APL meeting 2009, Rome, Italy. Sept 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. Brunet, J. Díaz-Mediavilla, C. Rivas, J. Bueno, J. de la Serna, E. Amutio, S. Negri, G. Milone, A. Holowiecka, J. Bergua, A. Novo, E. de Lisa, J. Mayer, B. Lowenberg, and 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 GIMEMA 1 (n = 134) European APL93 2 (n = 129) PETHEMA 3 (n = 104) CR, (%)86 84 Death in CR13198 Overall survival82 (3 y)*56 (4 y)-- Disease-free survival72 (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 trials including a significantly higher number of elderly patients and longer follow-up. Previous report Present report Analysis updated onJune 15, 2004July 15, 2009 No. of patients Follow up (months) median range 36 6 – – 151

PETHEMA LPA96 Trial All patientsCONSOLIDATION 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 ATRA 45 mg/m²/d until CR IDA 12 mg/m² d2, 4, 6, 8

PETHEMA LPA99 Trial Patients >60 years CONSOLIDATION INDUCTION AIDA MAINTENANCE 2 year ATRA + MP + MTX (Risk-adapted) ATRA 45 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 LPA 2005 Trial Patients >60 years INDUCTION AIDA MAINTENANCE 2 year ATRA + MP + MTX ATRA 45 mg/m²/d until CR IDA 12 mg/m² d2, 4, 6, 8 CONSOLIDATION 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 and high 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 low risk #1 #2 #3 (Dose reduction)

PETHEMA LPA96, 99 & 2005 Trials Accrual Study period: November 1996 – July 2009  Accrual270  Ineligible69 (25.5%)  Eligible201  Non evaluable 6 (2.9%)  Evaluable elderly (17.3%) of 1130 patients included

PETHEMA LPA96, 99 & 2005 Trials Demographic and baseline characteristics CharacteristicMedian (range)N (%) Age67 (60-83) Gender Female103 (52) PETHEMA trial LPA9630 (15) LPA99106 (55) LPA (30) ECOG Grade (36)

PETHEMA LPA96, 99 & 2005 Trials Demographic and baseline characteristics CharacteristicN (%) Relapse-risk score Low55 (28) Intermediate96 (49) High44 (23) FAB subtype Microgranular (M3v) 35 (18) BCR isoform BCR366 (44)

Induction Outcome with AIDA Regimen LPA96 (n = 30) LPA99 (n = 106) LPA2005 (n = 59) P CR, (%) Causes of failure (%) Hemorrhage NS Infection NS Diff. Syndrome NS Myocardial Infarct NS Resistance000NS

PETHEMA LPA96, 99 & 2005 Trials Post-remission events (154 of 159 completed the consolidation therapy)

PETHEMA LPA96, 99 & 2005 Trials Overall survival OS OS by LPA trial 67% 72% P = 0.13 LPA 99 LPA96 63% LPA % OS by Relapse Risk 63% 51% P = Intermediate High Low 73%

OS by Age 49% P = 0.06 Age >70 69% Age <70

PETHEMA LPA96, 99 & 2005 Trials Relapse-free survival Overall RFS RFS by Relapse Risk RFS by LPA trial 89% 87% P = 0.90 LPA 99 LPA96 LPA % 87% 82% P = 0.21 Intermediate High Low 95%

PETHEMA Trials in Elderly Patients Concluding 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 Patients Concluding remarks

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 )