title: Results of the APML3 trial incorporating all-trans-retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia.
abstract: BACKGROUND
  Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols.
  
  
  METHODS
  In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine.
  
  
  RESULTS
  Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001).
  
  
  CONCLUSIONS
  The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance to the protocol supports a role for maintenance in the context of relatively low chemotherapy exposure during consolidation. (actr.org.au identifier: ACTRN12607000410459).
authors: Royal Prince Alfred Hospital, Camperdown, Australia. harry@email.cs.nsw.gov.au
authors: Harry
authors: H
authors: Iland
authors: Ken
authors: K
authors: Bradstock
authors: John
authors: J
authors: Seymour
authors: Mark
authors: M
authors: Hertzberg
authors: Andrew
authors: A
authors: Grigg
authors: Kerry
authors: K
authors: Taylor
authors: John
authors: J
authors: Catalano
authors: Paul
authors: P
authors: Cannell
authors: Noemi
authors: N
authors: Horvath
authors: Sandra
authors: S
authors: Deveridge
authors: Peter
authors: P
authors: Browett
authors: Tim
authors: T
authors: Brighton
authors: Li
authors: L
authors: Chong
authors: Francisca
authors: F
authors: Springall
authors: Juliet
authors: J
authors: Ayling
authors: Alberto
authors: A
authors: Catalano
authors: Shane
authors: S
authors: Supple
authors: Marnie
authors: M
authors: Collins
authors: Juliana
authors: J
authors: Di Iulio
authors: John
authors: J
authors: Reynolds
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D060830:Consolidation Chemotherapy / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D060828:Induction Chemotherapy / Q000379:methods*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000401:mortality*; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage; D008875:Middle Aged; D015996:Survival Rate; D014212:Tretinoin / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D014212:Tretinoin; D015122:Mercaptopurine; D015255:Idarubicin