Novel Drugs for Older Patients with Acute Myeloid Leukemia

Home , Daunorubicin, Decitabine, Hypomethylating agent, Lintuzumab, Pracinostat, Sapacitabine

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),

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 Primary outcome measure: OS ⩾ 65 years) with 430% blasts (N = 480 planned) Decitabine Decitabine alone (NCT01633099) Older patients with AML (aged ⩾ 60 years; N = 46 Primary outcome measures: CR, OS, EFS, RFS planned)

Cytotoxic LDAC LDAC versus hydroxyurea (BSC) with or 217 Older patients (aged ⩾ 60 years) with AML or Improved CR rate of 18% with LDAC compared without ATRA (NCT00005823) high-risk MDS ineligible for intensive therapy 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 Clofarabine Clofarabine versus LDAC (NCT00454480) 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); Po0.0001). No improvement in OS with clofarabine treatment17 Sapacitabine Sapacitabine administered in alternating Patients aged ⩾ 70 years with newly diagnosed AML Primary outcome measures: OS cycles with decitabine versus decitabine for whom standard intensive treatment is not Secondary outcome measures: CR, CRi, PR (all with alone (NCT01303796) recommended, or the patient has decided not to duration), hematologic improvement, stable receive standard intensive treatment (N = 485 disease with duration, 1-year survival planned)

Cell cycle kinase Barasertib Barasertib alone and in combination with Patients aged ⩾ 60 years with newly diagnosed AML Primary outcome measures: CR, CRi LDAC in comparison with LDAC alone (N = 417 planned) Secondary outcome measures: OS, DOR, DFS, time (NCT00952588) to CR Volasertib Volasertib in combination with Patients aged ⩾ 65 years with previously untreated Primary outcome measures: CR, CRi subcutaneous low-dose cytarabine versus AML, ineligible for intensive remission induction Secondary outcome measures: OS, EFR, RFS placebo plus low-dose cytarabine therapy (N = 660 planned) (NCT01721876; POLO-AML-2)

Other Tipifarnib Tipifarnib versus BSC (NCT00093990) 457 Patients with previously untreated AML Improved OS end point not met; ineligible for intensive chemotherapy (age ⩾ 70 18 (8%) patients achieved CR with tipifarnib years; median age 76 years) treatment18 CPX-351 CPX-351 versus cytarabine and Previously untreated high-risk (secondary) AML Primary outcome measure: OS daunorubicin (7+3 regimen; (aged 60–75 years; N = 300 planned) NCT01696084) GO GO monotherapy versus standard Previously untreated AML ineligible for intensive Primary outcome measure: OS supportive care (NCT00091234) chemotherapy (aged ⩾ 61 years; N = 279 planned) 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 OS compared with hydroxyurea, with no significant differences in analysis, there was no significant OS benefit with decitabine toxicity or supportive care requirements. There was no apparent treatment despite improved CR/CRp rate (7.7 vs 5.0 months; benefit to treatment with LDAC for patients with adverse P = 0.108).27 An unplanned analysis using mature survival data cytogenetics. LDAC therapy has henceforth been used as a demonstrated that the survival benefit with decitabine treatment benchmark to compare new therapies, and as combination with 12 was significant (P = 0.037).27 However, in 2012, the Food and Drug new therapies in older patients with AML. Administration (FDA) rejected the supplemental new drug application for decitabine to treat older patients (⩾65 years old) Clofarabine. Clofarabine is a purine nucleoside analog prodrug ineligible for induction therapy, based on a review of the data that, when phosphorylated by deoxycytidine kinase, acts to impair from this trial, as the risk–benefit profile was deemed the synthesis and repair of DNA. Clofarabine also causes the unfavorable.28 disruption of mitochondrial membranes resulting in activation of apoptotic pathways.32 A randomized trial has compared single- agent clofarabine with LDAC in 406 untreated older patients with Cytotoxic agents AML or high-risk MDS. Clofarabine treatment resulted in a CR rate LDAC. Cytarabine administered at a low dose provides a low- of 22% that was significantly superior to the CR rate of 12% 29 intensity treatment option included in the NCCN guidelines. The achieved with LDAC (HR = 0.47 (0.28–0.79); P = 0.005). The overall mechanism of action of LDAC is not completely understood, but it response rate (ORR) was significantly improved with clofarabine is believed to be cytotoxic or to induce apoptosis through treatment (38%) compared with LDAC treatment (19%; HR = 0.41 induction of differentiation.30,31 A prospective randomized trial of (0.26–0.62); Po0.0001). However, this did not translate into an first-line LDAC versus hydroxyurea (BSC), with or without all-trans improvement in OS with clofarabine treatment, and the authors retinoic acid, was conducted in older patients with AML who were noted that this was because of superior survival of the patients ineligible for intensive therapy and patients with high-risk MDS.12 treated with LDAC who failed to enter CR or who relapsed from CR Treatment with LDAC was associated with improved CR rate and compared with the clofarabine-treated patients.13 Patients treated

Leukemia (2015) 760 – 769 © 2015 Macmillan Publishers Limited Novel agents for patients with AML G Montalban-Bravo 763 with clofarabine reported significantly more grade 3–4 gastro- reported an acceptable toxicity profile and preliminary efficacy in intestinal and hepatic toxicity, and clofarabine treatment was newly diagnosed, relapsed and patients with advanced AML.44,45 more myelosuppressive, leading to greater supportive care Single-agent barasertib has been investigated in a randomized, requirements, days in hospital and days on antibiotics.13 phase II study in older patients with newly diagnosed AML who Furthermore, in a phase II trial, single‐agent clofarabine was are considered unsuitable for intensive induction therapy.46 Here, found to be well tolerated and active in older adults (aged ⩾ 60 barasertib treatment resulted in a significant improvement in the years) with untreated AML with at least one unfavorable baseline objective complete response rate compared with LDAC (35% vs ⩾ prognostic factor (age 70 years; antecedent hematologic 12%, equating to a difference of 24% in favor of barasertib (95% disorder; an Eastern Cooperative Oncology Group (ECOG) – o 46 33 CI, 2.7 39.9; P 0.05)). Furthermore, the response to barasertib performance status of 2; or unfavorable cytogenetics). Of the was evident across all cytogenetic risk groups. Although the study 112 patients analyzed from 20 sites in the United States, the was not formally sized to compare survival outcomes, the median median age was 71 years, the ORR was 46%, including 38% CR, OS reported for the barasertib treatment group was 8.2 months and the all-cause 30-day mortality was 9.8%. This resulted in a compared with 4.5 months for the LDAC treatment group, a median OS of 41 weeks (95% CI, 28–53).33 difference that was not statistically significant (HR = 0.88; 95% CI, Phase II data are available for clofarabine in combination with – 46 LDAC versus clofarabine alone in older patients with AML or MDS, 0.49 1.58; P = 0.663). Febrile neutropenia and stomatitis/muco- the majority of whom were newly diagnosed with AML.34 sitis occurred with greater frequency in patients who received barasertib; 30-day mortality rates were similar between treatment Treatment with clofarabine plus LDAC gave superior ORR versus 46 treatment with clofarabine alone (67% vs 31%; P = 0.012); groups. Barasertib is being investigated in combination with however, the median OS was not significantly improved (11.4 vs LDAC, and results are available from a phase I study of barasertib 5.8 months; P = 0.10).34 More patients treated with clofarabine in combination with LDAC in older patients with newly diagnosed 47 plus LDAC experienced prolonged myelosuppression; however, AML who were ineligible for intensive therapy. Barasertib plus induction mortality (deaths occurring within the first treatment LDAC demonstrated acceptable tolerability and preliminary anti- cycle) was not significantly different between the two arms.34 AML activity, with 10/22 patients responding, giving an ORR of 45% (6 CR, 2 CR with incomplete blood count recovery (CRi) and 2 Sapacitabine. Sapacitabine is an oral, nucleoside analog prodrug. partial remission (PR)).46 The most common AEs included Its active major metabolite, CNDAC (1-(2-C-cyano-2-deoxy-β-D- infection, febrile neutropenia, nausea and diarrhea.46 Barasertib arabino-pentofuranosyl) cytosine), interferes with DNA synthesis, has been investigated in a phase II/III, randomized, open-label, causing double-strand breaks and resulting in cell death; CNDAC multicenter, two-stage, parallel-group study to assess the efficacy, 35,36 also causes an arrest of the cell cycle, resulting in apoptosis. safety and tolerability with or without LDAC versus LDAC alone in Repair of sapacitabine‐induced double-strand breaks is dependent patients aged ⩾ 60 years with newly diagnosed AML (SPARK- on the homologous recombination DNA repair pathway that in AML-1; NCT00952588). This study has been reported as com- 37 AML is known to contain defects. In a randomized, phase II study pleted; however, it is not clear whether the phase III portion was investigating three schedules of oral sapacitabine in 105 older initiated and whether clinical development of barasertib in AML is fi patients with AML who were either treatment naive or at rst continuing. relapse, sapacitabine was well tolerated and associated with ‐ 1 year OS of up to 35%; with median OS ranging from 102 to Volasertib. Volasertib (BI 6727, an investigational agent) is a 213 days for the three schedules. The 30- and 60-day mortality selective and potent cell cycle kinase inhibitor that targets polo- rates were 13% and 26%, respectively. The most common grade 48 fi – like kinases (Plks). Plks are a family of ve highly conserved 3 4 adverse events (AEs) were anemia, neutropenia, thrombo- serine/threonine protein kinases that play key roles in cell division cytopenia, febrile neutropenia and pneumonia. The authors 49,50 and checkpoint regulation of mitosis. Preclinical studies have recommended that future investigations should combine sapaci- demonstrated that targeting Plk with volasertib leads to the tabine with other low‐intensity regimens in older patients with 38 formation of abnormal mitotic spindles, disrupting cell division, AML. In a pooled analysis, 46 older patients with untreated AML 48 who were not candidates for standard induction chemotherapy and leading to polo arrest and apoptosis. Volasertib has shown antitumor efficacy in various animal xenograft models of human received sapacitabine and decitabine, administered in alternating 48 cycles in a phase I/II trial, and in the lead‐in phase of a phase III cancers, including AML. Volasertib is the most advanced Plk study. The authors indicated that this treatment combination had inhibitor in clinical development, and is currently being investi- an acceptable safety profile and evidence of efficacy in this patient gated in a phase III study in combination with LDAC in patients group; 17 patients (37%) responded, including 10 CRs, the median with newly diagnosed AML aged ⩾ 65 years who are ineligible OS was 238 days and the 60-day mortality rate was 13%.39 for intensive remission induction therapy (POLO-AML-2; Consequently, sapacitabine is currently being investigated in a NCT01721876). Results are available from a phase II trial of phase III, randomized trial in older patients with newly diagnosed volasertib plus LDAC versus LDAC alone in 87 previously untreated AML who are not candidates for standard intensive chemo- patients with AML considered ineligible for intensive remission therapy. The trial compares sapacitabine administered in induction therapy.51 Patients treated with volasertib plus LDAC alternating cycles with decitabine or decitabine alone (SEAMLESS; had higher rates of CR or CRi compared with patients who NCT01303796). 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 Cell cycle kinase inhibitors across genetic groups. Median event-free survival (5.6 vs Barasertib. Barasertib is a prodrug that rapidly undergoes 2.3 months; P = 0.021) and OS (8.0 vs 5.2 months; P = 0.047) were phosphatase-mediated cleavage in serum, and the resulting significantly improved for volasertib plus LDAC versus LDAC 51 barasertib-hydroxy-quinazoline pyrazole anilide is a reversible, alone. There was an increased frequency of grade ⩾ 3 selective, ATP-competitive inhibitor of Aurora B kinase.40 Aurora B nonhematologic AEs with volasertib plus LDAC compared with kinase is a serine/threonine kinase involved in the regulation of LDAC, especially for grade 3 gastrointestinal AEs (21% vs 7%), the spindle assembly checkpoint in mitosis,41 and increased grade 3 febrile neutropenia (38% vs 7%), and grade 3 infections expression of Aurora B kinase has been demonstrated in AML cell (38% vs 7%). The increase in frequency of AEs seen with the lines and patient samples.42,43 Clinical studies of barasertib have addition of volasertib was expected given its myelosuppressive

© 2015 Macmillan Publishers Limited Leukemia (2015) 760 – 769 Novel agents for patients with AML G Montalban-Bravo 764 mechanism of action; however, there was no difference in early an improved OS for older, untreated patients with AML and mortality for volasertib plus LDAC versus LDAC.51 whether this represents a new treatment option.

Gemtuzumab ozogamicin. Gemtuzumab ozogamicin (GO) is a Other mechanisms of action humanized anti-CD33 monoclonal antibody conjugated to cali- Tipifarnib. Tipifarnib is a selective, non-peptidomimetic, orally 61 fi cheamicin, a potent DNA-binding cytotoxic antibiotic. The CD33 active inhibitor of the enzyme farnesyltransferase and was the rst antigen is typically expressed on the surface of AML cells,62,63 and farnesyltransferase inhibitor to induce CRs in patients with GO binds to these antigens, facilitating internalization of the toxin relapsed or refractory AML, as reported by a phase I, dose- 64 52,53 that causes DNA strand breaks leading to cell death. GO was escalation study. Subsequently, tipifarnib versus BSC has been approved in the United States and Japan for the treatment of investigated in a prospective phase III study in older patients patients with relapsed AML aged 460 years who were ineligible (aged ⩾ 70 years) with newly diagnosed AML not eligible for 14 for intensive therapy; however, GO was subsequently withdrawn induction chemotherapy. A total of 457 patients were rando- from the United States because of an increased risk of induction mized and the median age was 76 years. The study end point of deaths with GO in a post-approval trial.65 A phase III trial of GO improved OS was not met; the median OS for patients treated monotherapy versus standard supportive care in previously – with tipifarnib was 107 days (95% CI, 85 129) and was 109 days untreated patients with AML who are not eligible for intensive – (95% CI, 93 136) for patients receiving BSC, and there was no chemotherapy is ongoing (NCT00091234). Results are available statistically significant difference in the 1-year OS rate (14.8% for 14 from phase II studies evaluating two schedules of GO mono- tipifarnib vs 17.7% for BSC). The lack of effect of tipifarnib on OS therapy in this patient population.66 CR, CRp or PR was achieved in 14 was consistent across all prognostic groups. In the tipifarnib 23% of patients across both treatment schedules; the early group, 18 (8%) patients achieved a CR; no patients receiving BSC mortality rate was 12% for the whole cohort. AEs included nausea/ 14 achieved a CR. The authors reflected that the lack of OS vomiting, diarrhea, stomatitis and transient elevations of serum improvement with tipifarnib may have been because of the low transaminases and bilirubin.66 rate of CR achieved that was lower than the rate reported in a GO has been investigated in combination with LDAC in the LRF phase II study of tipifarnib in older patients with AML.14,53 In this AML 14 and NCRI AML16 trials (NCT00005823, NCT00454480). study, tipifarnib treatment was associated with a slight increase in GO plus LDAC demonstrated an improved response rate infections, febrile neutropenia and more early deaths compared (CR or CRi) compared with LDAC alone (30 vs 17%; odds ratio, with BSC; in all patients, cytopenias were the most common grade 0.48; 95% CI, 0.32–0.73; P = 0.006); however, the response did not 3/4 AEs.14 translate into a difference in 12-month OS (27% vs 25%; HR = 0.99; Tipifarnib has also been studied in combination with LDAC in a 95% CI, 0.83–1.16; P = 0.9). In addition, there was no difference in trial in older patients with AML (NCRI AML 16). Compared with 30-day mortality (18% vs 16%). Nausea and vomiting and liver LDAC alone, tipifarnib plus LDAC was found to have no effect on toxicity were significantly increased in the GO plus LDAC response or survival, and following data review of the first 45 treatment group.67 patients, the combination was determined to be ineffective and GO has also been investigated in combination with azacitidine study closure was recommended.54 in a phase II trial of patients with AML aged ⩾ 60 years. Patients were stratified into good-risk (age 60–69 years and performance CPX-351. The 7+3 regimen of daunorubicin and cytarabine has status 0–1) and poor-risk (age ⩾ 70 years and performance status 2 been the standard induction treatment for AML for the past few or 3) cohorts. In the good-risk cohort, 35 (44%) patients achieved a decades. Despite numerous studies investigating optimal doses CR and the median OS was 11 months. In the poor-risk cohort, 19 and schedules, few improvements in response rates have been (35%) patients achieved a CR and median OS was 11 months. The made and no alternative doses and schedules have been 30-day mortality was 8% and 14% in the good-risk cohort and the approved.55,56 CPX-351 is a combination of cytarabine and poor-risk cohort, respectively.68 daunorubicin, fixed at a molar ratio of 5:1 within a liposomal membrane.55 CPX-351 is designed to increase the magnitude and OTHER NOVEL AGENTS IN EARLIER STAGES OF DEVELOPMENT duration of drug exposure by maintaining drug ratios until they reach the target leukemia cell in order to enhance efficacy.57,58 Because of the increasing understanding of leukemogenesis, both A phase III, multicenter, randomized trial of CPX-351 versus in de novo and secondary AML, new molecular targets have been cytarabine plus daunorubicin in patients aged 60–75 years of age discovered and have given rise to the development of a number with untreated high-risk AML is ongoing, with an estimated of new drugs. primary completion date of December 2014 (NCT01696084). This phase III trial was initiated based on results from a phase IIb study FLT3 inhibitors comparing CPX-351 with cytarabine plus daunorubicin in patients FMS-like tyrosine kinase receptor-3 (FLT3) is a tyrosine kinase with newly diagnosed AML aged 60–75 years.59 Response rates of receptor functionally associated with myeloid differentiation and 66.7% were achieved with CPX-351 compared with 51.2% proliferation that is normally expressed in early bone marrow achieved with the standard 7+3 regimen. Cytopenia-related AEs progenitors.69,70 High levels of expression of FLT3 can be found in were more frequent and median time to count recovery after up to 70–100% of AML cases.69 Internal tandem duplications in induction was longer in patients treated with CPX-351 versus the the juxtamembrane domain of the receptor (FLT3-ITD) and point 7+3 regimen. However, CPX-351 was associated with reduced mutations in the activation loop of the kinase domain (D835 being early mortality compared with the 7+3 regimen, with a 60-day the most frequent) can be found in ∼ 25% and 7% of AML cases, mortality rate of 4.7% for CPX-351 compared with 14.6% for the 7+3 respectively,70 and can induce a proliferative advantage through regimen.59 A significant improvement in OS was observed in constitutive activation of the downstream pathways including patients with secondary AML treated with CPX-351 compared with phosphatidylinositol 3-kinase (PI3K)/AKT, RAS and Janus kinase/ the 7+3 regimen (12.1 vs 6.1 months; P = 0.01).60 As such, the signal transducer and activator of transcription (JAK/STAT).70 This results from the phase III study will be important to determine has led to the development of various kinase inhibitors with whether the increased response rates with CPX-351 translate into inhibitory activity against FLT3, with promising results.

Leukemia (2015) 760 – 769 © 2015 Macmillan Publishers Limited Novel agents for patients with AML G Montalban-Bravo 765 Sorafenib. Sorafenib is an oral tyrosine kinase inhibitor with (NCT01522469 and NCT01657682) in patients aged ⩾ 18 years activity against several kinases (including FLT3) currently with an ECOG performance status of 0–2. approved for hepatocellular, renal and thyroid carcinomas.71 A phase I/II trial conducted at the MD Anderson Cancer Center Hypomethylating agents fi studied the ef cacy of sorafenib in combination with standard SGI-110. Despite the efficacy and increasing indications of idarubicin–cytarabine induction in 51 young patients (median age – current HMAs, resistance to or failure of these compounds has 53 years; range 18 65) with newly diagnosed AML. Results arisen as a major limitation to their potential impact on the clinic. showed a CR rate of 75% (38/51) with 93% response (14/15) As a result of this, investigational efforts into the understanding of among FLT3-ITD-mutated cases.72 A more recent trial conducted 4 the mechanism of resistance and the development of new at European centers in patients with AML aged 60 years did not therapies bypassing this phenomenon are underway.82,83 SGI-110, show improvement in event-free survival or OS when compared 73 a new DNA methyltransferase inhibitor with hypomethylating with chemotherapy alone. A phase I/II study with sorafenib in activity, is a dinucleotide of decitabine and deoxyguanosine that combination with LDAC for older patients with newly diagnosed increases in vivo exposure of decitabine by protecting it from AML or high-risk MDS (NCT00516828) has recently been deamination.84 Because of the potential resistance to deamination completed with results pending. by cytidine deaminase, SGI-110 may be a possible treatment in patients with failure to prior azacitidine or decitabine treatment. Quizartinib (AC220). Quizartinib has recently been shown to be As a result of the lower toxicity profile of HMAs compared with the most potent in vitro FLT3 inhibitor under clinical conventional chemotherapy, SGI-110 could be a promising development.74 A phase II study of quizartinib monotherapy, treatment in older, unfit patients with AML. A phase I/II trial in including a cohort of 134 patients aged 460 years with relapsed patients with MDS or AML in the frontline setting or at relapse or refractory AML, showed 54% and 32% composite CR (CR+CRp after chemotherapy or previous HMAs is currently ongoing +CRi) in FLT3-ITD-mutated and FLT3-wild-type cases, respectively. (NCT01261312), with initial data having been presented at the Median duration of composite CR was 12.7 weeks in patients with last American Society of Hematology (ASH) Annual meeting, with FLT3-ITD mutations and 22.1 weeks in patients with wild-type promising results.84 FLT3.75 Main AEs included myelosuppression and QTc prolonga- tion that was mitigated with dose modification.75 In an analysis of 83 patients from this study who were aged ⩾ 70 years with Histone deacetylase inhibitors relapsed/refractory AML, composite CR rates were 53% and 43% in Vorinostat. Vorinostat is a histone deacetylase inhibitor that has FLT3-ITD-mutated and wild-type cases, respectively, with 12/83 been shown to promote cell cycle arrest, growth inhibition, (14%) of patients surviving for 41 year.76 A current phase I/II trial apoptosis and differentiation of cells from AML and MDS with quizartinib in combination with 5-azacitidine or LDAC in patients.85 An initial phase II study in 37 patients with relapsed younger patients with relapsed/refractory AML and in patients or untreated AML, who were not candidates for chemotherapy, 460 years of age with previously untreated AML (NCT01892371) showed minimal activity in monotherapy.86 This led to several is ongoing in order to assess the therapeutic potential of this combination trials. In the setting of older adults with untreated combination. A phase III study of quizartinib monotherapy versus AML, a phase II study of vorinostat in combination with GO was salvage chemotherapy in patients aged ⩾ 18 years with relapsed recently completed.87 From the total of 31 patients included, or refractory FLT3-ITD-positive AML is planned (NCT02039726). 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 Midostaurin (PKC412). Midostaurin is a multitarget tyrosine an ECOG performance status of 0–3 and patients aged ⩾ 70 years kinase inhibitor that inhibits FLT3 in the nanomolar range.77 In a with an ECOG performance status of 0–1, the CR+CRp rate was proof-of-concept study of midostaurin in patients with AML 46.2% in those with normal or favorable cytogenetics, and 0% in harboring FLT3-ITD mutations, a ⩾ 50% reduction of bone marrow those with other cytogenetics.87 A trial of vorinostat in combina- blasts was seen in 70% of cases.78 These results led to the tion with azacitidine to assess its possible efficacy in patients with development of a phase IIb trial in 95 patients with AML who were newly diagnosed AML and high-risk MDS who are not eligible for ineligible to receive standard chemotherapy or with relapsed/ intensive treatments is currently ongoing at the MD Anderson refractory AML, or patients with MDS, with both wild-type or Cancer Center (NCT00948064). mutated FLT3. This study showed a ⩾ 50% reduction of bone marrow and peripheral blasts in 71% of patients. There were no Panobinostat. Another histone deacetylase inhibitor in develop- CRs and one patient with a FLT3-ITD mutation achieved a PR.79 ment, panobinostat, seems to potentiate the antileukemic effect The authors suggest that the clinical activity observed in this study of fludarabine88 and sensitizes leukemic blasts to cytarabine and support further investigation of midostaurin in combination with daunorubicin.89 Several trials in young patients and in fit older other agents such as chemotherapy, especially in patients with patients in combination with induction chemotherapy are AML with FLT3-ITD mutations.79 A phase III, randomized trial of ongoing. A phase I/II study of panobinostat plus decitabine in midostaurin in combination with daunorubicin and cytarabine in patients aged 460 years with newly diagnosed AML and MDS is frontline treatment for patients with AML aged o60 years has currently evaluating the efficacy and safety of this combination in completed accrual (NCT00651261). Two phase II trials studying the this setting (NCT00691938). Oral panobinostat is also under efficacy of midostaurin in combination with azacitidine investigation in a phase I/II study in combination with azacitidine (NCT01093573) or decitabine (NCT01846624) in older patients in adult patients with AML or MDS (NCT00946647). with AML are currently ongoing. Pracinostat. Pracinostat, an oral histone deacetylase inhibitor Crenolanib. Crenolanib is a highly selective and potent FLT3 with single-agent activity in MDS and AML, showed promising inhibitor that, unlike the previously described inhibitors, has results in a phase II study in combination with azacitidine in nine shown in vitro activity against D835 point mutations affecting the patients with high-risk MDS.90 The ORR, defined as CR+CRi+PR, activating loop of the FLT3 receptor.80,81 These encouraging was 89% with 78% CR+CRi, and a promising complete cytogenetic results have led to two phase II trials evaluating its potential in response rate of 56% was observed. Because of these encouraging patients with relapsed/refractory AML with FLT3-D835 mutations results, several studies are evaluating the potential of this

© 2015 Macmillan Publishers Limited Leukemia (2015) 760 – 769 Novel agents for patients with AML G Montalban-Bravo 766 combination in different scenarios including frail older patients treated patients achieving a 450% reduction in bone marrow with newly diagnosed AML (NCT01912274). blasts and 3/8 showing a hematological improvement.102 In a phase I trial evaluating the activity of rigosertib in 13 patients with Agents targeting leukemic stem cells MDS who were unresponsive to azacitidine or decitabine, 2/13 patients achieved hematological improvement, with 4/13 patients As in other types of cancer, there is increasing evidence of the achieving a marrow CR.103 Trials evaluating the activity of this importance of leukemic stem cells in the evolution and develop- drug in MDS and AML, both as intravenous monotherapy ment of leukemia. Several altered pathways (such as Wnt/β- (NCT01167166) and in an oral formation of rigosertib, in catenin, NOTCH, Hedgehog, PI3K/AKT, JAK/STAT and nuclear combination with azacitidine (NCT01926587), are currently factor (NF)-κB)91 and genes (EVI1 and EZH2)92,93 are known to be ongoing because of its potential, especially after failure to HMAs. important regulators of both normal and leukemic stem cell A phase III trial of intravenous rigosertib versus BSC in patients renewal and expansion. Several agents are in development to with MDS with excess blast who are relapsed or refractory to specifically target these pathways to improve responses with azacitidine or decitabine is ongoing (NCT01241500). standard treatments. Lintuzumab-Ac225 (Actimab). Lintuzumab is a humanized mono- Vismodegib. Vismodegib is a Hedgehog inhibitor approved by clonal antibody that, like GO, is directed against the CD33 antigen the FDA for the treatment of advanced basal cell carcinoma.94 expressed in malignant myeloid cells. In a phase I dose-escalation Because of its potential to target the leukemic stem cells, it is trial evaluating its potential in 17 patients with AML, 4 CRs and 2 currently being evaluated in combination with LDAC in patients PR were achieved in 17 evaluable patients. Drug was administered with relapsed/refractory AML or high-risk MDS (NCT01880437). intravenously at a dose range of 1.5–8 mg/kg/weekly in an outpatient setting.104 A randomized phase IIb study comparing PF-04449913. PF-04449913 is another Hedgehog inhibitor cur- LDAC versus lintuzumab+LDAC in older patients (median age of rently being tested in different solid tumors as a monotherapy. An 70 years) with untreated AML failed to show improved survival ongoing trial is evaluating its potential in combination with (4.7 months in combination arm vs 5.1 months with LDAC alone), chemotherapy in patients with AML and MDS (NCT01546038). This with patients in the combination arm presenting a higher rate of trial will analyze the efficacy of its combination with LDAC or infusion-related reactions (51% vs 7%).105 Because of these results, decitabine for unfit patients, and conventional cytarabine plus further trials were abandoned in 2010. In the past years, several daunorubicin (3+7) chemotherapy for patients eligible for efforts to reawaken the development of this drug have been intensive treatment. made. Combination of lintuzumab with bistmuth-213 to produce an immunoconjugate with increased antileukemic potency led to Other agents the development of a phase I/II trial in 31 patients with either Omacetaxine. Omacetaxine mepesuccinate is a purified semi- newly diagnosed or relapsed/refractory AML with a median age of synthetic derivative of homoharringtonine, a natural plant 67 years.106 In this study, patients were treated with cytarabine alkaloid, that has been approved by the FDA for the treatment 200 mg/m2/daily for 5 days followed by (213)Bi-lintuzumab). of chronic and accelerated chronic myeloid leukemia after failure Frequent infusion-related reactions with grade 3–4 liver function of more than two tyrosine kinase inhibitors.95,96 A recent phase III abnormalities were the most frequent AEs. Significant reductions trial in young patients with newly diagnosed AML showed in marrow blasts were seen at all dose levels with a median promising results in combination with standard induction response duration of 6 months. chemotherapy with an improved rate of CR (73% vs 61%; Conjugation of lintuzumab with Actinium-225 has also been P = 0.01) and event-free survival (35.4% vs 23.1%; Po0.001) in developed. Preliminary results from a phase I trial (NCT01756677) the group receiving homoharringtonine compared with chemo- of this conjugate in combination with LDAC in seven older therapy alone.97 An ongoing phase II trial is evaluating the patients with untreated AML107 were presented last year at ASH. possible efficacy and safety profile of omacetaxine in combination Bone marrow blast reductions were observed in 67% (4/6) of with LDAC in older patients with newly diagnosed AML or high- patients after cycle 1. However, no CRs were achieved and dose- risk MDS (NCT01272245). limiting toxicity in the form of grade 4 thrombocytopenia was seen in one patient. Median time to progression was 2.5 months. Vosaroxin. Vosaroxin, previously known as vorexolin, is a DNA- This study is currently recruiting and further results will be intercalating agent and topoisomerase II inhibitor with significant available in the next year. advantages over anthracyclines, including evasion of p53 and P-glycoprotein resistance pathways, as well as absence of SGN-CD33A. SGN-CD33A is another drug conjugate combining a generation of reactive oxygen species.98 A phase Ib trial of humanized anti-CD33 antibody with engineered cysteines con- vosaroxin in 73 patients with a median age of 65 years and jugated to a highly potent synthetic DNA crosslinking pyrrolo- relapsed or refractory AML showed an acceptable safety profile benzodiazepine dimer.108 In preclinical testing, this compound (including gastrointestinal symptoms and febrile neutropenia), showed to be more potent than GO against a panel of AML cell linear pharmacokinetics and encouraging clinical activity.99 lines.108 SGN-CD33A even showed antileukemic effects in Because of these apparent advantages and safety profile, a phase multidrug-resistant models. A phase I trial is currently ongoing II study in combination with decitabine in patients 460 years of to evaluate its safety in patients with AML (NCT01902329). age with newly diagnosed AML and high-risk MDS is currently ongoing (NCT01893320). CONCLUSIONS Rigosertib (ON01910). Rigosertib is a multikinase inhibitor with Despite the increasing knowledge in AML pathogenesis and activity against PI3K/AKT and Plks that has shown activity in pathways involved in its initiation and progression, this has still different hematologic and nonhematologic malignancies.100 The not been translated in available therapies in the clinical setting. exact mechanism of action of rigosertib has not been determined; Regardless of this fact, a number of novel agents with varying previous studies have demonstrated a direct effect of rigosertib on mechanisms of action are in development for the treatment of Plk1 but this could not be confirmed in subsequent studies.100,101 AML, some of which appear promising in the context of older, frail Recent in vitro assays in MDS and AML patient CD34+ cells with patients. The majority of novel agents are able to produce trisomy 8 showed activity through inhibition of cyclin D1, with 3/8 improved rates of CRs, but these rarely translate into improved OS

Leukemia (2015) 760 – 769 © 2015 Macmillan Publishers Limited Novel agents for patients with AML G Montalban-Bravo 767 in phase III studies. Only azacitidine (although in patients with 12 Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK et al. 20–30% blasts) and LDAC have significantly improved OS A comparison of low-dose cytarabine and hydroxyurea with or without all-trans compared with conventional or supportive care regimens, and retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syn- these agents remain category 2A recommendations in the NCCN drome in patients not considered fit for intensive treatment. Cancer 2007; 109: – guidelines. Results from the ongoing phase III trials of novel 1114 1124. agents are eagerly awaited to see whether they can improve OS. 13 Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K et al. Clofarabine doubles the response rate in older patients with acute myeloid With the array of new compounds in earlier phases of develop- 122 – fi leukemia but does not improve survival. Blood 2013; : 1384 1394. ment, we may be able to see a signi cant change in the 14 Harousseau JL, Martinelli G, Jedrzejczak WW, Brandwein JM, Bordessoule D, therapeutic armamentarium of patients with AML in the next Masszi T et al. A randomized phase 3 study of tipifarnib compared with best years. However, identification of subsets of patients who can supportive care, including hydroxyurea, in the treatment of newly diagnosed specifically benefit from inhibition of a specific pathway is still acute myeloid leukemia in patients 70 years or older. Blood 2009; 114: pending with exceptions such as FLT3 inhibitors. Disease 1166–1173. heterogeneity and clonal evolution remains a challenge in 15 Issa JP. DNA methylation as a therapeutic target in cancer. Clin Cancer Res 2007; 13 – achieving this goal. If we desire to improve the efficacy of the : 1634 1637. novel agents under development, we will have to better identify 16 Grövdal M, Khan R, Aggerholm A, Antunovic P, Astermark J, Bernell P et al. fi Negative effect of DNA hypermethylation on the outcome of intensive che- the ideal combination of therapies for each speci c patient to motherapy in older patients with high-risk myelodysplastic syndromes and attain optimal responses with minimal toxicities. The treatment of acute myeloid leukemia following myelodysplastic syndrome. Clin Cancer Res AML is facing a much-needed expansion with potential to 2007; 13: 7107–7112. revolutionize the concept of disease management in the following 17 Shen L, Kantarjian H, Guo Y, Lin E, Shan J, Huang X et al. DNA methylation years, especially in older patients in whom available effective predicts survival and response to therapy in patients with myelodysplastic therapies are lacking. syndromes. J Clin Oncol 2010; 28:605–613. 18 Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N et al. A comparison of azacitidine and decitabine activities in acute myeloid leukemia CONFLICT OF INTEREST cell lines. PLoS One 2010; 5: e9001. 19 Schmelz K, Wagner M, Dorken B, Tamm I. 5-Aza-2'-deoxycytidine induces The authors declare no conflict of interest. p21WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia. Int J Cancer 2005; 114:683–695. ACKNOWLEDGEMENTS 20 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Myelodysplastic SyndromeVersion 2. 2013. Available at http://www. We are fully responsible for all content and editorial decisions, were involved at all nccn.org. stages of manuscript development and have approved the final version of this review 21 Saunthararajah Y, Triozzi P, Rini B, Singh A, Radivoyevitch T, Sekeres M et al. that reflects the authors’ interpretation and conclusions. Medical writing assistance p53-Independent, normal stem cell sparing epigenetic differentiation therapy during the preparation of this review, supported financially by Boehringer Ingelheim for myeloid and other malignancies. Semin Oncol 2012; 39:97–108. Pharmaceuticals, Inc., was provided by Helen Wilkinson of GeoMed, part of 22 Kayser S, Zucknick M, Dohner K, Krauter J, Kohne CH, Horst HA et al. Monosomal KnowledgePoint360, an Ashfield Company. Boehringer Ingelheim was given the karyotype in adult acute myeloid leukemia: prognostic impact and outcome opportunity to review for factual accuracy only. This work was supported in part by after different treatment strategies. 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