Basis of standard treatment, landmark trials, newer therapy and future prospects of treatment of Acute Myeloid Leukemia

1. “AML”
How can we improve
upon standard
therapy?
Dr. Pritish Chandra Patra
Moderator: Dr. Shuvra Neel Baul 24/04/18

2. Outline
• Introduction
• Epidemiology
• History
• Trials and errors
• Targeted therapies
• Elderly patients
• Pediatric patients
• Conclusion
2

3. Introduction
AML: The Impending Doom 3

4. Introduction
• AML- a molecularly and clinically heterogeneous disease
• Despite many advances- standard therapy remained nearly
unchanged over the past four decades
• Poor survival for older and high risk patients and high
relapse rates
• Multiple studies are ongoing
• Novel therapies- changes in conventional cytotoxic
chemotherapies, genetic and epigenetic targeted drugs and
immunotherapies have been developed in recent years
4

5. Epidemiology
The morbid odyssey 5

6. Epidemiology: Data from SEER
6

7. Data from SEER
5 Year survival: Acute Myeloid Leukemia
7

8. Data from peers
8

9. ICMR Data: AML
• Annual incidence: 2-3 per 100,000
• Incidence increases with age
• < 1per 100,000 under 30 years of age
• 17 per 100,000 by 75 years of age
• In children:
• <10% of AL below 10 years of age
• 25-30% between 10-15 years
• In adults: 80-90% of AL
• Incidence in Males > Females
• As per Delhi population based Cancer Registry:
• AML constitutes about 3% of all cancers
9

10. National Cancer Registry Data:
Number of Incident Cancers by Five Year Age Group and Site: 2012-2014 in Kolkata
Male
Female
10

11. History
11
REGIMEN

12. Standard therapy for AML
12

13. Milestones
13

14. Trials & Errors
The Martials & The Martyrs
14

15. Case 1
• A 33 year male
• Presented with weakness, exertional dyspnea, fever and
gum bleed for 3 weeks
• O/E: Febrile with wet purpura
• No HSM or LN, bone pain present
• Chest: B/L VBS+
• CBC:
• Hb: 6.9 gm%
• TC: 98000/cu mm, 95% blast
• Platelet: 10000/cu mm

16. Case 1
• BMA: hypercellular with 95% blast
• IPT: AML
• Cytogenetics: 45 XY, t(3; 3)
• Molecular markers:
• NPM1: Negative
• Biallelic CEBPA: Negative
• FLT3-ITD: positive with high allelic burden (>0.5)
• Diagnosis: AML, adverse risk, with isolated FLT3
mutation

17. Anthracyclines
17
(3+7):D45 Vs D90
ECOG: 2009
CR: 70.6% Vs 57.3%, p<.001
OS: 23.7m Vs 15.7m, p=.003
(3+7):D90 Vs D60
MRC: 2014
CR (73% vs 75%, p = .6)
Death (10% vs 5%, p = .001)
OS 2yr (59% vs 60%, p = .15)
Meta-analysis of 29 RCTs
BJH: 2013
IDA >> DNR: CR, =Death
HD >> LD DNR: CR, Death
DA Vs DAClad Vs DAFlu
Polish Adult Leuk Grp 2012
DA Vs DAC
CR: 68% Vs 56%, p=.01
OS 3yr 45% vs 33%, p=.02
Clforabine+IA Vs IA(Historical)
MDACC: 2013
EFS, OS
FLAG-Ida Vs ADE
AML 15
CR, Death
No OS benefit

18. Cytarabine
18
12.L¨owenberg B, et al. NEJM. 2011;364(11):1027-1036.
13. Willemze R, et al. EORTC-GIMEMA AML-12 trial.JCO. 2014;32(3):219-228.
14. B¨uchner T, et al.JCO. 2012;30(29):3604-3610.

19. 19

20. 20
The vast molecular landscapeThe vast molecular landscape

21. Getting Precision
21
Hitting the Target

22. Novel agents
22
FDA APPROVALS IN 2017
Gemtuzumab Ozogamicin
Midostaurin
Enasidenib
CPX-351 (Vyxeos)

23. 23
GO
FDA approved on 1st SEP 2017:
Indications:
Adults with newly diagnosed CD33+ AML
≥ 2 yrs with CD33+ RR AML

24. GO: ALFA 0701 Trial
24
3+7+GO
(3mg/m2
d1,4,7)
Cyt:200mg/m2
DNR:60mg/m2
3+7
Cyt:200mg/m2
DNR:60mg/m2
2 x Consoliation
Cyt:1g/m2 BD x d1-4
DNR:60mg/m2 x 1/2 d
+GO (3mg/m2 d1)
Cyt:1g/m2 BD x d1-4
DNR:60mg/m2 x 1/2 d
Induction
Phase 3 RCT
de novo AML
50-70yrs
n=280
CR
CR
Lancet 2012; 379: 1508–16

25. 25
Per protocol analysis:
Estimated median EFS:
17.3m for chemo + GO
vs.
9.5m for chemo alone
GO: ALFA 0701 Trial

26. GO: AML-19 Trial
Phase 3 RCT
de novo or sAML
>75 or 61-75yrs + ECOG>2 or
unwilling
n=237
GO alone Vs BSC
26
GO
6mg/m2 d1
and
3mg/m2d8
BSC
8 x Continuation
GO
2mg/m2 d1 of
every 4 weeks
Hydroxyurea to keep
WBC ≤20,000/mm3
Induction
Median OS: 4.9m vs 3.6m
(HR: 0.69; 95% CI: 0.53-0.90; P= 0.005)
J Clin Oncol 34., 2016

27. FLT-3
inhibitors
Midostaurin: FDA approved on April’17
Indications: Adult de novo AML: FLT3+
Mol Cancer Ther. 2017 Jun; 16(6): 991–1001
FLT-3 Inhibitors Type1 Type2
1st Gen
Sunitinib Sorafenib
Midostaurin Ponatinib
Lestaurtinib Tandutinib
2nd Gen
Crenolanib Quizartinib
Glitertinib

28. SORAML trial: Sorafenib
28
Phase 2 RCT
18-60 yrs
de novo AML
N=267
134
133
Lancet Oncol, November 5, 2015
400 mg BD
Placebo Vs Sorafenib
Estimated EFS 9m Vs 21m
EFS 3yr 22% Vs 40% P=0.013
RFS 38% Vs 56% P=0.017
OS No benefit
AE fever, diarrhea,
bleeding, cardiac
events, hand-foot-skin
reaction, rash

29. 29
RCT
Older patients: 61–80 years
N=201
no improvement in EFS, CR, and OS
higher early mortality (17 Vs 7%, P = 0.052) Vs placebo

30. RATIFY trial: Randomized AML Trial In
FLT3 in patients less than 60 Years old
(3+7)+
Midostaurin
50 mg PO BD 8-21
(n= 360)
(3+7)+
Placebo
D8-21
(n = 357)
HiDAC(3gm/m2)+
Midostaurin
50 mg PO BID D8-21
(n = 231)
HiDAC(3gm/m2)+
Placebo
D8-21
(n = 210)
Midostaurin
50 mg PO BID D1-28
(n = 120)
Placebo
D1-28
(n = 85)
Stratified by
ITD/TKD,
randomized
Induction*
(1-2 cycles)
Consolidation
(up to 4 cycles)
Maintenance
(12 cycles)
CR
CR
*Hydroxyurea allowed for
≤ 5 days prior to induction
Phase 3, double blind RCT
de novo AML with FLT3
18-60 yrs of age
n=717
Midostaurin+(3+7) Vs Placebo
Primary endpoint: OS
Secondary endpoint: EFS
CR
Exclusion criteria:
Not tAML
Bilirubin > 2.5x ULN
Absence of other major coexisting illnesses
N Engl J Med 2017;377:454-64.

31. 31
Summary of Complete Remission
Variable Midostaurin
(N = 360)
Placebo
(N = 357)
P Value
CR (by d60) 212 (59%) 191 (54%) 0.15
Midostaurin in FLT3+ AML: RATIFY trial
N Engl J Med 2017;377:454-64.
Median follow-up: 59 months
Deaths:
5% (18/360) in midostaurin vs 5.3% (19/357) in placebo
Causes:
infection (4 midostaurin, 7 placebo)
pneumonitis (3 midostaurin, 0 placebo)
CNS hemorrhage (1 midostaurin, 2 placebo)

32. IDH2 Inhibitor: Enasidenib (AG-221)
• U.S. FDA approved on 1 August/ 2017
• Indication: R/R adult AML with IDH2 mutation
• Mutated IDH2 observed in 10% to 13% of pts with AML

33. 33

34. Enasidenib in IDH2-Mutant R/R AML: OS
OS in R/R AML Pts (n = 176)
OS by Best Response in R/R AML Pts (n = 176)
Stein EM, et al. ASCO 2017. Abstract 7004
27
Mos
Median OS: 9.3 mos (95% CI: 8.2-10.9)
SurvivalProbability
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 3 6 9 12 15 18 21 24
Censored
SurvivalProbability
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Median OS, Mos (95% CI)
19.7 (11.6-NE)
13.8 (8.3-17.0)
7.0 (5.0-8.3)
CR
Non-CR response
No response
Censored
Mos
0 3 6 9 12 15 18 21 24 27
Enasidenib currently being compared vs conventional care in phase III IDHentify study

35. CPX-351: Vyxeos: Secondary AML

36. CPX-351: Vyxeos
36

37. First-line CPX-351 in High-Risk AML: Study Design
• Primary endpoint: OS
• Secondary endpoints: EFS, CR + CRi, 60-day mortality
CPX-351 Induction, 1-2 Cycles
100 units/m2
C1: Days 1,3,5; C2: Days 1,3
(n = 153)
7 + 3 Induction, 1-2 Cycles
Cytarabine: 100 mg/m2/day
Daunorubicin: 60 mg/m2
C1: Ara-C, 7 days; Daun, 3 days
C2: Ara-C, 5 days; Daun, 2 days
(n = 156)
Until death
or 5-yr
follow-up
Lancet JE, et al. ASCO 2016..
*tAML; AML with h/o MDS ± prior HMA therapy or CMML; de novo AML with
MDS karyotype
Phase 3 Randomised
High Risk AML*
60-75 yrs of age
ECOG PS 0-2
ability to tolerate intensive therapy
(N = 309)

38. First-line CPX-351 in High-Risk AML: Efficacy
• Median follow up: 13.7m
Lancet JE, et al. ASCO 2016. .
Outcome
CPX-351
(n = 153)
7 + 3
(n = 156)
HR
Odds Ratio
(95% CI)
P
Value
Median OS,
months
(95% CI)
9.56
(6.60-11.86)
5.95
(4.99-7.75)
0.69 NA 0.005
Median EFS,
months
(95% CI)
2.53
(2.07-4.99)
1.31
(1.08-1.64)
0.74 NA 0.021
Response, %
CR
CR + CRi
37.3
47.7
25.6
33.3
NA
NA
1.69
(1.03-2.78)
1.77
(1.11-2.81)
0.04
0.016
60days
Mortality
13.7% 21.2%
Grade 3 to 5 adverse events (AEs)
CPX-351 Vs (3+7)
Febrile neutropenia (68% vs 71%)
Pneumonia (20% vs 15%)
Hypoxia (13% vs 15%)
Sepsis (9% vs 7%)
Hypertension (10% vs 5%)
Respiratory failure (7% each)
Fatigue (7% vs 6%)
Bacteremia (10% vs 2%)
Ejection fraction decreased (5% each)

39. The Difficult ones
Elderly & Pediatric patients 39

40. Case 2
• A 65 year old gentleman presented with fever and
progressive respiratory distress since 3 weeks.
• No bleed
• No LN & HSM
• ECOG: 2
• Co-morbidities: HTN, COPD
• CBC:
• Hb: 7.9 gm/dl
• TC: 21900, Blast 60%
• Platelet: 45000/cu mm

41. Case 2
• BMA: 80% blast
• IPT: AML with aberrant CD19
• Cytogenetics: 46 XY, t(8;21)
• Molecular markers: all negative
• NPM1
• Biallelic CEBPA
• FLT3-ITD & TKD
• Diagnosis: AML, Standard risk with HTN with suspected
fungal pneumonia

42. Older patients
• Generally: > 60 to 65 yrs
• Patient related factors (comorbidities)
• Disease related factors (chemo-resistance, sAML)
• Except for very old patients over the age of 80 to 85 yrs old,
age alone is not a good criterion for fitness assessment
• Comorbidity
• Cardiac, renal & liver functions & ECOG
• Charlson Comorbidity Index
• Hematopoietic Cell Transplantation Comorbidity Index
42

43. Recommendations
43
ELN 2017
ASH 2017
Aza: FDA & EMA, for adult patients not eligible for HCT with AML with 20%-30% blasts and multilineage dysplasia; in addition, approved by EMA for
patients who are not eligible for allogeneic HCT with AML with >30% marrow blasts
DAC: Approved by EMA (not by FDA) for patients with newly diagnosed de novo or sAML, who are not candidates for standard induction
chemotherapy

44. Case 3
• A 12 year old male presented with on and off fever
and proptosis
• No history of gum bleed
• No HSM or LN present
• CT Orbit: mass in left orbit
• CBC:
• Hb: 8.2 gm%
• TC: 24500, Blast 70%
• Platelet: 50000/cu mm

45. Case 3
• BMA: hypercellular with 80% blast
• IPT: AML, B & T markers negative
• Cytogenetics: 46, XY
• AML Panel: Negative for t(8;21), t(15;17), Inv16
• Molecular markers:
• NPM1 Negative
• Biallelic CEBPA: Negative
• FLT3-ITD: Negative
• Diagnosis: AML, intermediate risk, with granulocytic
sarcoma (left orbit)

46. Pediatric AML
46

47. Comparison
47

48. Allogenic HSCT
48
Standard risk Intermediate risk Poor risk
Long term survival
50-60%
HSCT not rec. in CR1
c-KIT mutation:
poor survival
relapse rate  poor risk
Long term survival
40-50%
FLT3-ITD mutant level
high levels Low levels
AR ≥0.5 AR <0.5
lower CR
clinically 
FLT3-ve
poor survival
HSCT
Long term survival
10-15% MK: 3-4%
HSCT:MSD/MUD
Long-term survival
30–40% 15%
TOC for
<60 years
Relapse
risk: 15%

49. Future Prospects
Novel combinations of drugs

59. Novel drugs:
at a glance

60. 60

61. 61

62. Have we reached?

63. 63
Thank You