Post on 07-Feb-2018
LEUCEMIE AIGUE PROMYELOCYTAIRE
DES HEMATOLOGIE
la LAP en 2013
OS
0 5 10 15 20 25 30 35
0.0
0
.2
0.4
0
.6
0.8
1
.0
Months
ARAC
ATO
ATRA
Caractéristiques
• Morphologie: M3, M3v
• Cytogénétique: t(15;17)
• Biologie moleculaire :PML-RAR (bcr1> bcr2>bcr3)
• Coagulopathie : CIVD et Fibrinolyse
Morphologie
– Standard M3 (80%) • Hypergranulaire
– M3 variant (20%) • Hypogranulaire
• Noyaux bilobés
• Souvent Hyperleucocytaire
Etiologies
• Moins de 10% des LAM
– ~2 nouveaux cas / millions l’habitant
– 150 cas par an en France
• Facteurs ethniques
– Incidence augmentée chez les ‘Latinos’ US
– Le BMI elevé est plus frequent dans les LAP
• Frequement secondaire (15% dans APL2006)
– Cancer du sein après inhibiteurs de topo II
LAP induites
• Etudes Française (1982-2001, 39 centres)
– n=106 t-APL
– 78 femmes / 28hommes
– 105 adultes / 1 enfant • Sein 60 57%
• LNH 15 14%
• Tumeur solide 25 24%
• Autres 4 4%
Beaumont et al, JCO 2003
Yin et al. Am J Clin Pathol 2005
Mistry et al , NEJM 2005
tAPL et point de cassure
• Hot spot de cassure sur PML a la MTZ
PML-RARa PLZF-RARa NuMA-RARa NPM-RARa STAT5b-RARa X-RARa
t(15;17) t(11;17) t(11;17) t(5;17) der(17) t(3;17)
> 95%
1%
1 case
< 1%
1 case
1 case
Cytogénétique
• 3 points de cassure différents sur le gène PML
Points de cassure PML-RARa
Exons 3 4 5 6 7a 3 4
Bcr3 Bcr1 Bcr2
PML
chromosome 15
RARa
chromosome 17
Bcr1 : 60%
Bcr2 : 10%
Bcr3 : 30%
Facteurs pronostiques classiques
• Leucocytes >10.000/mm3 – M3 variant – bcr (2)-3
• Plaquettes <40.000/mm3
– Sanz index
• Réponse au traitement – In vitro – In vivo : la MRD
0
0.2
0.4
0.6
0.8
1
0 20 40 60 80
Months
Pro
babi
lity
P <0.0001
High WBC >10
Intermediate WBC 10 & Plt 40
Low WBC 10 & Plt >40
Sanz et al, Blood 2000
Score de Sanz
PETHEMA-GIMEMA
RFS
RT-PCR PML-RARA
• The achievement of molecular remission AFTER CONSOLIDATION is considered a major treatment objective
• evidence obtained using conventional nested RT-PCR assays with relatively low sensitivity, typically detecting 1 leukemic cell in 103 to 104 cells in BM.
• Real-time quantitative PCR (RQ-PCR) assays are marginally more sensitive less prone to contamination, allow kinetics of disease response and relapse to be defined, enable poor quality samples that could have given rise to “false negative” results according to conventional RT-PCR assays to be identified based upon the level of endogenous control gene transcripts (eg, ABL)
- standards: plasmids
- reference gene: PBGD
- results: PML-RARa copy number / 104 PBGD copy number
RQ-PCR Protocol
Cassinat, 2000 et 2009
Mo
nth
s
N=5
N=3 0
1
2
3
4
5
6
7
8
9
10 to 102 copies 102 to103 copies >103 copies
Rechute et quantité de transcript
detectable
N=4
P=0.064
Evaluation of minimal residual disease (MRD) monitoring and
pre-emptive therapy to reduce rates of frank relapse
OUI, MAIS CHEZ QUI PROPOSER UNE TELLE SURVEILLANCE ??
• Blast culture during 3-6 days with ATRA 0.1µM
Good diffenciation Bad differenciation
Sensibilité à l’ATRA in vitro
Cassinat B et al. Blood 2001;98:2862-2864
Sensibilité à l’ATRA in vitro
Mutation de flt3
• European APL group study – N=119 APL patient
– 38% FLT3-ITD, 20% FLT3-D835
• FLT3-ITD associated with
– high WBC, high Sanz index
– M3-variant subtype, bcr-2/3
• Prognosis – No difference in ED, CR, or relapse rate
– Trend for a shorter survival (P=0.09), because of poor post-relapse outcome
Callens et al. Leukemia 2005
LE TRAITEMENT
La Mortalité INITIALE Problemes actuels
Study Number of patients
Period Early death rate
APL93 trial1 576 19931998 7.3%
APL 2000 trial2 356 20002004 3%
PETHEMA LPA 96,993 732 19962005 9%
US intergroup4 518 19992005 8%
Mortalité precoce
• 90-95% of APL patients included in APL clinical trials achieve complete remission.
• 5-10% have early deaths, due to bleeding, infection, activation syndrome and others.
1 Fenaux et al, Blood 3 De la Serna et al, Blood.
2 Ades et al, Blood 4 Powell et al, Blood
Study Number of patients
Period Early death rate
Swedish registry1 105 19972006 29%
SEER (US database)2 1400 19922007 17.3%
Stanford University3 70 19972009 26%
Chicago, New York, Haifa Universities4
205 19922009 12%
Recently, however, higher early death rates have been reported in several studies, that included many patients not recruited in clinical trials.
1 Lehmann et al, Leukemia 2011; 25(7):1128-34 2 Park et al, Blood 2011; 118(5):1248-54 3 McClellan et al, Haematologica 2012; 97(1) 4 Altman et al., Blood 2011 118: Abstract 942
Mortalité précoce
Cause of Early death
Cause of early death in pts who received ATRA N=27 patients
Differentiation syndrome 5
CNS bleeding 4
Sepsis 7
Myocardial Infarction 2
Multiple organ failure 4
Uncertain 5
355 LAP en France essai/hors essai 10% de deces precoces
8/35 (22%) of ED occurred before ATRA onset
Raison de la mortalité précoce
• Retard au diagnostic
• Retard a l’initiation du traitement
• Mauvaise prise en charge de la coagulopathie
• Mauvaise prise en charge du Syndrome de différenciation
Traitement des LAP
• La LAP est sensible à :
– Anthracyclines +/- AraC
– ATRA
– Arsenic
– Anti-CD33 -Gentuzumab ozogamycin (Mylotarg™)
Maladie Resistante ????
marrow blasts tend to disappear slowly from the bone marrow
potentially misleading cytomorphologic features due to incomplete blast maturation are occasionally seen even after several weeks from treatment initiation and a delayed differentiation of blasts can lead to the detection of cells with the t(15;17) by conventional cytogenetics or FISH when these tests are performed at an early time after induction, sometimes giving the impression of resistant disease.
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
APL 93 : ATRA syndrome
• The incidence of ATRA syndrome was 15%
• ATRA syndrome was responsible for death in only 1.2% of the total number of patients treated.
• However, occurrence of ATRA syndrome was associated with lower EFS and survival.
Prophylaxis and treatment of ATRA syndrome
1)Treatment :high dose DXM (10mg/12H)
2)Prophylaxis
increasing WBC:
- Add chemotherapy
- Add high dose DXM
QUEL EST LE MEILLEUR TRAITEMENT?
Stockholm 2005
GIMEMA LAP 0389 Traitement avant l’ATRA
Avvisati, Blood 2002
Stockholm 2005
GIMEMA LAP 0389 - EFS Traitement avant l’ATRA
Avvisati, Blood 2002
Stockholm 2005
ATRA followed by chemotherapy APL 91 trial
• >90 % CR rate
• 25% relapse (decrease in early relapses)
• Almost 65% of the patients were cured
• However: – Almost 10% absence of CR
– Still 25% relapses
– The treatment is intensive
Avec de l’ATRA et de la CxT Quel est le meilleur traitement ?
Sanz, Blood 2004
IDA 12 mg/m²/d x 4
ATRA 45 mg/m²
Induction
Consolidation 1 Consolidation 2
MA
INT
EN
AN
CE
AT
RA
+C
T
Consolidation 3
Ida 5 mg/m²
x 4
MTZ 10 mg/m²
x 5
Ida 12 mg/m²
x 1
LPA-96 trial
PETHEMA group
PETHEMA Results
Sanz et al, Blood 2004
Sanz, Blood 2004
IDA 12 mg/m²/d x 4
ATRA 45 mg/m²
Induction
Consolidation 1 Consolidation 2
MA
INT
EN
AN
CE
AT
RA
+C
T
Consolidation 3
Consolidation 1 Consolidation 2 Consolidation 3
ATRA
Ida 5 mg/m²
x 4
MTZ 10 mg/m²
x 5
Ida 12 mg/m²
x 1
Ida 7 mg/m²
x 4
MTZ 10 mg/m²
x 5
Ida 12 mg/m²
x 2
ATRA ATRA
LPA-99 trial
PETHEMA group
PETHEMA Results
Sanz et al, Blood 2004
APL-2000 trial (1)
• Arms with AraC
DNR 60 mg/m²/d x3
AraC 200 mg/m²/dx7
DNR 60 mg/m²/d x3
AraC 200 mg/m²/dx7
DNR 45 mg/m²/d x3
AraC 1 g/m²/12h x 8
ATRA 45 mg/m²
Induction Consolidation 1 Consolidation 2
MA
INT
EN
AN
CE
AT
RA
+C
T
DNR 60 mg/m²x3
AraC 200 mg/m²
DNR 45 mg/m² x3
AraC 2 g/m² x 10
Consolidation 1 Consolidation 2 Induction
DNR 60 mg/m²x3
AraC 200 mg/m²
ATRA 45 mg/m²
IT
IT
IT
IT
IT
APL-2000 trial (2)
Comparaison France/Espagne
Low Risk (WBC<10)
Haut risque
PETHEMA LPA 2005
Sanz et al Blood 2010
LPA2005 – High Risk
Sanz et al Blood 2010
Role of AraC
• These results suggest :
– The role of anthracyclines (and/or ATRA during consolidation) in low WBC patients
• Type
• Doses
• Schedule
– The role of AraC in high WBC patients
• HD-AraC ?
• Confirming German AMLCG results
Avec de l’ATO Quel est le meilleur traitement ?
ATO in relapsing APL
Ref N° CR rate Post-CR treatment Outcome As2O3 alone (n =18) 12/18 relapses Niu 47 85 % As2O3 + CT (n =11) 2/11 relapses Shen 20 80 % various 2 year RFS, 61% Kwong 8 100 % Ida 7/8 still in CR 6 in molecular CR Soignet 52 87 % Allo (n = 9) or auto (n = 3) 11 still in CR 83% PCR-neg As2O3 (n = 21) 9 still in CR Ohnishi 14 78 % As2O3 median CR duration : 8 months Raffoux 20 80% various 2-year DFS, 59%
1st line induction with ATRA & ATO (1)
• ATRA vs ATO vs ATO+ATRA
• followed by 3 cycles of chemotherapy
– DNR-AraC
– AraC
– homoharringtonine-AraC
• Maintenance :
– ATRA vs ATO vs ATO+ATRA
• 61 patients, similar CR rates
Shen et al, PNAS 2004
0/20 relapses in the combined arm vs 7/37 with monotherapy
(p<0.05)
Shen et al, PNAS 2004
1st line induction with ATRA & ATO (2)
Shen et al, PNAS 2004
1st line induction with ATRA & ATO (3)
• Molecular response (RQ-PCR)
ATO during first-line therapy
• Add arsenic to current treatment :
– 2 cycles during consolidation
• US Intergroup, in all patients
• European APL group
• Use arsenic to lower (omit ?) chemotherapy
Iranian experience with ATO
• 111 patients, 86% CR
• Fatal differentiation syndromes
• 24 relapses
• 2-year DFS, 64%
• 3-year survival if CR, 88%
Ghavamzadeh et al, Ann Oncol 2006
Mathews et al , Blood 2005
Indian experience with ATO
72 patients, 86% CR
3-year DFS, 87%
3-year survival, 86%
100% EFS in low-risk
(WBC<5, Plat>20)
MDACC experience w/o CTx
• ATRA + ATO – + GO or idarubicin if WBC>10.000
• 6-month maintenance – ATRA 15d/month
– ATO 5d/week 4w/month
• 32 patients
• 88% CR
• Only 3 relapses
Estey,blood
TWO CYCLES OF:
As2O3 O.15 mg/kg/d 5
days/wk for 5 wks Cycle
2 after 2 wk rest
TWO CYCLES OF:
ATRA 45 mg/m2
d1-3 Daunorubicin
50 mg/m2
Induction Therapy Consolidation Therapy
ATRA 45 mg/m2
Ara-C 200 mg/m2 IV d3-9
DNR 50 mg/m2, d3-6
ATRA 45 mg/m2
Ara-C 200 mg/m2 IV d3-9
DNR 50 mg/m2, d3-6
USA intergroup APL trial
Powell, Blood 2010
USA intergroup APL trial Event Free Survival at 3 Years
As203 81%
p*=0.0007
No As203 66%
USA intergroup APL trial Survival at 3 Years
As203 86%
p = 0.063
No As203 79%
ATRA
alone,
WBC
>10K
DFS By Treatment and WBC
No Arsenic
WBC <10K
Arsenic WBC <10K
Arsenic WBC >10K
p = 0.0016, HR 2.24 No Arsenic
WBC >10K
APL 2006 trial : patients< 70 years,
WBC<10G/L
Ida 12 mg/m2 x3
AraC 200 mg/m2 x7
ATRA until CR
Ida 12 mg/m2 x3
AraC 200 mg/m2 x7
Ida 9 mg/m2 x3
AraC 1g/m2 x8
Ida 12 mg/m2 x3
ATO 25 days
Ida 9 mg/m2 x3
ATO 25 days
Ida 12 mg/m2 x3
ATRA 15 days
Ida 9 mg/m2 x3
ATRA 15 days
Induction
Conso 1
Conso 2
R
2 year Maintenance with intermittent ATRA, and continuous MTX & 6MP
Maint.
APL 2006 trial: first interim analysis
• made at the reference date of 1 Jan 2010
• 186 patients aged < 70, included
• <70 years, WBC<10G/l n=141
• <70 years, WBC >10G/L n= 45
Induction treatment
• In low risk APL : CR rate: 96,5%
– 5 deaths during induction – 2 related to ATRA-syndrome
– 2 to cerebral hemorrhage
– 1 to an invasive aspergillosis.
• In High Risk APL, CR rate 91%
– 4 deaths during induction – hemorrhage (n=1)
– sepsis (n=2)
– stroke (n=2)
Outcome of pts<70 years with WBC<10G/l
0 5 10 15 20 25 30 35
0.0
0
.2
0.4
0
.6
0.8
1
.0
Months
CIR
ARAC
ATO
ATRA
OS
0 5 10 15 20 25 30 35
0.0
0
.2
0.4
0
.6
0.8
1
.0
Months
ARAC
ATO
ATRA
0 5 10 15 20 25 30 35
0.0
0
.2
0.4
0
.6
0.8
1
.0
Months
EF
S
ARAC
ATO
ATRA
Overall Survival EFS CIR
Italian/german Study
Italian/german Study
LES LAP Hyperleucocytaires
Questions additionnelles…
High WBC count in APL
• 20–25% ont des leucocytes > 10 G
• <5% des leucocytes > 50 G/L
• Classiquement associé à un taux de rechute plus élevé
Mortalité precoce (Hyperleuco)
Rechute (Hyperleuco)
Devenir des hyperlecocytaires
Pour peu qu’on adapte le traitement ….
Should CNS prophylaxis be made?
Questions additionnelles…
Extramedullary relapses European APL & PETHEMA Experience
• 806 pts included
– in APL91, APL 93
– and PETHEMA 96 trial
• 738 (92%) obtained CR .
• 174 relapses
• 14 EMD relapses 8% of the relapses
De Botton ,Leukemia 2005
• Extra Medullary site : – CNS (n=10),
– Skin (n=3),
– Orbital (n=1).
• Associated bone marrow (BM) relapse (n=9)
(only molecular in 4 of them)
Extramedullary relapses European APL & PETHEMA Experience
De Botton ,Leukemia 2005
Patients with EM relapse characterized, by
• younger age (p=.03)
• higher WBC counts (p=.007 )
• N0 high dose AraC (p=0.03)
Extramedullary relapses European APL & PETHEMA Experience
De Botton ,Leukemia 2005
• 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(>10.000)
-intrathecaI MTX+ AraC
-high dose AraC?
EM relapses : outcome European APL & PETHEMA Experience
De Botton ,Leukemia 2005
Should APL patients receive maintenance therapy?
APL 93 : maintenance treatment Second Randomized part of the Trial
R
No maintenance
Oral low dose CT
Intermitent ATRA
Both : CT+ATRA
Maintenance 2 years
• 6 mercaptopurine (90 mg/m2/day)
• Methotrexate (15 mg/m2/week)
• 45 mg/m2/d
• 15 days/ 3 months
Stockholm 2005
Side effect of Maintenance
• Increased Liver enzymes : • ATRA 7%
• CT 35%
• ATRA+CT 34%
• Cytopenias with CT • usual
• Pneumocystis pneumonia 3
• Deaths 6, from sepsis
P
1.0
0.8
0.6
0.4
0.2
P
P (
no r
elp
ase)
0 500 2000
0
1500
APL 93 : maintenance treatment CI of relapse according maintenance randomiaztion
No maintenance
ATRA
CT
ATRA+CT
Fenaux et al, Blood 98
Maintenance treatment in APL
• Only 2 randomized studies have investigated the role of maintenance therapy in APL.
• ATRA maintenance given intermittently (APL93, 2 year with CT) or continuously (US, 1year).
• Both show a a benefit
• Continuous ATRA – Not supported by pharmacokinetic data
– associated with significant toxicity
• Quel rôle éventuel depuis l’ATO??
Conclusions
• Une maladie très fréquemment curable
– Dans les formes non Hyperleucocytaires
• Par Chimiothérapie et ATRA
• Par ATO et ATRA
• Le role du Mylotarg eventuel…
– Dans les formes hyperleucocytaire
• Par Chimiotherapie et ATRA
• Role eventuel de l’ATO en plus, à la place?
A retenir
• Plusieurs schémas de traitement possible…
• Tous capable de guérir le patient…
• A condition de suivre le traitement dans son ensemble
• Et de ne pas perdre le patient de complication precoce