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Acute myeloid leukemia

Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy

Leukemia volume 32, pages 21–29 (2018)Cite this article

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Abstract

Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk- and age-adapted protocol (Programa Español de Tratamientos en Hematología (PETHEMA)/HOVON LPA2005), with dose reduction of consolidation chemotherapy. Patients aged ⩾60 years reported to the PETHEMA registry and were treated with all-trans retinoic acid (ATRA) plus anthracycline-based regimens according to three consecutive PETHEMA trials that were included. We compared the long-term outcomes of the LPA2005 trial with the preceding PETHEMA trials using non-age-adapted schedules (LPA96&LPA99). From 1996 to 2012, 389 older patients were registered, of whom 268 patients (69%) were eligible. Causes of ineligibility were secondary APL (19%), and unfit for chemotherapy (11%). Median age was 67 years, without relevant differences between LPA2005 and LPA96&LPA99 cohorts. Overall, 216 patients (81%) achieved complete remission with no differences between trials. The 5-year NRM, cumulative incidence of relapse, disease-free survival and overall survival in the LPA2005 vs the LPA96&99 were 5 vs 18% (P=0.15), 7 vs 12% (P=0.23), 87 vs 69% (P=0.04) and 74 vs 60% (P=0.06). A less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in improved outcomes in older APL patients.

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References

  1. Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Möllgård L et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia 2011; 25: 1128–1134.

    Article  CAS  Google Scholar 

  2. Chen Y, Kantarjian H, Wang H, Cortes J, Ravandi F . Acute promyelocytic leukemia: a population-based study on incidence and survival in the United States,1975–2008. Cancer 2012; 118: 5811–5818.

    Article  Google Scholar 

  3. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009; 113: 1875–1891.

    Article  CAS  Google Scholar 

  4. Sanz MA, Vellenga E, Rayón C, Díaz-Mediavilla J, Rivas C, Amutio E et al. All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia. Blood 2004; 104: 3490–3493.

    Article  CAS  Google Scholar 

  5. Mandelli F, Latagliata R, Avvisati G, Fazi P, Rodeghiero F, Leoni F et al. Treatment of elderly patients (> or =60 years) with newly diagnosed acute promyelocytic leukemia. Results of the Italian multicenter group GIMEMA with ATRA and idarubicin (AIDA) protocols. Leukemia 2003; 17: 1085–1090.

    Article  CAS  Google Scholar 

  6. Ades L, Chevret S, de Botton S, Thomas X, Dombret H, Beve B et al. Outcome of acute promyelocytic leukemia treated with all trans retinoic acid and chemotherapy in elderly patients: the European group experience. Leukemia 2004; 19: 230–233.

    Article  Google Scholar 

  7. Ades L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S et al. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood 2010; 115: 1690–1696.

    Article  CAS  Google Scholar 

  8. Latagliata R, Breccia M, Fazi P, Vignetti M, Di Raimondo F, Sborgia M et al. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia. Long-term results and prognostic factors. Br J Haematol 2011; 154: 564–568.

    Article  CAS  Google Scholar 

  9. Ono T, Takeshita A, Kishimoto Y, Kiyoi H, Okada M, Yamauchi T et al. Long-term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia. Cancer Sci 2012; 103: 1974–1978.

    Article  CAS  Google Scholar 

  10. Lengfelder E, Hanfstein B, Haferlach C, Braess J, Krug U, Spiekermann K et al. Outcome of elderly patients with acute promyelocytic leukemia: results of the German Acute Myeloid Leukemia Cooperative Group. Ann Hematol 2013; 92: 41–52.

    Article  Google Scholar 

  11. Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G et al. 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 2010; 115: 5137–5146.

    Article  CAS  Google Scholar 

  12. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006; 107: 3469–3473.

    Article  CAS  Google Scholar 

  13. Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol 2015; 16: 1295–1305.

    Article  CAS  Google Scholar 

  14. Sanz MA, Martín G, Rayon C, Esteve J, González M, Díaz-Mediavilla J et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood 1999; 94: 3015–3021.

    CAS  PubMed  Google Scholar 

  15. Sanz MA, Martín G, González M, León A, Rayón C, Rivas C et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004; 103: 1237–1243.

    Article  CAS  Google Scholar 

  16. Sanz MA, Montesinos P, Vellenga E, Rayón C, de la Serna J, Parody R et al. 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. Blood 2008; 112: 3130–3134.

    Article  CAS  Google Scholar 

  17. Montesinos P, Rayón C, Vellenga E, Brunet S, González J, González M et al. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens. Blood 2011; 117: 1799–1805.

    Article  CAS  Google Scholar 

  18. De la Serna J, Montesinos P, Vellenga E, Rayón C, Parody R, León A et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood 2008; 111: 3395–3402.

    Article  CAS  Google Scholar 

  19. Montesinos P, Bergua JM, Vellenga E, Rayón C, Parody R, de la Serna J et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood 2009; 113: 775–783.

    Article  CAS  Google Scholar 

  20. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH et al. 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 2003; 21: 4642–4649.

    Article  Google Scholar 

  21. Sanz MA, Lo-Coco F, Martín G, Avvisati G, Rayón C, Barbui T et al. 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 2000; 96: 1247–1253.

    CAS  PubMed  Google Scholar 

  22. Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP Jr . The 'retinoic acid syndrome' in acute promyelocytic leukemia. Ann Intern Med 1992; 117: 292–296.

    Article  CAS  Google Scholar 

  23. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  24. Mantel N . Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–170.

    CAS  PubMed  Google Scholar 

  25. Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Statist 1988; 16: 1141–1154.

    Article  Google Scholar 

  26. Pepe MS, Mori M . Kaplan–Meier, marginal or conditional probability curves in summarizing competing risks failure time data? Stat Med 1993; 12: 737–751.

    Article  CAS  Google Scholar 

  27. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  Google Scholar 

  28. Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH . Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial. Blood 1999; 93: 4131–4143.

    CAS  PubMed  Google Scholar 

  29. Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999; 94: 1192–1200.

    CAS  PubMed  Google Scholar 

  30. Zhang Y, Zhang Z, Li J, Li L, Han X, Han L et al. Long-term efficacy and safety of arsenic trioxide for first-line treatment of elderly patients with newly diagnosed acute promyelocytic leukemia. Cancer 2013; 119: 115–125.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank María D García, Carlos Pastorini and Mar Benlloch for data collection and management. This work was partially financed with FEDER funds (CIBERONC (CB16/12/00284)). This study was presented in the 21st Congress of the European-Hematology-Association.

Author contributions

DM-C, PM and MAS conceived the study, analyzed and interpreted the data; DM-C, PM and MAS wrote the paper; DM-C and PM performed the statistical analyses; EV, TB, OS, AH, SB, PF, CB, J-MR, MP-E, JS, JE, VR, JG-C, LE, MEA, MA, JA, SN and BL included data of patients treated in their institutions, reviewed the manuscript and contributed to the final draft.

Author information

Author notes

  1. D Martínez-Cuadrón, P Montesinos, E Vellenga, T Bernal, O Salamero, A Holowiecka, S Brunet, C Gil, C Benavente, J M Ribera, M Pérez-Encinas, J De la Serna, J Esteve, V Rubio, J González-Campos, L Escoda, M E Amutio, M Arnan, J Arias, S Negri, B Lowënberg and M A Sanz: Members of the group are listed before References.

Authors and Affiliations

  1. Hospital Universitari i Politècnic La Fe, Valencia, Spain

    D Martínez-Cuadrón, P Montesinos & M A Sanz

  2. CIBERONC, Instituto Carlos III, Madrid, Spain

    D Martínez-Cuadrón, P Montesinos & M A Sanz

  3. University Hospital, Groningen, The Netherlands

    E Vellenga

  4. Hospital Central de Asturias, Oviedo, Spain

    T Bernal

  5. Hospital Universitario Vall d´Hebron, Barcelona, Spain

    O Salamero

  6. Silesian Medical University, Katowice, Poland

    A Holowiecka

  7. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

    S Brunet

  8. Hospital General, Alicante, Spain

    C Gil

  9. Hospital Clínico San Carlos, Madrid, Spain

    C Benavente

  10. ICO-Hospital Universitari Germans Trias i Pujol, Jose Carreras Research Institute, Badalona, Spain

    J M Ribera

  11. Hospital Clínico, Santiago de Compostela, Spain

    M Pérez-Encinas

  12. Hospital 12 de Octubre, Madrid, Spain

    J De la Serna

  13. Hospital Clinic, Barcelona, Spain

    J Esteve

  14. Hospital General, Jerez de la Frontera, Spain

    V Rubio

  15. Hospital Universitario Virgen del Rocío, Sevilla, Spain

    J González-Campos

  16. Hospital Joan XXIII, Tarragona, Spain

    L Escoda

  17. Hospital Universitario Cruces, Bizkaia, Spain

    M E Amutio

  18. ICO-Hospital Duran i Reynals, Hospitalet del Llobregat, Spain

    M Arnan

  19. Hospital Universitario Lucus Augusti, Lugo, Spain

    J Arias

  20. Hospital Regional Universitario Carlos Haya, Málaga, Spain

    S Negri

  21. Erasmus University Medical Center, Rotterdam, The Netherlands

    B Lowënberg

  22. Department of Medicine, University of Valencia, Valencia, Spain

    M A Sanz

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  1. D Martínez-Cuadrón
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  22. M A Sanz
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Consortia

on behalf of the PETHEMA, HOVON, PALG and GATLA groups

Corresponding author

Correspondence to P Montesinos.

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The authors declare no conflict of interest.

Additional information

This study was presented in the 21st Congress of the European-Hematology-Association.

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Martínez-Cuadrón, D., Montesinos, P., Vellenga, E. et al. Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy. Leukemia 32, 21–29 (2018). https://doi.org/10.1038/leu.2017.178

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