Background: The HR-NBL1/SIOPEN trial randomised 2 essential treatment concepts: Randomisation R1 investigated BUMEL superiority (plenary session ASCO 2012), whilst the R2 randomisation tested the benefits of adding subcutaneous interleukin 2 (scIL2) to ch14.18/CHO mAB immunotherapy(IT) and 13 cis retinoic acid (13-cis RA). The R2 population reached the target population of 400 patients (pts) in August 2013. Methods: After Rapid Cojec induction pts were randomised in R1 (296 BuMel, 302 CEM) till 09/2010. Median follow up is 6.2 years. Eligibility included complete bone marrow remission and ≤3, but improved mIBG positive spots. Local control included surgery and radiotherapy of 21 Gy. Eligibility to R2 included previous R1 eligibility. R2 was initiated in 2009 aiming at 400pts receiving ch14.18/CHOmAB as 8-hour infusion with 20mg/m² over 5 days and 13 cis RA over a total of 5 IT cycles. The schedule requires high dose morphine to control for neuropathic pain. R2 addressed a scIL2 question, using a dose of 6x10E6/m²/day over 5 days twice in a weekly interval, given in week 2 in parallel with ch14.18/CHOmAb. Results: The superiority of BuMel in EFS and OS over CEM (3-years EFS&OS 50%/61% vs. 38%/52%; p<0.001) is maintained with a significantly lower relapse and progression rate with BuMel (48% vs. 58%) as major factor. Severe toxicity rates (ICU, toxic deaths) are below 10%, but are higher for CEM (p=0.012). Hence the MAT toxicity profile still favours BuMel in spite of a VOD rate of 24% (grade 3: 4%) vs. 10% in CEM (Grade3: 1%). Having reached the R2 target in August 2013, the randomisation is currently suspended expecting "last patient out" in 02/2014 with liberation of the randomised R2 data by the DMC thereafter. The R2 population undisclosed for treatment arms currently reveals a 2 year EFS/OS of 56%/68%. The scIL2 arm carries a significantly higher toxicity burden related to IL2 associated side effects like fever and capillary leak with a number of pts in the IL2 arm stopping treatment early. Conclusions: BuMel is maintained as SIOPEN standard treatment whilst R2 results will have a major impact on the future management of immunotherapy. Clinical trial information: NCT01704716.