50 th ash meeting 2008, san francisco, ca, usa treatment with all-trans retinoic acid and...
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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)