.42,43 Clinical studies of barasertib have © 2015 Macmillan Publishers Limited

reported an acceptable toxicity profile and preliminary efficacy in newly diagnosed, relapsed and patients with advanced AML.44,45 Single-agent barasertib has been investigated in a randomized, phase II study in older patients with newly diagnosed AML who are considered unsuitable for intensive induction therapy.46 Here, barasertib treatment resulted in a significant improvement in the objective complete response rate compared with LDAC (35% vs 12%, equating to a difference of 24% in favor of barasertib (95% CI, 2.7–39.9; P o0.05)).46 Furthermore, the response to barasertib was evident across all cytogenetic risk groups. Although the study was not formally sized to compare survival outcomes, the median OS reported for the barasertib treatment group was 8.2 months compared with 4.5 months for the LDAC treatment group, a difference that was not statistically significant (HR = 0.88; 95% CI, 0.49–1.58; P = 0.663).46 Febrile neutropenia and stomatitis/mucositis occurred with greater frequency in patients who received barasertib; 30-day mortality rates were similar between treatment groups.46 Barasertib is being investigated in combination with LDAC, and results are available from a phase I study of barasertib in combination with LDAC in older patients with newly diagnosed AML who were ineligible for intensive therapy.47 Barasertib plus LDAC demonstrated acceptable tolerability and preliminary antiAML activity, with 10/22 patients responding, giving an ORR of 45% (6 CR, 2 CR with incomplete blood count recovery (CRi) and 2 partial remission (PR)).46 The most common AEs included infection, febrile neutropenia, nausea and diarrhea.46 Barasertib has been investigated in a phase II/III, randomized, open-label, multicenter, two-stage, parallel-group study to assess the efficacy, safety and tolerability with or without LDAC versus LDAC alone in patients aged ⩾ 60 years with newly diagnosed AML (SPARKAML-1; NCT00952588). This study has been reported as completed; however, it is not clear whether the phase III portion was initiated and whether clinical development of barasertib in AML is continuing. Volasertib. Volasertib (BI 6727, an investigational agent) is a selective and potent cell cycle kinase inhibitor that targets pololike kinases (Plks).48 Plks are a family of five highly conserved serine/threonine protein kinases that play key roles in cell division and checkpoint regulation of mitosis.49,50 Preclinical studies have demonstrated that targeting Plk with volasertib leads to the formation of abnormal mitotic spindles, disrupting cell division, and leading to polo arrest and apoptosis.48 Volasertib has shown antitumor efficacy in various animal xenograft models of human cancers, including AML.48 Volasertib is the most advanced Plk inhibitor in clinical development, and is currently being investigated in a phase III study in combination with LDAC in patients with newly diagnosed AML aged ⩾ 65 years who are ineligible for intensive remission induction therapy (POLO-AML-2; NCT01721876). Results are available from a phase II trial of volasertib plus LDAC versus LDAC alone in 87 previously untreated patients with AML considered ineligible for intensive remission induction therapy.51 Patients treated with volasertib plus LDAC had higher rates of CR or CRi compared with patients who received LDAC alone (31.0% vs 13.3%; odds ratio, 2.91; P = 0.052) and the responses achieved with volasertib plus LDAC were seen across genetic groups. Median event-free survival (5.6 vs 2.3 months; P = 0.021) and OS (8.0 vs 5.2 months; P = 0.047) were significantly improved for volasertib plus LDAC versus LDAC alone.51 There was an increased frequency of grade ⩾ 3 nonhematologic AEs with volasertib plus LDAC compared with LDAC, especially for grade 3 gastrointestinal AEs (21% vs 7%), grade 3 febrile neutropenia (38% vs 7%), and grade 3 infections (38% vs 7%). The increase in frequency of AEs seen with the addition of volasertib was expected given its myelosuppressive Leukemia (2015) 760 – 769

Novel agents for patients with AML G Montalban-Bravo

764 mechanism of action; however, there was no difference in early mortality for volasertib plus LDAC versus LDAC.51 Other mechanisms of action Tipifarnib. Tipifarnib is a selective, non-peptidomimetic, orally active inhibitor of the enzyme farnesyltransferase and was the first farnesyltransferase inhibitor to induce CRs in patients with relapsed or refractory AML, as reported by a phase I, doseescalation study.52,53 Subsequently, tipifarnib versus BSC has been investigated in a prospective phase III study in older patients (aged ⩾ 70 years) with newly diagnosed AML not eligible for induction chemotherapy.14 A total of 457 patients were randomized and the median age was 76 years. The study end point of improved OS was not met; the median OS for patients treated with tipifarnib was 107 days (95% CI, 85–129) and was 109 days (95% CI, 93–136) for patients receiving BSC, and there was no statistically significant difference in the 1-year OS rate (14.8% for tipifarnib vs 17.7% for BSC).14 The lack of effect of tipifarnib on OS was consistent across all prognostic groups.14 In the tipifarnib group, 18 (8%) patients achieved a CR; no patients receiving BSC achieved a CR.14 The authors reflected that the lack of OS improvement with tipifarnib may have been because of the low rate of CR achieved that was lower than the rate reported in a phase II study of tipifarnib in older patients with AML.14,53 In this study, tipifarnib treatment was associated with a slight increase in infections, febrile neutropenia and more early deaths compared with BSC; in all patients, cytopenias were the most common grade 3/4 AEs.14 Tipifarnib has also been studied in combination with LDAC in a trial in older patients with AML (NCRI AML 16). Compared with LDAC alone, tipifarnib plus LDAC was found to have no effect on response or survival, and following data review of the first 45 patients, the combination was determined to be ineffective and study closure was recommended.54 CPX-351. The 7+3 regimen of daunorubicin and cytarabine has been the standard induction treatment for AML for the past few decades. Despite numerous studies investigating optimal doses and schedules, few improvements in response rates have been made and no alternative doses and schedules have been approved.55,56 CPX-351 is a combination of cytarabine and daunorubicin, fixed at a molar ratio of 5:1 within a liposomal membrane.55 CPX-351 is designed to increase the magnitude and duration of drug exposure by maintaining drug ratios until they reach the target leukemia cell in order to enhance efficacy.57,58 A phase III, multicenter, randomized trial of CPX-351 versus cytarabine plus daunorubicin in patients aged 60–75 years of age with untreated high-risk AML is ongoing, with an estimated primary completion date of December 2014 (NCT01696084). This phase III trial was initiated based on results from a phase IIb study comparing CPX-351 with cytarabine plus daunorubicin in patients with newly diagnosed AML aged 60–75 years.59 Response rates of 66.7% were achieved with CPX-351 compared with 51.2% achieved with the standard 7+3 regimen. Cytopenia-related AEs were more frequent and median time to count recovery after induction was longer in patients treated with CPX-351 versus the 7+3 regimen. However, CPX-351 was associated with reduced early mortality compared with the 7+3 regimen, with a 60-day mortality rate of 4.7% for CPX-351 compared with 14.6% for the 7+3 regimen.59 A significant improvement in OS was observed in patients with secondary AML treated with CPX-351 compared with the 7+3 regimen (12.1 vs 6.1 months; P = 0.01).60 As such, the results from the phase III study will be important to determine whether the increased response rates with CPX-351 translate into Leukemia (2015) 760 – 769

an improved OS for older, untreated patients with AML and whether this represents a new treatment option. Gemtuzumab ozogamicin. Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, a potent DNA-binding cytotoxic antibiotic.61 The CD33 antigen is typically expressed on the surface of AML cells,62,63 and GO binds to these antigens, facilitating internalization of the toxin that causes DNA strand breaks leading to cell death.64 GO was approved in the United States and Japan for the treatment of patients with relapsed AML aged 460 years who were ineligible for intensive therapy; however, GO was subsequently withdrawn from the United States because of an increased risk of induction deaths with GO in a post-approval trial.65 A phase III trial of GO monotherapy versus standard supportive care in previously untreated patients with AML who are not eligible for intensive chemotherapy is ongoing (NCT00091234). Results are available from phase II studies evaluating two schedules of GO monotherapy in this patient population.66 CR, CRp or PR was achieved in 23% of patients across both treatment schedules; the early mortality rate was 12% for the whole cohort. AEs included nausea/ vomiting, diarrhea, stomatitis and transient elevations of serum transaminases and bilirubin.66 GO has been investigated in combination with LDAC in the LRF AML 14 and NCRI AML16 trials (NCT00005823, NCT00454480). GO plus LDAC demonstrated an improved response rate (CR or CRi) compared with LDAC alone (30 vs 17%; odds ratio, 0.48; 95% CI, 0.32–0.73; P = 0.006); however, the response did not translate into a difference in 12-month OS (27% vs 25%; HR = 0.99; 95% CI, 0.83–1.16; P = 0.9). In addition, there was no difference in 30-day mortality (18% vs 16%). Nausea and vomiting and liver toxicity were significantly increased in the GO plus LDAC treatment group.67 GO has also been investigated in combination with azacitidine in a phase II trial of patients with AML aged ⩾ 60 years. Patients were stratified into good-risk (age 60–69 years and performance status 0–1) and poor-risk (age ⩾ 70 years and performance status 2 or 3) cohorts. In the good-risk cohort, 35 (44%) patients achieved a CR and the median OS was 11 months. In the poor-risk cohort, 19 (35%) patients achieved a CR and median OS was 11 months. The 30-day mortality was 8% and 14% in the good-risk cohort and the poor-risk cohort, respectively.68 OTHER NOVEL AGENTS IN EARLIER STAGES OF DEVELOPMENT Because of the increasing understanding of leukemogenesis, both in de novo and secondary AML, new molecular targets have been discovered and have given rise to the development of a number of new drugs. FLT3 inhibitors FMS-like tyrosine kinase receptor-3 (FLT3) is a tyrosine kinase receptor functionally associated with myeloid differentiation and proliferation that is normally expressed in early bone marrow progenitors.69,70 High levels of expression of FLT3 can be found in up to 70–100% of AML cases.69 Internal tandem duplications in the juxtamembrane domain of the receptor (FLT3-ITD) and point mutations in the activation loop of the kinase domain (D835 being the most frequent) can be found in ∼ 25% and 7% of AML cases, respectively,70 and can induce a proliferative advantage through constitutive activation of the downstream pathways including phosphatidylinositol 3-kinase (PI3K)/AKT, RAS and Janus kinase/ signal transducer and activator of transcription (JAK/STAT).70 This has led to the development of various kinase inhibitors with inhibitory activity against FLT3, with promising results. © 2015 Macmillan Publishers Limited

Novel agents for patients with AML G Montalban-Bravo

Sorafenib. Sorafenib is an oral tyrosine kinase inhibitor with activity against several kinases (including FLT3) currently approved for hepatocellular, renal and thyroid carcinomas.71 A phase I/II trial conducted at the MD Anderson Cancer Center studied the efficacy of sorafenib in combination with standard idarubicin–cytarabine induction in 51 young patients (median age 53 years; range 18–65) with newly diagnosed AML. Results showed a CR rate of 75% (38/51) with 93% response (14/15) among FLT3-ITD-mutated cases.72 A more recent trial conducted at European centers in patients with AML aged 460 years did not show improvement in event-free survival or OS when compared with chemotherapy alone.73 A phase I/II study with sorafenib in combination with LDAC for older patients with newly diagnosed AML or high-risk MDS (NCT00516828) has recently been completed with results pending. Quizartinib (AC220). Quizartinib has recently been shown to be the most potent in vitro FLT3 inhibitor under clinical development.74 A phase II study of quizartinib monotherapy, including a cohort of 134 patients aged 460 years with relapsed or refractory AML, showed 54% and 32% composite CR (CR+CRp +CRi) in FLT3-ITD-mutated and FLT3-wild-type cases, respectively. Median duration of composite CR was 12.7 weeks in patients with FLT3-ITD mutations and 22.1 weeks in patients with wild-type FLT3.75 Main AEs included myelosuppression and QTc prolongation that was mitigated with dose modification.75 In an analysis of 83 patients from this study who were aged ⩾ 70 years with relapsed/refractory AML, composite CR rates were 53% and 43% in FLT3-ITD-mutated and wild-type cases, respectively, with 12/83 (14%) of patients surviving for 41 year.76 A current phase I/II trial with quizartinib in combination with 5-azacitidine or LDAC in younger patients with relapsed/refractory AML and in patients 460 years of age with previously untreated AML (NCT01892371) is ongoing in order to assess the therapeutic potential of this combination. A phase III study of quizartinib monotherapy versus salvage chemotherapy in patients aged ⩾ 18 years with relapsed or refractory FLT3-ITD-positive AML is planned (NCT02039726). Midostaurin (PKC412). Midostaurin is a multitarget tyrosine kinase inhibitor that inhibits FLT3 in the nanomolar range.77 In a proof-of-concept study of midostaurin in patients with AML harboring FLT3-ITD mutations, a ⩾ 50% reduction of bone marrow blasts was seen in 70% of cases.78 These results led to the development of a phase IIb trial in 95 patients with AML who were ineligible to receive standard chemotherapy or with relapsed/ refractory AML, or patients with MDS, with both wild-type or mutated FLT3. This study showed a ⩾ 50% reduction of bone marrow and peripheral blasts in 71% of patients. There were no CRs and one patient with a FLT3-ITD mutation achieved a PR.79 The authors suggest that the clinical activity observed in this study support further investigation of midostaurin in combination with other agents such as chemotherapy, especially in patients with AML with FLT3-ITD mutations.79 A phase III, randomized trial of midostaurin in combination with daunorubicin and cytarabine in frontline treatment for patients with AML aged o 60 years has completed accrual (NCT00651261). Two phase II trials studying the efficacy of midostaurin in combination with azacitidine (NCT01093573) or decitabine (NCT01846624) in older patients with AML are currently ongoing. Crenolanib. Crenolanib is a highly selective and potent FLT3 inhibitor that, unlike the previously described inhibitors, has shown in vitro activity against D835 point mutations affecting the activating loop of the FLT3 receptor.80,81 These encouraging results have led to two phase II trials evaluating its potential in patients with relapsed/refractory AML with FLT3-D835 mutations © 2015 Macmillan Publishers Limited

(NCT01522469 and NCT01657682) in patients aged ⩾ 18 years with an ECOG performance status of 0–2. Hypomethylating agents SGI-110. Despite the efficacy and increasing indications of current HMAs, resistance to or failure of these compounds has arisen as a major limitation to their potential impact on the clinic. As a result of this, investigational efforts into the understanding of the mechanism of resistance and the development of new therapies bypassing this phenomenon are underway.82,83 SGI-110, a new DNA methyltransferase inhibitor with hypomethylating activity, is a dinucleotide of decitabine and deoxyguanosine that increases in vivo exposure of decitabine by protecting it from deamination.84 Because of the potential resistance to deamination by cytidine deaminase, SGI-110 may be a possible treatment in patients with failure to prior azacitidine or decitabine treatment. As a result of the lower toxicity profile of HMAs compared with conventional chemotherapy, SGI-110 could be a promising treatment in older, unfit patients with AML. A phase I/II trial in patients with MDS or AML in the frontline setting or at relapse after chemotherapy or previous HMAs is currently ongoing (NCT01261312), with initial data having been presented at the last American Society of Hematology (ASH) Annual meeting, with promising results.84 Histone deacetylase inhibitors Vorinostat. Vorinostat is a histone deacetylase inhibitor that has been shown to promote cell cycle arrest, growth inhibition, apoptosis and differentiation of cells from AML and MDS patients.85 An initial phase II study in 37 patients with relapsed or untreated AML, who were not candidates for chemotherapy, showed minimal activity in monotherapy.86 This led to several combination trials. In the setting of older adults with untreated AML, a phase II study of vorinostat in combination with GO was recently completed.87 From the total of 31 patients included, those aged ⩾ 70 years with an ECOG performance status of 2–3 had a CR+CRp rate of 10%. Among patients aged 60–69 years with an ECOG performance status of 0–3 and patients aged ⩾ 70 years with an ECOG performance status of 0–1, the CR+CRp rate was 46.2% in those with normal or favorable cytogenetics, and 0% in those with other cytogenetics.87 A trial of vorinostat in combination with azacitidine to assess its possible efficacy in patients with newly diagnosed AML and high-risk MDS who are not eligible for intensive treatments is currently ongoing at the MD Anderson Cancer Center (NCT00948064). Panobinostat. Another histone deacetylase inhibitor in development, panobinostat, seems to potentiate the antileukemic effect of fludarabine88 and sensitizes leukemic blasts to cytarabine and daunorubicin.89 Several trials in young patients and in fit older patients in combination with induction chemotherapy are ongoing. A phase I/II study of panobinostat plus decitabine in patients aged 460 years with newly diagnosed AML and MDS is currently evaluating the efficacy and safety of this combination in this setting (NCT00691938). Oral panobinostat is also under investigation in a phase I/II study in combination with azacitidine in adult patients with AML or MDS (NCT00946647). Pracinostat. Pracinostat, an oral histone deacetylase inhibitor with single-agent activity in MDS and AML, showed promising results in a phase II study in combination with azacitidine in nine patients with high-risk MDS.90 The ORR, defined as CR+CRi+PR, was 89% with 78% CR+CRi, and a promising complete cytogenetic response rate of 56% was observed. Because of these encouraging results, several studies are evaluating the potential of this Leukemia (2015) 760 – 769

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766 combination in different scenarios including frail older patients with newly diagnosed AML (NCT01912274). Agents targeting leukemic stem cells As in other types of cancer, there is increasing evidence of the importance of leukemic stem cells in the evolution and development of leukemia. Several altered pathways (such as Wnt/βcatenin, NOTCH, Hedgehog, PI3K/AKT, JAK/STAT and nuclear factor (NF)-κB)91 and genes (EVI1 and EZH2)92,93 are known to be important regulators of both normal and leukemic stem cell renewal and expansion. Several agents are in development to specifically target these pathways to improve responses with standard treatments. Vismodegib. Vismodegib is a Hedgehog inhibitor approved by the FDA for the treatment of advanced basal cell carcinoma.94 Because of its potential to target the leukemic stem cells, it is currently being evaluated in combination with LDAC in patients with relapsed/refractory AML or high-risk MDS (NCT01880437). PF-04449913. PF-04449913 is another Hedgehog inhibitor currently being tested in different solid tumors as a monotherapy. An ongoing trial is evaluating its potential in combination with chemotherapy in patients with AML and MDS (NCT01546038). This trial will analyze the efficacy of its combination with LDAC or decitabine for unfit patients, and conventional cytarabine plus daunorubicin (3+7) chemotherapy for patients eligible for intensive treatment. Other agents Omacetaxine. Omacetaxine mepesuccinate is a purified semisynthetic derivative of homoharringtonine, a natural plant alkaloid, that has been approved by the FDA for the treatment of chronic and accelerated chronic myeloid leukemia after failure of more than two tyrosine kinase inhibitors.95,96 A recent phase III trial in young patients with newly diagnosed AML showed promising results in combination with standard induction chemotherapy with an improved rate of CR (73% vs 61%; P = 0.01) and event-free survival (35.4% vs 23.1%; P o0.001) in the group receiving homoharringtonine compared with chemotherapy alone.97 An ongoing phase II trial is evaluating the possible efficacy and safety profile of omacetaxine in combination with LDAC in older patients with newly diagnosed AML or highrisk MDS (NCT01272245). Vosaroxin. Vosaroxin, previously known as vorexolin, is a DNAintercalating agent and topoisomerase II inhibitor with significant advantages over anthracyclines, including evasion of p53 and P-glycoprotein resistance pathways, as well as absence of generation of reactive oxygen species.98 A phase Ib trial of vosaroxin in 73 patients with a median age of 65 years and relapsed or refractory AML showed an acceptable safety profile (including gastrointestinal symptoms and febrile neutropenia), linear pharmacokinetics and encouraging clinical activity.99 Because of these apparent advantages and safety profile, a phase II study in combination with decitabine in patients 460 years of age with newly diagnosed AML and high-risk MDS is currently ongoing (NCT01893320). Rigosertib (ON01910). Rigosertib is a multikinase inhibitor with activity against PI3K/AKT and Plks that has shown activity in different hematologic and nonhematologic malignancies.100 The exact mechanism of action of rigosertib has not been determined; previous studies have demonstrated a direct effect of rigosertib on Plk1 but this could not be confirmed in subsequent studies.100,101 Recent in vitro assays in MDS and AML patient CD34+ cells with trisomy 8 showed activity through inhibition of cyclin D1, with 3/8 Leukemia (2015) 760 – 769

treated patients achieving a 450% reduction in bone marrow blasts and 3/8 showing a hematological improvement.102 In a phase I trial evaluating the activity of rigosertib in 13 patients with MDS who were unresponsive to azacitidine or decitabine, 2/13 patients achieved hematological improvement, with 4/13 patients achieving a marrow CR.103 Trials evaluating the activity of this drug in MDS and AML, both as intravenous monotherapy (NCT01167166) and in an oral formation of rigosertib, in combination with azacitidine (NCT01926587), are currently ongoing because of its potential, especially after failure to HMAs. A phase III trial of intravenous rigosertib versus BSC in patients with MDS with excess blast who are relapsed or refractory to azacitidine or decitabine is ongoing (NCT01241500). Lintuzumab-Ac225 (Actimab). Lintuzumab is a humanized monoclonal antibody that, like GO, is directed against the CD33 antigen expressed in malignant myeloid cells. In a phase I dose-escalation trial evaluating its potential in 17 patients with AML, 4 CRs and 2 PR were achieved in 17 evaluable patients. Drug was administered intravenously at a dose range of 1.5–8 mg/kg/weekly in an outpatient setting.104 A randomized phase IIb study comparing LDAC versus lintuzumab+LDAC in older patients (median age of 70 years) with untreated AML failed to show improved survival (4.7 months in combination arm vs 5.1 months with LDAC alone), with patients in the combination arm presenting a higher rate of infusion-related reactions (51% vs 7%).105 Because of these results, further trials were abandoned in 2010. In the past years, several efforts to reawaken the development of this drug have been made. Combination of lintuzumab with bistmuth-213 to produce an immunoconjugate with increased antileukemic potency led to the development of a phase I/II trial in 31 patients with either newly diagnosed or relapsed/refractory AML with a median age of 67 years.106 In this study, patients were treated with cytarabine 200 mg/m2/daily for 5 days followed by (213)Bi-lintuzumab). Frequent infusion-related reactions with grade 3–4 liver function abnormalities were the most frequent AEs. Significant reductions in marrow blasts were seen at all dose levels with a median response duration of 6 months. Conjugation of lintuzumab with Actinium-225 has also been developed. Preliminary results from a phase I trial (NCT01756677) of this conjugate in combination with LDAC in seven older patients with untreated AML107 were presented last year at ASH. Bone marrow blast reductions were observed in 67% (4/6) of patients after cycle 1. However, no CRs were achieved and doselimiting toxicity in the form of grade 4 thrombocytopenia was seen in one patient. Median time to progression was 2.5 months. This study is currently recruiting and further results will be available in the next year. SGN-CD33A. SGN-CD33A is another drug conjugate combining a humanized anti-CD33 antibody with engineered cysteines conjugated to a highly potent synthetic DNA crosslinking pyrrolobenzodiazepine dimer.108 In preclinical testing, this compound showed to be more potent than GO against a panel of AML cell lines.108 SGN-CD33A even showed antileukemic effects in multidrug-resistant models. A phase I trial is currently ongoing to evaluate its safety in patients with AML (NCT01902329). CONCLUSIONS Despite the increasing knowledge in AML pathogenesis and pathways involved in its initiation and progression, this has still not been translated in available therapies in the clinical setting. Regardless of this fact, a number of novel agents with varying mechanisms of action are in development for the treatment of AML, some of which appear promising in the context of older, frail patients. The majority of novel agents are able to produce improved rates of CRs, but these rarely translate into improved OS © 2015 Macmillan Publishers Limited

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767 in phase III studies. Only azacitidine (although in patients with 20–30% blasts) and LDAC have significantly improved OS compared with conventional or supportive care regimens, and these agents remain category 2A recommendations in the NCCN guidelines. Results from the ongoing phase III trials of novel agents are eagerly awaited to see whether they can improve OS. With the array of new compounds in earlier phases of development, we may be able to see a significant change in the therapeutic armamentarium of patients with AML in the next years. However, identification of subsets of patients who can specifically benefit from inhibition of a specific pathway is still pending with exceptions such as FLT3 inhibitors. Disease heterogeneity and clonal evolution remains a challenge in achieving this goal. If we desire to improve the efficacy of the novel agents under development, we will have to better identify the ideal combination of therapies for each specific patient to attain optimal responses with minimal toxicities. The treatment of AML is facing a much-needed expansion with potential to revolutionize the concept of disease management in the following years, especially in older patients in whom available effective therapies are lacking. CONFLICT OF INTEREST The authors declare no conflict of interest.

ACKNOWLEDGEMENTS We are fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version of this review that reflects the authors’ interpretation and conclusions. Medical writing assistance during the preparation of this review, supported financially by Boehringer Ingelheim Pharmaceuticals, Inc., was provided by Helen Wilkinson of GeoMed, part of KnowledgePoint360, an Ashfield Company. Boehringer Ingelheim was given the opportunity to review for factual accuracy only. This work was supported in part by the MD Anderson Cancer Center Leukemia Support Grant (CCSG) CA016672, philanthropic support from the MD Anderson Cancer Center Moon Shot Program and the Fundacion Ramon Areces.

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