Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group

The outcome of patients with acute promyelocytic leukemia (APL) has dramatically improved with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy, which has been adopted as the standard treatment for APL.¹  Using this combination, the cooperative group Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA) reported that a risk-adapted strategy combining ATRA with anthracycline monochemotherapy for both induction and consolidation, followed by maintenance with ATRA and low-dose methotrexate and mercaptopurine (LPA99 trial), results in a higher antileukemic efficacy than in the previous LPA96 trial.²  In this study, the improvement of the antileukemic efficacy was attributed to the novel addition of ATRA to consolidation therapy, combined with a moderate increase in the dose of anthracycline for patients with intermediate or high risk of relapse.³  This benefit was coupled with a moderate toxicity and a high degree of compliance.

To know if the advantage provided by a risk-adapted strategy including ATRA in consolidation therapy for intermediate- and high-risk APL patients is maintained long term, we have now performed an updated analysis of a significantly enlarged cohort of patients treated with the LPA99 protocol with more than 5-year median follow-up. The long-term outcome in these patients was compared with those treated with the LPA96 trial.

The eligibility criteria in this study were a diagnosis of de novo APL with demonstration of the t(15;17) or PML/RARA rearrangement, normal hepatic and renal function, no cardiac contraindication to anthracyclines, and Eastern Cooperative Oncology Group (ECOG) performance status less than 4. Informed consent was obtained from all patients. In accordance with the Declaration of Helsinki, the protocols were approved by the Research Ethics Board of each participating hospital.

Details of laboratory studies for diagnosis, assessment of response, and molecular monitoring of minimal residual disease, as well as a complete description of the therapeutic management, are given elsewhere.^2,4  Briefly, induction therapy consisted of oral ATRA 45 mg/m² per day until morphologic complete remission (CR) and intravenous idarubicin 12 mg/m² on days 2, 4, 6, and 8. The idarubicin on day 8 was omitted for patients older than 70 years in the LPA99 protocol. For patients 20 years of age or younger, the ATRA dose was adjusted to 25 mg/m². Patients in CR received 3 monthly risk-adapted consolidation courses. In the LPA96 protocol, the first course consisted of idarubicin (5 mg/m² per day for 4 days), the second of mitoxantrone (10 mg/m² per day for 5 days), and the third of idarubicin (12 mg/m² per day for 1 day). From November 1, 1999 (LPA99 trial), intermediate- and high-risk patients, as previously defined,³  received ATRA (45 mg/m² per day for 15 days) combined with the reinforced single-agent chemotherapy courses.²  This reinforcement consisted of increasing the idarubicin dose in the first course to 7 mg/m² per day and of administering idarubicin for 2 consecutive days instead of 1 in the third course. Patients who tested negative for PML/RARA at the end of consolidation were started on maintenance therapy with oral mercaptopurine (50 mg/m² per day), intramuscular methotrexate (15 mg/m² per week), and oral ATRA (45 mg/m² per day for 15 days every 3 months) over 2 years.

Unadjusted time-to-event analyses were performed using the Kaplan-Meier estimate⁵  and, for comparisons, log-rank tests.⁶  The probability of relapse was also estimated by the cumulative incidence method (for marginal probability).^7,8  For all estimates in which the event “relapse” was considered as an end point, hematologic and molecular relapse, as well as molecular persistence (PML/RARA positive by reverse-transcribed–polymerase chain reaction (RT-PCR) at the end of consolidation), were each considered as uncensored events. Patient follow-up was updated on April 15, 2008. Median follow-up of patients is 68 months (range, 34-104 months) from diagnosis. Multivariate analysis was performed using the Cox proportional hazards model.⁹ 

Between November 1996 and June 2005, 792 patients with APL enrolled in 2 consecutive trials (LPA96 and LPA99) were registered from 82 institutions from Spain, The Netherlands, Belgium, Argentina, Uruguay, and the Czech Republic (see  Appendix). Details about noneligible, nonevaluable, and evaluable patients have been reported elsewhere.¹⁰  Briefly, a total of 42 patients (5%) were not eligible because of a severe clinical condition contraindicating the administration of chemotherapy: 8 (4%) and 34 (6%) in the LPA96 and LPA99 trial, respectively. Eighteen additional patients were not evaluated because of protocol violations during induction therapy (8 of 181 and 10 of 570 in the LPA96 and LPA99 trials, respectively). The major clinical and biologic characteristics of the remaining 732 evaluable patients, the percentage and timing of response to induction therapy, and prognostic factors of the major categories of induction failure have all been previously described.¹⁰ 

An interim analysis of the postremission outcome of 384 of these patients (updated on April 15, 2003) was reported in 2004.²  This study showed a reduction in the cumulative incidence of relapse (CIR), disease-free survival (DFS), and overall survival (OS), with no significant increase of severe toxicity, for patients treated with the LPA99 protocol (227 patients) compared with the LPA96 (157 patients). In the present study, we have performed an updated analysis of a considerably enlarged cohort of 560 patients treated under the LPA99 trial with a more mature median follow-up of 68 months (21 months in the previous analysis). The clinical and hematologic characteristics of these patients are shown in Table 1.

Except for one 81-year-old patient, who died from volvulus before starting consolidation, and another 42-year-old patient, who developed severe cardiac toxicity during induction and was given directly maintenance therapy, all the remaining 508 patients who achieved CR proceeded to consolidation therapy. Because of the occurrence of severe complications, 7 patients received only 1 or 2 consolidation courses (2 and 5 patients, respectively). After a median follow-up of almost 5.5 years, all these patients with incomplete consolidation and the one not receiving consolidation continue in first CR. These observations may suggest that at least some APL patients receiving what is currently considered a state-of-the-art treatment (ie, up-front ATRA and intensive chemotherapy) may actually be overtreated. An accurate identification of this particular population of patients who could be cured with reduced chemotherapy intensity is a challenge that warrants further investigation. Seven toxic deaths occurred during consolidation, and 6 additional patients died after consolidation (3 on maintenance therapy and 3 off therapy). The total rate of death in remission was 2.3%. Probability of death correlated with age: 0.9% (4 of 428), 5.4% (3 of 56), and 23.1% (6 of 26) of patients younger than 60, between 60 and 70, and older than 70 years of age, respectively (P < .001). All patients alive after completing consolidation therapy proceeded to receive maintenance therapy.

RT-PCR tests for PML/RARA were carried out in 448 cases at the end of consolidation, with only 3 high-risk patients being PCR-positive at this time. These data compare favorably with the LPA96 trial (P = .028), in which 5 of 138 evaluable patients (4 of 44 high-risk and 1 of 97 intermediate-risk patients) showed molecular persistence at the end of consolidation.²  As in previous reports of the PETHEMA trials,^2,4  the molecular status at the end of induction has no predictive value on patient outcome, being the 5-year CIR 11% and 12% in patients testing PCR-positive (49%) and PCR-negative (51%), respectively.

In addition to the 3 cases of molecular disease persistence, 52 patients relapsed (13 molecular and 39 clinical relapse), including 6 isolated in central nervous system. The median time to relapse was 16 months (range, 5-74 months), with only 2 relapses occurring beyond 45 months. Nine additional patients died after developing other malignancies (6 acute myeloid leukemia/myelodysplastic syndrome, 1 acute lymphoblastic leukemia, 1 lung cancer, and 1 pancreatic cancer). The median interval from diagnosis of APL to that of therapy-related acute myeloid leukemia/myelodysplastic syndrome was 41 months (range, 16-54 months).

The overall 5-year CIR, DFS, and OS rates of patients under the LPA99 protocol were 11%, 84%, and 82%, respectively. These results compare favorably with those obtained in the previous LPA96 study (Figure 1A). When we exclude the low-risk patients to better evaluate the impact of risk-adapted consolidation, the 5-year CIR, DFS, and OS rates were 21%, 75%, and 75%, respectively, in the LPA96 study and 13%, 83%, and 81%, respectively, in the LPA99 study. Univariate analysis of CIR, DFS, and OS is shown in Table 1. Relapse-risk score and male gender were identified in multivariate analysis as the only independent adverse factors for relapse-free survival in the LPA99 trial (P < .001 and P = .003, respectively). Despite the improved outcome of non–low-risk patients treated with the modified consolidation, the originally defined risk score³  maintained its predictive value (Figure 1B). The relationship between male sex and increased risk of relapse, which has been widely recognized in children with acute lymphoblastic leukemia,^11,12  has been previously reported in an independent series of 806 APL patients included in 3 multicenter trials of the European APL Group (APL91, APL93) and PETHEMA Group (LPA96).¹³  The significance of this finding is at present unclear and deserves further investigation.

In conclusion, the antileukemic benefit previously reported with the reinforcement of idarubicin and the addition of ATRA to consolidation therapy²  has been confirmed in a significantly enlarged series of APL patients with longer follow-up. Although we cannot discern the relative contribution to this benefit by the addition of ATRA, as it has been established for induction and maintenance therapy, it is reasonable that the safe combination of this agent with chemotherapy may also apply to the consolidation phase. Risk-adapted strategies focusing on patients with high risk of relapse should be a major focus of future studies.

The authors thank Miguel Priego for data collection and management.

This study was supported in part by the Fundación para la Investigación Hospital Universitario La Fe-Ayudas Bancaja (2006/0137), Red Temática de Investigación Cooperativa en Cáncer (RD06/0020/0031), Fondo de Investigación Sanitaria, and Ministerio de Sanidad of Spain (PI030400 and PI060657).

A complete list of participating institutions appears in the  Appendix.

Contribution: M.A.S. and P.M. conceived the study and analyzed and interpreted the data; M.A.S., P.M., and B.L. wrote the paper; P.M. performed the statistical analyses; M.G., D.C., M.J.C., C.C., E.B., and P.B. performed the RT-PCR analyses; and E.V., C. Rayón., J.d.l.S., R.P., J.M.B., A.L., S.N., M.G., C. Rivas, J.E., G.M., J.D.G., E.A., S.B., and J.G.-L. included data of patients treated in their institutions, reviewed the manuscript, and contributed to the final draft.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Miguel A. Sanz, Department of Hematology, University Hospital La Fe, Avenida Campanar 21, 46009 Valencia, Spain; e-mail: msanz@uv.es.

The following institutions and clinicians participated in the study: Argentina (Grupo Argentino de Tratamiento de la Leucemia Aguda)–Complejo Médico Policia Federal, La Plata: L. Palmer; Fundaleu, Buenos Aires: S. Pavlovsky, G. Milone, I. Fernández; Hospital Clemente Álvarez, Rosario: S. Ciarlo, F. Bezares; Hospital de Clínicas, Buenos Aires: H. Longoni; Hospital General San Martín, La Plata: M. Gelemur, P. Fazio; Hospital Rossi, La Plata: C. Canepa, S. Saba; Hospital San Martín de Paraná, Entre Ríos: P. Negri; Instituto Privado de Hematología, Paraná: M. Giunta;Instituto de Trasplante de Mídula ”sea, La Plata: J. Milone, V. Prates; Czech Republic–Faculty Hospital, Brno: M. Protivankova; Spain (Programa Español de Tratamiento de las Hemopatías Malignas)–Basurtuko Ospitalea, Bilbao: J. M. Beltrán de Heredia; Complejo Hospitalario de Segovia: J. M. Hernández; Complexo Hospitalario Xeral-Calde, Lugo; J. Arias; Complejo Hospitalario, León: F. Ramos; Fundación Jiménez Díaz, Madrid: A. Román; Hospital 12 de Octubre, Madrid: J. de la Serna; Hospital Carlos Haya, Málaga: S. Negri; Hospital Central de Asturias, Oviedo: C. Rayón; Hospital Clinic, Barcelona: J. Esteve, D. Colomer; Hospital Clínico de Valladolid: F.J. Fernández-Calvo; Hospital Clínico San Carlos, Madrid: J. Díaz Mediavilla; Hospital Clínico San Carlos (H. Infantil), Madrid: C. Gil; Hospital Clínico Universitario, Santiago de Compostela: M. Pírez; Hospital Clínico Universitario, Valencia: M. Tormo; Hospital Clínico Universitario Lozano Blesa, Zaragoza: M. Olave; Hospital de Cruces, Baracaldo: E. Amutio; Hospital del Mar, Barcelona: C. Pedro; Hospital de Navarra, Pamplona: A. Gorosquieta; Hospital Dr Negrín, Las Palmas: T. Molero; Hospital Dr Peset, Valencia: M. J. Sayas; Hospital Dr Trueta, Girona: R. Guardia; Hospital General de Albacete: J. R. Romero; Hospital General de Alicante: C. Rivas; Hospital General de Alicante (Oncología Pediátrica): C. Esquembre; Hospital General de Castellón: R. García; Hospital General de Especialidades Ciudad de Jaén: A. Alcalá; Hospital General de Jerez de la Frontera: A. León; Hospital General de Murcia: M. L. Amigo; Hospital General de Valencia: M. Linares; Hospital Germans Trias i Pujol, Badalona: J. M. Ribera; Hospital Insular de Las Palmas: J. D. González San Miguel; Hospital Juan Canalejo, A Coruña: G. Debín; Hospital Joan XXIII, Tarragona: L. Escoda; Hospital La Princesa, Madrid: R. de la Cámara; Hospital Materno-Infantil de Las Palmas: A. Molines; Hospital do Meixoeiro, Vigo: C. Loureiro; Hospital Montecelo, Pontevedra: M. J. Allegue; Hospital Mutua de Terrasa: J. M. Martí; Hospital Niño Jesús, Madrid: L. Madero; Hospital Ntra. Sra. de Sonsoles, Ávila: M. Cabezudo; Hospital Ramón y Cajal, Madrid: J. García-Laraña; Hospital Reina Sofía, Córdoba: R. Rojas, J. Román; Hospital Río Carrión, Palencia: F. Ortega; Hospital Río Hortega, Valladolid: M. J. Peñarrubia; Hospital San Jorge, Huesca: F. Puente; Hospital San Rafael, Madrid: B. López-Ibor; Hospital Sant Pau, Barcelona: S. Brunet; Hospital San Pedro de Alcántara, Cáceres: J. M. Bergua; Hospital Santa María del Rosell, Cartagena: J. Ibáñez; Hospital Severo Ochoa, Leganís: P. Sánchez; Hospital Son Dureta, Palma de Mallorca: A. Novo; Hospital de Tortosa: L. L. Font; Hospital Txagorritxu, Vitoria: J. M. Guinea; Hospital Universitario del Aire, Madrid: A. Montero; Hospital Universitario de Salamanca: M. González, C. Chillón; Hospital Universitario La Fe, Valencia: M. A. Sanz, P. Montesinos, J. Martínez, P. Bolufer, E. Barragán; Hospital Universitario La Fe (Hospital Infantil), Valencia: A. Verdeguer; Hospital Universitario La Paz (Hospital Infantil), Madrid: P. García; Hospital Universitario Marqués de Valdecilla, Santander: E. Conde; Hospital Universitario Príncipe de Asturias, Alcalá de Henares: J. García; Hospital Universitario Puerta del Mar, Cádiz: F. J. Capote; Hospital Universitario Puerta de Hierro, Madrid: I. Krsnik; Hospital Universitario Vall D'Hebron, Barcelona: J. Bueno; Hospital Universitario Materno-Infantil Vall D'Hebron, Barcelona: P. Bastida; Hospital Universitario Virgen de la Arrixaca, Murcia: P. Rosique; Hospital Universitario Virgen de la Arrixaca (Pediatría), Murcia: J. L. Fuster; Hospital Universitario Virgen del Rocío, Sevilla: R. Parody; Hospital Universitario Virgen de la Victoria, Málaga: I. Pérez; Hospital Virgen del Camino, Pamplona: J. Molina; Hospital Xeral Cíes, Vigo; C. Poderós; Institut Catala d'Oncologia, Hospitalet de Llobregat; R. Duarte; Universidad de Navarra: M. J. Calasanz; The Netherlands (The Dutch-Belgian Hemato-Oncology Cooperative Group, HOVON)-VU Medical Center Amsterdam: G. J. Ossenkoppele; Academic Medical Center, University of Amsterdam: J. van der Lelie; Erasmus University Medical Center, Rotterdam: B. Lowenberg, P. Sonneveld, M. Zijlmans; University Medical Center, Groningen: E. Vellenga; Gasthuisberg Hospital, Leuven: J. Maertens; OLVG Hospital, Amsterdam: B. de Valk; Den Haag Hospital, Leyenburg: P.W. Wijermans; Medical Spectrum Twente Hospital, Enschede: M. R. de Groot; Academic Hospital Maastricht: H. C. Schouten; St. Antonius Hospital, Nieuwegein: D.H. Biesma; Sophia Hospital, Zwolle: M. van Marwijk Kooy; Uruguay-Hospital Maciel, Montevideo: E. de Lisa.