Ideal induction regimen for AML in adolescents and young adults. Dr Swami Iyer

1. SWAMI IYER, MD
Houston, USA
• Associate Professor, Leader, early drug
development in Oncology, the Methodist Cancer
Center
• Dr Iyer is the Leader for Early Drug Development
Program in Hematology and Oncology at the Methodist
Cancer Center, Houston, Texas. He recently served as
the Director of Hematological Malignancies at CTRC,
and as an Assistant Professor of Medicine at the
University of Texas Health Science Center (UTHSCSA).
He is a physician scientist with laboratory interests in
Heat shock proteins and has extensive expertise in
clinical studies.

2. Considerations for AML treatment in
AYA.
Swami Padmanabhan Iyer, MD
Associate Professor, Weill Cornell Medical College
Houston Methodist Cancer Center

3. NCI Definition- adolescent and young adult (AYA)
are cancer patients between the ages of 15 to 29
years old when they first had a diagnosis of cancer)

4. Considerations for Treatment in
young patients with AML
• Overcome kinetics of AML- dose escalation
of chemotherapy,
• Addition of a third chemotherapeutic agent
• Are all younger age groups the same?
• Understanding the biology-TCGA
• Find the right targeted partners
• Consolidation Intensification
• Bone Marrow Transplantation

5. • 27 years old with WBC-34.6, Hgb-8.5 and platelets-
20K.
• Trilineage dysplasia, t(6,9) and Flt-3 ITD positive.
Patient A
10 1 10 2 10 3 10 4
CD33 PC -->
101102103104
CD13PE-->

6. Age-Specific Incidence
Rates for AML
0
5
10
15
20
25
30
35
00-04 05-09 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+
AverageAnnualRateper100,000
Male
Female
All persons
NCI SEER Program, 1995-1999.
Age (yrs)
1995-1998
• 80% of acute leukemia in adults
• Median age of AML = 64 years- Public health
• Incidence in USA rises by age group
• Most common cause of cancer death in young
*Rates are per 100,000 and are age-adjusted.

7. Age-Specific Incidence
Rates for AML

8. Survival in Adult AML by
Time Period
Kantarjian H, et al. Cancer. 2010;116:4896-4901.
Overall
< 60 yrs
≥ 60 yrs
1.0
0.8
0.6
0.4
0.2
0
0 1 2 3 4 5 6 7 8
Yrs
SurvivalProbability
Era
1960s
1970s
1980s
1990s
2000s
Total
104
530
652
1007
909
Died
103
492
586
849
560
P < .001
1.0
0.8
0.6
0.4
0.2
0
0 1 2 3 4 5 6 7 8
Yrs
SurvivalProbability
Era
1960s
1970s
1980s
1990s
2000s
Total
104
530
652
1007
909
Died
103
492
586
849
560
P < .001
1.0
0.8
0.6
0.4
0.2
0
0 1 2 3 4 5 6 7 8
Yrs
SurvivalProbability
Era
1960s
1970s
1980s
1990s
2000s
Total
39
166
263
495
486
Died
39
164
259
461
350
P < .001

9. Survival in AML by Age
group

10. Considerations for Treatment in
Adolescent Young Adults with AML
• Overcome kinetics of AML- dose escalation
of chemotherapy, third agent, intensification
• Find the right targeted partner
• Intensification and Consolidation
• Bone Marrow Transplantation

11. Remission Induction in the
young driven by the biology-
activating mutations
Cure
Clinically Detectable Disease
Induction Relapse Relapse
Time

12. Questions to consider
• What is the ideal induction therapy?
• What is the best anthracycline?
• What is the best dose of cytarabine?
• What is the ideal third agent?
• Are all younger age groups the same?
• What are the targeted agents?
• What is the best consolidation?

13. Considerations for Treatment in
young patients with AML
• Overcome kinetics of AML- dose escalation
of chemotherapy,
• Addition of a third chemotherapeutic agent
• Are all younger age groups the same?
• Understanding the biology-TCGA
• Find the right targeted partners
• Consolidation Intensification
• Bone Marrow Transplantation

14. Considerations for Treatment in
young patients with AML
• Overcome kinetics of AML- dose escalation
of chemotherapy,
• Addition of a third chemotherapeutic agent
• Are all younger age groups the same?
• Find the right targeted partner- Sorafanib and
Gemtuzumabd
• Consolidation
• Bone Marrow Transplantation

15. Recent Randomized Trials of
Dose-Intensification In AML
1. Fernandez HF, et al. N Engl J Med. 2009;361:1249-1259. 2. Lowenberg B, et al. N Eng J Med.
2009;361:1235-1248. 3. Pautas C, et al. J Clin Oncol. 2010;28:808-814. 4. Burnett AK, et al. ASH 2009.
Abstract 484. 5. Lowenberg B, et al. N Engl J Med. 2011;364:1027-1036.
Trial Agent Results
ECOG E1900[1] Daunorubicin
90 mg/m2/day x 3
45 mg/m2/day x 3
 Superior OS,CR with higher dose in pts < 60 yrs
 No benefit with higher dose if age ≥ 50 yrs,
adverse cytogenetics, or FLT3-ITD mutation
HOVON[2] Daunorubicin
90 mg/m2/day x 3
45 mg/m2/day x 3
 No significant difference in pts ≥ 60 yrs
 Superior OS, CR, EFS with high dose in patients
60-65 yrs
ALFA-9801[3] Idarubicin
12 mg/m2/day x 4 or x 3
Daunorubicin
80 mg/m2/day x 3
 Superior CR with idarubicin x 3 or x 4 vs
daunorubicin
 No significant differences in EFS, OS, or relapse
incidence
MRC AML15[4] FLAG-Ida
DA
ADE
 More durable CR with FLAG-Ida than with ADE or
DA, but higher initial toxicity; no survival benefit
HOVON/SAKK[5] High-dose cytarabine
Intermediate-dose cytarabine
 Remission, relapse, survival identical with high- vs
intermediate-dose cytarabine for remission
induction
 Is intermediate dose superior to “standard” dose?

16. Holoweicki et al, J Clin Onc April 2012
Cladribine better than
Fludarabine as third agent
A survival advantage of
the DAC arm vs. DA arm
was observed among:
• age 50 years or older
(P = .005),
• leukocyte count > 50 ×
109/L (P = .03), and
• unfavorable karyotype
(P = .03).

17. Pediatric vs.Adult Protocol

18. Treatment approaches in “standard
arm” in Phase III US studies

19. AYA differences between ALL and AML
procols

20. Considerations for Treatment in
young patients with AML
• Overcome kinetics of AML- dose escalation
of chemotherapy,
• Addition of a third chemotherapeutic agent
• Are all younger age groups the same?
• Understanding the biology-TCGA
• Find the right targeted partner- Sorefanib and
Gemtuzumab
• Consolidation
• Bone Marrow Transplantation

21. Considerations for Treatment in
young patients with AML
• Overcome kinetics of AML- dose escalation
of chemotherapy,
• Addition of a third chemotherapeutic agent
• Are all younger age groups the same?
• Find the right targeted partner
• Consolidation
• Bone Marrow Transplantation

22. Creutzig, et al. Cancer. 2007 562-571
Age Groups in AML- <30 years studies-
AML BFM 93/98, AMLCG 92/99 AML
HD93/98

23. Creutzig, et al. Cancer. 2007 562-571
Age Groups in AML- <30 years studies-
AML BFM 93/98, AMLCG 92/99 AML
HD93/98

24. Creutzig, et al. Cancer. 2007 562-571
Age Groups in AML- <30 years-EFS
by age group and cytogenetics

25. Tanner JA, et al. JCO suppl. 2009, Abstract#9506
MRC 10 study

26. AYA treated on Adult vs.
Pediatric protocols comparison
Woods et al. ASH 2001, Abstract#462

27. CCG2891 Intensive
vs.Standard Timing
Woods et al.Blood, 1996, 4979-4989

28. CCG2891 Intensive
vs.Standard Timing
Woods et al.Blood, 1996, 4979-4989

29. CCG2891 Intensive
vs.Standard Timing
Woods et al.Blood, 1996, 4979-4989

30. AYA treated on Adult vs. Pediatric
protocols- Conclusions

31. Is survival lagging
behind?

32. Considerations for Treatment in
young patients with AML
• Overcome kinetics of AML- dose escalation
of chemotherapy,
• Addition of a third chemotherapeutic agent
• Are all younger age groups the same?
• Understanding the biology-TCGA
• Find the right targeted partner- Sorefanib and
Gemtuzumab
• Consolidation
• Bone Marrow Transplantation

33. Cytogenetics by Age group –
Normal, CBF and 11q23

34. Grimwade. et al. Blood 1998,92-2322
MRC AML 10 clinical trial

35. TCGA Characterization of the-
“Blackbox”- Mutations in AML.
The Cancer Genome Atlas Research Network. N Engl J Med
2013;368:2059-2074.
• First recognized
somatic mutations-
Transcription factors
• DNMT3, NPM1,
CEBPA, IDH1/2 and
RUNX1 mutually
exclusive.
• Also for mutations in
certain biologic
classes- cohesins,
splicesosome,
signaling proteins
and histone
modifying proteins.
• TP53 worst outcome

36. Molecular risk-based therapies for AML
with normal karyotype are based on new
markers
• Favorable mutations
– NPM1: nucleophosmin member 1 gene
– CEBPA: CCAAT/enhancer binding protein alpha
– DNMT3
• Unfavorable mutations
– FLT3-ITD: internal tandem duplication of the fms-related tyrosine
kinase 3 (FLT3) gene
– MLL-PTD: partial tandem duplication of mixed-lineage leukemia
gene
– BAALC: brain and acute leukemia gene, cytoplasmic
– ERG: v-ets erythroblastosis virus E26 oncogene like (avian)
– WT1
– TP53
ASH Education Book 2006: Mrosek and Bloomfield

37. Prevalance of Mutations
by age
Grimwade. et al. Blood 1998,92-2322

38. Hollink. et al. Leukemia, 2009;23-262-270, Schnittger et.al Blood 2005, 106
NPM1

39. Frohling et al, Blood, 2002, Meschinchi et.al Blood, 2006
Age prevalence of FLT3
ITD

40. Overall survival for FLT-3
in AYA
Frohling et al, Blood, 2002, Meschinchi et.al Blood, 2006

41. CBF AML with and without
c-kit
Pollard et al, Blood 2010 and Paschka et al, JCO 2006

42. DNMT3A in AYA AML
Ostronoff et al,Leukemia 2012

43. NUP98-NSD1 cryptic
translocations

44. NUP98-NSD1 cryptic
translocation with FLT3 ITD
Ostronoff et al,ASH, 2012

45. Ostronoff et al,ASH, 2012
NUP98-NSD1 with FLT3 ITD in
COG AML- Outcome

46. Is survival lagging
behind?

47. Conclusions- Clinical Trials

48. • Psychosocial Challenges
• Fertility Issues
• Survivorship
Butow P et al.JCO,2010, 4800
Factors to consider in treating
AYA patients with AML

49. Conclusions- Participation in
Clinical Trials!!

50. Considerations for Treatment in
young patients with AML
• Overcome kinetics of AML- dose escalation
of chemotherapy,
• Addition of a third chemotherapeutic agent
• Are all younger age groups the same?
• Find the right targeted partner- Sorefanib,
Bortezomib, Gemtuzumab etc
• Consolidation
• Bone Marrow Transplantation

51. New Agents and
Strategies for AML
Mechanism of Action Drug
Amino acid depletion Tosedostat
FLT3 kinase inhibition Quizartinib, sorafenib
Modified chemotherapy
Liposomal formulation
Lipid conjugate
CPX-351
Elacytarabine
Topoisomerase II inhibition Vosaroxin
Epigenetic modulation Azacytidine/decitabine ± others
Polo-like kinase inhibitor Volasertib
Conjugated monoclonal antibody Gemtuzumab ozogamicin

52. Risk stratified COG AAML 1031

53. Guiding Light
‘From making the cure of the disease more
grievous than the endurance of the same, Good
Lord, deliver us.’
Sir Robert Hutchison, 20th century physician,
British Medical Journal, 1953; 1: 671.