1. Clinical Focus: Acute Promyelocytic Leukemia
Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC
Clinical Focus: Acute Promyelocytic Leukemia
Farhad Ravandi, MD
Professor of Medicine
Department of Leukemia
University of Texas
M. D. Anderson Cancer Center
Houston, Texas
This program is supported by an educational grant from
Image: Meullemiestre/Copyright©2012 Photo Researchers, Inc. All Rights Reserved

2. Acute Promyelocytic Leukemia
5% to 15% of all adult acute leukemias in the US
More common
Young/middle age adults
Hispanics and obese (BMI > 30)
Incidence worldwide: 0.6/106 people
FAB: AML M3
Caused by balanced translocation, usually t(15;17)
Chromosome 17
Chromosome 15
AML, acute myeloid leukemia; BMI, body mass index; FAB, French-American-British.
der 15 +
der 17
1. Chen Y, et al. Cancer. 2012;118: Wang ZY, et al. Blood. 2008;111:

3. APL Diagnosis: Pathology
Leukopenia
M3v often hyperleukocytosis
Circulating promyelocytes
Irregular azurophilic granules
Auer rods (bundle of sticks)
Bilobed or reniform nucleus
Immunophenotype
CD33+, CD13+
Neg/low: CD34, CD11b, CD117, HLA-DR
M3v (microgranular) often CD2+, CD34+
DIC common
APL, acute promyelocytic leukemia; DIC, disseminated intravascular coagulation.
3. Sanz MA, et al. Blood. 2009;113:

4. APL: Molecular Variants
PML-RARa+ insertions 4%
PML-RARa+ variants 2%
PZLF-RARa
t(11;17)(q23,q21)
0.8%
NPM-RARa
t(5;17)(q35,q21)
0.2%
NuMa-RARa
t(11;17)(q13,q21)
< 0.1%
Stat5b-RARa
der(17)
No RARa 1%
APL, acute promyelocytic leukemia; PML, promyelocytic leukemia; RARα, retinoic acid receptor alpha.
PML-RARa
t(15;17)(q22;q21)
92%
4. Grimwade D, et al. Leukemia. 2002;16:

5. Anti-PML Immunofluorescent Antibody Test (“POD” Test)
Sensitivity and specificity of 98.7% and 98.9%
APL, acute promyelocytic leukemia.
5. Dimov N, et al. Cancer. 2010;116:

6. APL Therapy: History 1960 1970 1980 1990 2000 HIGHLY FATAL
Discovery t(15;17) in APL
ATO frontline
ATRA therapy
First description:
Hyperacute fatal illness associated with hemorrhagic syndrome
Daunorubicin in APL
Differentiation of APL cells with RA
ATO in relapse
ATRA + ATO ± GO
In vivo leukemic cell differentiation
ATRA + CT
APL, acute promyelocytic leukemia; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CT, chemotherapy; GO, gemtuzumab ozogamicin.
HIGHLY FATAL
HIGHLY CURABLE
6. Chen Y, et al. Cancer. 2012;118: Nowak D, et al. Blood. 2009;113:

7. Survival Functions by Diagnosis Time Periods
Life Table Survival Curves
1.0
Log-rank P = .0002 x
0.8
0.6
Survival Probability
0.4
Diagnosis yr:
Diagnosis yr:
Diagnosis yr:
0.2 x 10 20 30
Survival Time (Mos)
8. Park JH, et al. Blood. 2011;118:

8. North American Intergroup Protocol I0129: DFS and OS
1.0
0.8
ATRA → CT
0.6
Probability of DFS
0.4
0.2
CT → CT
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5 Yr
1.0
ATRA, all-trans-retinoic acid; CT, chemotherapy; DFS, disease-free survival; OS, overall survival.
0.8
ATRA → CT
0.6
Probability of OS
0.4
CT → CT
0.2
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5 Yr
9. Tallman MS, et al. N Engl J Med. 1997;337:

9. North American Intergroup Protocol I0129
1.0
ATRA → CT → ATRA
0.8
ATRA→ CT → Observation
0.6
Probability of DFS
0.4
CT→ CT → ATRA
ATRA, all-trans-retinoic acid; CT, chemotherapy; DFS, disease-free survival.
CT = daunorubicin + cytarabine
ATRA→ CT →ATRA
ATRA→ CT →Observation
CT→ CT →ATRA
CT→ CT →Observation
0.2
CT→ CT → Observation
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0 Yr
10. Tallman MS, et al. N Engl J Med. 1997;337:

10. North American Intergroup Protocol I0129: Maintenance
1.0
0.8
0.6
ATRA
Probability of DFS
Observation
0.4
ATRA, all-trans-retinoic acid; DFS, disease-free survival.
0.2
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0 Yr
11. Tallman MS, et al. N Engl J Med. 1997;337:

11. ATRA + CT: Sequential vs Concurrent European APL Group: Relapse and EFS
1.0
1.0
0.8
0.8
0.7
0.7
0.6
0.6
0.5
0.5
Proportion of Patients Relapsing
Proportion of Patients Event Free
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
APL, acute promyelocytic leukemia; ATRA, all-trans-retinoic acid; CT, chemotherapy; EFS, event-free survival. 1 2 3 4 1 2 3 4
Yrs
Yes
Patients, n
101 93
Events, n 16 7
Patients, n
101 99
Events, n 32 19
ATRA → CT
ATRA + CT
ATRA → CT
ATRA + CT
Log-rank P = .04
Log-rank P = .10
16. Fenaux P, et al. Blood. 1999;94:

12. Cumulative Incidence of (A) Relapse, (B) EFS, and (C) OS by Ara-C or No Ara-C
1.0
1.0
1.0
0.8
0.8
0.8
P = .011
0.6
0.6
0.6
Cumulative Incidence of First Relapse
Ara-C
No Ara-C
EFS
Ara-C
No Ara-C OS
Ara-C
No Ara-C
0.4
0.4
0.4
P = .0066
0.2
Ara-C, cytarabine; EFS, event-free survival; OS, overall survival.
0.2
0.2
P = .0021 10 20 30 40 50 10 20 30 40 50 10 20 30 40 50
Mos
Mos
Mos
17. Ades L, et al. J Clin Oncol. 2006;24:

13. Cumulative Incidence of (A) Relapse, (B) EFS, and (C) OS of Younger Pts With WBC > 10 x 109/L
1.0
1.0
1.0
0.8
0.8
0.8
0.6
0.6
0.6
Cumulative Incidence of First Relapse
EFS OS
0.4
0.4
0.4
0.2
EFS, event-free survival; OS, overall survival; WBC, white blood cell.
0.2
0.2 10 20 30 40 50 10 20 30 40 50 10 20 30 40 50
Mos
Mos
Mos
18. Ades L, et al. J Clin Oncol. 2006;24:

14. ATO in Relapsed Disease: OS and RFS
100
100 80 80 60 60
Patients Achieving OS (%)
Patients Achieving RFS (%) 40 40
ATO, arsenic trioxide; OS, overall survival; RFS, relapse-free survival.
At Risk, n
Deaths, n
18-Mo OS, %
At Risk, n
Deaths, n
18-Mo OS, % 20 20 6 12 18 24 30 6 12 18 24 30
Mos
Mos
19. Soignet SL, et al. J Clin Oncol. 2001;19:

15. 5-Yr KM Product Limit Estimate of (A) OS of the Entire Cohort (N = 72)
1.0 B
1.0
74.2 ± 5.2%
0.8
0.8
69 ± 5.5%
0.6
0.6
OS (Proportion)
EFS (Proportion)
0.4
0.4
0.2
0.2 24 48 72 96
120
144 24 48 72 96
120
144 C
1.0
GR (n =11) D
1.0
GR (n = 22)
100 ± 0%
0.8
IR (n = 45)
0.8
0.6
0.6
HR (n =50)
EFS (Proportion)
OS (Proportion)
63 ± 7%
0.4
HR (n = 16)
0.4
0.2
0.2
DFS, disease-free survival; EFS, event-free survival; GR, good-risk group; HR, high-risk group; IR, intermediate-risk group; KM, Kaplan-Meier; OS, overall survival.
P = .158
P = .003 24 48 72 96
120
144 24 48 72 96
120
144 E
1.0 F
1.0
(n = 23)
0.8
91 ± 6%
0.8
0.6
(n = 39)
Cumulative Incidence of Relapse (Proportion)
0.6
DFS (Proportion)
73.5 ± 7.2%
0.4
0.4
0.2
0.2
P = .062 24 48 72 96
120
144 24 48 72 96
120
144
Mos
Mos
20. Mathews V, et al. J Clin Oncol. 2010;28:

16. DFS and OS for 197 New Cases of Acute Promyelocytic LeukemiaB
1.0
1.0
0.8
0.8
0.6
0.6
DFS (Proportion)
OS (Proportion)
0.4
0.4
DFS, disease-free survival; OS, overall survival.
0.2
0.2 20 40 60 80
100
120 20 40 60 80
100
120
Mos
Mos
21. Ghavamzadeh A, et al. J Clin Oncol. 2011;29:

17. DFS With 1 Consolidation Course vs 4 Consolidation Courses
1.0
1 consolidation course
4 consolidation courses
0.8
0.6
DFS (Proportion)
0.4
DFS, disease-free survival.
0.2 20 40 60 80
100
120
Mos
22. Ghavamzadeh A, et al. J Clin Oncol. 2011;29:

18. PML-RARα Negative Post CR %
ATRA + ATO
Study N
CR, %
PML-RARα Negative Post CR %
EFS/DFS/RFS,
OS,
Hu et al
China 85 94 NR 89
(5-yr DFS) 91
(5-yr)
Ravandi et al MD Anderson 82
90*
100 80
(2-yr RFS)
(2-yr)
Dai et al 90 93 92
(3-yr EFS)
ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete remission; DFS, disease-free survival; EFS, event-free survival; NR, not reported; OS, overall survival; PML, promyelocytic leukemia; RARα, retinoic acid receptor alpha.
*95% in low risk, 81% in high risk.
23. Hu J, et al. Proc Natl Acad Sci U S A. 2009;106: Ravandi F, et al. J Clin Oncol. 2009;27: Dai CW, et al. Acta Haematol. 2009;121:1-8.

19. Gemtuzumab Ozogamicin
CD33 conjugated to calicheamicin
CD33 heavily expressed on APL cells
Single agent
Induced molecular response in high proportion of relapsed patients
ATRA + gemtuzumab ozogamicin (19 patients)
84% CR
Remissions more durable than ATRA alone
APL, acute promyelocytic leukemia; ATRA, all-trans-retinoic acid; CR, complete remission.
26. Takeshita A, et al. Leukemia. 2005;19: Estey EH, et al. Blood : Lo-Coco F, et al. Blood. 2004;104:

20. Kaplan-Meier Curve of EFS and OS for the Entire Group
1.0 +
0.8
0.6
Survival (Probability)
0.4
EFS, event-free survival; OS, overall survival.
Survival OS
EFS
Patients, n
82 82
Events, n 13 14
0.2 52
104
156
208
260
Wks
29. Ravandi F, et al. J Clin Oncol. 2009; 27:

21. ATRA + ATO ± GO: Longer Follow-up
1.0
0.8
0.6
Survival Probability
0.4
ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; GO, gemtuzumab ozogamicin.
Survival
Overall Remission
Event Free
Total
104
102
Events 10 5 13
0.2 52
104
156
208
260
312
364
416
Wks
30. Ravandi F, et al. ASH Abstract 1080.

22. PML-RARα newly diagnosed APL
ATRA/CT → ATO vs ATRA/CT in Newly Diagnosed APL Intergroup Protocol C9710
PML-RARα newly diagnosed APL
confirmed by RT-PCR
(N = 480,
adults)
RANDOMIZED
ATRA
Ara-C
Daunorubicin
ATO x 2
ATRA
DNR
x 2
RANDOMIZED
ATRA CR
ATRA
Ara-C
Daunorubicin
ATRA
DNR
x 2
ATRA
6-MP
MTX
APL, acute promyelocytic leukemia; Ara-C, cytarabine; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete remission; CT, chemotherapy; IV, intravenous; MTX, methotrexate; PCR, polymerase chain reaction; PML, promyelocytic leukemia; PO, orally; RARα, retinoic acid receptor alpha; RT, reverse transcriptase; 6-MP, 6-Mercaptopurine; DNR, daunorubicin.
Induction
Consolidation
Maintenance
Agent
Induction
Consolidation
Maintenance
ATRA
45 mg/m2 PO on Days 1-CR
45 mg/m2 PO on Days 1-7
45 mg/m2 PO on Days 1-7 every other wk
Ara-C
200 mg/m2 IV on Days 3-9
DNR
50 mg/m2 IV on Days 3-6
50 mg/m2 IV on Days 1-3
ATO
0.15 mg/kg 5 days/wk x 5 wks
6-MP
60 mg/m2/day PO
MTX
20 mg/m2 once/wk
31. Powell BL, et al. ASCO Abstract 2.

23. EFS by Treatment and Risk Group
Event-Free Survival
EFS by Treatment
EFS by Treatment and Risk Group
1.0
1.0
0.8
0.8
0.6
0.6
EFS (Proportion)
EFS (Proportion)
0.4
0.4
0.2
0.2
EFS, event-free survival. 6 18 30 42 54 66 78 90
102
114 6 18 30 42 54 66 78 90
102
114
Mos From Study Entry
Mos From Study Entry
Arsenic No arsenic
n = 244
n = 237
Events: 51
Events: 97
Log-rank
P < .0001
Arsenic low/inter risk No arsenic low/inter risk
Arsenic high risk
No arsenic high risk
n = 189
n = 179
n = 55
n = 58
Events: 31
Events: 59
Events: 20
Events: 38
32. Powell BL, et al. Blood. 2010;116:

24. Disease-Free Survival
DFS by Treatment
DFS by Treatment and Risk Group
1.0
1.0
0.8
0.8
0.6
0.6
DFS (Proportion)
DFS (Proportion)
0.4
0.4
0.2
0.2
DFS, disease-free survival. 6 18 30 42 54 66 78 90
102
114 6 18 30 42 54 66 78 90
102
114
Mos From Study Entry
Mos From Study Entry
Arsenic No arsenic
n = 213
n = 211
Events: 22
Events: 72
Log-rank
P < .0001
Arsenic low/inter risk No arsenic low/inter risk
Arsenic high risk
No arsenic high risk
n = 172
n = 163
n = 41
n = 48
Events: 16
Events: 44
Events: 6
Events: 28
33. Powell BL, et al. Blood. 2010;116:

25. OS for All 481 Randomized Patients by Treatment Arm
OS by Treatment
1.0
0.8
0.6
OS (Proportion)
0.4
0.2
OS, overall survival. 6 18 30 42 54 66 78 90
102
114
Mos from Study Entry
Arsenic No arsenic
n = 243
n = 236
Events: 38
Events: 54
Log-rank
P = .059
34. Powell BL, et al. Blood. 2010;116:

26. Kaplan-Meier Survival Curves
100
100
100 80 80 80 60 60 60
Low Intermediate
High
Alive and Failure Free (%)
APML4
Surviving (%)
APML4
Alive and Failure Free (%) 40 40 40
14 failures in 124 patients 2-yr FFS: 88.1% 95% CI: 80.7% to 92.8%
7 deaths in 124 patients 2-yr OS: 93.2% 95% CI: 85.8% to 96.8% 20 20 20
P (trend) = yr FFS: 97%, 88%, 76% 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5
ATRA, all-trans-retinoic acid; CI, confidence interval; FFS, failure-free survival; OS, overall survival.
Yrs From Start of ATRA Therapy
Yrs From Start of ATRA Therapy
Yrs From Start of ATRA Therapy
Pts at Risk, n 124
Pts at Risk, n 124
Pts at Risk, n 32 67 24 77 51 26 11 1 86 57 28 12 1
Low
Inter
High 20 45 11 10 31 9 7 13 6 2 7 1
35. Iland HJ, et al. Blood. 2012;120:

27. Overall Survival 98.7% 100 91.1% 75 ATRA + ATO ATRA + chemo
OS Probability 50
P = 0.02
ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; OS, overall survival. 25 12 24 36 48 60
Mos From Diagnosis
37. Lo-Coco F, et al. ASH Abstract 6.

28. Minimal Residual Disease Monitoring in APL
Best done by QT-PCR for PML-RARα
Frequently positive at the time of achieving CR
Must become negative after consolidation
Best monitored by bone marrow initially
Peripheral blood can be substituted later
APL, acute promyelocytic leukemia; CR, complete remission; PCR, polymerase chain reaction; PML, promyelocytic leukemia; RARα, retinoic acid receptor alpha, QT, quantitative.

29. Therapy-Related APL 1.0 ATRA ± ATO ATRA ± Chemo 0.8 0.6 P = .35 0.4
Survival Probability
0.4
APL, acute promyelocytic leukemia; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid.
0.2 12 24 36 48 60 72 84 96
108
120
132
Mos
38. Dayyani F, et al. Cancer. 2011;117:

30. Treatment of Relapsed APL
European registry of ATO in relapsed APL (7 countries)
69 pts in first relapse (25 molecular, 42 hematologic, 2 isolated CNS/EMD)
All treated with ATO
Second molecular CR higher (and complications less—no coagulopathy, no hyperleukocytosis, no DS) with induction after molecular relapse rather than hematologic
Importance of serial monitoring
APL, acute promyelocytic leukemia; ATO, arsenic trioxide; CNS, central nervous system; CR, complete remission; EMD, extrameduallary disease; DS, differentiation syndrome.
39. Lengfelder E, et al. ASH Abstract 15.

31. GO in APL Salvage OS Treated With GO in APL and AML RFS Treated With
100
100 90
Log-rank P ≤ .0001 90
Log-rank P = .0074 80 80
APL 70 70
APL 60 60
OS (%) 50
RFS (%) 50 40 40
APL, acute promyelocytic leukemia; AML, acute myeloid leukemia; GO, gemtuzumab ozogamicin; RFS, relapse-free survival; OS, overall survival. 30 30
Non-APL
Non-APL 20 20 10 10 6 12 18 24 6 12 18 24
Mos
Mos
40. Takeshita A, et al. ASH Abstract 1532.

32. Remaining Challenges Early diagnosis to avoid early mortality
20% to 30% of patients relapse
Extramedullary disease
Therapy-related MDS
Delayed cardiomyopathy
Special populations
Elderly patients
Cardiac patients
Underserved populations
MDS, myelodysplastic syndromes.