novel therapies for children with acute myeloid leukaemia306969/moore... · 2019. 10. 9. · moore...
TRANSCRIPT
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Moore et al. Novel therapies for childhood AML
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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
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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
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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
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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
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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
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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
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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
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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
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(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
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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
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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
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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
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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
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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
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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
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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
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Moore et al. Novel therapies for childhood AML
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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
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Moore et al. Novel therapies for childhood AML
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
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Moore et al. Novel therapies for childhood AML
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
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Moore et al. Novel therapies for childhood AML
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
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Moore et al. Novel therapies for childhood AML
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
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Moore et al. Novel therapies for childhood AML
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
-
Moore et al. Novel therapies for childhood AML
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
-
Moore et al. Novel therapies for childhood AML
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
-
Moore et al. Novel therapies for childhood AML
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
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Moore et al. Novel therapies for childhood AML
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
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Moore et al. Novel therapies for childhood AML
27
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