This document discusses directions and issues in the treatment of acute myeloid leukemia (AML). It addresses challenging existing treatment dogmas regarding chemotherapy drug doses and post-remission therapies. Specifically, it summarizes several studies investigating optimal dose levels of cytarabine and anthracyclines during induction and consolidation for AML. It also reviews evidence comparing the effectiveness of autologous stem cell transplantation versus chemotherapy alone as post-remission consolidation approaches. The document advocates moving beyond conventional chemotherapy regimens to more personalized precision medicine approaches for AML patients.

1. Directions in the Treatment of AML
Bob Löwenberg- Erasmus University Medical Center,
Rotterdam, Netherlands
April 7, 2017 – Sint Petersburg

2. AML
Personal reflections about issues and directions in AML
therapeutics
§ Challenging our treatment dogmas
§ Precision therapeutics
§ Opportunities

3. A comparative study of two regimens of combination
chemotherapy in acute leukemia.
Frei III, E, Holland JF, Schneiderman, MA, Pinkel D et al, Blood.1958
OS (responders)
OS (nonresponders)

4. Place Slide Title Here
• Response à better survival
• Better understanding of variability of response
among patients needed
• Need to overcome treatment resistance

5. Conventional
Escalated
Logrank
N
431
429
F
257
248
P =0.85
Conventional
Escalated
22 Oct 2009-07:31:48
At risk:
431
429
258
254
205
196
134
150
72
86
Conventional
Escalated
0
25
50
75
100
months0 60
Cumulativepercentage
Conventional vs Escalation
Overall survivalAML Overall survival 18-60 yrs of age

6. Overall survival – AML patients (n=1975)
Prognostic heterogeneity
Breems, D. A. et al. J Clin Oncol; 26:4791-4797 2008
78%

7. Progression over more than 15 years from severe congenital
neutropenia to AML
Beekman R et al. Blood 2012;119:5071-5077
sampling
Germline ELANE mutation

8. AML Development
§ Emergence over many years
§ On the base of preleukemic clonal alterations
§ Leukemia development a dynamic process
§ Extent of heterogeneity among mutations across the genome can
reveal a disease’s life history

9. Clonal evolution of SCN to AML. The sequential genetic events,
starting with clonal hematopoiesis
Gain of 9 additional mutations (RUNX1, EP300,
ASXL1 etc) and trisomy 21 in the mutated population
preceed transformation to full AML.
CSF3R-d715-d730 indicates CSF3Rδ mutations at
amino acid positions 715-730.Beekman R et al. Blood 2012;119:5071-5077
RUNX1
ASXL1
SUZ12
monosomy -7
trisomy 21

10. Game of clones: Evolu8on towards AML
Beekman et al, Blood 2012
Recurrent gene mutations are prototypic for
secondary leukemia and clinical phenotypes often
similar.
Early events not consequently followed by
leukemia development
What is the underlying process driving
leukemia development?
Are there common pathways?
What are the preceding initiating events?

11. Multiple cycles of cytarabine at high dose levels (2000 -3000 mg/m2)
still being used in AML
§ Our dogma’s ?

12. Cytarabine dose: 100 mg, 200 mg, 400 mg, 1000 mg, 2000 mg, 3000 mg …
Anthracyclines: …
Remission Induction Therapy in AML
cytarabine and anthracyclines: standard but what about dose level ?

13. HOVON-SAKK AML-42 (2003; amended in February 2006)
AML/RAEB/RAEB-t, 18-60 yrs
Induction cycle I Induction cycle II
Consolidation cycle(s)
R
R
R
-
+
-
+
R
Good risk
Ida 12 mg/m2
Ara-C 200 mg/m2
Ida 12 mg/m2
Ara-C 1000 mg/
m2
AMSA 120 mg/m2
Ara-C 1000 mg/m2
AMSA 120 mg/m2
Ara-C 2000 mg/m2
§ Dose level of Ara-C
Löwenberg et al. Cytarabine Dose for Acute Myeloid Leukemia.
N.Engl J Med. 2011; 364 (11): 1027-36

14. HOVON/SAKK AML-42, Intermediate-dose Ara-C vs High-dose Ara-C
Intermediate dose
High dose
Logrank
N
431
429
F
260
251
P =0.87
Intermediate dose
High dose
At risk:
431
429
259
254
206
196
167
174
109
123
Intermediate dose
High dose
0
25
50
75
100
months0 60
Cumulativepercentage
Overall Survival
Intermediate dose
High dose
Logrank
N
431
429
F
288
281
P =0.79
Intermediate dose
High dose
At risk:
431
429
196
193
165
164
135
145
95
99
Intermediate dose
High dose
0
25
50
75
100
months0 60
Cumulativepercentage
Event-free Survival
Median follow-up of patients alive: 60 months

15. Ara-C dose response relationship in AML: adults <60 yrs of age
§ Dose level of Ara-C above 1000 mg/m2 confers excess toxicity with no gain in benefit.
§ Thus HD-Ara-C above 1000 mg/m2 implies an overdose, ie above plateau of the dose-
response relationship as regards antileukemic efficacy.

16. §
Cytarabine dose 3000 mg/m2 better than 100 mg/m2 or 400 mg/m2’
Phase III study
§ n= 742 pts less than 60 yrs age, 467 randomized (subgroup)
§ 4 consolidation cycles
§ 100 mg/m2 ci days 1-5 versus 400 mg/m2 ci days 1-5 versus 3000 mg/m2 3-hr infusion q
12 hrs days 1, 3, and 5
§ OS at 5 yrs: 52% versus 40% versus 35%
Ara-C dose level requirements in AML: consolidation
adults <60 yrs of age
Mayer et al, N Engl J Med 1994, 331: 896-903

17. Ara-C dose response relationship to AML genotype
§ CBF AML
§ Retrospective CALGB analysis – 57 pts over 3 arms
§ 3000 mg/m2 twice daily as compared with standard dose 100 mg/m2 and 400
mg/m2 cytarabine was
§ Bloomfield C et al Cancer Res 1998; 58: 4173-4179

18. §
Cytarabine dose 3000 mg/m2 better than 100 mg/m2 or 400 mg/m2’
Phase III study
§ n= 742 pts less than 60 yrs age, 467 randomized (subgroup)
§ 4 consolidation cycles
§ 100 mg/m2 ci days 1-5 versus 400 mg/m2 ci days 1-5 versus 3000 mg/m2 3-hr infusion q
12 hrs days 1, 3, and 5
§ OS at 5 yrs: 52% versus 40% versus 35%
Ara-C dose level requirements in AML: consolidation
adults <60 yrs of age
Mayer et al, N Engl J Med 1994, 331: 896-903
Toxic, and too toxic in pts above 60 yrs of age
Advantage apparent only in a subgroup analysis
3000 versus 400 versus 100 mg/m2
DNR at a suboptimal dose level of 45 mg/m2

19. Ara-C dose response relationship to AML CBF genotype :
Dose escalation above 1000 mg/m2 bid no benefit
§ Japanese JALSG AML 201 study – 218 pts
§ HDAC treatment 2000 mg/m2 versus conventional dose 200 mg/m2 cytarabine,
no difference as regards OS
§ Miyawaki S et al Blood 2011; 117 (8): 2366-2372
§ HOVON/SAKK study – 88 pts over 2 arms
§ 2000 mg/m2 twice daily as compared with 1000 mg/m2 cytarabine in one cycle
§ Lowenberg B et al. New Engl J Med 2011; 364: 1027-1036
§ SAL - AML study – 272 pts
§ HDAC treatment (3000 mg/m2) no better OS or DFS than 1000 mg/m2
cytarabine,
§ Schaich M et al. J ClinOncol. 2011; 29 (19): 2696-2702

20. Ara-C dose response relationship in AML: adults <60 yrs of age
Question at least in this era of active novel drug development: why
use a regimen of HDAC in AML at supramaximal dose levels ?

21. The anthracyclin dose issue
§ Our dogma’s ?

22. Anthracyclin dose level
Dauno 80-90 / Ida12 for induction

23. High-dose Dauno
HF. Fernandez et al. N Engl J Med 2009;361:1249-59.
• ECOG trial.
• 657 patients aged 60 years or
less (median, 48 years).
• Primary or therapy-related
AML.
• Dauno90 vs Dauno45
• Autologous or allogeneic
HSCT, according to AML risk.
• Higher CR rate.
• No delayed hematopietic recovery.
• Prolonged OS.
• No benefit in adverse-risk AML.
• No benefit over 50 years of age.
• No benefit in FLT3 or MLL ITD

24. High-dose Dauno
B. Löwenberg et al. N Engl J Med 2009;361:1235-48.
• HOVON-SAKK-AMLSG trial
• 813 patients aged 60 years or
more (median, 67 years)
• Primary or therapy-related
AML.
• Dauno90 vs Dauno45
• One IDAC consolidation
course.
• Higher CR rate.
• No delayed hematopietic recovery.
• Prolonged OS.
• No benefit over 65 years of age.
• Marked benefit in CBF-AML

25. Ida versus high-dose Dauno
S. Ohtake et al. Blood. 2011;117(8): 2358-2365
• JALSG trial
• 1,057 patients aged 65 years
or less (median, 47 years)
• de novo AML.
• Dauno 50x5 vs Ida 12x3.
• Similar CR rate.
• Similar RFS.
• Similar OS.

26. Alan K. Burnett et al.
Blood 2015;125:3878
Trial design AML17
DNR 60 vs 90

27. Daunorubicin dose randomization
60 versus 90 mg/m2
Alan K. Burnett et al. Blood 2015;125:3878

28. CONSORT diagram for AML17 daunorubicin dose randomization.
Alan K. Burnett et al. Blood 2015;125:3878

29. Anthracyclin dose level
Dauno 90 / Ida12 for induction (single)
Dauno 60 enough when embedded in a program with additional
Dauno

30. Autologous SCT for post remission consolidation in AML: an ignored option?
§ Our dogma’s ?

31. cycle III
autoSCT
Logrank
N
259
258
F
187
164
P =0.06
cycle III
autoSCT
11 Feb 2010-21:01:02
At risk:
259
258
114
126
87
108
74
97
62
82
cycle III
autoSCT
0
25
50
75
100
months0 60
Cumulativepercentage
AuSCT vs III consolidation
Event free survival
HOVON/SAKK AML 29 + 42
Autologous SCT vs chemo consolidation
Vellenga et al. Blood 2011
EFS

32. Kaplan-Meier estimates
of overall survival
probabilities after
complete remission
stratified according to
post remission therapy in
the AML96 trial in
PRT=post-remission
treatment..
Lancet Oncol. Pfirrmann et al, 2012 Feb;13(2):207-214. Epub 2011 Dec 22.
Prediction of post-remission overall
survival in acute myeloid leukemia
190 patients in the
favourable PRT
score group,
198 patients in the
intermediate PRT
score group
64 patients in the
unfavourable PRT score
autologous
allogeneic
chemothx
OS at 3
yrs 82%
OS at 3
yrs 62%
at 3 yrs 44%
and 41%
OS at 3
yrs 33%

33. 1,828 pa$ents aged 40-60 years included in
HOVON-SAKK 29, 42, and 92 studies
1,446 pa$ents obtained CR aCer 1 or 2
chemotherapy induc$on cycles
1,161 pts received post-remission treatment
525
chemotherapy
259
autoHSCT
243
alloMAB
181 alloRIC
285 received no post-
remission treatment
95 excessive toxicity
63 AML progression
54 early death
20 no compliance
8 hypoplasia
1 second cancer
44 unknown reasons
382 No CR aCer 2 cycles
*counted at risk in the transplant group as from day of transplant
Comparative therapeutic value of post-remission approaches in patients with
acute myeloid leukemia aged 40–60 years j.J. Cornelissen et al - Blood 2016;127:62

34. Overall survival of patients with AML intermediate-risk in CR1,
age 40 to 60 years, by type of postremission therapy
(HOVON-SAKK)
Jan J. Cornelissen - Blood 2016;127:62-70 setting

35. Ara-C 200mg/m2 d1-7c.i.
Idarubicin 12 mg/m2 3-hr d1-3
Ara-C 1000mg/m2 3-hr bid d1-6
Amsacrine 120 mg/m2 iv d4, 5, 6
R
Cycle III, autoSCT, alloSCT
Ara-C 200mg/m2 d1-7c.i.
Idarubicin 12 mg/m2 3-hr d1-3
Clofarabine days 1-5
Ara-C 1000mg/m2 3-hr bid d1-6
Amsacrine 120 mg/m2 iv d4, 5, 6
Clofarabine, assigned dose
iv days 1-5
HOVON-SAKK AML-102
phase III study in AML/RAEB, 18-65 yrs
Löwenberg et al. Blood 2017

36. HO102 (Cyto)genetic Risk
§
§
§ | Treatment arm
§ | Standard Clofa 10mg | Total
§ | [# and column %] |
§ -----------------------------|-------------------------|-----------
§ Total | 402 100% 393 100% | 795 100%
§
§ Risk AML (as in ELN 2010 criteria) (P=0.503, Chi2)
§ Favorable | 100 25% 83 21% | 183 23%
§ Intermediate-I | 114 28% 112 28% | 226 28%
§ Intermediate-II | 99 25% 112 28% | 211 27%
§ Adverse | 89 22% 86 22% | 175 22%
Löwenberg et al. Blood 2017; on line

37. AML Overall survival 18-65 yrs of age
Standard
Clofa 10mg
Logrank P =0.56
N
402
393
F
216
197
Standard
Clofa 10mg
At risk:
402
393
263
253
187
186
102
95
28
27
Standard
Clofa 10mg
0
25
50
75
100
Cumulativepercentage
months0 48
Treatment arm
Overall survival
OS at 4 yrs 44%
OS at 4 yrs 42%
Median age 55 yrs
No more than 3 cycles of therapy
Löwenberg et al. Blood 2017; on line

38. leukemia post remission
induction
‘7+3’ like chemothx
ARA-C + DNR/IDA
AML: Induction and Post Induction Therapy
induction
Chemothx 43%
Auto SCT 9%
Allo SCT 47%
707 CR
47% allo (n=331)
43% chemo (n=301)
9% Auto (n=66)

39. HO102 clinical endpoints
| Control Clofarabine
| [# and column %]
-------------------------------------------------------------
Patients randomized | 402 100% 393 100%
Complete remission (CR/CRi) | 355 88% 352 90%
CR attained with cycle I 267 67% 293 75%
CR attained after cycle II | 88 21% 59 15%
Early Death within 30 days of start
Yes | 18 4% 21 5%
Early Death within 60 days of start
Yes | 32 8% 33 8%
Survival and relapse probability at 4 yrs
Overall survival(±SD) | 42% (±2) 44% (±2)
Event-free survival | 35% (±3) 37% (±39)
Relapse probability | 38% (±3) 30% (±2)
Death in CR1
Probability at 12mo | 8% (±1) 12% (±2)

40. | Control Clofarabine
| [# and column %]
-------------------------------------------------------------
CR/CRi |
18-45 | 96% 98%
46-60 | 89% 88%
61-65 | 79% 83%
Death within 60 days
18-45 | 3% 0
46-60 | 9% 7%
61-65 | 12% 18%
HO102 age 18-45 (n=220); 46-60 (n=361); 61-65 (n=214)
Löwenberg et al. Blood 2017; on line

41. | Control Clofarabine
| [# and column %]
-------------------------------------------------------------
EFS at 4 yrs |
18-45 | 47% (±5) 54% (±5)
46-60 | 37% (±4) 38% (±4)
61-65 | 17% (±4) 24% (±5)
OS at 4 yrs |
18-45 | 60% (±5) 61% (±6)
46-60 | 45% (±4) 46% (±4)
61-65 | 20% (±4) 26% (±6)
Death in CR1 at 4 yrs
18-45 | 7% (±3) 9% (±3)
46-60 | 14% (±3) 18% (±3)
61-65 | 15% (±4) 28% (±5)
Relapse probability at 4 yrs
18-45 | 38% (±5) 33% (±5)
46-60 | 35% (±4) 29% (±4)
61-65 | 44% (±5) 30% (±4)
HO102 age 18-45 (n=220); 46-60 (n=361); 61-65 (n=214)

42. HOVON 103 – Elderly AML (65-84 yrs) - patients (n=222)
Overall Survival
ELN 2017 AML Recommendations:
Age alone should rarely be the sole
determinant of therapy
recommendation

43. Molecular classes of AML and concurrent gene mutations in adult
patients up to the age of ∼65 years.
Hartmut Döhner et al. Blood 2017;129:424-447

44. ELN Risk Classification 2017

45. Two types of C/EBPA mutations: in 5-8% of human AML,
often both alleles affected
42 kD 30 kD
bZIPTAD2TAD1
gene
Two types of mutations:
N-terminal
C-terminal
truncation
in frame insertion
or deletion in bZIP
N-terminal C-terminal

46. § Include all slide content in this area (text; images; graphs; tables; etc.)
§ This master slide MUST be used for all slides you submit.
§ Thank you in advance for adhering to this requirement.
Wouters et al, Blood 2009
Bi-allelic CEBPA mutations define a distinct AML subgroup
with a favorable prognosis

47. ELN Risk Classification 2017

48. Ara-C 200mg/m2 d1-7c.i.
Idarubicin 12 mg/m2 3-hr d1-3
Ara-C 1000mg/m2 3-hr bid d1-6
Amsacrine 120 mg/m2 iv d4, 5, 6
R
Cycle III, autoSCT, alloSCT
Ara-C 200mg/m2 d1-7c.i.
Idarubicin 12 mg/m2 3-hr d1-3
Clofarabine days 1-5
Ara-C 1000mg/m2 3-hr bid d1-6
Amsacrine 120 mg/m2 iv d4, 5, 6
Clofarabine, assigned dose
iv days 1-5
HOVON-SAKK AML-102
phase III study in AML/RAEB, 18-65 yrs
Löwenberg et al. Blood 2017

49. HO102

50. HO102 Subgroup OS –according molecular markers NPM1,
TP53, RUNX1, ASXL1 mutations
neg
pos
Cox LR P <.001
N
543
211
F
318
74
neg
pos
At risk:
543
211
332
160
226
134
121
76
34
32
neg
pos
0
25
50
75
100
Cumulativepercentage
months0 48
NPM1
Overall survival
neg
pos
Cox LR P <.001
N
552
57
F
275
50
neg
pos
At risk:
552
57
370
17
279
5
154
2
50
0
neg
pos
0
25
50
75
100
Cumulativepercentage
months0 48
TP53
Overall survival
neg
pos
Cox LR P =0.09
N
529
80
F
276
49
neg
pos
At risk:
529
80
344
43
250
34
139
17
47
3
neg
pos
0
25
50
75
100
Cumulativepercentage
months0 48
RUNX
Overall survival
neg
pos
Cox LR P =0.02
N
546
63
F
282
43
neg
pos
At risk:
546
63
350
37
262
22
146
10
46
4
neg
pos
0
25
50
75
100
Cumulativepercentage
months0 48
asxl1
Overall survival
P < 0.001 Log Rank P < 0.001 Log Rank
P = 0.02 Log RankP = 0.09 Log Rank
Overall Survival
Nucleophosmin-1 mutated AML
Overall Survival
TP53 deleted AML
Overall Survival
RUNX-1 mutated AML
Overall Survival
ASXL1 mutant AML

51. Welch JS et al. N Engl J Med 2016;375:2023.
Clinical Responses in Patients with TP53 Mutations.

52. Welch JS et al. N Engl J Med 2016;375:2023.
Correlation between Clinical Variables and Survival.

53. Organization of Mutations into Categories of Related Genes.
The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:2059-2074

54. Organization of Mutations into Categories of Related Genes.
The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:2059-2074
Signaling genes
(FLT3, KIT, RAS,
PTPN11)
DNA methyla$on
genes
(DNMT3A, TET2,
IDH1/IDH2)
Chroma$n modifiers/
Polycomb genes
(ASXL1, EZH2,
KMT2A, SUZ12)
Spliceosome
complex genes
(SRSF2, SF3B1,
U2AF1, ZRSR2)
DNA-repair/cellular
stress response/
tumor suppressor
genes
(TP53, PHF6)
Cohesin complex
genes
(STAG2, RAD21)
Nucleophosmin-1
gene
(NPM1)
Transcrip$on factor
genes
(RUNX1, CEBPA)

55. AML: Precision Medicine: pitfalls?.
The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:2059-2074
Majority are passenger events not providing any selective
benefit to the transformed cell
A small subset of these aberrations will represent driver
mutations
Leukemias inhomogeneous: multiple(sub) clones

56. Towards personalized therapy: Quo Vadis???

57. Precision Medicine: Pitfalls
Not targeting the right cells of the tumor (clones)
Not targeting the right cells of the tumor (leukemic stem cells)
Dealing with with smart escape mechanisms that tumors have
Disease monitoring needed

58. Co-existing leukemic cell clones
Diagnosis 1st Cycle 2nd Cycle CR Relapse
%
Courtesy: Gert
Ossenkoppele

59. Treatment: from start to finish
Cycle 1
1st cycle
--
Further therapy
? ? ? ?
? ? ?
Cycle 2
? ? ?
? ? ?
Cycle x
2nd cycle
cycle x

60. Relapse incidence aJer different therapy cycles and aJer cycle II in different risk
groups - FLOW CYTOMETRY - HOVON-42
After cycle 1 After cycle 2
After cycle 3 FAVORABLE RISK
INTERMEDIATE UNFAVORABLE RISK
Terwijn et al, J Clin Oncol 2013

61. Relapse incidence aJer different therapy cycles and aJer cycle II in different risk
groups - FLOW CYTOMETRY - HOVON-42
After cycle 1 After cycle 2
After cycle 3 FAVORABLE RISK
INTERMEDIATE UNFAVORABLE RISK
Terwijn et al, J Clin Oncol 2013
Flow cytometric MRD asssessment
Applicable to the majority
Profound prognostic significance
Independent of risk or molecular subtype
Dynamic in time

62. Ivey A et al. N Engl J Med 2016;374:422-433
OS Relapse
Relapse in AML
without FLT3-ITD
Relapse in AML
with FLT3-ITD
Relapse in AML
w/o DNMT3A mut
Relapse in AML
with DNMT3A mut
Ivey et al, NEJM 2016; 374(5):422-433
NPM1-mutant Minimal Residual Disease
Peripheral Blood after the Second Cycle of Chemotherapy and Clinical Outcomes

63. Risk stratification HO132 – MRD after cycle 2
MRD+ (>0.1%)
Terwijn et al., 2013
Immunophenotyping (LAIP) and RQ-
PCR mutant NPM1 AML
MRD+ (>0.1%)
Risk Group Criteria at diagnosis and early/late CR
Good t(8;21) or AML1-ETO, WBC≤20
inv16/t(16;16) or CBFB-MYH11
CEBPA-biallelic mutant+
FLT3ITD-/NPM1+
Intermediate CN –X –Y, WBC≤100, CRe
t(8;21) or AML1-ETO, plus WBC>20 or
mutant KIT
Poor CN –X –Y, WBC≤100, CRe
t(8;21) or AML1-ETO, WBC>20
and/or mutant KIT
CN –X –Y, WBC≤100, not CRe
CN –X –Y, WBC>100,
CA, but non-CBF, MK-, no abn3q26
Very Poor CN –X –Y, WBC>100
CA, but non CBF, MK-, no abn3q26,
EVI1-neg
MK+
abn3q26
Non CBF, EVI1+
Non CBF, mutant p53, mutant RUNX1,
mutant ASXL1
bi-allelic FLT3-ITD with FLT3-ITD/FLT3wt
ratio of >0.6

64. Minimal Residual Disease: What next ?
impact

65. Towards Personalized Medicine in Acute Myeloid Leukemia
§ Molecular diversity of the disease
§ Personalizing current treatment: monitorfing post treatment effect
§ Personalizing current treatment: drugs

66. Midostaurin: The RATIFY trial
o Randomized, placebo controlled trial of Midostaurin (PKC412) in
combination with chemotherapy in AML < 60 years
R.M. Stone et al. Blood 2015;126:6 (abstract)

67. Midostaurin: The RATIFY trial
Improvement in both OS and EFS in midostaurin treated patients:
5-years OS: 51% vs. 43%; p=0.007
Richard M. Stone et al. Blood 2015;126:6 (abstract)

68. Towards targeted treatment in acute myeloid leukemia
AML
Genetic characterization
IDH 1/2FLT3
Targeted treatment instructed by
genetic abberancies
Other/no mutations

69. Colleagues of HOVON-SAKK Dutch-Belgian and Swiss Leukemia Cooperative
Groups
Gert Ossenkoppele and numerous colleagues
My colleagues at Erasmus University Medical Center Rotterdam
Peter Valk, Mojca Jongen, Ruud Delwel, Ivo Touw, et al
Acknowledgements