novel therapies for children with acute myeloid leukaemia306969/moore... · 2019. 10. 9. · moore...

Moore et al. Novel therapies for childhood AML

1

Novel therapies for children with acute myeloid leukaemia 1 2

Authors: Andrew S. Moore PhD1,2,3, Pamela R. Kearns PhD4,5, Steven Knapper DM6, 3

Andrew D.J. Pearson MD3,5, C. Michel Zwaan PhD5,7 4

5

Author Affiliations: 1Queensland Children’s Medical Research Institute, The University of 6

Queensland, Brisbane, Australia; 2Children’s Health Queensland Hospital and Health 7

Service, Brisbane, Australia; 3Divisions of Clinical Studies and Therapeutics, The Institute of 8

Cancer Research and Royal Marsden, Sutton, UK; 4School of Cancer Sciences, University of 9

Birmingham, Birmingham, UK; 5Innovative Therapies for Children with Cancer (ITCC) 10

European Consortium; 6Department of Haematology, School of Medicine, Cardiff University, 11

Cardiff, UK; 7Pediatric Oncology/Hematology, Erasmus MC/Sophia Children’s Hospital, 12

Rotterdam, The Netherlands. 13

Running title: Novel therapies for childhood AML. 14

Funding: ASM is supported by the National Health and Medical Research Council 15

(Australia) and the Children’s Health Foundation Queensland. ADJP is supported by Cancer 16

Research UK (programme grant C1178/A10294). 17

18

Corresponding author: Dr A.S. Moore, Queensland Children’s Medical Research Institute, 19

Royal Children’s Hospital, Herston Rd, Herston, Qld, 4029, Australia. Ph: +67 7 3636 3981, 20

Fax: +61 7 3636 5578, Email: [email protected] 21

22

Word count: 6,285 (including headings and parentheses; abstract word count = 163) 23

24 References: 125 25


2

Abstract 26

Significant improvements in survival for children with acute myeloid leukaemia (AML) have 27

been made over the past three decades, with overall survival rates now approximately 60-28

70%. However, these gains can be largely attributed to more intensive use of conventional 29

cytotoxics made possible by advances in supportive care, and although over 90% of children 30

achieve remission with frontline therapy, approximately one third in current protocols 31

relapse. Furthermore, late effects of therapy cause significant morbidity for many survivors. 32

Novel therapies are therefore desperately needed. Early phase paediatric trials of several new 33

agents such as clofarabine, sorafenib and gemtuzumab ozogamicin have shown encouraging 34

results in recent years. Due to the relatively low incidence of AML in childhood, the success 35

of paediatric early-phase clinical trials is largely dependent upon collaborative clinical trial 36

design by international cooperative study groups. Successfully incorporating novel therapies 37

into frontline therapy remains a challenge, but the potential for significant improvement in 38

the duration and quality of survival for children with AML is high. 39

40

Keywords 41

Acute myeloid leukaemia, AML, children, novel therapeutics, inhibitors, chemotherapy 42

43

44


3

Introduction 45

Acute myeloid leukemia (AML) is a heterogeneous class of leukaemias with an age-related 46

incidence.1 AML is relatively rare in children, accounting for 15-20% of paediatric 47

leukaemias, but causes a disproportionate number of childhood cancer deaths. For children 48

less than 15 years of age overall survival (OS) rates are now approximately 60-70%.2-5 49

Although there has been a steady and gradual improvement in survival for younger adults, it 50

is clear that progress has plateaued for children, with survival rates being substantially 51

inferior to those being achieved for acute lymphoblastic leukaemia (ALL), where OS exceeds 52

80%.4,6 53

54

Conventional AML therapy is essentially the same for adults and children and based on 55

intensive use of cytarabine or other nucleoside analogs and anthracyclines. Etoposide is 56

frequently used in paediatric induction regimens, although there is no good evidence it is of 57

benefit in adult studies and when combined with cytarabine and daunorubicin in children, 58

etoposide provided no advantage compared to thioguanine with cytarabine and 59

daunorubicin.2,7 Although chemotherapy will induce complete remission (CR) in 60

approximately 90% of children, approximately one third relapse.4,5 Relapsed AML is 61

associated with high morbidity and mortality, with allogeneic haematopoietic stem cell 62

transplantation (HSCT) generally regarded as the most effective anti-leukaemic therapy 63

available.6 Most re-induction regimens, at least in children, involve high-dose cytarabine in 64

combination with other agents such as anthracyclines. Addition of liposomal daunorubicin to 65

the commonly utilized FLAG regimen (fludarabine, high-dose cytarabine and G-CSF) has 66

been shown to improve the early response rates to chemotherapy from 58% to 68% (P = 67

0.047).8 Not surprisingly, the likelihood of achieving a second CR decreases dramatically 68


4

with each failed therapeutic attempt, with only one third of children with relapsed AML 69

becoming long-term survivors.8,9 70

71

Although the past 30 years has seen major improvements in overall survival for childhood 72

AML, additional gains are unlikely to be achieved by simply intensifying conventional 73

cytotoxic chemotherapy further.6 Chemotherapy such as etoposide and anthracyclines is 74

limited not only by acute toxicity, but also late effects such as increased risks of secondary 75

malignancy and cardiotoxicity.10,11 Such late effects are of particular concern in paediatrics 76

since treatment occurs during periods of growth and development, and the duration of 77

survivorship is much greater than adults. Less toxic and more effective therapies for AML in 78

children, and adults, are therefore urgently needed. The ever-expanding array of molecular 79

abnormalities associated with AML promises to further refine current risk-stratified treatment 80

and facilitate individualised therapy with novel therapeutics specifically targeting these 81

leukaemogenic abnormalities.5 Such an approach should improve outcomes for those children 82

who have historically done poorly and, potentially, permit de-intensification of therapy for 83

those children with low-risk disease, as has been achieved with paediatric ALL. 84

85

Several early-phase clinical trials of novel therapies have been completed over the past 86

decade and an encouraging number of studies are in progress (Table I). A major limitation for 87

progress in childhood AML, however, is that paediatric studies with novel agents usually 88

don’t commence until preliminary toxicity and efficacy profiles have been established in 89

adults. Whilst this may be justifiable from a patient-safety perspective, it slows the process of 90

paediatric drug development. Furthermore, it is increasingly recognized that AML biology is 91

at least partially different in children compared to adults, so extrapolating anticipated efficacy 92

from adult studies to children can be challenging. For example, ‘epigenetic’ mutations of 93


5

DNMT3A, IDH1/2, TET2 and NPM1 all occur much less frequently in children than in 94

adults.12-16 95

Novel classes of therapeutics investigated in childhood AML in recent years include purine 96

nucleoside analogs, small molecule kinase inhibitors and immunomodulatory therapies. Here 97

we review the results of these trials and highlight some of the more promising agents 98

emerging from adult trials. 99

100

Novel purine nucleoside analogs 101

The cytidine analog and DNA polymerase inhibitor cytarabine forms the backbone of 102

conventional AML therapy in both children and adults. It is not surprising that novel 103

cytarabine derivatives have delivered some promising results. Cladribine and fludarabine 104

were the first two such derivatives developed. Unlike cytarabine, they inhibit both DNA 105

polymerase and ribonucleotide reductase, thereby depleting deoxynucleotide pools.17 106

Cladribine has shown encouraging results in combination with cytarabine18, topotecan19 and 107

idarubicin.20 Interestingly, the FAB M5 subtype of AML appears more responsive to 108

cladribine than other morphological subtypes.21 Fludarabine, in combination with cytarabine 109

± an anthracycline, has become a widely used re-induction regimen for children with relapsed 110

AML.8,9,22,23 The dose-limiting neurotoxicity of cladribine and fludarabine however, 111

prompted the development of clofarabine. After efficacy was demonstrated for 112

relapsed/refractory ALL, in December 2004 clofarabine became the first anti-leukaemic drug 113

approved for use in childhood prior to adult use approval.17 The efficacy and potential role of 114

clofarabine in paediatric AML is discussed in detail below. 115

116


6

Clofarabine 117

Clofarabine is a structural hybrid of cladribine and fludarabine, designed to have improve 118

efficacy, through reduced deamination by adenosine deaminase and improved stability, whilst 119

avoiding the formation of toxic metabolites such as 2-F adenine caused by glycosidic bond 120

cleavage of fludarabine.17 Clofarabine is converted intracellularly to clofarabine 121

monophosphate by deoxycytidine kinase (dCK), then to clofarabine triphosphate by 122

additional kinases. The triphosphate form of clofarabine impairs DNA synthesis and repair 123

via inhibition of both ribonucleotide reductase and DNA polymerase and induces apoptosis 124

via mitochondrial pathways.24 As a potent ribonucleotide reductase inhibitor, clofarabine 125

increases dCK activity, thus potentiating its own activation and theoretically that of other 126

drugs such as cytarabine.24 The maximum tolerated dose (MTD) as a single-agent is 52 127

mg/m2/day for 5 days in children and 40mg/m2/day for 5 days in adults with hematologic 128

malignancies, with reversible hepatotoxicity and skin rash being the main non-129

haematological dose limiting toxicities (DLTs).25 Although the liver and skin toxicities are 130

reversible when clofarabine is given as a single agent, it should be noted that a potential 131

interaction with intrathecal methotrexate exists, with at least one case report describing fatal 132

skin and hepatoxicity in a child with a CNS-relapse of pre-B ALL given clofarabine 52 133

mg/m2/day for 5 days, together with triple intrathecal therapy (hydrocortisone, methotrexate 134

and cytarabine).26 135

136

A phase II study of clofarabine as a single agent in children with relapsed/refractory AML 137

had an overall response rate (ORR) of 26%, comprising one CR with incomplete platelet 138

recovery (CRp) and 10 partial responses (PR).25 Although most responses were partial, the 139

trial population was heavily pretreated, with patients having received a median of two prior 140

treatment regimens (range one to five). Furthermore, six of 28 (21%) patients refractory to 141


7

prior therapy responded and approximately one third of clofarabine treated patients 142

proceeded to HSCT.25 Subsequent interpretation of the HSCT data is problematic however, 143

considering that most patients went to HSCT in PR, rather than CR. The toxicity profile was 144

reported as being expected for the patient population, with frequent (≥ 15%) grade 3 adverse 145

events being febrile neutropaenia, catheter-related infection, epistaxis, hypotension, nausea, 146

fever, elevated transaminases and hypokalaemia.25 147

148

Clofarabine has also been trialed in combination with conventional and targeted therapeutic 149

agents. In a phase I study of the multi-kinase/FLT3 inhibitor sorafenib in combination with 150

clofarabine and cytarabine, responses were seen in both FLT3-wild type (-WT) and FLT3-151

ITD+ patients.27 This trial is discussed further below. A phase I trial of clofarabine in 152

combination with etoposide and cyclophosphamide for children with relapsed and refractory 153

acute leukemias resulted in an ORR of 55% (9/20 CR + 2/20 CRp) for ALL patients and 154

100% (1/5 CR + 4/5 CRp) for AML patients.28 When given for five consecutive days during 155

induction and four consecutive days in consolidation for up to eight cycles (median time 156

between cycles 34 days), the recommended phase II doses (RP2D) of clofarabine, 157

cyclophosphamide and etoposide were 40, 440 and 100 mg/m2 respectively. The toxicity 158

profile was similar to that seen in the monotherapy phase II study of clofarabine.28 159

160

A phase I study of clofarabine in combination with liposomal daunorubicin for children with 161

relapsed/refractory AML was recently completed. Patients received clofarabine on days 1-5 162

(30 mg/m2, escalated to 40 mg/m2), and liposomal daunorubicin (60 mg/m2) days 1, 3 and 5. 163

Nine patients were enrolled, with the most common severe adverse event being febrile 164

neutropaenia, but no DLTs observed. One third of patients achieved CR and proceeded to 165

HSCT. The 40 mg/m2 clofarabine cohort is being extended to accrue more efficacy data.29 166


8

167

There is intense ongoing interest in clofarabine for AML in adults and children, with no 168

fewer than 35 open studies of the drug in AML currently registered on ClinicalTrials.gov. A 169

major challenge, however, remains in defining how best to use clofarabine in both upfront 170

and second-line AML treatment regimens. Results of randomised studies in adults are 171

expected in the near future, including the NCRI AML16 trial for adults over 60 years of age, 172

which randomised newly-diagnosed patients to induction with either daunorubicin and 173

cytarabine or daunorubicin and clofarabine (ISRCTN 11036523). The current NCRI AML17 174

trial for younger adults with AML is randomising poor risk patients (defined by a 175

statistically-derived risk score based on presenting disease characteristics and remission 176

status after course I chemotherapy), to either daunorubicin plus clofarabine or FLAG-Ida 177

prior to HSCT (ISRCTN55675535). For childhood AML, a randomised phase II study 178

sponsored by St Jude Children’s Research Hospital (SJCRH) is ongoing, comparing end-of-179

induction MRD for children treated with clofarabine and cytarabine to conventional ADE 180

therapy (cytarabine, daunorubicin, etoposide; NCT00703820). 181

182

FLT3 inhibition 183

Internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutations of the fms-like 184

tyrosine kinase 3 (FLT3) gene occur frequently in AML, resulting in constitutive FLT3 185

signaling and stimulation of leukaemic proliferation.30 The incidence of FLT3-ITD in AML 186

increases with age, occurring in approximately 23% of adults and 12% of children overall 187

with de novo AML, whilst the incidence of FLT3-TKD is relatively constant across all age 188

groups at approximately 7%.31,32 Although FLT3-TKD mutations do not appear to impact on 189

prognosis, the presence of FLT3-ITD has consistently been associated with inferior outcome, 190

principally as a result of increased relapse rate.33 High FLT3-ITD/FLT3-WT allelic ratios 191


9

(AR) carry a particularly poor prognosis, with survival rates of less than 20% in both adults 192

and children.31,34,35 Furthermore, ex vivo studies have demonstrated increased dependence of 193

high AR FLT3-ITD+ AML blasts to FLT3 signaling, consistent with the concept of 194

“oncogene addiction”.36 The identification of secondary FLT3-TKD mutations in patients 195

treated with FLT3 inhibitors is also evidence of clonal selection and cellular dependency on 196

constitutive FLT3 signaling.37-39 197

198

Small molecule inhibition of FLT3 kinase has therefore been vigorously pursued as a 199

therapeutic strategy over the past decade and detailed critiques of each individual FLT3 200

inhibitor developed to date have recently been published.33,40 Initial “first generation” FLT3 201

inhibitors, such as CEP-701 (lestaurtinib) and PKC412 (midostaurin), were non-selective 202

compounds already in early clinical development and subsequently identified as having 203

potent anti-FLT3 activity. These compounds have undergone extensive preclinical and 204

clinical evaluation with major phase III trials ongoing. So-called “second-generation” FLT3 205

inhibitors such as AC220 (quizartinib), designed with increased potency and selectivity for 206

FLT3, are currently being evaluated in early-phase clinical trials. 207

208

Preclinical studies have demonstrated that sustained inhibition of FLT3 phosphorylation to 209

less than 15% of baseline is required to achieve cytotoxicity.41,42 Furthermore, several 210

pharmacokinetic (PK) and pharmacodynamic (PD) studies from clinical trials have 211

consistently confirmed that clinical responses are unlikely in patients who do not achieve 212

adequate FLT3 inhibition.41-45 213

214

Finally, although newer more potent and selective FLT3 inhibitors such as AC220 are 215

showing encouraging results in single-agent trials, it appears that FLT3 inhibitors are likely to 216


10

be of most benefit when used in combination with conventional chemotherapy.33 It is worth 217

noting that myelosuppression from conventional chemotherapy itself has been shown to 218

increase the production of FLT3 ligand (FL) which can decrease the efficacy of a number of 219

FLT3 inhibitors, at least in vitro.46 These observations highlight the need for effective PD 220

biomarker assays to monitor how effectively FLT3 is being targeted. Assays such as the 221

plasma inhibitory activity (PIA) assay have been used to demonstrate that effective FLT3 222

inhibition can still be achieved clinically however, despite elevations in FL (discussed in 223

more detail below).47 224

225

Sorafenib 226

The multi-kinase inhibitor, sorafenib, has potent activity against FLT3 and increased activity 227

against FLT3-ITD+ AML cells compared to FLT3-WT cells.48 Although sorafenib was 228

assessed by the Pediatric Preclinical Testing Program (PTPP), only one AML cell line was 229

tested.49 In the PTPP screen, the FLT3-WT cell line Kasumi-1 had an in vitro IC50 of 0.02 230

M.49 Pre-clinical studies of sorafenib and another multi-kinase inhibitor, sunitinib, at 231

SJCRH examined a broader panel of AML cell lines and demonstrated similar in vitro 232

sensitivity of Kasumi-1 (sorafenib IC50 0.04 M), but markedly increased sensitivity of the 233

FLT3-ITD+ paediatric cell line MV4-11 (sorafenib IC50 0.002 M). In vitro activity of 234

sorafenib against primary paediatric AML samples (4/6 FLT3-WT, 2/6 unknown FLT3 235

status) was also demonstrated.50 Increased in vitro sensitivity of FLT3-mutated, primary 236

paediatric AML samples has also been demonstrated for SU11657, a compound similar to 237

sunitinib with anti-FLT3 activity51 Unlike sorafenib, sunitinib is no longer being evaluated as 238

a FLT3 inhibitor in AML due to poor tolerability at doses required to inhibit FLT3.33 239

240


11

Several clinical trials of sorafenib in adult AML have been reported33, with a recent phase I/II 241

study in combination with cytarabine and idarubicin demonstrating overall CR rates of 93% 242

(14/15, plus 1 with CRp) in FLT3-ITD+ patients and 66% (24/36 plus 3 with CRp) in FLT3-243

WT patients.52 In the phase II arm of the study, sorafenib was given at a dose of 400 mg 244

twice daily for up to 28 days during induction and consolidation (both with concurrent 245

cytarabine and idarubicin), then continued as maintenance therapy for up to one year.52 In 246

contrast, a placebo-controlled, randomized phase II study of sorafenib combined with 247

standard 7+3 induction chemotherapy and intermediate-dose cytarabine consolidation then 248

continued for 1 year as maintenance in 197 older patients (> 60 years) failed to show any 249

difference in CR rates, EFS, OS for FLT3-WT or FLT3-ITD+ patients, although the small 250

number of FLT3-ITD+ patients (n = 28; 14.2%) may have limited the power of subset 251

analysis. Despite being reportedly well tolerated, there was a trend towards slower leucocyte 252

and platelet recovery in the sorafenib arm during the induction cycles.53 253

254

Encouraging results from a paediatric phase I study of sorafenib in combination with 255

cytarabine and clofarabine for children with relapsed/refractory acute leukaemia were 256

recently published. Sorafenib was given as a single agent on days 1 to 7 and then 257

concurrently with clofarabine (40 mg/m2, or 20 mg/m2 if the patient had HSCT within 6 258

months or fungal infection within 1 month) and cytarabine (1 g/m2) on days 8 to 12. If 259

tolerated, sorafenib alone was continued until day 28. Repeated courses of sorafenib, 260

clofarabine and cytarabine, maintenance therapy with single-agent sorafenib, or 261

transplantation were administered according to clinical judgment.27 Eleven of the 12 patients 262

(aged 6-17 years) had AML, including 3 who had previously undergone allogeneic HSCT (2 263

FLT3-ITD+, 1 FLT3-WT). Of these 11 AML patients, 5 were FLT3-ITD+ and all achieved 264

morphological CR on day 22 (3 CR + 2 CRp) in combination with cytarabine and 265


12

clofarabine, including both patients who had previous allogeneic HSCT.27 Of the 6 FLT3-WT 266

AML patients, 3 achieved morphological CR and one a PR. Of note, the initial seven-day 267

course of single-agent sorafenib reduced bone marrow blast percentages in 10 patients 268

(median 66%, range 9-95%), including all FLT3-ITD+ patients. Ten patients had PD studies 269

performed (flow cytometric analysis of phosphorylated AKT, 4E-BP1 and S6RP), with 270

decreases in percentage of positive cells and mean fluorescence intensity unrelated to FLT3-271

mutational status.27 Six patients proceeded to HSCT.27 The most common toxicity associated 272

with sorafenib was skin toxicity, with all 12 patients experiencing some degree of hand-foot 273

skin reaction and/or rash. Skin toxicity was dose-limiting at 200 mg/m2 but not 150 mg/m2, 274

which was the final recommended dose of sorafenib.27 The hand-foot skin (HFS) reaction to 275

sorafenib is classically characterised by tender, scaling skin with erythematous halos on areas 276

of pressure or skin creases which may blister and can progress to hyperkeratosis and impaired 277

movement and function.54 Consensus guidelines for the management of sorafenib and 278

sunitinib induced HFS reactions have been developed and include avoidance of skin trauma, 279

liberal use of emollients and dose reduction/cessation of sorafenib.54 The high incidence of 280

skin toxicity in this paediatric study compared to previous single agent adult trials was 281

attributed the concurrent use of cytarabine and clofarabine, as well as the higher 282

concentration of the active metabolite sorafenib N-oxide observed in the paediatric trial.27 283

284

The current Children’s Oncology Group phase III trial (AAML1031, NCT01371981) is using 285

a FLT3-ITD/FLT3-WT allelic ratio >0.4 (high-AR) to non-randomly stratify children with 286

FLT3-ITD+ AML to receive sorafenib and HSCT in first remission, if an appropriate donor is 287

available. Although the HSCT data for adults is inconclusive2, matched related donor 288

allogeneic HSCT has been demonstrated to be of benefit for FLT3-ITD+ children with a high-289

AR.31 The dismal prognosis for children with high-AR FLT3-ITD+ AML (3 year DFS/OS ≤ 290


13

20% ) clearly warrants novel treatment approaches however, the number of children with 291

high-AR disease transplanted on the CCG-2941 and CCG-2961 trials was small (total FLT3-292

ITD+ = 11; high-AR = 6), and all high-AR patients on the current COG AAML1031 trial will 293

receive both sorafenib and allogeneic HSCT, so it may be difficult to determine the extent to 294

which sorafenib further improves survival when compared to this historical control. 295

296

Paediatric trials of other FLT3 inhibitors, including AC220, CEP-701 and PKC412, are 297

currently in progress (Table I). An emerging issue with a number of FLT3 inhibitors, 298

including midostaurin and the more selective compounds AC220 and sorafenib, is resistance 299

mediated by secondary FLT3-TKD mutations.37-39,55,56 Given the biologically similar nature 300

of FLT3-ITD+ AML in children and adults, similar resistance patterns could be expected 301

although the relatively small number of children with FLT3-ITD+ AML may make this a rare 302

occurrence. Finally, the benefit of “maintenance” FLT3 inhibition (e.g. post-HSCT) is yet to 303

be proven, however it is plausible that such strategies with compounds like AC220 or 304

sorafenib may promote acquired resistance, mediated by secondary FLT3-TKD mutations. 305

Despite the compelling preclinical data supporting FLT3 inhibition as a therapeutic strategy 306

in FLT3-mutated AML, until therapeutic benefit is proven from ongoing clinical trials in 307

adults and children, up-front use of FLT3 inhibitors for childhood AML should be limited to 308

clinical trials. However, for children with relapsed or refractory FLT3-ITD+ AML, limited 309

therapeutic options (e.g. from anthracycline cardiotoxicity) and no access to a clinical trial, 310

FLT3 inhibition could be considered to help achieve disease control, e.g., prior to HSCT or 311

possibly even as a palliative strategy. 312

313


14

Immunotherapy 314

Gemtuzumab ozogamicin 315

Gemtuzumab ozogamicin (GO), a humanized anti-CD33 monoclonal antibody conjugated to 316

the cytotoxic compound N-acetyl-γ-calicheamicin dimethylhydrazine, has been extensively 317

investigated in adults and children over the past decade. Therapeutic targeting of CD33 has a 318

sound rationale in AML, since approximately 80% of AML cases express CD33.57 High 319

CD33 expression in childhood AML is associated with adverse disease characteristics such as 320

FLT3-ITD and independently predicts poor outcome.58 Initial experience with GO 321

monotherapy in children with relapsed/refractory AML demonstrated response rates of 53% 322

(8/15 patients), with 6 patients proceeding to HSCT.59 Subsequent trials, including GO 323

combined with chemotherapy and HSCT have demonstrated its safety.60-63 Monotherapy 324

studies and case reports of GO in relapsed/refractory childhood AML have resulted in a 325

number clinically meaningful responses, whilst phase II studies in combination with 326

chemotherapy have shown similar results to historical controls. The recently reported multi-327

centre AML02 phase III trial included a randomization of GO (3 mg/m2) during induction II 328

chemotherapy with cytarabine, daunorubicin and etoposide.64 Although the specific effects of 329

GO versus no GO were not reported, GO in combination with ADE resulted in reductions in 330

minimal residual disease (MRD) in 93% (27/29) of patients who had responded poorly to 331

induction I, including all 8 patients with MRD > 25% after induction I. Of the 8 patients with 332

MRD > 25%, half became MRD-negative with ADE+GO. Of the remaining 21 patients, who 333

all had MRD > 1% after induction I, the ADE+GO combination reduced MRD in 19 (90%), 334

with 9 patients becoming MRD-negative (43%).64 Paediatric phase III studies of GO in 335

combination with conventional chemotherapy are ongoing. 336

337

The potential for veno-occlusive disease (VOD) of the liver following GO has been of 338


15

concern in adult patients, particularly in those patients proceeding to HSCT within 3.5 339

months of receiving 6 or 9 mg/m2 GO.65 The recently reported UK NCRI AML15 trial (1,113 340

patients) administered a lower GO dose (3 mg/m2) in adults and failed to show an increased 341

risk of hepatic toxicity, even when administered within 120 days of HSCT66 The successor 342

trial, AML17 is randomizing adult patients to 3 vs. 6 mg/m2. In pediatric studies liver toxicity 343

has been less of an issue, and GO seems better tolerated in children.67 344

345

Other dosing strategies of GO have also been examined, including fractionated therapy, 346

facilitating cumulative doses of up to 27 mg/m2 (ref 68-70). A phase I study in combination 347

with busulfan and cyclophosphamide HSCT conditioning for 12 children with CD33+ AML 348

(median age 3 years, range 1-17) failed to identify any GO-associated DLTs at 3.0, 4.5, 6.0 or 349

7.5 mg/m2 and had no 100-day transplant-related mortality.61 350

351

In June 2010 the United States Food and Drug Administration (FDA) withdrew marketing 352

approval for GO, based on lack of benefit in relapsed/refractory AML and increased 353

induction mortality in adults. It has been highlighted, however, that the increased induction 354

mortality associated with GO was relative to an unusually low mortality in the control arm of 355

one of the studies the FDA based their decision on.66 Furthermore, subsequent data from 356

1,113 newly diagnosed patients treated on the UK NCRI AML15 trial have demonstrated a 357

significant benefit of GO for patients with core binding factor (CBF) AML when given as a 358

single dose of 3 g/m2 during courses one and three.66 The biological explanation for this is 359

somewhat unclear, since responses to GO were not related to blast CD33 expression.66 360

Interestingly, children with CBF AML on the NOPHO-AML 2004 trial accounted for 35% 361

(N = 17) of relapses, independent of whether or not GO (5 mg/m2 x 2 doses) was given as 362

post-consolidation therapy.71 Definitive results from larger paediatric trials of GO are 363


16

awaited. The recently reported French trial ALFA-0701 confirmed the survival advantage for 364

adults with de novo AML and favourable cytogenetics, but also for those with intermediate-365

risk cytogenetics. A notable feature of the ALFA-0701 study was the delivery of fractionated, 366

higher cumulative doses of GO (3 g/m2 days 1, 4 and 7 during induction and in two 367

consolidation cycles).70 On the basis of these adult studies with fractionated dosing, further 368

evaluation of GO in children is planned. 369

370

Stem cell targeting 371

Bortezomib 372

The proteasome inhibitor, bortezomib, was initially approved for use in multiple myeloma. 373

Pre-clinical studies of proteasomal inhibition in combination with idarubicin in AML 374

demonstrated down-regulation of NF-κB and preferential cell death in leukaemic stem cells 375

but not normal haemopoietic stem cells (HSCs).72 A single-agent phase I study in children 376

demonstrated acceptable toxicity, with a RP2D of 1.3 mg/m2 per dose when administered 377

twice weekly for 2 weeks.73 Although NF-κB inhibition was observed in 2 of 5 evaluated 378

patients, there were no objective clinical responses. Phase I studies of bortezomib (twice 379

weekly for two weeks) in combination with chemotherapy in adult AML74 and paediatric 380

ALL75 were also well tolerated, with predictable, chemotherapy-related toxicity. In the adult 381

phase I combination study, nine patients were less than 60 years of age with relapsed AML, 382

with the remaining 22 patients being over 60 years with untreated AML.74 Overall, 7/9 (78%) 383

of relapsed patients and 15/22 (68%) untreated older patients achieved CR (including 3 384

CRp).74 In addition to administering Sorafenib to children with high-AR FLT3-ITD+ AML, 385

the current Children’s Oncology Group phase III trial (AAML1031, NCT01371981) is 386


17

randomising patients with de novo AML (including those with low-AR FLT3-ITD) to receive 387

conventional chemotherapy with or without Bortezomib for all courses. 388

389

Novel agents with promising data in adults 390

Aurora kinase inhibition 391

Aurora kinases are a family of serine/threonine kinases with critical roles in mitosis.76 Aurora 392

A kinase plays a key role in centrosome maturation and mitotic spindle assembly whilst 393

Aurora B kinase regulates the mitotic checkpoint, forms part of the chromosomal passenger 394

complex (with inner centromere protein, Borealin and Survivin) and is required for final 395

cytokinesis.76 Although therapeutic success in solid tumours has been limited, Aurora kinase 396

inhibitors have shown encouraging responses in leukaemia, particularly AML and 397

Philadelphia-positive leukaemias.77 A recent phase I/II trial of the selective Aurora B 398

inhibitor, AZD1152 (barasertib) had an overall response rate of 25%.78 The toxicity profile, 399

including mucositis and myelosuppression, was reported as being manageable in an older 400

population. FLT3 kinase is a secondary target of AZD115279 and although the FLT3 status of 401

patients on the trial was not reported, it is of interest that a number of responses occurred 402

below the MTD and 55% of patients on the trial had cytogenetically normal AML (CN-403

AML). Given the high incidence of FLT3 mutations in CN-AML, it is possible that the anti-404

FLT3 activity of AZD1152 may have contributed to efficacy in patients with FLT3 405

mutations. A phase II/III study of AZD1152, alone and in combination with low-dose 406

cytarabine in older adults (> 60 years), is currently ongoing (NCT00952588). A recent 407

preclinical study has demonstrated that paediatric AML cell lines are sensitive to Aurora B 408

knockdown by shRNA and small molecule inhibition with AZD1152.80 One potential 409

limitation of the AZD1152 compound is its delivery via a 7 day continuous IV infusion. 410


18

The selective Aurora A inhibitor MLN8237 (alisertib), has shown response rates of 17% in 411

an adult phase II trial 81 and preclinical activity in paediatric leukaemia.82 Of note, a recent 412

preclinical study in acute megakaryoblastic leukaemia (AMKL) demonstrated that Aurora A 413

inhibition with MLN8237 could induce polyploidization in both a Down Syndrome (DS) 414

AMKL cell line (CMK) and primary blasts from children with non-DS-AMKL. MLN8237 415

also had in vivo activity against a non-DS-AMKL model.83 A paediatric phase II trial of 416

MLN8237 in children with relapsed/refractory solid tumours and leukaemia is currently 417

ongoing (NCT01154816, COG-ADVL0921). Similarly, the Aurora kinase inhibitor AT9283, 418

which also has potent activity against ABL, JAK2 and FLT3 kinases, has shown encouraging 419

responses in adult leukaemia trials and is currently being assessed in a paediatric phase I 420

study (EudraCT No. 2009-016952-36; NCT01431664). 421

422

MEK inhibition 423

Mutations of N- and K-RAS in AML are examples of class I mutations, conferring a 424

proliferative/survival stimulus.84 A recent comprehensive pre-clinical predictive biomarker 425

analysis of 218 solid tumor and 81 haematological cancer cell lines revealed AML and CML 426

cell lines as being particularly sensitive to the MEK inhibitor, GSK1120212.85 Amongst solid 427

tumour cell lines, RAF/RAS mutations were predictive of sensitivity.85 In a panel of 12 AML 428

cell lines, single-nanomolar IC50’s were reported for all 6 RAS-mutant (N- or K-RAS) cell 429

lines, as well as 2 RAS-wt cell lines. The paediatric cell line Kasumi-1 (RAS-wt) was 430

resistant, although other paediatric cell lines, THP-1 (N-RAS mutant) and MV4-11 (FLT3-431

ITD+, RAS-wt), were sensitive.85 A phase I trial of GSK1120212 was reported at the 2010 432

ASH meeting, with 12 of 14 patients treated having AML (including 2 transformed from 433

MDS).86 Preliminary anti-leukaemic activity was reported, with one patient achieving CR. A 434

phase I/II study of GSK1120212 in AML is ongoing (NCT00920140). 435


19

436

Aminopeptidase inhibition 437

Aminopeptidases play a key role in removing amino acids from cellular peptides, a process 438

required for protein regulation and recycling. Aminopeptidase inhibition depletes intracellular 439

amino acids required for new protein synthesis.87 AML cells have been shown to be sensitive 440

to aminopeptidase inhibition, undergoing apoptosis, whilst normal bone marrow cells are less 441

susceptible.88 The aminopeptidase inhibitor Tosedostat has shown promising activity in phase 442

I/II trials of older adults with predominantly relapsed/refractory AML, with single-agent 443

response rates of up to 27%.89,90 Tosedostat appears well tolerated with thrombocytopaenia 444

being the most common adverse event reported. 445

446

c-KIT inhibition 447

Activating c-KIT mutations are common in paediatric and adult AML, particularly in CBF 448

AML (incidence 21-54.5% with inv(16) and 17-46.8%% with t(8;21)).91-95 Although c-KIT 449

mutations confer an increased risk of relapse in adults with CBF AML93, this does not appear 450

to be the case in children.94,95 Murine models have demonstrated c-KIT mutations cooperate 451

with AML1-ETO to cause aggressive AML in vivo, but are responsive to c-KIT inhibition 452

with dasatinib.96 Dasatanib has also been shown to have single-agent activity against the 453

t(8;21) paediatric cell line, Kasumi-1, which also harbours an N822K point mutation in the 454

activation loop of c-KIT.97,98 Results of several ongoing clinical trials in AML, particularly 455

those enriched with CBF patients, are eagerly awaited. 456

457

CXCR4 antagonism 458

The critical role of the bone marrow micro-environment, or “niche” in regulating normal and 459

malignant haematopoiesis is becoming increasingly recognised. The CXCR4 antagonist, 460


20

plerixafor, has demonstrated efficacy in the mobilization of normal HSCs from the marrow 461

for use in autologous transplantation in non-Hodgkin lymphoma and multiple myeloma.99,100 462

Plerixafor has also been demonstrated to be a feasible and effective second-line strategy in 463

mobilizing HSCs in children.101,102 Based on pre-clinical data demonstrating AML blasts 464

could be mobilized into the peripheral blood, a recent phase I/II study demonstrated the 465

feasibility of combining plerixafor with cytotoxic chemotherapy in adults with 466

relapsed/refractory AML. When used in combination with mitoxantrone, etoposide and 467

cytarabine, plerixafor increased mobilization of AML blasts into the peripheral circulation.103 468

Overall CR rates of 46% were achieved and no dose-limiting toxicities were observed. 469

470

Epigenetic therapies 471

Genes regulating DNA methylation and demethylation such as DNMT3A, IDH1/2 and TET2 472

are frequently mutated in adult AML and have prognostic significance.104-107 Consequently, 473

targeting epigenetic processes has become an attractive therapeutic strategy in adult AML. 474

The DNA methyltransferase inhibitors decitabine and azacitidine are currently being 475

evaluated in clinical trials of adults with AML and paediatric evaluation programs are being 476

designed. A recent analysis of 46 patients treated on two trials of decitabine has shown an 477

improved response rate in patients with DNMT3A mutations compared to those with wild-478

type DNMT3A (CR rate 75% (6/8) vs. 34% (13/38) respectively, P=0.05).108 Studies of 479

azacitidine alone and in sequential combination with lenalidomide have shown responses of 480

approximately 50% in older adults with newly-diagnosed AML compared to those with 481

relapsed disease.109,110 482

483

Another focus of epigenetic therapy has been histone deacetylase (HDAC) inhibition with 484

compounds such as valproic acid, vorinostat and panabinostat. Widely used as an anti-485


21

convulsant, valproic acid was first demonstrated to inhibit HDAC and cause partial 486

differentiation of the paediatric AML cell line Kasumi-1 over a decade ago.111 Preclinical 487

studies, including paediatric models, have also demonstrated single cytotoxic synergy with 488

cytarabine and clofarabine.112,113 Clinical responses to valproic acid alone or in combination 489

with cytarabine in adults with AML however, have been variable.114-116 It should be noted 490

that when combined with decitabine, valproic acid has been associated with 491

encephalopathy.117 492

493

Although a single-agent randomised phase II trial of vorinostat in adults with relapsed or 494

high-risk untreated AML showed only minimal responses (1 CR from 37 patients)118 a recent 495

phase II trial of vorinostat in combination with idarubicin and cytarabine (IA) in patients with 496

AML and no CBF abnormalities resulted in an EFS of 47 weeks (range, 3 to 134 weeks) and 497

a CR rate of 76%. Although not randomised, these responses compared favourably to 498

historical data, the combination was reported as not excessively toxic compared to IA alone 499

and all 11 FLT3-ITD+ patients responded (10 CR, 1 CRp).119 As discussed above, the relative 500

rarity of mutations in genes regulating DNA methylation in childhood AML may limit the 501

broader applicability of these agents for children, particularly if responses are confirmed to be 502

associated with mutational status. 503

504

Although adult clinical trials have only recently been initiated, it is worth noting one potential 505

epigenetic therapy that may be of significant importance to childhood leukemias with MLL 506

gene rearrangements, given their relatively high incidence (AML 18%, ALL 8.3%).4 The 507

histone H3 methyltransferase, DOT1L, plays a key role in MLL-fusion mediated 508

leukemogenesis (reviewed in Ref 120). A small molecule inhibitor of DOT1L, EPZ004777, 509

was recently shown to have in vivo preclinical efficacy against MLL-rearranged 510


22

leukemia.121,122 A phase I trial of an optimized compound, EPZ-5676, opened in September 511

2012 for adults patients with advanced hematological malignancies, including MLL-512

rearranged AML and ALL (NCT01684150). 513

514

Finding and Hitting the Right Target in AML: Predictive and 515

Pharmacodynamic Biomarkers 516

Of critical importance for the rational and efficient development of targeted agents in cancer 517

and leukaemia is the use of validated predictive and PD biomarkers. Predictive biomarkers 518

are those that identify which patients are most likely to derive benefit from a given targeted 519

agent, whilst PD biomarkers are needed to verify whether or not the desired molecular target 520

is being modulated, and establish how target modulation relates to dose, toxicity and 521

response. This information, together with careful examination of any resistance mechanisms 522

or treatment failures, not only decreases the attrition rate of targeted therapeutics, but also 523

improves the ongoing pre-clinical development of new agents. 524

525

FLT3 inhibitors provide arguably the best example of how robust predictive and PD 526

biomarkers have been successfully applied in AML. It is well established that patients 527

without activating mutations of FLT3 are less likely to benefit from FLT3 inhibition.33 Even 528

with potent, second generation FLT3 inhibitors such as AC220, response rates in FLT3-WT 529

patients are lower than in FLT3-ITD+ patients (34 vs. 44%).123 FLT3 mutational status 530

therefore serves as a robust predictive biomarker for personalized AML therapy. 531

Furthermore, results from trials of CEP-701 clearly demonstrate the importance of combining 532

a predictive biomarker with a robust PD assay, since adequate FLT3 inhibition correlates 533

with outcome for FLT3-mutated patients treated with CEP-701.45,47 An important PD assay 534

developed for FLT3 inhibitors is the PIA assay.42 This assay involves incubation of a FLT3-535


23

ITD+ cell line in the plasma of patients treated with FLT3 inhibitors. The degree of FLT3 536

inhibition seen ex vivo for a patient at a given time-point during or after therapy is normalized 537

to the amount of FLT3 phosphorylation observed when cells are incubated with that patient’s 538

pre-treatment plasma. FLT3 ligand (FL) levels and protein binding can impact on the efficacy 539

of FLT3 inhibition.46 The PIA assay is therefore superior to simply calculating the free drug 540

concentration, since the plasma sample used to treat the cell line ex vivo contains not only 541

free drug, but also the patient’s actual FL and plasma proteins at that time-point. Using the 542

PIA assay, it has recently been demonstrated that when adequate FLT3 inhibition is achieved 543

in combination with chemotherapy, relapse rates are lower and overall survival can be 544

improved.47 545

546

The relatively small circulating blood volume and need for general anaesthetic when 547

performing bone marrow aspiration can limit the number and nature of PD assays undertaken 548

in paediatric leukaemia trials. Assays such as the PIA assay have been successfully adapted 549

for use in children, such that smaller blood volumes are required, permitting use in phase I 550

paediatric trials.124 Furthermore, the PIA assay has been successfully adapted and validated 551

for therapeutic targets other than FLT3, with inhibition of phosphorylated histone H3 being 552

used as a PD biomarker of Aurora kinase inhibition in a paediatric trial of AT9283 (EudraCT 553

No. 2009-016952-36, NCT01431664).124 554

555

Future Directions and Trial Design 556

Although the prognosis for children with AML has improved over recent decades, such 557

improvements are largely attributable to more intensive use of cytotoxic chemotherapy and 558

better supportive care.6 Although a number of novel therapeutic agents have been recently 559

developed and show promising efficacy in adult AML, significant issues still exist for 560


24

executing early phase clinical trials of such drugs in children. Often, patients may progress 561

rapidly between screening and commencing a novel therapy, by which time they may become 562

ineligible with poor performance status or complicating conditions such as uncontrolled, 563

invasive infection. Furthermore, patients relapsing soon after allogeneic HSCT may have 564

poor organ function deeming them ineligible. One possible solution is to treat patients with 565

primary refractory or first-relapsed AML with targeted novel agents in a “window” period 566

prior to allogeneic HSCT. Several factors need to be considered for this approach though, 567

including the likelihood of achieving CR with second or third line chemotherapy, the 568

potential of the novel agent causing organ toxicity which could compromise the success of 569

subsequent HSCT and the time required to screen, enroll and treat patients with the novel 570

agent prior to HSCT. 571

572

Accelerating drug development for childhood AML will rely heavily on effective 573

international collaboration, particularly if enrolment on targeted therapeutic trials is to be 574

restricted to the relatively small number of patients with predictive biomarkers of response. 575

Groups such as the Innovative Therapies for Children with Cancer (ITCC) European 576

Consortium and the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL) 577

consortium have an existing focus on early-phase trials of novel agents for childhood 578

leukaemia. Although legislative, regulatory and pharmaceutical supply barriers prevent the 579

enrolment of children from outside Europe or North America on certain trials, attempts to 580

facilitate truly international early-phase studies are ongoing. Novel approaches to early-phase 581

trial design are also critical in accelerating drug development, particularly in children. 582

Important strategies include phase I trials with expansion cohorts at the RP2D enrolling 583

patients with predictive biomarkers, and adaptive randomised trials incorporating a number of 584

new agents with the aim of “picking-the-winner” or “dropping-the-loser”.125 Such approaches 585


25

hold promise of reducing the number of large phase III trials needed and improving the 586

likelihood of beneficial treatments being identified for malignancies like AML with 587

increasingly heterogeneous biology. The important question of how much can be extrapolated 588

from adult biology and trial data remains difficult to answer, hence defining the minimum 589

dataset in children is an ongoing challenge. 590

591

Although significant challenges remain for novel drug development in paediatric oncology, 592

particularly AML, the encouraging results of initial paediatric trials of therapies such as 593

clofarabine and sorafenib, together with the large number of new agents in the pipeline is 594

encouraging. Although survival rates in childhood AML are significantly better than adults 595

with the disease, outcomes for children with AML are dramatically inferior compared with 596

paediatric ALL.4 Improving outcomes in AML with cytotoxic chemotherapy alone is highly 597

unlikely, given the current intensity of conventional therapy. Continued efforts to find 598

effective novel therapies are therefore of critical importance if survival is to be improved and 599

long-term morbidity reduced. 600

601


26

Acknowledgements 602

ASM is supported by the National Health and Medical Research Council (Australia) and the 603

Children’s Health Foundation Queensland. ADJP is supported by Cancer Research UK 604

(programme grant C1178/A10294). ASM and ADJP acknowledge NHS funding to the NIHR 605

Biomedical Research Centre at The Institute of Cancer Research and the Royal Marsden 606

NHS Foundation Trust. 607

608

Conflicts of Interest 609

ASM and ADJP are past and present employees respectively of The Institute of Cancer 610

Research, which has a commercial interest in drug development programmes (see 611

www.icr.ac.uk), and are subject to a “Rewards to Inventors Scheme” which may reward 612

contributors to a programme that is subsequently licensed. ASM has received competitive 613

research funding from Pfizer Inc., by way of a Pfizer Australia Cancer Research Grant. 614

615


27

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