P. Montesinos Disclosures 49 th ASH Annual Meeting–Atlanta, Georgia Research Support/P.I.No conflict of interest to disclose EmployeeNo conflict of interest to disclose ConsultantNo conflict of interest to disclose Major StockholderNo conflict of interest to disclose Speakers BureauNo conflict of interest to disclose HonorariaNo conflict of interest to disclose Scientific Advisory BoardNo conflict of interest to disclose

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 Parody, A Leon, J Esteve, J Bergua, G Milone and MA Sanz on behalf of the PETHEMA, HOVON and GATLA 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

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 10 9 /L) is the only well established independent risk factor for CNS relapse 1. Other factors with less or no evidence: age <45 year 1, BCR3 1,2,3, RA syndrome 4, adhesion molecules (CD11b, CD56). 1. de Botton S, Leukemia 2006; 20: Liso V, Cancer 1998, 83: ; 3. Specchia G, JCO 2001, 19: ; 4. Ko BS, Leukemia 1999, 13:

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.

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.

CONSOLIDATION PETHEMA LPA99 Trials addition of ATRA 45 mg/m 2 /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 year ATRA + MP + MTX (Risk-adapted)

Patient Characteristics PETHEMA LPA 96 PETHEMA LPA99 No. of patients Age, median (range)39 (2-78)40 (2-83) WBC, median (range)2.0 ( )2.2 ( ) Patients achieving CR156 (91%)510 (91%) Follow up (months) median range – – 98 Results updated on Nov. 30, 2007.

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

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.

11% % CI of CNS Relapse: LPA96 and LPA99 Trials n = 10 / 666

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

Characteristics and Outcome of CNS Relapses: LPA96 Trial Sex/ Age WBC (x10 9 /L) Relapse riskBCRDS Time to CNS relapse (months) Bone marrow relapse Survival from CNS relapse (months) F/613.6High3No49No54+ M/3367.9High1No16No14 F/43162High3No7Yes5 F/577.7Interm.1No32Yes2 M/1626.7High3No6Yes0.5

Characteristics and Outcome of CNS Relapses: LPA99 Trial Sex/ Age WBC (x10 9 /L) Relapse riskBCRDS Time to CNS relapse (months) Bone marrow relapse Survival from CNS relapse (months) M/326.2Interm.3No10No47+ F/2266.5High3No29No45+ M/2934.5High3No13No42+ F/501.9Interm.3No41No13 F/7068.8High1No14No3

11% % 1.0% P = 0.07 CI of CNS Relapse: LPA96 Trial vs LPA99 Trial LPA99 (n = 5 / 510) LPA96 (n = 5 / 156)

11% % 0.8% P = Intermediate (n = 3 / 380) Low (n = 0 / 136) CI of CNS Relapse According to Risk Group High (n = 7 / 149) 0%

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

11% P = 0.11 CI of CNS Relapse in LPA99 Trial According to Relapse Risk Group Intermediate (n = 2 / 294) Low (n = 0 / 103) High (n = 3 / 112) 2.7% 0.7% 0%

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.

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

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