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Predictors of thrombohemorrhagic early death in children and adolescents with t(15;17)-positive acute promyelocytic leukemia treated with ATRA and chemotherapy

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Abstract

Clinical trials on childhood acute promyelocytic leukemia (APL) report early death (ED) rates of 3–8%, but predictors of thrombohemorrhagic (TH)-ED are not well understood. In a retrospective study, we aimed to determine the incidence and predictors of TH-ED in childhood APL. Data were analyzed from children and adolescents with t(15;17)-positive APL (n = 683) who started treatment with all-trans retinoic acid (ATRA) and chemotherapy in different international studies. Demographic data; initial white blood cell (WBC), peripheral blood (PB) blast, and platelet counts; hemoglobin value; coagulation parameters; morphologic variant (M3 or M3v); and induction details were analyzed. Early death was defined as death occurring within 30 days of presentation. The incidence of ED was 4.7% (32 of 683 patients). Predictors of TH-ED were identified by univariable and multivariable Cox proportional hazard regression analyses (n = 25). In univariable analysis, high WBC (>10 × 109/L) (P < 0.001) and high PB blast (>30 × 109/L) (P < 0.001), M3v (P < 0.01), and black ethnicity (P < 0.001) were independent predictors of TH-ED. In multivariable analysis, high WBC count (P < 0.01) and obesity (i.e., body mass index ≥95th percentile for age) (P = 0.03) were predictors of TH-ED. Initial high WBC counts and obesity are likely predictors of TH-ED in childhood APL. The efficacy of novel drugs for APL-associated coagulopathy or of frontline arsenic trioxide and ATRA combination regimens in reducing ED rates in childhood APL remains to be established.

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Acknowledgments

The authors thank Vani Shanker for reviewing the manuscript.

Author information

Authors and Affiliations

  1. Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada

    Oussama Abla, Lillian Sung, Giancarlo Di Giuseppe, Derek Stephens & Johann Hitzler

  2. Division of Leukemia/Lymphoma, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA

    Raul C. Ribeiro

  3. Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy

    Anna Maria Testi

  4. Department of Hematology, Hospital Universitari i Politecnic La Fe, Valencia, and Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, Spain

    Pau Montesinos

  5. Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany

    Ursula Creutzig

  6. Division of Hematology/Oncology, Children’s Hospital and Research Center Oakland, Oakland, USA

    James H. Feusner

  7. Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, USA

    Bayard L. Powell

  8. Department of Paediatrics, Aarhus University Hospital, Aarhus, Denmark

    Henrik Hasle

  9. Department of Pediatric Oncology/Hematology, University Medical Center, Amsterdam, Netherlands

    Gertjan J. L. Kaspers

  10. Department of Oncology, The Children’s Hospital at Westmead, Westmead, Australia

    Luciano Dalla-Pozza

  11. Pediatric Hematology-Oncology Department, Instituto Carlos III, Madrid, Spain

    Alvaro Lassaletta

  12. Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, USA

    Martin S. Tallman

  13. Department of Pediatric Hematology-Oncology, IRCCS Ospedale Bambino Gesù, Rome, Italy

    Franco Locatelli

  14. University of Pavia, Pavia, Italy

    Franco Locatelli

  15. Department of Haematology-Oncology, University of Essen, Duisburg, Germany

    Dirk Reinhardt

  16. Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italy

    Francesco Lo-Coco

  17. Department of Hematology, Hospital Universitari i Politecnic La Fe, Department of Medicine, University of Valencia, Valencia, Spain

    Miguel A. Sanz

  18. Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, Spain

    Miguel A. Sanz

Authors
  1. Oussama Abla
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  2. Raul C. Ribeiro
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  3. Anna Maria Testi
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  4. Pau Montesinos
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  5. Ursula Creutzig
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  6. Lillian Sung
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  7. Giancarlo Di Giuseppe
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  8. Derek Stephens
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  9. James H. Feusner
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  10. Bayard L. Powell
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  11. Henrik Hasle
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  12. Gertjan J. L. Kaspers
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  13. Luciano Dalla-Pozza
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  14. Alvaro Lassaletta
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  15. Martin S. Tallman
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  16. Franco Locatelli
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  17. Dirk Reinhardt
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  18. Francesco Lo-Coco
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  19. Johann Hitzler
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  20. Miguel A. Sanz
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Contributions

O.A., M.A.S, R.C.R., J.H., and L.S. designed the study; G.D. and D. S. performed the statistical analyses; O.A., R.C.R., A.M.T., F.L., P.M., U.C., D.R., L.S., J.H.F., B.L.P., H.H., G.J.L.K., L.D.P., A.L., and M.A.S. provided the patient data; F.L., J.H., L.S., M.S.T., and F. L.C. edited the paper; O.A. and M.A.S. wrote the paper with input from all authors.

Corresponding author

Correspondence to Oussama Abla.

Ethics declarations

The study was approved by the ethics boards of participating institutions.

Conflict of interest

The authors declare no competing financial interests.

Additional information

Key points

– Initial high white blood cell count and obesity appear to be predictors of thrombohemorrhagic early death in childhood APL.

– New and more effective measures for APL-associated coagulopathy are urgently needed.

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Abla, O., Ribeiro, R.C., Testi, A.M. et al. Predictors of thrombohemorrhagic early death in children and adolescents with t(15;17)-positive acute promyelocytic leukemia treated with ATRA and chemotherapy. Ann Hematol 96, 1449–1456 (2017). https://doi.org/10.1007/s00277-017-3042-6

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  • DOI: https://doi.org/10.1007/s00277-017-3042-6

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