• Event-free Survival (EFS) [ Designated as safety issue: No ]
  

• Rates of complete remission after induction therapy (CR) [ Designated as safety issue: No ]
  
• Cumulative incidences of relapse (CIR) and death in CR (CID) [ Designated as safety issue: No ]
  
• Overall survival [ Designated as safety issue: No ]
  
• Days in hospital during each cycle and during the whole intervention [ Designated as safety issue: No ]
  
• Rate of ED/HD [ Designated as safety issue: Yes ]
  
• Type, frequency, severity, timing and relatedness of AEs and laboratory abnormalities observed during different treatment cycles [ Designated as safety issue: Yes ]
  
• Incidence of infection after induction and consolidation therapy [ Designated as safety issue: Yes ]
  
• Duration of neutropenia and thrombocytopenia after induction and consolidation therapy [ Designated as safety issue: Yes ]
  
• Quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases, late treatment effects, and demographics according to Messerer et al [49] [ Designated as safety issue: No ]
  

5.2.1. Choice of Standard Regimen

The protocol is based on the previous front line AMLSG protocols: AMLHD93 [50], AMLHD98A [51], AMLHD98B [22], AMLSG 06-04 [52], AMLSG 07-04 [30]. In all these trials induction therapy consisted on a combination of standard-dose cytarabine in combination with the anthracycline idarubicin and the epipodophyllotoxin etoposide. The regimen is abbreviated with ICE. Based on overall good results with ICE in terms of achievement of CR and, in particular, the fact, that NPM1mut was established as a favourable predictive factor for achievement of a complete remission after an induction therapy with ICE [13,16] the chemotherapeutic components in the induction therapy of the AMLSG 09-09 protocol have remained unchanged. As outlined in section 3.3, ATRA showed favourable results in NPM1mut AML in one retrospective analysis of a randomized study [13] and in one interim analysis of an active prospective randomized trial [30]. Since it is not possible to await the final results of the AMLSG 07-04 protocol before start of the current AMLSG 09-09 protocol ATRA is incorporated in both arms of the study based on the favourable clinical results in the absence of additional ATRA-related toxicity.

Postremission therapy is based on repetitive cycles of HDAC as a standard therapy in patients with normal karyotype AML [48,53]. Results of the German-Austrian AMLSG suggest that two cycles of HDAC - in combination with an anthracycline or mitoxantrone - may be equally effective [16]. In the current study, three courses of postremission with HDAC will be given according to the preceding AMLSG 07-04 protocol for comparability [30].

5.2.2. Choice of Study Design

A standard two-arm randomized phase-III study design was chosen because all components and additionally the combinations of treatment regimens had been evaluated in dosage and efficacy in several phase II/III trials [13,16,22,30,34,52]. Based on these studies efficacy and toxicity of the standard arm of the study is well established. The addition of GO to induction and consolidation therapy in NPM1mut AML seems to be reasonable based on the consistent association of NPM1mut AML with a characteristic immunophenotype, i.e., low or absent CD34 expression and strong CD33 expression [7-11]. Due to the constitutional high CD33 expression and potential efficacy in that high expression was correlated to high response rates [33], GO represents a potentially highly effective agent in the treatment of patients with NPM1mut AML. The combination of GO in a dosage of 3mg/m² to intensive induction and consolidation treatment [32] as well as in combination with intensive salvage therapy including ATRA [34] has been demonstrated to be save and well tolerated.