APL Pierre Fenaux (Hopital Avicenne,Paris 13 University)

APLAPL

Pierre Fenaux Pierre Fenaux (Hopital Avicenne,Paris 13 (Hopital Avicenne,Paris 13

University)University)

Etiology of APLEtiology of APL

About 10% of AML (about 130 new About 10% of AML (about 130 new cases/year in Francecases/year in France,probably more ,probably more than 2000/year in India)than 2000/year in India)

Incidence depending on ethnic (or Incidence depending on ethnic (or environmental) factorsenvironmental) factors

More and more often therapy related More and more often therapy related (after brest carcinoma)(after brest carcinoma)

APL characteristicsAPL characteristics

Morphology:M3, M3vMorphology:M3, M3v Cytogenetics: t(15;17) (t(11;17,t(5;17) very Cytogenetics: t(15;17) (t(11;17,t(5;17) very

rare)rare)

complex or variant translocationscomplex or variant translocations molecular biology:PML-RAR (bcr1> molecular biology:PML-RAR (bcr1>

bcr2>bcr3)bcr2>bcr3)

others (PLZF-RAR,etc very rare)others (PLZF-RAR,etc very rare) Coagulopathy:DIC+fibrinolysisCoagulopathy:DIC+fibrinolysis

Prognostic factors in APLPrognostic factors in APL

WBC >10000/mm3WBC >10000/mm3 (and (and platelets<40000/mm3) (Sanz score)platelets<40000/mm3) (Sanz score)

RT-PCR analysis after consolidation RT-PCR analysis after consolidation treatment treatment (but depends on sensitivity of the (but depends on sensitivity of the assay used)assay used)

other factors (M3v,bcr other factors (M3v,bcr breakpoint….:generally redundant with breakpoint….:generally redundant with WBC count))WBC count))

Treatment of APLTreatment of APL

APL sensitive toAPL sensitive to Anthracycline+/- AraC Anthracycline+/- AraC

chemotherapychemotherapy ATRAATRA Arsenic derivativesArsenic derivatives

Treatment of APLTreatment of APL

« classical » treatment« classical » treatmentTreatment with no or Treatment with no or limited amount of limited amount of chemotherapy?chemotherapy?

« Classical » treatment of « Classical » treatment of APL?APL?

1)Newly diagnosed APL1)Newly diagnosed APL

2)Relapsing APL2)Relapsing APL

3)Specific situations3)Specific situations ChildrenChildren Elderly patientsElderly patients

Newly diagnosed APL :Newly diagnosed APL :

Induction and consolidation Induction and consolidation treatment should combine treatment should combine ATRA and anthracycline based ATRA and anthracycline based chemotherapychemotherapy::

Slightly increases the CR rate (from 80 Slightly increases the CR rate (from 80 to>90%)to>90%)

considerably reduces relapses (from 50 to considerably reduces relapses (from 50 to 25%)25%)

Newly diagnosed APLNewly diagnosed APL

Remaining issues:Remaining issues:

1)with ATRA chemotherapy combinations1)with ATRA chemotherapy combinations-when to start chemotherapy?-when to start chemotherapy?

--anthracycline alone or with AraC?anthracycline alone or with AraC?

-prophylaxis and treatment of « ATRA syndrome »?-prophylaxis and treatment of « ATRA syndrome »?

- treatment of coagulopathy?- treatment of coagulopathy?

-CNS prophylaxis?-CNS prophylaxis?

-maintenance treatment-maintenance treatment

2)introduction of new agents 2)introduction of new agents (Arsenic,gentuzumab GO)(Arsenic,gentuzumab GO)

3)Role of allo SCT in first CR3)Role of allo SCT in first CR

When should When should chemotherapy be chemotherapy be

started?started?

APL 93:INDUCTION TREATMENTAPL 93:INDUCTION TREATMENT. .

ATRA : 45 mg/mATRA : 45 mg/m22/d until CR/d until CR

chemotherapy : daunorubicin (DNR) 60 mg/mchemotherapy : daunorubicin (DNR) 60 mg/m22/d d/d d1-31-3

AraC 200 mg/mAraC 200 mg/m22/d d/d d1-71-7

ATRA followed by ATRA followed by chemotherapychemotherapy

ATRA + chemotherapyATRA + chemotherapystarted day 3started day 3

ATRA ATRA CT CT groupgroup

ATRA + CT ATRA + CT groupgroup

RR

WBC 5000/mm3 and age 65: 65:

CONSOLIDATION AND MAINTENANCE TREATMENTCONSOLIDATION AND MAINTENANCE TREATMENT

AraC 200 mg/m2/d d 1-7 AraC 1g/m2/12h d 1-4

patients 66-75 yearspatients 66-75 years

patients patients << 65 years 65 years

chemotherapychemotherapy

.6 mercaptopurine

(90 mg/m2/day)

. methotrexate

(15 mg/m2/week)

no maintenanceno maintenance

45 mg/m2/d

15 days/ 3 months

intermittent ATRAintermittent ATRA

bothboth

2 years2 years

DNR 60 mg/mDNR 60 mg/m22/d d /d d 1-31-3 DNR 45 mg/m DNR 45 mg/m22/d d /d d 1-31-3

R

ATRACT ATRA+CT p

n 122 185

CR (%) 93 96 0.12

Relapseat 5 years (%) 19 12 0.04

EFS at 5 years (%) 66 77 0.01

Survivalat 5 years (%) 77 84 0.29

Patients randomized for inductionPatients randomized for induction

Prophylaxis and Prophylaxis and treatment of ATRA treatment of ATRA

syndrome?syndrome?High dose steroids or High dose steroids or

chemotherapy?chemotherapy?

ATRA syndrome or leukocyte ATRA syndrome or leukocyte activation syndrome (can activation syndrome (can

occur after arsenic)occur after arsenic) FeverFever Pleural +/- pericardial effusionPleural +/- pericardial effusion Pumonary infiltratesPumonary infiltrates Weight gainWeight gain Cardiac failureCardiac failure Renal failureRenal failure Generally preceded by increasing Generally preceded by increasing

WBC countsWBC counts

Prophylaxis and Prophylaxis and treatment of ATRA treatment of ATRA

syndromesyndrome 1)1)Treatment Treatment :high dose DXM :high dose DXM

(10mg/12H)(10mg/12H)

2)2)ProphylaxisProphylaxis increasing WBC:increasing WBC: - Add chemotherapy?- Add chemotherapy? - Add high dose DXM?- Add high dose DXM?

Incidence of ATRA syndrome Incidence of ATRA syndrome

according to initial randomizationaccording to initial randomization

(age < 66 and WBC < 5,000) (age < 66 and WBC < 5,000) (De Botton(De Botton, , Leukemia,2002Leukemia,2002))

ATRAATRA CT *CT * 100 (82%)100 (82%) 22 22 (18%)(18%)

ATRA + CTATRA + CT 167 (91%)167 (91%) 17 17 (9%)(9%)

p =p = .026.026]

No ATRA SdNo ATRA Sd ATRA SdATRA Sd

Should AraC be Should AraC be added to added to

anthracyclines?anthracyclines?

CONSOLIDATIONRisk-Adapted

CONSOLIDATIONRisk-Adapted

PETHEMA LPA99PETHEMA LPA99PETHEMA LPA99PETHEMA LPA99

Nov/99 - PresentNov/99 - PresentNov/99 - PresentNov/99 - Present

PETHEMA LPA96PETHEMA LPA96PETHEMA LPA96PETHEMA LPA96

AIDAAIDA

INDUCTIONINDUCTION

CONSOLIDATIONCONSOLIDATION

MTX + 6-MP + ATRAMTX + 6-MP + ATRA

MAINTENANCEMAINTENANCE

Nov/96 - Oct/99Nov/96 - Oct/99Nov/96 - Oct/99Nov/96 - Oct/99

Median follow up70 mo.




PETHEMA LPA96PETHEMA LPA96PETHEMA LPA96PETHEMA LPA96 PETHEMA LPA99PETHEMA LPA99PETHEMA LPA99PETHEMA LPA99

Sanz Sanz et alet al, Blood 2004, Blood 2004Sanz Sanz et alet al, Blood 2004, Blood 2004

LPA96LPA96n = 174n = 174LPA96LPA96n = 174n = 174

LPA99LPA99n = 441n = 441LPA99LPA99n = 441n = 441

CR (%)CR (%)CR (%)CR (%) 156 (90)156 (90)156 (90)156 (90) 403 (91)403 (91)403 (91)403 (91) 559 (91)559 (91)559 (91)559 (91)

Induction failureInduction failureInduction failureInduction failure 18 (10)18 (10)18 (10)18 (10) 38 (9)38 (9)38 (9)38 (9) 56 (9)56 (9)56 (9)56 (9)

ResistanceResistanceResistanceResistance 3333 1111 4444

TOTALTOTALn = 615n = 615TOTALTOTALn = 615n = 615

Early deathEarly deathEarly deathEarly death 15151515 37373737 52525252

AIDAAIDA

INDUCTIONINDUCTION

LPA96LPA96LPA96LPA96 LPA99LPA99LPA99LPA99

Molecular persistenceMolecular persistenceMolecular persistenceMolecular persistence 5555

Molecular relapseMolecular relapseMolecular relapseMolecular relapse

Clinical relapse*Clinical relapse*Clinical relapse*Clinical relapse*

CNS relapseCNS relapseCNS relapseCNS relapse

2222

7777 6666

16161616 13131313

44(8 to 28 mo)(8 to 28 mo)

44(8 to 28 mo)(8 to 28 mo)

55(5 to 49 mo)(5 to 49 mo)

55(5 to 49 mo)(5 to 49 mo)

N=156N=156N=156N=156 N=403N=403N=403N=403

LPA96 & LPA99 TrialsLPA96 & LPA99 TrialsClinical and molecular relapseClinical and molecular relapse

LPA96 & LPA99 TrialsLPA96 & LPA99 TrialsClinical and molecular relapseClinical and molecular relapse

28 21

P = 0.03P = 0.03P = 0.03P = 0.03

LPA96LPA96LPA96LPA96 LPA99LPA99LPA99LPA99

BeforeBefore consolidation consolidationBeforeBefore consolidation consolidation 0000

DuringDuring consolidation consolidationDuringDuring consolidation consolidation

AfterAfter consolidation consolidationAfterAfter consolidation consolidation

11(81 yrs)(81 yrs)

11(81 yrs)(81 yrs)

22(50, 54 yrs)(50, 54 yrs)

22(50, 54 yrs)(50, 54 yrs)

44(58, 64, 69, 72 yrs) (58, 64, 69, 72 yrs)

44(58, 64, 69, 72 yrs) (58, 64, 69, 72 yrs)

11(73 yrs)(73 yrs)

11(73 yrs)(73 yrs)

33(33, 78, 81 yrs)(33, 78, 81 yrs)

33(33, 78, 81 yrs)(33, 78, 81 yrs)

N=156N=156N=156N=156 N=403N=403N=403N=403

LPA96 & LPA99 TrialsLPA96 & LPA99 TrialsDeaths in CRDeaths in CR

LPA96 & LPA99 TrialsLPA96 & LPA99 TrialsDeaths in CRDeaths in CR

3 8

APL 93:DEATHS IN CR

DEATHS IN CR 43 (7.9%)

Unrelated disorders 8 (18%)Disease related 29 (67.4%)Indirectly Disease related 3 (7%)Sudden death at home 3 (7%)

APL 93:DEATHS IN CR

AGE INCIDENCE

<55 4%

55-65 20%

>65 24%

APL 2000 trialAPL 2000 trial

Patients aged <60 with Patients aged <60 with WBC<10000/mm3:WBC<10000/mm3:

Reference arm (APL 93): Reference arm (APL 93): ATRA+DNR+ AraC+ combined ATRA+DNR+ AraC+ combined maintenance (maintenance (ARA C+)ARA C+)

VSVS

same without AraC (same without AraC (ARA C -)ARA C -)

Chemotherapy:Chemotherapy:AraC + vs AraC + vs AraC-AraC-

nn CR CR raterate

LeukLeukemic emic resisresistancetance

2 yr 2 yr cumcum

relaprelapsese

2 yr2 yr

EFSEFS2 yr2 yr

OSOS

NONO

ARAARACC

--

8787 94%94% 22 11.911.9%%

83.483.4%%

89.989.9%%

ARAARACC

++

8080 98%98% 00 3.8%3.8% 93.693.6%%

97.497.4%%

P P valuevalue

NSNS 0.020.0211

0.010.0199

0.080.0855

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

Overall survival AraC+ vs AraC-Overall survival AraC+ vs AraC-

(p=0.085)(p=0.085)

APL 2000 :patients with APL 2000 :patients with WBC>10000/mm3WBC>10000/mm3

<60 yrs: reference APL 93 but with <60 yrs: reference APL 93 but with AraC 2g/m2/12h d1to 5AraC 2g/m2/12h d1to 5 during during last consolidation courselast consolidation course

>60 yrs: reference APL 93 with >60 yrs: reference APL 93 with

AraC 1g/m2/12h d1 to 4AraC 1g/m2/12h d1 to 4 during during last consolidation course last consolidation course

APL 2000 trial:patients APL 2000 trial:patients with WBC>10000/mm3with WBC>10000/mm3

n CR rate

Resis tance

2y C I relap se

2y EFS

2y survi val

<60yr 68 97% 0% 2.6% 88.4% 91%

>60yr 16 87% 0% 0% 78.3% 78.3%

survival survival WBC>10000,age<60WBC>10000,age<60

High dose AraC in APL High dose AraC in APL (Lengfelder,ASH 2003)(Lengfelder,ASH 2003)

133 pts treated with 133 pts treated with ATRA and ATRA and DAT-HAM-DAT -maintenanceDAT-HAM-DAT -maintenance

89% CR, 9% relapse89% CR, 9% relapse WBC<5000: 6% relapseWBC<5000: 6% relapse WBC>5000:14% relapseWBC>5000:14% relapse

AraC in APL?AraC in APL?

Probably required in Probably required in high risk high risk patientspatients (ie high WBC (ie high WBC counts ,persisting PML-RAR counts ,persisting PML-RAR levels)levels)

In In standard risk patientsstandard risk patients : :

- can - can high cumulativehigh cumulative doses of doses of anthracyclines can be substituted anthracyclines can be substituted for AraC?for AraC?

--IdarubicinIdarubicin better than DNR better than DNR??

Should CNS Should CNS prophylaxis be prophylaxis be

made?made?

Extramedullary relapses: Extramedullary relapses: European and European and Pethema group experiencePethema group experience

806 pts806 pts included in APL91 , APL93 , PETHEMA included in APL91 , APL93 , PETHEMA 96 trial 96 trial

738 (92%) CR . 174 relapses 738 (92%) CR . 174 relapses 14 EMD relapses14 EMD relapses = =

8% of the relapses8% of the relapses

EM site EM site : CNS (n=10), skin (n=3), orbital (n=1: CNS (n=10), skin (n=3), orbital (n=1)) Associated bone marrow (BM) relapse (n=9) Associated bone marrow (BM) relapse (n=9)

(only molecular in 4 of them) (only molecular in 4 of them)

Patients with EM relapse characterized, byPatients with EM relapse characterized, by

younger ageyounger age (p=.03) (p=.03)

higher WBC countshigher WBC counts (p=.007 ) (p=.007 )

N0 high dose AraCN0 high dose AraC (p=0.03) (p=0.03)

Outcome of EMD relapsesOutcome of EMD relapses

4 (29%) pts still alive after 41+ to 53+ months4 (29%) pts still alive after 41+ to 53+ months.. Median survival from EMD 13 months, Median survival from EMD 13 months,

Supports CNS treatment in Supports CNS treatment in pts with high WBC pts with high WBC counts(>10000)counts(>10000)-intrathecaI MTX+ AraC-intrathecaI MTX+ AraC-high dose AraC?-high dose AraC?

Treatment of Treatment of coagulopathycoagulopathy

Intensive platelet support Intensive platelet support (maintain plts>50000/mm3(maintain plts>50000/mm3))

0thers measures 0thers measures (heparin,antifibrinolytic (heparin,antifibrinolytic agents,fibrinogen)?agents,fibrinogen)?

Should APL Should APL patients receive patients receive

maintenance maintenance therapy?therapy?

Maintenance treatment Maintenance treatment in APLin APL

Is it useful?Is it useful? What should be used?What should be used? For how long?For how long?

CONSOLIDATION AND MAINTENANCE TREATMENTCONSOLIDATION AND MAINTENANCE TREATMENT

AraC 200 mg/m2/d d 1-7 AraC 1g/m2/12h d 1-4

patients 66-75 yearspatients 66-75 years

patients patients << 65 years 65 years

chemotherapychemotherapy.6 mercaptopurine

(90 mg/m2/day)

. methotrexate

(15 mg/m2/week)

no maintenanceno maintenance

45 mg/m2/d

15 days/ 3 months

intermittent ATRAintermittent ATRA

bothboth

2 years2 years

DNR 60 mg/mDNR 60 mg/m22/d d /d d 1-31-3 DNR 45 mg/m DNR 45 mg/m22/d d /d d 1-31-3

R

No ATRAATRA

n 205 196

N. of relapses61 43

No CT CT

n 155 246

N. of relapses 57 47

relapsesat 5 years 37% 21%

relapses at 5 years

34% 21%

p=10-4

p=10-4

Time to relapse according to maintenanceTime to relapse according to maintenance

days

P(n

o r

ela

pse

)

0 500 1000 1500 2000 2500

0.0

0.2

0.4

0.6

0.8

1.0

no

CT

Time to relapse according to ChemotherapyTime to relapse according to Chemotherapy

p = 0.0004p = 0.0004

days

P(n

o re

laps

e)

0 500 1000 1500 2000 2500

0.0

0.2

0.4

0.6

0.8

1.0

noATRA

Time to relapse according to ATRATime to relapse according to ATRA

p = 0.0017p = 0.0017

No ATRA ATRA

n 205 196

N. of deaths37 31

p=0.3

No CT CT

n 155 246

N. of deaths 36 32

Survival 77% 87% p= 0.004

Survival 81% 85%

Survival according to maintenance

days

P(s

urvi

val)

0 500 1000 1500 2000 2500

0.0

0.2

0.4

0.6

0.8

1.0

no

CT

Overall survival according to ChemotherapyOverall survival according to Chemotherapy

p = 0.01p = 0.01

days

P(s

urv

iva

l)

0 500 1000 1500 2000 2500

0.0

0.2

0.4

0.6

0.8

1.0

no

ATRA

Overall survival according to ATRAOverall survival according to ATRA

p = 0.15p = 0.15

Time to relapse according to second randomizationTime to relapse according to second randomizationP

1.0

0.8

0.6

0.4

0.2

P

days

P (

no r

elpa

se)

0 500 1000 2000 2500

p=10-4

0

1500

CTATRA

ATRA+CT

CTATRA

ATRA+CT

no

days

P(no relapse)

0 500 1000 1500 2000 2500

0.0

0.2

0.4

0.6

0.8

1.0

noCTATRAboth

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

Maintenance treatment Maintenance treatment in APLin APL

USEFULUSEFUL:US intergroup (continuous :US intergroup (continuous ATRA during one year)ATRA during one year)

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

Duration of maintenance treatment (APL 93 trial):

SIDE EFFECTS OF MAINTENANCE TREATMENT

. Increased Liver enzymes : - ATRA 7%

- CT 35%- ATRA+CT 34%

• Cytopenias with CT usual

• Pneumocystis pneumonia 3

• Deaths 6, from sepsis

Introduction of new Introduction of new agents (ATO,GO) in agents (ATO,GO) in first line treatmentfirst line treatment

--

Role of arsenic during first Role of arsenic during first line treatment of APL?line treatment of APL?

1) 1) high risk patientshigh risk patients: add arsenic to : add arsenic to current treatmentcurrent treatment

--US intergroup studyUS intergroup study: in all patients: in all patients

--European APL studyEuropean APL study: in patients : in patients with WBC >10000/mm3with WBC >10000/mm3

2) 2) standard risk patientsstandard risk patients: : Arsenic Arsenic used to lower the amount (avoid?) used to lower the amount (avoid?) chemotherapychemotherapy

A role for allo SCT in A role for allo SCT in first CR?first CR?

Allo SCT in first CRAllo SCT in first CR:rarely indicated:rarely indicated

For patients remaining RT-PCR For patients remaining RT-PCR positive after induction?positive after induction?

For patients with VERY high WBC For patients with VERY high WBC counts (eg>50000/mm3)?counts (eg>50000/mm3)?

First line First line treatment of APL treatment of APL with limited (or with limited (or

no?) no?) chemotherapychemotherapy

Treatment of APL with Arsenic Treatment of APL with Arsenic and limited amounts of and limited amounts of

chemotherapychemotherapyLu et alLu et al (Blood, 2002) : (Blood, 2002) :As4S 4As4S 4

1. 1. 103 APL in CR103 APL in CR after after ATRA (n = 19)ATRA (n = 19)ATRA + CT (n = 84)ATRA + CT (n = 84)

- - As4S4 2 weeks on/2 weeks off during As4S4 2 weeks on/2 weeks off during 4 years4 years

- - 9 relapses9 relapses

2.2. 19 19 newly diagnosed APLnewly diagnosed APL- As4S4 for induction- As4S4 for induction- 19 CR - 19 CR

- As4S4 for maintenance : - As4S4 for maintenance : 3/15 3/15 patients relapsedpatients relapsed

Induction treatment of APL with Induction treatment of APL with

ATRA and ATOATRA and ATO (Shen,PNAS,2004,101,5328)(Shen,PNAS,2004,101,5328)

ATRAvs ATO vs ATO+ATRA ATRAvs ATO vs ATO+ATRA followed by 9 cycles of followed by 9 cycles of chemotherapy chemotherapy (3 DNR-AraC,3 AraC, (3 DNR-AraC,3 AraC, 3 homoharringtonine-AraC)3 homoharringtonine-AraC)

61 pts; similar CR rates61 pts; similar CR rates lower PML-RAR in the combined armlower PML-RAR in the combined arm 0/20 relapses in the combined 0/20 relapses in the combined

arm, vs 7/37 with monotherapy arm, vs 7/37 with monotherapy (p<0.05)(p<0.05)

ATRA+ATO without ATRA+ATO without chemotherapy in standard chemotherapy in standard

risk APL (Estey et al)risk APL (Estey et al) ATRA 45mg/m2/d+ATO 0.15mg/kg.d ATRA 45mg/m2/d+ATO 0.15mg/kg.d

(+GO or idarubicin if WBC>10000)(+GO or idarubicin if WBC>10000) then ATRA 15 d/month +ATO 5d/w then ATRA 15 d/month +ATO 5d/w

4w/month during 6 months4w/month during 6 months 32 pts,88% CR (including molecular 32 pts,88% CR (including molecular

CR)CR) Only 3 relapsesOnly 3 relapses

Treatment of newly Treatment of newly diagnosed APL with ATO diagnosed APL with ATO alone (Ghavamzabeh,ASH alone (Ghavamzabeh,ASH

2004)2004) ATO 0.15 mg/kg/d during 60 ATO 0.15 mg/kg/d during 60

days,then 28 daysdays,then 28 days 68 pts.90.4% CR68 pts.90.4% CR Treatment Complications:Treatment Complications:

»ATRA syndrome « (10 cases,4 fatal)»ATRA syndrome « (10 cases,4 fatal)

liver abn (19 cases)liver abn (19 cases) 13 relapses,2 year survival 86% 13 relapses,2 year survival 86%

Treatment of Treatment of relapsing APLrelapsing APL

TREATMENT OF RELAPSING APL(European TREATMENT OF RELAPSING APL(European APL group experience) (APL group experience) (De Botton,JCO,in press)De Botton,JCO,in press)

564 patients <66 years564 patients <66 years in APL 91 and APL 93 trials :525 (93%) achieved CR. in APL 91 and APL 93 trials :525 (93%) achieved CR.

122 /140 (87%) relapsing patients achieved CR2122 /140 (87%) relapsing patients achieved CR2 ATRA:8ATRA:8 ATO:4ATO:4 Chemotherapy(CT):24Chemotherapy(CT):24 ATRA+CT:98ATRA+CT:98

Arsenic trioxyde in relapsing Arsenic trioxyde in relapsing APLAPL

RefRef Dosing Nb pts CR rate Dosing Nb pts CR rate Post induction treatment Post induction treatment Long term outcome Long term outcome

AsAs22OO33 alone (n =18) alone (n =18) 12/18 relapses 12/18 relapsesNiu et al Niu et al 0.15mg/kg/d 47 0.15mg/kg/d 47 85 % 85 % median DFS median DFS

17months17months AsAs22OO33 + CT (n =11) 2/11 relapses + CT (n =11) 2/11 relapses

Shen et a Shen et a 0.08 mg/kg/d 20 0.08 mg/kg/d 20 80 % variable 80 % variable 2 year 2 year relapse freerelapse free

survival : 61 %survival : 61 %

Kwong et alKwong et al 10 mg/d 10 mg/d 8 8 100 % 100 % Ida Ida 7/8 still 7/8 still in CRin CR

6 in molecular CR6 in molecular CR

Soignet Soignet 0.15 mg/kg0.15 mg/kg 52 52 87 % 87 % Allo (n = 9) or auto (n = 3) Allo (n = 9) or auto (n = 3) 11 11 still in CRstill in CR

transplantationtransplantation AsAs22OO33 (n = 21) (n = 21) 9 still in CR 9 still in CR

OhnishiOhnishi 0.15 mg/kg 0.15 mg/kg 14 14 78 % 78 % As As22OO33 median CR duration median CR duration ::

8 months8 months

APL in CR2:Allo and auto SCTAPL in CR2:Allo and auto SCT(De Botton,JCO,2005)(De Botton,JCO,2005)

39%)39%)39%39%6%6%25%25% TRMTRM

52%52%58%58%60% 60% (@7 (@7 yrs.)yrs.)

48%48% OSOS

52%52%57%57%79% 79% (@7 (@7 yrs.)yrs.)

45%45% DFS DFS

8%8%15%15%2121%@ 7 yrs%@ 7 yrs44%44% RelapseRelapse

25251271275050151151 No. PtsNo. Pts

APL Study APL Study Group** Group** (Europe(Europe))

EBMTEBMT

(1993–(1993–1999)*1999)*

APL Study APL Study Group** Group** (Europe(Europe))

EBMT EBMT

(1993–(1993–1999)*1999)*

Allo SCTAllo SCTAuto SCTAuto SCT

Event-free survival (EFS) from Event-free survival (EFS) from transplantationtransplantation

Days from transplant

P(N

o e

ven

t)

0 500 1000 1500 2000 2500 3000

0.0

0.2

0.4

0.6

0.8

1.0

AUTOALLO

Allo SCT after ATO Allo SCT after ATO SalvageSalvage

Post-transplant survival Post-transplant survival (Soignet,Dombret)(Soignet,Dombret)

0 12 24 36 480 %

20 %

40 %

60 %

80 %

100 %

Median follow-up: 30 months post SCT (range, 9.5 to 45)

Months Months

At risk deaths 2-year est. 22 4 86%

At risk deaths 2-year est. 16 3 88% 6 1 83%

1st rel.> 2nd rel.

0 12 24 36 480 %

20 %

40 %

60 %

80 %

100 %

European APL group European APL group recommendationsrecommendations

for APL patients in first relapsefor APL patients in first relapse

Induction with ATO (0.15 mg/kg, max Induction with ATO (0.15 mg/kg, max 50 days)50 days)

Consolidation with ATO (5 days/w for Consolidation with ATO (5 days/w for 25 doses)25 doses)donor and<40yrsdonor and<40yrs:allo:allo no donorno donor:Ida AraC:Ida AraC elderly ptselderly pts:maintenance :maintenance

-if PCR neg:auto -if PCR neg:auto ATO,ATRAATO,ATRA -if PCR pos:GO,etc.. -if PCR pos:GO,etc.. low dose CT,GO low dose CT,GO

,,

Treatment of APLmolecular Treatment of APLmolecular relapse by Gentuzumab relapse by Gentuzumab

ozogamycin(GO)ozogamycin(GO) (Lo (Lo Coco,Blood,2004)Coco,Blood,2004) 16 pts with molecular relapse 16 pts with molecular relapse

(8,5,2,1)(8,5,2,1) GO 6mg/m2 x 2 + 1GO 6mg/m2 x 2 + 1 14 molecular CR achieved14 molecular CR achieved 7 pts still in CR (7+ to 31+ 7 pts still in CR (7+ to 31+

months),7 relapses after 3 to 15 months),7 relapses after 3 to 15 monthsmonths

Treatment of APL Treatment of APL in children and in children and elderly patientselderly patients

APL in children APL in children (De Botton,JCO,2004)(De Botton,JCO,2004)

10% of APL10% of APL Often high WBC countsOften high WBC counts Similar response to ATRA+ chemo Similar response to ATRA+ chemo

as in adultsas in adults Concerns aboutConcerns about::

Initial doses of ATRA (25 mg/m2)Initial doses of ATRA (25 mg/m2)

High cumulative doses of High cumulative doses of anthracyclinesanthracyclines

5-year OS5-year OS

DaysDays

P (

Su

rviv

al)

P (

Su

rviv

al)

00 500500 10001000 15001500 20002000 25002500 30003000

0.0

0.0

0.2

0.2

0.4

0.4

0.6

0.6

0.8

0.8

1.0

1.0

Children 91%Children 91%Adults 77%Adults 77%

APL in the elderlyAPL in the elderly (Ades,Leukemia,in press)(Ades,Leukemia,in press)

20% of APL aged>6020% of APL aged>60

CR rate (APL 93)CR rate (APL 93)

< 60< 60 94 %94 % difference due todifference due to

> 60> 60 86 %86 % early deathearly death

> 70> 70 85 %85 % raterate

APL in the elderly (2)APL in the elderly (2)

Relapse at 4 yearsRelapse at 4 years

- 26 % in pts < 60- 26 % in pts < 60

- 20 % in pts > 60- 20 % in pts > 60 Survival at 4 yearsSurvival at 4 years

- 79 % in pts < 60- 79 % in pts < 60

- 55 % in pts > 60- 55 % in pts > 60

due to deaths in CRdue to deaths in CR

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96

Time (months)

Pro

bab

ility

of

rela

pse

Sanz et al, Blood (in press) Sanz et al, Blood (in press)

Elderly Patients with APL (n = 104)Elderly Patients with APL (n = 104)Cumulative incidence of relapseCumulative incidence of relapse

8.5%

60-70 y

>70 y

P = 0.18

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96

Time (months)

Rel

apse

-fre

e su

rviv

al (

%)

Sanz et al, Blood (in press) Sanz et al, Blood (in press)

Elderly Patients with APL (n = 104)Elderly Patients with APL (n = 104)Relapse-free survivalRelapse-free survival

Arsenic derivatives for APL Arsenic derivatives for APL in children and elderly in children and elderly

patients?patients? ChildrenChildren: add Arsenic to reduce the : add Arsenic to reduce the

cumuIative dose of anthracyclines?cumuIative dose of anthracyclines? Elderly patients (or cardiac Elderly patients (or cardiac

problemsproblems…): add arsenic to reduce …): add arsenic to reduce the total amount of chemotherapythe total amount of chemotherapy

Question 1:All but one of the Question 1:All but one of the following parameters are following parameters are prognostic factors in APLprognostic factors in APL

A: pretreatment WBC countA: pretreatment WBC count B: ageB: age C: hemoglobin levelC: hemoglobin level D: PML-RAR alpha transcript after D: PML-RAR alpha transcript after

consolidation treatmentconsolidation treatment

Question 2:all but one of the Question 2:all but one of the following symptoms are hallmarks following symptoms are hallmarks

of the ATRA syndromeof the ATRA syndrome A:pulmonary infiltratesA:pulmonary infiltrates B:pleural effusionB:pleural effusion C: clinical bleedingC: clinical bleeding D: unexplained feverD: unexplained fever

Question 3:what is the major Question 3:what is the major component of treatment of component of treatment of

initial coagulopathy in APL?initial coagulopathy in APL? A: heparinA: heparin B: platelet transfusionsB: platelet transfusions C: tranexamic acid or other C: tranexamic acid or other

antifibrinolytic drugsantifibrinolytic drugs D: fibrinogen infusionsD: fibrinogen infusions

Question 4: APL patient with Question 4: APL patient with WBC=15000/mm3.First line WBC=15000/mm3.First line

treatment?treatment? A:ATRA followed by anthracycline A:ATRA followed by anthracycline

based CTbased CT B: anthracycline based CTB: anthracycline based CT`̀ C:ATRA plus anthracycline based CTC:ATRA plus anthracycline based CT D: arsenic derivative aloneD: arsenic derivative alone

Question 5: what is your Question 5: what is your induction treatment for first induction treatment for first

relapse APL (WBC< relapse APL (WBC< 10000/mm3)10000/mm3) A: ATRA aloneA: ATRA alone

B: Arsenic derivative aloneB: Arsenic derivative alone`̀ C: ATRA+ anthracycline based CTC: ATRA+ anthracycline based CT D: Gentuzumab (mylotarg)D: Gentuzumab (mylotarg)

LUNG PNEUMOCYSTISINFECTION

3 patients ATRA+CT at 5 monthsATRA+CT at 13 monthsCT at 19 months

maintenance prematurely stopped 1 relapse

Prophylaxis required

Initial characteristics of the 122 APL patients in second hematological complete Initial characteristics of the 122 APL patients in second hematological complete

remission according to post-remission therapyremission according to post-remission therapy

n=17n=17

n=18n=18

n=4n=4

n=4n=4

n=2n=2

n=3n=3

Radiotherapy alone Radiotherapy alone (n=1)(n=1)

n=9n=9

n=5n=5

n=2n=2

n=4n=4

n=1n=1

n=2n=2

n=32n=32

n=11n=11

n=3n=3

n=3n=3

n=1n=1

Salvage therapySalvage therapy

ATRA+EMAATRA+EMA

ATRA+other CTATRA+other CT

EMA aloneEMA alone

Other CT aloneOther CT alone

ATO aloneATO alone

ATRA aloneATRA alone

14.5 (10.1-23.9)14.5 (10.1-23.9)

2020

2929

14.6 (11.5-23.9)14.6 (11.5-23.9)

66

1717

23.4 (13.9-39.7)23.4 (13.9-39.7)

1010

4040

CR 1 duration (months)CR 1 duration (months)

Median (Q1-Q3)Median (Q1-Q3)

< 12 months< 12 months

> 12 months> 12 months

5.3 (1.4-31.2)5.3 (1.4-31.2)6.9 (2.4-25.9)6.9 (2.4-25.9)3.95 (1.1-13.7)3.95 (1.1-13.7)

WBC at diagnosis (10 9/L)WBC at diagnosis (10 9/L)

Median (Q1-Q3)Median (Q1-Q3)

30/1930/1912/1112/1134/1634/16Gender (M/F)Gender (M/F)

45 (37-54)45 (37-54)32.5 (22-43)32.5 (22-43)45 (29-49)45 (29-49)Median Age (Q1-Q3)Median Age (Q1-Q3)

N=49N=49N=23N=23N=50N=50

Other consolidation +/- Other consolidation +/- maintenance treatmentsmaintenance treatments

AllogeneicAllogeneic

stem cell transplantationstem cell transplantation

AutologousAutologous


Pretransplant characteristics and transplantation procedures in the 73 APL patients Pretransplant characteristics and transplantation procedures in the 73 APL patients autografted (n=50) or allografted (n=23) in second complete remissionautografted (n=50) or allografted (n=23) in second complete remission

33

2020

HLA identical sibling (n=18)HLA identical sibling (n=18)

Unrelated donor (n=5)Unrelated donor (n=5)

4343

77

Stem cell sourceStem cell source

Peripheral Blood Peripheral Blood

Bone marrowBone marrow

DonorDonor

*Cy-TBI (n=17)*Cy-TBI (n=17)

*Bu-Cy (n=6)*Bu-Cy (n=6)

*Cy-TBI (n=28)*Cy-TBI (n=28)

*Bu-Cy (n=17)*Bu-Cy (n=17)

Bu-Melphalan (n=4)Bu-Melphalan (n=4)

Cy-Melphalan (n=1)Cy-Melphalan (n=1)

Conditioning regimen for SCTConditioning regimen for SCT

99

66

33

1414

3030

22

2828

2020

RT-PCR analysis before SCTRT-PCR analysis before SCT

PositivePositive

NegativeNegative

Not assessed Not assessed

80.5 (55-125)80.5 (55-125)

1919

44

112 (82-137)112 (82-137)

4444

66

Time to SCT after CR2 achievement Time to SCT after CR2 achievement

Median (Q1-Q3) (days)Median (Q1-Q3) (days)

< 6 months< 6 months

> 6 months> 6 months

N=23N=23N=50N=50

AllogeneicAllogeneic


AutologousAutologous


;;

7-year RFS7-year RFS, , EFSEFS and and OSOS in the in the auto SCTauto SCT group were group were 79.479.4%, %, 60.660.6% and % and 59.859.8%, respectively, with a %, respectively, with a TRM TRM of of 66%. %.

7-year RFS7-year RFS, , EFSEFS and and OSOS in the in the allo SCTallo SCT group were group were 92.392.3%, %, 52.252.2% and % and 51.851.8%, respectively, with a %, respectively, with a TRMTRM of of 3939%. %.

No significant differences in RFS and EFS were seen between auto and allo 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 (p=.19 and p=.11, respectively) but was OS significantly better in the auto SCT group than in the allo SCT group (p=.04). SCT group than in the allo SCT group (p=.04).

In non-transplanted patients, 7-year RFS,In non-transplanted patients, 7-year RFS, EFSEFS and and OSOS were were 3838%, %, 30.430.4% % and and 39.539.5%, respectively. %, respectively.

Patients with very high WBC counts (> 50 Patients with very high WBC counts (> 50 000/mm000/mm33))

n = 44n = 44

M = 24, F = 20M = 24, F = 20

36/44 (82%) CR36/44 (82%) CR

2 deaths during consolidation 2 deaths during consolidation courses, courses, 3 relapses before second 3 relapses before second randomizationrandomization15 subsequent relapses15 subsequent relapses

AsAs22OO33 alone versus As alone versus As22OO3 3 + ATRA in + ATRA in relapsing APL (1) relapsing APL (1)

(Raffoux et al, JCO,2003)(Raffoux et al, JCO,2003)

N = 20N = 20

First relapse = 7 ; second or subsequent First relapse = 7 ; second or subsequent relapse = 13relapse = 13

AsAs22OO3 3 : 0,15 mg/kg/d: 0,15 mg/kg/d

ATRA : 45 mg/m²/dATRA : 45 mg/m²/d


(Raffoux et al, JCO, in press)(Raffoux et al, JCO, in press)

CR 80 % in each treatment groupCR 80 % in each treatment group median time to CR 42 days in each treatment median time to CR 42 days in each treatment

groupgroup similar improvement in coagulopathysimilar improvement in coagulopathy 3 pts reached molecular CR after one course. All 3 pts reached molecular CR after one course. All

3 had also received chemotherapy (for high WBC 3 had also received chemotherapy (for high WBC counts)counts)

pharmacokinetic profile of Aspharmacokinetic profile of As22OO33 similar in the 2 similar in the 2 armsarms

adverse events similar in both armsadverse events similar in both arms


(Raffoux et al, JCO, in press)(Raffoux et al, JCO, in press)

10 pts received As10 pts received As22OO33 ± ATRA ± ATRA consolidation (2 courses). consolidation (2 courses). Only 2/8 PCR Only 2/8 PCR negative after 2negative after 2 consolidation coursesconsolidation courses

8 allo or autologous SCT8 allo or autologous SCT Similar survivalSimilar survival

Role of Arac in the incidenceRole of Arac in the incidence

of CNS relapsesof CNS relapses

5 CNS5 CNS relapses in relapses in 159 PETHEMA pts 159 PETHEMA pts (3%)(3%) (treated without AraC)(treated without AraC) vs vs 5 in 579 APL91 and 93 5 in 579 APL91 and 93 pts pts (0.9%)(0.9%) (treated with high dose AraC) (treated with high dose AraC) (p=.07)(p=.07). .

CNS involvement at relapse in PETHEMA (28% of CNS involvement at relapse in PETHEMA (28% of relapses) more frequent than in APL 91 and 93 (3%)relapses) more frequent than in APL 91 and 93 (3%)(p=.001).(p=.001).

Documents

APL Pierre Fenaux (Hopital Avicenne,Paris 13 University)