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P. Montesinos Disclosures

P. Montesinos Disclosures. 49 th ASH Annual Meeting–Atlanta, Georgia. Central Nervous System Relapse in Patients with Acute Promyelocytic Leukemia Treated with All-trans Retinoic Acid and Reinforced Anthracycline Monochemotherapy.

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P. Montesinos Disclosures

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  1. P. Montesinos Disclosures 49th ASH Annual Meeting–Atlanta, Georgia

  2. 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 Parody, A Leon, J Esteve, J Bergua, G Milone and MA Sanz on behalf of the PETHEMA, HOVON and GATLA Groups 2007 ASH Meeting, Atlanta, GO

  3. 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

  4. 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.

  5. Study Aims • 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). • Compare LPA99 and LPA96 trials, with or without risk-adapted consolidation including ATRA. • Identify risk-factors for CNS relapse in APL.

  6. PETHEMA LPA99 Trials INDUCTION AIDA CONSOLIDATION (Risk-adapted) low risk intermediate and high risk IDA 7 mg/m²/d × 4 + ATRA× 15 #1 #1 IDA 5 mg/m²/d × 4 MTZ 10 mg/m²/d× 5 + ATRA × 15 #2 MTZ 10 mg/m²/d× 5 #2 IDA 12 mg/m²/d× 2 + ATRA × 15 #3 #3 IDA 12 mg/m²/d× 1 MAINTENANCE 2 year ATRA + MP + MTX addition of ATRA 45 mg/m2/d for intermediate- and high-risk patients

  7. Patient Characteristics Results updated on Nov. 30, 2007.

  8. Diagnosis of CNS Relapse • Neurological signs and symptoms (clinical or radiological). • Positive lumbar puncture (compatible cytology + genetic diagnosis). • Positive biopsy of CNS granulocytic sarcoma.

  9. 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.

  10. 12 24 36 48 60 72 84 CI of CNS Relapse: LPA96 and LPA99 Trials n = 10 / 666 1. 6% 11%

  11. Relative Frequency of CNS Relapses Molecular relapse/persistence CNS relapse Clinical bone marrow relapse

  12. Characteristics and Outcome of CNS Relapses: LPA96 Trial

  13. Characteristics and Outcome of CNS Relapses: LPA99 Trial

  14. 12 24 36 48 60 72 84 CI of CNS Relapse: LPA96 Trial vs LPA99 Trial LPA96 (n = 5 / 156) LPA99 (n = 5 / 510) P = 0.07 3.2% 1.0% 11%

  15. 12 24 36 48 60 72 84 CI of CNS Relapse According to Risk Group High (n = 7 / 149) Intermediate (n = 3 / 380) Low (n = 0 / 136) 4.9% P = 0.004 0.8% 0% 11%

  16. Multivariate Analysis (LPA96 and LPA99) N=596, variables included: age, sex, protocol, WBC, risk, BCR and FAB subtype.

  17. 12 24 36 48 60 72 84 CI of CNS Relapse in LPA99 Trial According to Relapse Risk Group High (n = 3 / 112) Intermediate (n = 2 / 294) Low (n = 0 / 103) P = 0.11 2.7% 0.7% 0% 11%

  18. Conclusions • The relapse risk score is the main risk factor for CNS relapse in patients with APL. • The LPA99 risk-adapted protocol has proved effective in reducing CNS relapses. • 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. • Our results do not support the systematic use of CNS prophylaxis in APL patients.

  19. Participating Institutions H.U. La Fe, Valencia H. Carlos Haya, Málaga H. Dr. Negrin, Las Palmas H. Central, Asturias H.C.U. Santiago H. M-Infantil, Las Palmas H.J. Canalejo, Coruña H. Reina Sofia, Córdoba H. Basurto, Bilbao H. General, Jerez H. Dr. Peset, Valencia H. R. Hortega, Valladolid H. Clinic, Barcelona H. San Pau, Barcelona H.C.U. Zaragoza H.G.E. Ciudad de Jaén H. Joan XXIII, Tarragona H.C. S. Carlos, Madrid H.U. V. Victoria, Málaga H. Clínico, Valencia H.U. V. D'Hebron, Barcelona H.General, Castellón H. Cruces, Baracaldo C.H. León H.U. V. Arrixaca, Murcia H. 12 Octubre, Madrid H. Navarra, Pamplona H. Montecelo, Pontevedra H.C.U. Salamanca H.C. Valladolid F. Jiménez Díaz, Madrid H. Son Dureta, Mallorca H. G. Albacete C.H. de Segovia H.U. P. del Mar, Cádiz H. M. Valdecilla, Santander H. Meixoeiro, Vigo H. Insular, Las Palmas H.U. V. D'Hebron (Inf), Barna H. Severo Ochoa, Leganés C.H. Xeral-Calde, Lugo H. La Princesa, Madrid H.G. Murcia H. General, Alicante H. Ramón y Cajal, Madrid H.S.P.Alcántara, Cáceres H.U. G. Trias i Pujol, Barna H. San Jorge, Huesca

  20. GATLA (Argentina) Fundaleu, Buenos Aires H. Clemente Álvarez, Rosario H. General San Martín, La Plata H. Rossi, La Plata H. General San Martín, Paraná I. Trasplante de Médula Ósea, La Plata I. P. de Hematología, Paraná H. de Clínicas, Buenos Aires Participating Institutions H.U. del Aire, Madrid H. Sta María Rosell, Cartagena H. del Mar, Barcelona H. San Rafael, Madrid H. Dr. Trueta, Gerona H. Virgen de la Cinta, Tortosa H. Niño Jesús, Madrid H. C. Haya (Inf), Málaga H. Virgen del Rocío, Sevilla H.C. San Carlos (Inf), Madrid H.G. Valencia I.C.O., Hospitalet de Llobregat H. Xeral-Cies, Vigo H. N.S. Sonsoles, Ávila SHOP (Spain) H. Txagorritxu, Vitoria H.U. La Fe (Inf), Valencia H. General (Inf), Alicante H. La Paz (Inf), Madrid H. Río Carrión, Palencia H. Maciel, Montevideo (Uruguay) H.U. Arrixaca (Inf), Murcia H. C. Haya (Inf), Málaga H. P. Asturias, A. Henares H. Mutua, Terrasa HOVON (The Netherlands) F. Hospital, Brno (Czec Rep.)

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