50 th 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, Pau Montesinos, Pilar Bastida, Amparo Verdeguer, Javier De la Serna, Antonio Molines, Purificacion Garcia, Jose Luis Fuster, Maria jose Allegue, Rafael Rojas, and Miguel A. Sanz, on behalf of the PETHEMA, 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/m 2.

Background Ortega et al., J Clin Oncol 2005 Cumulative incidence of relapseDisease-free survival

Study Aims Update the analysis of the LPA96 and LPA99 trials including a significantly higher number of children and longer follow-up than in the previous report (Ortega et al., J Clin Oncol 2005). Previous report Present report Analysis updated onJune15, 2004Oct. 15, 2008 No. of patients66108 Follow up (months) median range 39 6 – – 143

PETHEMA LPA96, 99 & 2005 Trials CONSOLIDATION INDUCTION AIDA All patients MTZ 10 mg/m²/d × 5 IDA 5 mg/m²/d × 4 IDA 12 mg/m²/d × 1 #1 #2 #3 MAINTENANCE 2 year ATRA + MP + MTX (Risk-adapted) ATRA 25 mg/m²/d until CR IDA 12 mg/m² d2, 4, 6, 8 low risk MTZ 10 mg/m²/d × 5 IDA 5 mg/m²/d × 4 IDA 12 mg/m²/d × 1 #1 #2 #3 intermediate and high risk MTZ 10 mg/m²/d × 5 + ATRA × 15 d IDA 7 mg/m²/d × 4 + ATRA × 15 d IDA 12 mg/m²/d × 2 + ATRA × 15 d #1 #2 #3

PETHEMA LPA96, 99 & 2005 Trials INDUCTION AIDA MAINTENANCE 2 year ATRA + MP + MTX ATRA 25 mg/m²/d until CR IDA 12 mg/m² d2, 4, 6, 8 low risk MTZ 10 mg/m²/d × 3 + ATRA x15d IDA 5 mg/m²/d × 4 + ATRA x15d IDA 12 mg/m²/d × 1 + ATRA x15d #1 #2 #3 CONSOLIDATION(Risk-adapted) MTZ 10 mg/m²/d × 3 + ATRA x15d IDA 7 mg/m²/d × 4 + ATRA x15d IDA 12 mg/m²/d × 2 + ATRA x15d #1 #2 #3 Intermediate risk IDA 5 mg/m²/d × 4 + Ara-C + ATRA x15d MTZ 10 mg/m²/d × 5 + ATRA x15d IDA 12 mg/m²/d × 2 + Ara-C + ATRA x15d High risk

PETHEMA LPA96, 99 & 2005 Trials Accrual Study period: November 1996 – October 2008  Accrual113  Ineligible4 (3.5%)  Eligible109  Non evaluable (addition of Ara-C) 1 (0.9%)  Evaluable children (10.1%) of 1066 patients included

PETHEMA LPA96, 99 & 2005 Trials Demographic and baseline characteristics CharacteristicMedian (range)N (%) Age14 (2-18) Gender Female59 (55) Hepatosplenomegaly Yes21 (23) ECOG Grade (30) Fever Yes48 (45) Hemoglobin, g/dL 10 or higher 25 (23)

PETHEMA LPA96, 99 & 2005 Trials Demographic and baseline characteristics CharacteristicN (%) WBC count, × 10 9 /L 10 or higher36 (33) Relapse-risk score Low11 (10) Intermediate61 (57) High36 (33) FAB subtype Microgranular (M3v) 23 (22) BCR isoform BCR336 (42)

Induction Outcome with AIDA Regimen LPA96 (n = 18) LPA99 (n = 66) LPA2005 (n = 24) P CR, (%) NS Causes of failure (%) Hemorrhage NS Infection000NS Diff. Syndrome NS Other000NS Resistance000NS

PETHEMA LPA96, 99 & 2005 Trials Differentiation syndrome P=0.65

PETHEMA LPA96, 99 & 2005 Trials Pseudotumor cerebri 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 Trials Post-remission events * 1 patient presented CNS involvement at first relapse

PETHEMA LPA96, 99 & 2005 Trials Overall survival OS OS by WBC count 91% 85% P = 0.44 WBC <10 x 10 9 /L WBC >10 x 10 9 /L OS by LPA trial 89% 79% P = 0.11 LPA 99 LPA96 89% LPA %

PETHEMA LPA96, 99 & 2005 Trials Disease-free survival Overall DFS DFS by WBC count DFS by LPA trial 84% 89% 69% P = 0.04 LPA 99 LPA96 LPA % 90% 73% P = 0.03 WBC <10 x 10 9 /L WBC >10 x 10 9 /L

PETHEMA LPA96, 99 & 2005 Trials Concluding 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 Trials Concluding remarks Risk-adapted strategies focusing on high-risk patients (WBC count > 10 x 10 9 /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, 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 )