50th ASH meeting 2008, San Francisco, CA, USA

Treatment with All-trans Retinoic Acid and Anthracycline

Monochemotherapy for Children with Acute Promyelocytic

Leukemia: a Multicenter Study by the PETHEMA Group

Luis Madero, Luis Madero, Pau MontesinosPau Montesinos, Pilar Bastida, Amparo , Pilar Bastida, Amparo Verdeguer, Javier De la Serna, Antonio Molines, Verdeguer, Javier De la Serna, Antonio Molines,

Purificacion Garcia, Jose Luis Fuster, Maria jose Allegue, Purificacion Garcia, Jose Luis Fuster, Maria jose Allegue, Rafael Rojas, and Miguel A. Sanz, oRafael Rojas, and Miguel A. Sanz, on behalf of the n behalf of the

PETHEMAPETHEMA, HOVON and GATLA Groups, HOVON and GATLA Groups

Background

• Information about therapy results in pediatric APL patients is scarce, particularly on long-term outcomes.

• More frequently hyperleukocytosis, M3v, BCR3.

• Pseudotumor and headache ATRA 25mg/m2.

Background

Ortega et al., J Clin Oncol 2005

Cumulative incidence of relapse Disease-free survival

Study Aims

Update the analysis of the LPA96 and LPA99 Update the analysis of the LPA96 and LPA99 trials including a significantly higher number of trials including a significantly higher number of

children and longer follow-up than in the previous children and longer follow-up than in the previous report (Ortega et al., J Clin Oncol 2005).report (Ortega et al., J Clin Oncol 2005).

Previous report

Presentreport

Analysis updated on June15, 2004 Oct. 15, 2008

No. of patients 66 108

Follow up (months) median range

396 – 90

741 – 143

PETHEMA LPA96, 99 & 2005 Trials

CONSOLIDATIONCONSOLIDATION

INDUCTIONINDUCTION

AIDAAIDA

All patientsAll patients

MTZ 10 mg/m²/dMTZ 10 mg/m²/d × 5× 5

IDA 5 mg/m²/d × 4IDA 5 mg/m²/d × 4

IDA 12 mg/m²/dIDA 12 mg/m²/d × 1 × 1

#1#1

#2#2

#3#3

MAINTENANCE MAINTENANCE

2 year2 year

ATRA + MP + MTXATRA + MP + MTX

(Risk-adapted)(Risk-adapted)

ATRA 25 mg/m²/d until CRATRA 25 mg/m²/d until CR IDA 12 mg/m² d2, 4, 6, 8IDA 12 mg/m² d2, 4, 6, 8

low risklow risk

MTZ 10 mg/m²/dMTZ 10 mg/m²/d × 5× 5

IDA 5 mg/m²/d × 4IDA 5 mg/m²/d × 4

IDA 12 mg/m²/dIDA 12 mg/m²/d × 1 × 1

#1#1

#2#2

#3#3

intermediate and high riskintermediate and high risk

MTZ 10 mg/m²/dMTZ 10 mg/m²/d × 5 + ATRA × 15 d × 5 + ATRA × 15 d

IDA 7 mg/m²/d × 4 IDA 7 mg/m²/d × 4 ++ ATRA ATRA × 15 d× 15 d

IDA 12 mg/m²/dIDA 12 mg/m²/d × 2 + ATRA × 15 d × 2 + ATRA × 15 d

#1#1

#2#2

#3#3

PETHEMA LPA96, 99 & 2005 Trials

INDUCTIONINDUCTION

AIDAAIDA

MAINTENANCE MAINTENANCE

2 year2 year

ATRA + MP + MTXATRA + MP + MTX

ATRA 25 mg/m²/d until CRATRA 25 mg/m²/d until CR IDA 12 mg/m² d2, 4, 6, 8IDA 12 mg/m² d2, 4, 6, 8

low risklow risk

MTZ 10 mg/m²/dMTZ 10 mg/m²/d × 3 + ATRA x15d× 3 + ATRA x15d

IDA 5 mg/m²/d × 4 IDA 5 mg/m²/d × 4 + ATRA x15d+ ATRA x15d

IDA 12 mg/m²/dIDA 12 mg/m²/d × 1 × 1 + ATRA x15d+ ATRA x15d

#1#1

#2#2

#3#3

CONSOLIDATIONCONSOLIDATION (Risk-adapted)(Risk-adapted)

MTZ 10 mg/m²/dMTZ 10 mg/m²/d × 3× 3 + ATRA x15d + ATRA x15d

IDA 7 mg/m²/d × 4 + ATRA x15dIDA 7 mg/m²/d × 4 + ATRA x15d

IDA 12 mg/m²/dIDA 12 mg/m²/d ×× 2 + ATRA x15d 2 + ATRA x15d

#1#1

#2#2

#3#3

Intermediate riskIntermediate risk

IDAIDA 5 5 mg/m²/d × 4 mg/m²/d × 4 + Ara-C+ Ara-C + ATRA x15d + ATRA x15d

MTZ 10 mg/m²/dMTZ 10 mg/m²/d × 5 + ATRA x15d× 5 + ATRA x15d

IDA 12 mg/m²/dIDA 12 mg/m²/d × 2× 2 + Ara-C+ Ara-C + ATRA x15d + ATRA x15d

High riskHigh risk

PETHEMA LPA96, 99 & 2005 TrialsAccrual

• Study period: November 1996 – October 2008 Accrual

113 Ineligible 4 (3.5%) Eligible

109 Non evaluable (addition of Ara-C) 1 (0.9%) Evaluable 108

• 108 children (10.1%) of 1066 patients included

PETHEMA LPA96, 99 & 2005 TrialsDemographic and baseline characteristics

Characteristic Median (range) N (%)

Age 14 (2-18)Gender Female 59 (55)Hepatosplenomegaly Yes 21 (23)ECOG Grade 2-3 24 (30)Fever Yes 48 (45)Hemoglobin, g/dL 10 or higher 25 (23)

PETHEMA LPA96, 99 & 2005 TrialsDemographic and baseline characteristics

Characteristic N (%)WBC count, × 109/L

10 or higher 36 (33)Relapse-risk score Low 11 (10) Intermediate 61 (57) High 36 (33)FAB subtype Microgranular (M3v) 23 (22)BCR isoform BCR3 36 (42)

Induction Outcome with AIDA Regimen

LPA96(n = 18)

LPA99(n = 66)

LPA2005(n = 24)

P

CR, (%) 88.9 94.5 100 NS

Causes of failure (%)

Hemorrhage 5.5 3.5 0 NS

Infection 0 0 0 NS

Diff. Syndrome 5.5 2.0 0 NS

Other 0 0 0 NS

Resistance 0 0 0 NS

PETHEMA LPA96, 99 & 2005 TrialsDifferentiation syndrome

P=0.65

9,3

9,3

12,3

12.2

0

5

10

15

20

25

Children Adults

%

Severe DS Moderate DS

PETHEMA LPA96, 99 & 2005 TrialsPseudotumor cerebri

1413

7

20,3

0

5

10

15

20

0-10years

11-18years

19-25years

26-50years

>50years

• Headache occurred in 39 children (36%), vs 249 (26%) in adults (P=0.03)

P=0.03

• Pseudotumor cerebri occurred in 14 children (13%)

PETHEMA LPA96, 99 & 2005 TrialsPost-remission events

2

6 6

0 10

2

4

6

8

10

Nº

of

Pat

ien

ts

MolecularPersistence

MolecularRelapse

ClinicalRelapse*

t-MDS/AML Death in CR

* 1 patient presented CNS involvement at first relapse

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

PETHEMA LPA96, 99 & 2005 Trials

Overall survival

OS

OS by WBC count

91%

85%

P = 0.44

WBC <10 x 109/L

WBC >10 x 109/L

0

0.2

0.4

0.6

0.8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

0

0.2

0.4

0.6

0.8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

OS by LPA trial

89%

79%P = 0.11

LPA 99

LPA96

89%

LPA 2005

100%

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

PETHEMA LPA96, 99 & 2005 Trials Disease-free

survival

Overall DFS

DFS by WBC count

0

0.2

0.4

0.6

0.8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

0

0.2

0.4

0.6

0.8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

0

0,2

0,4

0,6

0,8

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months

Pro

bab

ility

DFS by LPA trial

84%

89%

69%

P = 0.04LPA 99

LPA96

LPA 2005

83%

90%

73%

P = 0.03

WBC <10 x 109/L

WBC >10 x 109/L

PETHEMA LPA96, 99 & 2005 TrialsConcluding remarks

• This study shows that a risk-adapted strategy combining ATRA and anthracycline monochemotherapy provides a high antileukemic efficacy coupled with relatively low toxicity and high degree of compliance.

• Our results confirm a high incidence of headache and pseudotumor cerebri in children. Nevertheless, these complications were manageable and did not impact on mortality.

PETHEMA LPA96, 99 & 2005 TrialsConcluding remarks

• Risk-adapted strategies focusing on high-risk patients (WBC count > 10 x 109/L) should be a major subject of future studies. The role of the addition of cytarabine in this setting should be better established with more patients and longer follow-up.

Participating Institutions

H.U. La Fe, ValenciaH. Central, AsturiasH.J. Canalejo, CoruñaH. General, Jerez H. Clinic, BarcelonaH.C. S. Carlos, MadridH. Clínico, ValenciaH. Cruces, BaracaldoH. 12 Octubre, MadridH.C.U. SalamancaH. Son Dureta, MallorcaH.U. P. del Mar, CádizH. Insular, Las PalmasC.H. Xeral-Calde, LugoH. General, AlicanteH.S.P.Alcántara, Cáceres

H. Carlos Haya, MálagaH.C.U. SantiagoH. Reina Sofia, CórdobaH. Dr. Peset, ValenciaH. San Pau, BarcelonaH. Joan XXIII, TarragonaH.U. V. D'Hebron, BarcelonaC.H. LeónH. Navarra, PamplonaH.C. ValladolidH. G. AlbaceteH. M. Valdecilla, SantanderH.U. V. D'Hebron (Inf), BarnaH. La Princesa, Madrid

H.U. G. Trias i Pujol, Barna

H. Dr. Negrin, Las PalmasH. M-Infantil, Las PalmasH. Basurto, BilbaoH. R. Hortega, ValladolidH.C.U. ZaragozaH.G.E. Ciudad de JaénH.U. V. Victoria, MálagaH.General, CastellónH.U. V. Arrixaca, MurciaH. Montecelo, PontevedraF. Jiménez Díaz, MadridC.H. de SegoviaH. Meixoeiro, VigoH. Severo Ochoa, LeganésH.G. Murcia

H. San Jorge, HuescaH. Ramón y Cajal, Madrid

Participating Institutions

Fundaleu, Buenos Aires

H. Rossi, La PlataH. General San Martín, La Plata

H. General San Martín, ParanáI. Trasplante de Médula Ósea, La Plata

H. Clemente Álvarez, Rosario

GATLA (Argentina)

I. P. de Hematología, ParanáH. de Clínicas, Buenos Aires

H.U. del Aire, MadridH. del Mar, Barcelona H. Dr. Trueta, GeronaH. Niño Jesús, Madrid

H.G. Valencia

F. Hospital, Brno (Czec Rep.)

H.U. Arrixaca (Inf), Murcia

H. Xeral-Cies, Vigo

H. Txagorritxu, VitoriaH. General (Inf), AlicanteH. Río Carrión, PalenciaH. C. Haya (Inf), MálagaH. P. Asturias, A. HenaresH. Mutua, Terrasa

H. N.S. Sonsoles, Ávila

H. Sta María Rosell, CartagenaH. San Rafael, MadridH. Virgen de la Cinta, TortosaH. C. Haya (Inf), Málaga

H. Virgen del Rocío, Sevilla

H. Maciel, Montevideo (Uruguay)

HOVON (The Netherlands)

H. La Paz (Inf), Madrid

H.C. San Carlos (Inf), MadridI.C.O., Hospitalet de Llobregat

H.U. La Fe (Inf), ValenciaSHOP (Spain)