p. montesinos disclosures 49 th ash annual meeting–atlanta, georgia research support/p.i.no...
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P. Montesinos Disclosures
4949thth ASH Annual Meeting–Atlanta, Georgia ASH Annual Meeting–Atlanta, Georgia
Research Support/P.I. No conflict of interest to disclose
Employee No conflict of interest to disclose
Consultant No conflict of interest to disclose
Major Stockholder No conflict of interest to disclose
Speakers Bureau No conflict of interest to disclose
Honoraria No conflict of interest to disclose
Scientific Advisory Board No conflict of interest to disclose
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2007 ASH Meeting, Atlanta, GO
Central Nervous System Relapse in Patients with Acute
Promyelocytic Leukemia Treated with All-trans Retinoic Acid and
Reinforced Anthracycline Monochemotherapy
P Montesinos, J.D Gonzalez, E Vellenga, C Rayon, R P Montesinos, J.D Gonzalez, E Vellenga, C Rayon, R Parody, A Leon, J Esteve, J Bergua, G Milone and MA Parody, A Leon, J Esteve, J Bergua, G Milone and MA Sanz on behalf of the PETHEMA, HOVON and GATLA Sanz on behalf of the PETHEMA, HOVON and GATLA
Groups
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Background
• CNS relapse can complicate the course of APL in first CR.
• Incidence of CNS relapse is still not well established (from 0.6% to 5%1,2).
• WBC count (>10 x 109/L) is the only well established independent risk factor for CNS relapse1.
• Other factors with less or no evidence: age <45 year1, BCR31,2,3, RA syndrome4, adhesion molecules (CD11b, CD56).
1. de Botton S, Leukemia 2006; 20: 35-41 2. Liso V, Cancer 1998, 83: 1522-28; 3. Specchia G, JCO 2001, 19: 4023-28; 4. Ko BS, Leukemia 1999, 13: 1406-8
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Background
• ATRA and anthracyclines do not cross the cerebrospinal barrier use of intrathecal prophylaxis or high-dose cytarabine.
• The advantage of CNS prophylaxis in APL patients is still controversial.
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Study Aims
1. Analyze the incidence and characteristics of CNS involvement at first relapse in APL patients treated with risk-adapted consolidation, without CNS prophylaxis (PETHEMA LPA99 trial).
2. Compare LPA99 and LPA96 trials, with or without risk-adapted consolidation including ATRA.
3. Identify risk-factors for CNS relapse in APL.
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CONSOLIDATION
PETHEMA LPA99 Trials
addition of ATRA 45 mg/m2/d for intermediate- and high-risk patients
INDUCTION
AIDA
low risk
MTZ 10 mg/m²/d × 5
IDA 5 mg/m²/d × 4
IDA 12 mg/m²/d × 1
#1#2
#3
MAINTENANCE
intermediate and high risk
MTZ 10 mg/m²/d × 5 + ATRA × 15
IDA 7 mg/m²/d × 4 + ATRA × 15
IDA 12 mg/m²/d × 2 + ATRA × 15
#1#2
#3
2 yearATRA + MP + MTX
(Risk-adapted)
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Patient Characteristics
PETHEMA LPA 96
PETHEMA LPA99
No. of patients 172 560
Age, median (range) 39 (2-78) 40 (2-83)
WBC, median (range) 2.0 (0.3-210) 2.2 (0.2-460)
Patients achieving CR 156 (91%) 510 (91%)
Follow up (months) median range
11396 – 133
6328 – 98
Results updated on Nov. 30, 2007.
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Diagnosis of CNS Relapse
• Neurological signs and symptoms (clinical or radiological).
• Positive lumbar puncture (compatible cytology + genetic diagnosis).
• Positive biopsy of CNS granulocytic sarcoma.
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End-points and Statistical Methods
• Cumulative incidence (CI) of CNS involvement at first relapse.
• Risk competing events:
• Isolated bone marrow molecular relapse.
• Isolated bone marrow clinical relapse.
• Death in CR.
• Secondary MDS/AML.
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11%11%
12 24 36 48 60 72 84
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1
0 12 24 36 48 60 72 84 96 108 120 132 144
Months after CR
Pro
bab
ility
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1
0 12 24 36 48 60 72 84 96 108 120 132 144
Months after CR
Pro
bab
ility
1. 6%1. 6%
CI of CNS Relapse: LPA96 and LPA99 TrialsCI of CNS Relapse: LPA96 and LPA99 Trials
n = 10 / 666
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Relative Frequency of CNS Relapses
LPA99 (n=5/53)
30%61%
9%
LPA96 (n=5/28)
39%
43%
18%
Molecular relapse/persistence
Clinical bone marrow relapseCNS relapse
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Characteristics and Outcome of CNS Relapses: LPA96 Trial
Sex/Age
WBC (x109/L)
Relapse risk BCR DS
Time to CNS relapse (months)
Bone marrow relapse
Survival from CNS relapse (months)
F/6 13.6 High 3 No 49 No 54+
M/33 67.9 High 1 No 16 No 14
F/43 162 High 3 No 7 Yes 5
F/57 7.7 Interm. 1 No 32 Yes 2
M/16 26.7 High 3 No 6 Yes 0.5
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Characteristics and Outcome of CNS Relapses: LPA99 Trial
Sex/Age
WBC (x109/L)
Relapse risk BCR DS
Time to CNS relapse (months)
Bone marrow relapse
Survival from CNS relapse (months)
M/32 6.2 Interm. 3 No 10 No 47+
F/22 66.5 High 3 No 29 No 45+
M/29 34.5 High 3 No 13 No 42+
F/50 1.9 Interm. 3 No 41 No 13
F/70 68.8 High 1 No 14 No 3
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11%11%
12 24 36 48 60 72 84
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1
0 12 24 36 48 60 72 84 96 108 120 132 144
Months after CR
Pro
bab
ility
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1
0 12 24 36 48 60 72 84 96 108 120 132 144
Months after CR
Pro
bab
ility
3.2%3.2%
1.0%1.0%
P = 0.07P = 0.07
CI of CNS Relapse: LPA96 Trial vs LPA99 TrialCI of CNS Relapse: LPA96 Trial vs LPA99 Trial
LPA99 (n = 5 / 510) LPA96 (n = 5 / 156)
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11%11%
12 24 36 48 60 72 84
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1
0 12 24 36 48 60 72 84 96 108 120 132 144
Months after CR
Pro
bab
ility
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1
0 12 24 36 48 60 72 84 96 108 120 132 144
Months after CR
Pro
bab
ility
4.9%4.9%
0.8%0.8%
P = 0.004P = 0.004
Intermediate (n = 3 / 380) Low (n = 0 / 136)
CI of CNS Relapse According to Risk GroupCI of CNS Relapse According to Risk Group
High (n = 7 / 149)
0%0%
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Multivariate Analysis (LPA96 and LPA99)
Prognostic factor Hazard Ratio
P value
Risk group 7.4 0.003
PETHEMA trial 0.07
N=596, variables included: age, sex, protocol, WBC, risk, BCR and FAB subtype.
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11%11%
12 24 36 48 60 72 84
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1
0 12 24 36 48 60 72 84 96 108
Months after CR
Pro
bab
ility
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1
0 12 24 36 48 60 72 84 96 108
Months after CR
Pro
bab
ility
P = 0.11P = 0.11
CI of CNS Relapse in LPA99 Trial According CI of CNS Relapse in LPA99 Trial According to Relapse Risk Groupto Relapse Risk Group
Intermediate (n = 2 / 294) Low (n = 0 / 103)
High (n = 3 / 112)
2.7%2.7%
0.7%0.7%
0%0%
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Conclusions
1. The relapse risk score is the main risk factor for CNS relapse in patients with APL.
2. The LPA99 risk-adapted protocol has proved effective in reducing CNS relapses.
3. Despite the lack of intrathecal prophylaxis or high-dose cytarabine in the LPA99 trial, the overall 5 year CI of CNS relapse was 0%, 0.8% and 2.7% in the low-, intermediate- and high-risk groups, respectively.
4. Our results do not support the systematic use of CNS prophylaxis in APL patients.
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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
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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)