apl meeting 2009, rome, italy. sept. 25 2009 all-trans retinoic acid and anthracycline...
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APL meeting 2009, Rome, Italy. Sept. 25 2009
All-trans Retinoic Acid and Anthracycline Monochemotherapy
for the Treatment of Elderly Patients with Acute Promyelocytic
Leukaemia
P. Montesinos, E. Vellenga, C. Rayón, V. Rubio, S. P. Montesinos, E. Vellenga, C. Rayón, V. Rubio, S. Brunet, J. Díaz-Mediavilla, C. Rivas, J. Bueno, J. de la Brunet, J. Díaz-Mediavilla, C. Rivas, J. Bueno, J. de la
Serna, E. Amutio, S. Negri, G. Milone, A. Holowiecka, J. Serna, E. Amutio, S. Negri, G. Milone, A. Holowiecka, J. Bergua, A. Novo, E. de Lisa, J. Mayer, B. Lowenberg, Bergua, A. Novo, E. de Lisa, J. Mayer, B. Lowenberg,
and M.A. Sanz on behalf of the PETHEMA Groupand M.A. Sanz on behalf of the PETHEMA Group
Background
Therapeutic results in elderly patients with acute promyelocytic leukemia (APL) have been generally reported as less effective than for younger patients.
Results of the GIMEMA, European APL Group, and PETHEMA studies
GIMEMA1
(n = 134)
European APL932
(n = 129)
PETHEMA3
(n = 104)
CR, (%) 86 86 84
Death in CR 13 19 8
Overall survival 82 (3 y)* 56 (4 y) --
Disease-free survival 72 (3 y)* -- 79 (6 y)
CI of relapse -- 16 (4 y) 9 (6 y)
1- Leukemia 2003; 2- Leukemia 2005; 3- Blood 2004
More low-risk among elderly
Sanz et al., Blood 2004
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
elderly patients and longer follow-up.elderly patients and longer follow-up.
Previous report
Presentreport
Analysis updated on June 15, 2004 July 15, 2009
No. of patients 104 195
Follow up (months) median range
366 – 87
715 – 151
PETHEMA LPA96 TrialAll patients
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
ATRA 45 mg/m²/d until CRATRA 45 mg/m²/d until CR IDA 12 mg/m² d2, 4, 6, 8IDA 12 mg/m² d2, 4, 6, 8
PETHEMA LPA99 TrialPatients >60 years
CONSOLIDATIONCONSOLIDATION
INDUCTIONINDUCTION
AIDAAIDA
MAINTENANCE MAINTENANCE
2 year2 year
ATRA + MP + MTXATRA + MP + MTX
(Risk-adapted)(Risk-adapted)
ATRA 45 mg/m²/d until CRATRA 45 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 LPA 2005 TrialPatients >60 years
INDUCTIONINDUCTION
AIDAAIDA
MAINTENANCE MAINTENANCE
2 year2 year
ATRA + MP + MTXATRA + MP + MTX
ATRA 45 mg/m²/d until CRATRA 45 mg/m²/d until CR IDA 12 mg/m² d2, 4, 6, 8IDA 12 mg/m² d2, 4, 6, 8
CONSOLIDATIONCONSOLIDATION
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 and high riskIntermediate and high 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
low risklow risk
#1#1
#2#2
#3#3
(Dose reduction)(Dose reduction)
PETHEMA LPA96, 99 & 2005 TrialsAccrual
• Study period: November 1996 – July 2009
Accrual270
Ineligible 69 (25.5%) Eligible
201 Non evaluable 6 (2.9%) Evaluable 195
• 195 elderly (17.3%) of 1130 patients included
PETHEMA LPA96, 99 & 2005 TrialsDemographic and baseline characteristics
Characteristic Median (range) N (%)
Age 67 (60-83)
Gender
Female 103 (52)
PETHEMA trial
LPA96 30 (15)
LPA99 106 (55)
LPA2005 59 (30)
ECOG
Grade 2-3 63 (36)
PETHEMA LPA96, 99 & 2005 TrialsDemographic and baseline characteristics
Characteristic N (%)
Relapse-risk score
Low 55 (28)
Intermediate 96 (49)
High 44 (23)
FAB subtype
Microgranular (M3v) 35 (18)
BCR isoform
BCR3 66 (44)
Induction Outcome with AIDA Regimen
LPA96(n = 30)
LPA99(n = 106)
LPA2005(n = 59)
P
CR, (%) 80.0 78.3 88.1 0.12
Causes of failure (%)
Hemorrhage 10.0 8.5 5.1 NS
Infection 6.7 8.5 3.4 NS
Diff. Syndrome 3.3 2.8 1.7 NS
Myocardial Infarct. 0 1.9 1.7 NS
Resistance 0 0 0 NS
PETHEMA LPA96, 99 & 2005 TrialsPost-remission events (154 of 159 completed the consolidation therapy)
4
10
67 8
0
5
10
15
Nº o
f Pat
ient
s
MolecularRelapse
ClinicalRelapse
t-MDS/AML SolidNeoplasia
Toxic Deathin CR
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Pro
bab
ility
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Pro
bab
ility
PETHEMA LPA96, 99 & 2005 Trials
Overall survival
OS
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Pro
bab
ility
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Pro
bab
ility
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Prob
abilit
y
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Prob
abilit
y
OS by LPA trial
67%
72%
P = 0.13
LPA 99LPA96
63%
LPA 2005 75%
OS by Relapse Risk
63%
51%
P = 0.003IntermediateHigh
Low
73%
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Pro
babi
lity
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Pro
babi
lity
OS by Age
49%
P = 0.06Age >70
69%
Age <70
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Pro
bab
ility
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Pro
bab
ility
PETHEMA LPA96, 99 & 2005 Trials Relapse-free survival
Overall RFS
RFS by Relapse Risk
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Pro
bab
ility
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Pro
bab
ility
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Prob
abilit
y
0
0,2
0,4
0,6
0,8
1
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Months
Prob
abilit
y
RFS by LPA trial
89%
89%
87%
P = 0.90
LPA 99LPA96
LPA 2005
91%
87%
82%
P = 0.21IntermediateHigh
Low
95%
PETHEMA Trials in Elderly PatientsConcluding remarks
• This study confirms the high antileukemic efficacy and high degree of compliance of protocols using ATRA and anthracycline monochemotherapy for induction and consolidation therapy in elderly patients.
• Induction death remains the most challenging cause of therapeutic failure, especially in patients with WBC >10.000xµL.
• Consolidation and maintenance chemotherapy was relatively well tolerated in low-risk patients and in younger than 70 years.
• “Age-adapted” strategies focusing on decreasing the intensity of chemotherapy, while maintaining the antileukemic efficacy, should be a major objective in future studies.
PETHEMA Trials in Elderly PatientsConcluding remarks
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)