DES HEMATOLOGIE LEUCEMIE AIGUE PROMYELOCYTAIRE...

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, 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


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)





• 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

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Months

CIR

ARAC

ATO

ATRA

OS

0 5 10 15 20 25 30 35

0.0

0

.2

0.4

0

.6

0.8

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.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

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)



Patients with EM relapse characterized, by

• younger age (p=.03)

• higher WBC counts (p=.007 )

• N0 high dose AraC (p=0.03)



• 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


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

DES HEMATOLOGIE LEUCEMIE AIGUE PROMYELOCYTAIRE...

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