Download presentation
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
ATRACT 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).
Similar presentations
© 2025 SlidePlayer.com. Inc.
All rights reserved.