Blood Journal
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CME article

All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4)

  1. Harry J. Iland1,2,
  2. Ken Bradstock2,3,
  3. Shane G. Supple1,
  4. Alberto Catalano1,
  5. Marnie Collins4,
  6. Mark Hertzberg2,3,
  7. Peter Browett5,
  8. Andrew Grigg6,7,
  9. Frank Firkin7,8,
  10. Amanda Hugman1,
  11. John Reynolds4,
  12. Juliana Di Iulio4,
  13. Campbell Tiley9,10,
  14. Kerry Taylor11,
  15. Robin Filshie7,8,
  16. Michael Seldon10,12,
  17. John Taper13,
  18. Jeff Szer6,7,
  19. John Moore14,15,
  20. John Bashford16, and
  21. John F. Seymour4,7
  22. for the Australasian Leukaemia and Lymphoma Group
  1. 1Royal Prince Alfred Hospital, Camperdown, Australia;
  2. 2University of Sydney, Sydney, Australia;
  3. 3Westmead Hospital, Westmead, Australia;
  4. 4Peter MacCallum Cancer Centre, East Melbourne, Australia;
  5. 5University of Auckland, Auckland, New Zealand;
  6. 6Royal Melbourne Hospital, Parkville, Australia;
  7. 7University of Melbourne, Melbourne, Australia;
  8. 8St Vincent's Hospital, Fitzroy, Australia;
  9. 9Gosford Hospital, Gosford, Australia;
  10. 10University of Newcastle, Callaghan, Australia;
  11. 11Mater Medical Centre, South Brisbane, Australia;
  12. 12Calvary Mater Hospital, Newcastle, Australia;
  13. 13Nepean Hospital, Kingswood, Australia;
  14. 14St Vincent's Hospital, Darlinghurst, Australia;
  15. 15University of New South Wales, Kensington, Australia; and
  16. 16Wesley Medical Centre, Auchenflower, Australia


The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry ( as ACTRN12605000070639.

  • Submitted February 15, 2012.
  • Accepted June 9, 2012.
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