1. Pierre Fenaux (Hopital Avicenne,Paris 13 University)
APL
Pierre Fenaux
(Hopital Avicenne,Paris 13 University)

2. Etiology of APL
About 10% of AML (about 130 new cases/year in France,probably more than 2000/year in India)
Incidence depending on ethnic (or environmental) factors
More and more often therapy related (after brest carcinoma)

3. APL characteristics Morphology:M3, M3v
Cytogenetics: t(15;17) (t(11;17,t(5;17) very rare)
complex or variant translocations
molecular biology:PML-RAR (bcr1> bcr2>bcr3)
others (PLZF-RAR,etc very rare)
Coagulopathy:DIC+fibrinolysis

4. Prognostic factors in APL
WBC >10000/mm3 (and platelets<40000/mm3) (Sanz score)
RT-PCR analysis after consolidation treatment (but depends on sensitivity of the assay used)
other factors (M3v,bcr breakpoint….:generally redundant with WBC count))

5. Treatment of APL APL sensitive to Anthracycline+/- AraC chemotherapy
ATRA
Arsenic derivatives

6. « classical » treatment
Treatment of APL
« classical » treatment
Treatment with no or limited amount of chemotherapy?

7. « Classical » treatment of APL?
1)Newly diagnosed APL
2)Relapsing APL
3)Specific situations
Children
Elderly patients

8. Newly diagnosed APL :
Induction and consolidation treatment should combine ATRA and anthracycline based chemotherapy:
Slightly increases the CR rate (from 80 to>90%)
considerably reduces relapses (from 50 to 25%)

9. Newly diagnosed APL Remaining issues:
1)with ATRA chemotherapy combinations
-when to start chemotherapy?
-anthracycline alone or with AraC?
-prophylaxis and treatment of « ATRA syndrome »?
- treatment of coagulopathy?
-CNS prophylaxis?
-maintenance treatment
2)introduction of new agents (Arsenic,gentuzumab GO)
3)Role of allo SCT in first CR

10. When should chemotherapy be started?

11. APL 93:INDUCTION TREATMENT.
WBC  5000/mm3 and age  65:
ATRA followed by chemotherapy
ATRA CT group R
ATRA + chemotherapy
started day 3
ATRA + CT group
ATRA : 45 mg/m2/d until CR
chemotherapy : daunorubicin (DNR) 60 mg/m2/d d1-3
AraC mg/m2/d d1-7

12. CONSOLIDATION AND MAINTENANCE TREATMENT
no maintenance
chemotherapy
.6 mercaptopurine
(90 mg/m2/day)
. methotrexate
(15 mg/m2/week)
AraC 200 mg/m2/d d AraC 1g/m2/12h d 1-4 R
DNR 60 mg/m2/d d DNR 45 mg/m2/d d 1-3
intermittent ATRA
patients < 65 years
45 mg/m2/d
15 days/ 3 months
patients years
both
2 years

13. Patients randomized for induction
ATRACT ATRA+CT p n
CR (%)
Relapse
at 5 years (%)
EFS
at 5 years (%)
Survival
at 5 years (%)

14. Prophylaxis and treatment of ATRA syndrome?
High dose steroids or chemotherapy?

15. ATRA syndrome or leukocyte activation syndrome (can occur after arsenic)
Fever
Pleural +/- pericardial effusion
Pumonary infiltrates
Weight gain
Cardiac failure
Renal failure
Generally preceded by increasing WBC counts

16. Prophylaxis and treatment of ATRA syndrome
1)Treatment :high dose DXM (10mg/12H)
2)Prophylaxis
increasing WBC:
- Add chemotherapy?
- Add high dose DXM?

17. Incidence of ATRA syndrome according to initial randomization (age < 66 and WBC < 5,000) (De Botton, Leukemia,2002)
No ATRA Sd
ATRA Sd
ATRA
CT *
100 (82%)
22 (18%)
ATRA + CT
167 (91%)
17 (9%)
p = .026 ]

18. Should AraC be added to anthracyclines?

19. PETHEMA LPA96 PETHEMA LPA99 Nov/96 - Oct/99 Nov/99 - Present INDUCTION
AIDA
Nov/96 - Oct/99
Nov/99 - Present
CONSOLIDATION
CONSOLIDATION
Risk-Adapted
Median follow up
70 mo.
MAINTENANCE
Median follow up
30 mo.
MTX + 6-MP + ATRA

20. PETHEMA LPA96 PETHEMA LPA99 LPA96 n = 174 LPA99 n = 441 TOTAL n = 615
INDUCTION
AIDA
LPA96
n = 174
LPA99
n = 441
TOTAL
n = 615
CR (%)
156 (90)
403 (91)
559 (91)
Induction failure
18 (10)
38 (9)
56 (9)
Early death 15 37 52
Resistance 3 1 4
Sanz et al, Blood 2004

21. Clinical and molecular relapse
LPA96 & LPA99 Trials
Clinical and molecular relapse
LPA96
LPA99
N=156
N=403
Molecular persistence 5
P = 0.03 2
Molecular relapse 7 28 6 21
Clinical relapse* 16 13
CNS relapse 5
(5 to 49 mo) 4
(8 to 28 mo)

22. LPA96 & LPA99 Trials Deaths in CR LPA96 LPA99 N=156 N=403
Before consolidation 1
(81 yrs)
During consolidation 2
(50, 54 yrs) 4
(58, 64, 69, 72 yrs) 3 8
After consolidation 1
(73 yrs) 3
(33, 78, 81 yrs)

23. DEATHS IN CR 43 (7.9%) APL 93:DEATHS IN CR Unrelated disorders 8 (18%)
Disease related (67.4%)
Indirectly Disease related (7%)
Sudden death at home (7%)

24. APL 93:DEATHS IN CR
AGE INCIDENCE
< % %
> %

25. APL 2000 trial Patients aged <60 with WBC<10000/mm3:
Reference arm (APL 93): ATRA+DNR+ AraC+ combined maintenance (ARA C+) VS
same without AraC (ARA C -)

26. Chemotherapy:AraC + vs AraC-n
CR rate
Leukemic resistance
2 yr cum
relapse
2 yr
EFS OS NO
ARAC - 87
94% 2
11.9%
83.4%
89.9% + 80
98%
3.8%
93.6%
97.4%
P value NS
0.021
0.019
0.085

27. C.I.Relapse AraC+ vs AraC- (p=0.021)

28. Overall survival AraC+ vs AraC- (p=0.085)

29. APL 2000 :patients with WBC>10000/mm3
<60 yrs: reference APL 93 but with AraC 2g/m2/12h d1to 5 during last consolidation course
>60 yrs: reference APL 93 with AraC 1g/m2/12h d1 to 4 during last consolidation course

30. APL 2000 trial:patients with WBC>10000/mm3

31. survival WBC>10000,age<60

32. High dose AraC in APL (Lengfelder,ASH 2003)
133 pts treated with ATRA and DAT-HAM-DAT -maintenance
89% CR, 9% relapse
WBC<5000: 6% relapse
WBC>5000:14% relapse

33. AraC in APL?
Probably required in high risk patients (ie high WBC counts ,persisting PML-RAR levels)
In standard risk patients :
- can high cumulative doses of anthracyclines can be substituted for AraC?
-Idarubicin better than DNR?

34. Should CNS prophylaxis be made?

35. Extramedullary relapses: European and Pethema group experience
806 pts included in APL91 , APL93 , PETHEMA 96 trial
738 (92%) CR relapses
14 EMD relapses =
8% of the relapses

36. EM site : CNS (n=10), skin (n=3), orbital (n=1)
Associated bone marrow (BM) relapse (n=9)
(only molecular in 4 of them)

37. Patients with EM relapse characterized, by
younger age (p=.03)
higher WBC counts (p=.007 )
N0 high dose AraC (p=0.03)

38. Outcome of EMD relapses
4 (29%) pts still alive after 41+ to 53+ months.
Median survival from EMD 13 months,
Supports CNS treatment in pts with high WBC counts(>10000)
-intrathecaI MTX+ AraC
-high dose AraC?

39. Treatment of coagulopathy
Intensive platelet support (maintain plts>50000/mm3)
0thers measures (heparin,antifibrinolytic agents,fibrinogen)?

40. Should APL patients receive maintenance therapy?

41. Maintenance treatment in APL
Is it useful?
What should be used?
For how long?

42. CONSOLIDATION AND MAINTENANCE TREATMENT
no maintenance
chemotherapy
.6 mercaptopurine
(90 mg/m2/day)
. methotrexate
(15 mg/m2/week)
AraC 200 mg/m2/d d AraC 1g/m2/12h d 1-4 R
DNR 60 mg/m2/d d DNR 45 mg/m2/d d 1-3
intermittent ATRA
patients < 65 years
45 mg/m2/d
15 days/ 3 months
patients years
both
2 years

43. Time to relapse according to maintenance
No CT CT n
155
246
N. of
relapses 57 47
relapses
at 5 years
37%
21%
p=10-4
ATRA
No ATRA n
205
196
N. of relapses 61 43
relapses
at 5 years
34%
21%
p=10-4

44. Time to relapse according to Chemotherapy
1.0
0.8
0.6
P(no relapse)
0.4
p =
0.2 no CT
0.0
500
1000
1500
2000
2500
days

45. Time to relapse according to ATRA
1.0
0.8
0.6
P(no relapse)
0.4
p =
0.2 no
ATRA
0.0
500
1000
1500
2000
2500
days

46. Survival according to maintenance
No ATRA
ATRA n
205
196
N. of deaths 37 31
p=0.3
No CT CT
155
246
N. of
deaths 36 32
Survival
77%
87% p= 0.004
81%
85%

47. Overall survival according to Chemotherapy
1.0
0.8
0.6
P(survival)
0.4
p = 0.01
0.2 no CT
0.0
500
1000
1500
2000
2500
days

48. Overall survival according to ATRA
1.0
0.8
0.6
P(survival)
0.4
p = 0.15
0.2 no
ATRA
0.0
500
1000
1500
2000
2500
days

49. Time to relapse according to second randomization
1.0
0.8
0.6
0.4
0.2
days
P (no relpase)
500
1000
2000
2500
p=10-4
1500 CT
ATRA
ATRA+CT no

50. Time to relapse according to second randomization
in patients with WBC counts >5000/mm3

51. Maintenance treatment in APL
USEFUL:US intergroup (continuous ATRA during one year)

52. Duration of maintenance treatment (APL 93 trial):
46 patients < 1 year ( due to side effects): 21/46 (45%) relapses
313 patients > 1 year: 49/313 (16%) relapses
Maintenance discontinuation <1 year may be
deleterious

53. Cytopenias with CT usual Pneumocystis pneumonia 3
SIDE EFFECTS OF MAINTENANCE TREATMENT
. Increased Liver enzymes :
- ATRA 7%
- CT 35%
- ATRA+CT 34%
Cytopenias with CT usual
Pneumocystis pneumonia
Deaths , from sepsis

54. Introduction of new agents (ATO,GO) in first line treatment-

55. Role of arsenic during first line treatment of APL?
1) high risk patients: add arsenic to current treatment
-US intergroup study: in all patients
-European APL study: in patients with WBC >10000/mm3
2) standard risk patients: Arsenic used to lower the amount (avoid?) chemotherapy

56. A role for allo SCT in first CR?

57. Allo SCT in first CR :rarely indicated
For patients remaining RT-PCR positive after induction?
For patients with VERY high WBC counts (eg>50000/mm3)?

58. First line treatment of APL with limited (or no?) chemotherapy

59. Treatment of APL with Arsenic and limited amounts of chemotherapy
Lu et al (Blood, 2002) :As4S 4
APL in CR after ATRA (n = 19)
ATRA + CT (n = 84)
- As4S4 2 weeks on/2 weeks off during 4 years
- 9 relapses
2. 19 newly diagnosed APL
- As4S4 for induction
- 19 CR
- As4S4 for maintenance : 3/15 patients relapsed

60. Induction treatment of APL with ATRA and ATO (Shen,PNAS,2004,101,5328)
ATRAvs ATO vs ATO+ATRA followed by 9 cycles of chemotherapy (3 DNR-AraC,3 AraC, 3 homoharringtonine-AraC)
61 pts; similar CR rates
lower PML-RAR in the combined arm
0/20 relapses in the combined arm, vs 7/37 with monotherapy (p<0.05)

61. ATRA+ATO without chemotherapy in standard risk APL (Estey et al)
ATRA 45mg/m2/d+ATO 0.15mg/kg.d (+GO or idarubicin if WBC>10000)
then ATRA 15 d/month +ATO 5d/w 4w/month during 6 months
32 pts,88% CR (including molecular CR)
Only 3 relapses

62. Treatment of newly diagnosed APL with ATO alone (Ghavamzabeh,ASH 2004)
ATO 0.15 mg/kg/d during 60 days,then 28 days
68 pts.90.4% CR
Treatment Complications:
  »ATRA syndrome « (10 cases,4 fatal)
liver abn (19 cases)
13 relapses,2 year survival 86%

63. Treatment of relapsing APL

64. 122 /140 (87%) relapsing patients achieved CR2
TREATMENT OF RELAPSING APL(European APL group experience) (De Botton,JCO,in press)
564 patients <66 years in APL 91 and APL 93 trials :525 (93%) achieved CR.
122 /140 (87%) relapsing patients achieved CR2
ATRA:8
ATO:4
Chemotherapy(CT):24
ATRA+CT:98

65. Arsenic trioxyde in relapsing APL
Ref Dosing Nb pts CR rate Post induction treatment Long term outcome
As2O3 alone (n =18) /18 relapses
Niu et al 0.15mg/kg/d % median DFS 17months
As2O3 + CT (n =11) /11 relapses
Shen et a mg/kg/d % variable year relapse free
survival : 61 %
Kwong et al 10 mg/d % Ida /8 still in CR
6 in molecular CR
Soignet 0.15 mg/kg % Allo (n = 9) or auto (n = 3) still in CR
transplantation
As2O3 (n = 21) still in CR
Ohnishi 0.15 mg/kg % As2O median CR duration :
8 months

66. APL in CR2:Allo and auto SCT (De Botton,JCO,2005)
39%)
39% 6%
25%
TRM
52%
58%
60% yrs.)
48% OS
57%
79% yrs.)
45%
DFS 8%
15%
7 yrs
44%
Relapse 25
127 50
151
No. Pts
APL Study Group** (Europe)
EBMT
(1993–1999)*
Allo SCT
Auto SCT

67. Event-free survival (EFS) from transplantation
Days from transplant
P(No event)
500
1000
1500
2000
2500
3000
0.0
0.2
0.4
0.6
0.8
1.0
AUTO
ALLO

68. Allo SCT after ATO Salvage
Post-transplant survival (Soignet,Dombret) 1 2 4 3 6 8 % 1 2 4 3 6 8 %
At risk deaths year est. % %
At risk deaths year est. %
1st rel.
> 2nd rel.
Months
Months
Median follow-up: 30 months post SCT (range, 9.5 to 45)

69. European APL group recommendations for APL patients in first relapse
Induction with ATO (0.15 mg/kg, max 50 days)
Consolidation with ATO (5 days/w for 25 doses)
donor and<40yrs:allo no donor:Ida AraC elderly pts:maintenance -if PCR neg:auto ATO,ATRA
-if PCR pos:GO,etc.. low dose CT,GO ,

70. Treatment of APLmolecular relapse by Gentuzumab ozogamycin(GO) (Lo Coco,Blood,2004)
16 pts with molecular relapse (8,5,2,1)
GO 6mg/m2 x
14 molecular CR achieved
7 pts still in CR (7+ to 31+ months),7 relapses after 3 to 15 months

71. Treatment of APL in children and elderly patients

72. APL in children (De Botton,JCO,2004)
10% of APL
Often high WBC counts
Similar response to ATRA+ chemo as in adults
Concerns about:
Initial doses of ATRA (25 mg/m2)
High cumulative doses of anthracyclines

73. 5-year OS P (Survival) Days Children 91% Adults 77% 500 1000 1500 2000
500
1000
1500
2000
2500
3000
0.0
0.2
0.4
0.6
0.8
1.0

74. APL in the elderly (Ades,Leukemia,in press)
20% of APL aged>60
CR rate (APL 93)
< % difference due to
> % early death
> % rate

75. APL in the elderly (2) Relapse at 4 years - 26 % in pts < 60
Survival at 4 years
- 79 % in pts < 60
- 55 % in pts > 60
due to deaths in CR

76. Elderly Patients with APL (n = 104)
Cumulative incidence of relapse 20 40 60 80
100 12 24 36 48 72 84 96
Time (months)
Probability of relapse
8.5%
Sanz et al, Blood (in press)

77. Elderly Patients with APL (n = 104)
Relapse-free survival
60-70 y
>70 y
P = 0.18 20 40 60 80
100 12 24 36 48 72 84 96
Time (months)
Relapse-free survival (%)
Sanz et al, Blood (in press)

78. Arsenic derivatives for APL in children and elderly patients?
Children: add Arsenic to reduce the cumuIative dose of anthracyclines?
Elderly patients (or cardiac problems…): add arsenic to reduce the total amount of chemotherapy

80. Question 1:All but one of the following parameters are prognostic factors in APL
A: pretreatment WBC count
B: age
C: hemoglobin level
D: PML-RAR alpha transcript after consolidation treatment

81. Question 2:all but one of the following symptoms are hallmarks of the ATRA syndrome
A:pulmonary infiltrates
B:pleural effusion
C: clinical bleeding
D: unexplained fever

82. Question 3:what is the major component of treatment of initial coagulopathy in APL?
A: heparin
B: platelet transfusions
C: tranexamic acid or other antifibrinolytic drugs
D: fibrinogen infusions

83. Question 4: APL patient with WBC=15000/mm3.First line treatment?
A:ATRA followed by anthracycline based CT
B: anthracycline based CT`
C:ATRA plus anthracycline based CT
D: arsenic derivative alone

84. Question 5: what is your induction treatment for first relapse APL (WBC< 10000/mm3)
A: ATRA alone
B: Arsenic derivative alone`
C: ATRA+ anthracycline based CT
D: Gentuzumab (mylotarg)

86. 3 patients ATRA+CT at 5 months maintenance prematurely stopped
LUNG PNEUMOCYSTIS
INFECTION
3 patients ATRA+CT at 5 months
ATRA+CT at 13 months
CT at 19 months
maintenance prematurely stopped
 1 relapse
Prophylaxis required

87. Initial characteristics of the 122 APL patients in second hematological complete remission according to post-remission therapy
n=17
n=18
n=4
n=2
n=3
Radiotherapy alone (n=1)
n=9
n=5
n=1
n=32
n=11
Salvage therapy
ATRA+EMA
ATRA+other CT
 EMA alone
 Other CT alone
ATO alone
ATRA alone
14.5 ( ) 20 29
14.6 ( ) 6 17
23.4 ( ) 10 40
CR 1 duration (months)
Median (Q1-Q3)
< 12 months
> 12 months
5.3 ( )
6.9 ( )
3.95 ( )
WBC at diagnosis (10 9/L)
30/19
12/11
34/16
Gender (M/F)
45 (37-54)
32.5 (22-43)
45 (29-49)
Median Age (Q1-Q3)
N=49
N=23
N=50
Other consolidation +/- maintenance treatments
Allogeneic
stem cell transplantation
Autologous

88. stem cell transplantation
Pretransplant characteristics and transplantation procedures in the 73 APL patients autografted (n=50) or allografted (n=23) in second complete remission 3 20
HLA identical sibling (n=18)
Unrelated donor (n=5) 43 7
Stem cell source
Peripheral Blood
Bone marrow
Donor
*Cy-TBI (n=17)
*Bu-Cy (n=6)
*Cy-TBI (n=28)
*Bu-Cy (n=17)
Bu-Melphalan (n=4)
Cy-Melphalan (n=1)
Conditioning regimen for SCT 9 6 14 30 2 28
RT-PCR analysis before SCT
Positive
Negative
Not assessed
80.5 (55-125) 19 4
112 (82-137) 44
Time to SCT after CR2 achievement
Median (Q1-Q3) (days)
< 6 months
> 6 months
N=23
N=50
Allogeneic
stem cell transplantation
Autologous

89. ;
7-year RFS, EFS and OS in the auto SCT group were 79.4%, 60.6% and 59.8%, respectively, with a TRM of 6%.
7-year RFS, EFS and OS in the allo SCT group were 92.3%, 52.2% and 51.8%, respectively, with a TRM of 39%.
No significant differences in RFS and EFS were seen between auto and allo SCT (p=.19 and p=.11, respectively) but was OS significantly better in the auto SCT group than in the allo SCT group (p=.04).
In non-transplanted patients, 7-year RFS, EFS and OS were 38%, 30.4% and 39.5%, respectively.

90. Patients with very high WBC counts (> 50 000/mm3)
M = 24, F = 20
36/44 (82%) CR
2 deaths during consolidation courses, 3 relapses before second randomization 15 subsequent relapses

91. First relapse = 7 ; second or subsequent relapse = 13
As2O3 alone versus As2O3 + ATRA in relapsing APL (1) (Raffoux et al, JCO,2003)
N = 20
First relapse = 7 ; second or subsequent relapse = 13
As2O3 : 0,15 mg/kg/d
ATRA : 45 mg/m²/d

92. As2O3 alone versus As2O3 + ATRA in relapsing APL (2) (Raffoux et al, JCO, in press)
CR 80 % in each treatment group
median time to CR 42 days in each treatment group
similar improvement in coagulopathy
3 pts reached molecular CR after one course. All 3 had also received chemotherapy (for high WBC counts)
pharmacokinetic profile of As2O3 similar in the 2 arms
adverse events similar in both arms

93. As2O3 alone versus As2O3 + ATRA in relapsing APL (3) (Raffoux et al, JCO, in press)
10 pts received As2O3 ± ATRA consolidation (2 courses). Only 2/8 PCR negative after 2 consolidation courses
8 allo or autologous SCT
Similar survival

94. Role of Arac in the incidence
of CNS relapses
5 CNS relapses in 159 PETHEMA pts (3%) (treated without AraC) vs 5 in 579 APL91 and 93 pts (0.9%) (treated with high dose AraC) (p=.07).
CNS involvement at relapse in PETHEMA (28% of relapses) more frequent than in APL 91 and 93 (3%)(p=.001).