Skip to main content

All-trans retinoic acid with daunorubicin or idarubicin for risk-adapted treatment of acute promyelocytic leukaemia: a matched-pair analysis of the PETHEMA LPA-2005 and IC-APL studies

Abstract

Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diagnosed APL were compared using matched-pair analysis. One was conducted by the PETHEMA/HOVON group with idarubicin and the other by the International Consortium on APL (IC-APL) using daunorubicin. Three hundred and fifty patients from the PETHEMA/HOVON cohort were matched with 175 patients in the IC-APL cohort, adjusting for the significantly unbalanced presenting features of the two entire cohorts. Complete remission (CR) rate was significantly higher in the PETHEMA/HOVON (94 %) than in the IC-APL cohort (85 %) (P = 0.002). The distribution of causes of induction failure and the time to achieve CR were similar in both cohorts. Patients who achieved CR had comparable cumulative incidence of relapse and disease-free survival rates, but lower overall and event-free survivals were observed in the IC-APL cohort, which was mainly due to a higher death rate during induction therapy. A higher death rate during consolidation therapy was also observed in the IC-APL. These results show that daunorubicin and idarubicin have similar antileukaemic efficacy in terms of primary resistance, molecular persistence, as well as molecular and haematological relapse rates when combined with ATRA in treatment of APL. However, a higher toxic death rate during induction and consolidation therapy was observed in the IC-APL cohort. This trial was registered at www.clinicaltrials.gov as #NCT00408278 [ClinicalTrials.gov].

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Rego EM, Kim HT, Ruiz-Argüelles GJ et al (2013) Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood 121:1935–1943. doi:10.1182/blood-2012-08-449918

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Jácomo RH, Melo RAM, Souto FR et al (2007) Clinical features and outcomes of 134 Brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines. Haematologica 92:1431–1432. doi:10.3324/haematol.10874

    PubMed  Article  Google Scholar 

  3. 3.

    Sanz MA, Montesinos P, Rayón C et al (2010) Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 115:5137–5146. doi:10.1182/blood-2010-01-266007

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Adès L, Sanz MA, Chevret S et al (2008) Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood 111:1078–1084. doi:10.1182/blood-2007-07-099978

    PubMed  Article  Google Scholar 

  5. 5.

    Oken MM, Creech RH, Tormey DC et al (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Cheson BD, Bennett JM, Kopecky KJ et al (2003) Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21:4642–4649. doi:10.1200/JCO.2003.04.036

    PubMed  Article  Google Scholar 

  7. 7.

    Sanz MA, Lo-Coco F, Martín G et al (2000) Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 96:1247–1253

    CAS  PubMed  Google Scholar 

  8. 8.

    Montesinos P, Bergua JM, Vellenga E et al (2009) Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood 113:775–783. doi:10.1182/blood-2008-07-168617

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Diamond A, Sekhon JS (2013) Genetic matching for estimating causal effects: a general multivariate matching method for achieving balance in observational studies. Rev Econ Stat 95:932–945. doi:10.1162/REST_a_00318

    Article  Google Scholar 

  10. 10.

    Gray RJ (1988) A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141–1154. doi:10.1214/aos/1176350951

    Article  Google Scholar 

  11. 11.

    Pepe MS, Mori M (1993) Kaplan—Meier, marginal or conditional probability curves in summarizing competing risks failure time data? Stat Med 12:737–751. doi:10.1002/sim.4780120803

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Lo-Coco F, Avvisati G, Vignetti M et al (2013) Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369:111–121. doi:10.1056/NEJMoa1300874

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Powell BL, Moser B, Stock W et al (2010) Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 116:3751–3757. doi:10.1182/blood-2010-02-269621

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  14. 14.

    Iland HJ, Bradstock K, Supple SG et al (2012) All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 120:1570–1580. doi:10.1182/blood-2012-02-410746, quiz 1752

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Gore SD, Gojo I, Sekeres MA et al (2010) Single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia. J Clin Oncol 28:1047–1053. doi:10.1200/JCO.2009.25.5158

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  16. 16.

    Ravandi F, Estey E, Jones D et al (2009) Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27:504–510. doi:10.1200/JCO.2008.18.6130

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Hu J, Liu Y-F, Wu C-F et al (2009) Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 106:3342–3347. doi:10.1073/pnas.0813280106

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. 18.

    Ghavamzadeh A, Alimoghaddam K, Rostami S et al (2011) Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol 29:2753–2757. doi:10.1200/JCO.2010.32.2107

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Mathews V, George B, Chendamarai E et al (2010) Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol 28:3866–3871. doi:10.1200/JCO.2010.28.5031

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgments

The authors thank all participating institutions and clinicians in the PETHEMA/HOVON and IC-APL studies. This work was supported in part by Cooperative Research Thematic Network Grant RD12/0036/014 (Instituto de Salud Carlos III and European Regional Development Fund). The authors are thankful for the support of the American Society of Hematology, Fondazione Umberto Veronesi, Roche South Arabia, Fundação de Apoio à Pesquisa do Estado de São Paulo (Grant No. 1998/14247-6), Fundacion Mexicana para la Salud, St. Jude Children’s Research Hospital and Cephalon Europe.

Authors’ contribution

M.A.S. conceived the study and analysed and interpreted the data; M.A.S., F.L-C., A.G., N.B., R.C.R., B.L. and E.M.R. wrote the paper; P.M. and H. K. performed the statistical analyses; E.M.R., G.J.R.-A., M.S.U. and L.M. were the national coordinators in Brazil, Mexico, Chile and Uruguay, respectively; M.R.U., R.H.J., H. G-A., R.A.M.M., R.B., R.P., K.P., E.M.F., E.V., A.H., Ch.R., P.F., J.d.S., S.B., E.d.L, J.G-C., J.M.R. and I.K. included data of patients treated in their institutions, reviewed the manuscript and contributed to the final draft.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Affiliations

Authors

Consortia

Corresponding author

Correspondence to Miguel A. Sanz.

Appendix

Appendix

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: F. Rojas; H. Longoni; Hospital General San Martín, La Plata: M. Gelemur, P. Fazio; Hospital Rossi, La Plata: C. Canepa, S. Saba, G. Balladares; Hospital San Martín de Paraná, Entre Ríos: P. Negri; Instituto Privado de Hematología, Paraná: M. Giunta; Instituto de Trasplante de Médula Ósea, La Plata: J. Milone, MV. Prates; Hospital Tornú, Buenos Aires: D. Lafalse; Colombia—Fundación Valle del Lili, Cali: F.J. Jaramillo Echevarry; FOSCAL, Bucaramanga: C. Sossa Melo; Czech Republic—Faculty Hospital, Brno: J. Mayer, M. Protivankova; IHBT, Prague: J. Scwarz; Slovakia—UNLP, Kosice: Jana Jurkovicova; 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; 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. Pérez-encinas; Hospital Clínico Universitario, Valencia: M. Tormo; Hospital Clínico Universitario Lozano Blesa, Zaragoza: M. Olave; Hospital de Cruces, Barakaldo: E. Amutio; Hospital del Mar, Barcelona: C. Pedro; Hospital de Navarra, Pamplona: A. Gorosquieta; M. Viguria; M. Zudaire; Hospital Dr Negrín, Las Palmas: T. Molero; Hospital Dr Peset, Valencia: M. J. Sayas; Hospital Dr Trueta, Girona: R. Guardia; Hospital General de Albacete: F. Manso; 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; J.A. López; Hospital General de Jerez de la Frontera: V. Rubio; 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. Debén; 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; L. Amador; Hospital Mutua de Terrasa: J.M. Martí; Hospital Niño Jesús, Madrid: L. Madero; A. Lassaletta; Hospital Ntra. Sra. de Sonsoles, Ávila: M. Cabezudo; Hospital Ramón y Cajal, Madrid: J. García-Laraña; Hospital Reina Sofía, Córdoba: R. Rojas; 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, Leganés: P. Sánchez; Hospital Son Dureta, Palma de Mallorca: A. Novo; Hospital de Tortosa: LL. Font; Hospital Txagorritxu, Vitoria: J. M. Guinea; Hospital Universitario del Aire, Madrid: A. Montero; Hospital Universitario de Salamanca: M. González; Hospital Universitario La Fe, Valencia: M. A. Sanz, G. Martín, J. Martínez, P. Montesinos; 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: A. Rubio; Hospital Universitario Virgen de la Arrixaca (Pediatría), Murcia: J.L. Fuster; Hospital Universitario Virgen del Rocío, Sevilla: J. González; Hospital Universitario Virgen de la Victoria, Málaga: I. Pérez; Hospital Virgen del Camino (Infantil), Pamplona: J. Molina; Hospital Virgen del Camino (Adultos), Pamplona: M.C. Mateos; M.A. Ardaiz; Clínica San Miguel, Pamplona: M. Rodríguez-calvillo; Hospital Xeral Cíes, Vigo; C. Poderós; Institut Català d’Oncologia, Hospitalet de Llobregat; M. Arnán, R. Duarte; Hospital de Fuenlabrada, Fuenlabrada: J.A. Hernández; Hospital General de Guadalajara, Guadalajara: M. Díaz-Morfa; Hospital Juan Ramón Jimenez, Huelva: E. Martín-Chacón; Hospital Doctor José Molina Orosa, Lanzarote: J.M. Calvo-Villas; Hospital Madrid Norte Sanchinarro, Madrid: D. García-Belmonte; Hospital U. La Paz, Madrid: D. Hernández-Maraver; Poland (Polish Adult Leukemia Group, PALG)—Silesian Medical University, Katowice: A. Holowiecka-Goral; Collegium Medicum Jagiellonian University, Krakow: B. Jakubas; City Hospital, Rzeszów: A. Skret-Norwicz; City Hospital, Poznan: P. Bizgalska-Skrzypek; Medical University, Lodz: A. Pluta; Universitary Hospital, Szczecin: R. Becht; Universitary Hospital, Wroclaw: M. Kielbinski; Center of Oncology, Kielce: M. Watek; Medical University, Warsaw: M. Paluszewska; City Hospital, Bydgoszcz: A. Gadomska; City Hospital, Krakow: E. Rzenno; Medical University, Bialystok: J. Piszcz; Institut of Hematology, Warsaw: A. Ejduk, J. Dobrzanska; City Hospital, Tornú: M. Calbecka, A. Kostyra; Medical University, Lublin: M. Malek; City Hospital, Chorzow: S. Grosicki; Medical University School, Gdansk: W. Knopinska; 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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sanz, M.A., Montesinos, P., Kim, H.T. et al. All-trans retinoic acid with daunorubicin or idarubicin for risk-adapted treatment of acute promyelocytic leukaemia: a matched-pair analysis of the PETHEMA LPA-2005 and IC-APL studies. Ann Hematol 94, 1347–1356 (2015). https://doi.org/10.1007/s00277-015-2393-0

Download citation

Keywords

  • Acute promyelocytic leukaemia
  • Risk-adapted therapy
  • All-trans retinoic acid
  • Anthracyclines
  • Cytarabine
  • Prognostic factors
  • Matched-pair analysis