LAUSR

Although the UK National Cancer Research Institute’s SPIRIT 1 trial closed in 2009 due to poor recruitment, we thought it would be useful to the haematology community to report the outcome. This study closed early as it failed to recruit adequate numbers and our present report addresses the reasons, makes some observations about tolerability and the difficulty of delivering interferon-alpha (IFN) in the UK. The SPIRIT 1 study (EUDRACT Number 2004-001622-24) was originally conceived in conjunction with other international groups, and patients with newly diagnosed chronicphase chronic myeloid leukaemia (CML) were randomised to receive either standardor higher-dose imatinib or imatinib in combination with PEGylated IFN (PEG-IFN). There have been four sizeable studies comparing imatinib with imatinib combined with IFN. In the French study, although complete cytogenetic response rates were similar at 12 months between the arms, a higher rate of deep molecular response [reduction in breakpoint cluster region-Abelson (BCR-ABL) transcripts measured by quantitative polymerase chain reaction] was seen in the imatinib + PEG-IFN group. The Nordic study also showed a superior molecular response rate for imatinib + PEG-IFN combined therapy. In contrast, neither the German study nor a study from the MD Anderson Cancer Centre showed a significant difference in molecular response rates. None of these combination studies have demonstrated a superior progression-free (PFS) or overall survival (OS) advantage for patients who received combined treatment. In this context, between June 2005 and January 2009, 258 patients in the UK with newly diagnosed CML were randomised 1:1:1 to one of three treatment groups: (i) imatinib 400 mg daily; (ii) imatinib 800 mg daily; or (iii) imatinib 400 mg daily plus PEG-IFN at a starting dose of 90 μg/week, escalating to 180 μg/week if tolerated. The primary end-point for the SPIRIT 1 study was 5-year OS. The study was powered to show an improvement of 6% in OS and the predicted sample size was 822 patients per arm, 2466 in total. By 2008 it was evident that recruitment was slow, and we undertook a survey of clinicians to help us understand the reasons. Investigators gave a clear message that PEG-IFN was increasingly unpopular with patients and physicians due to side-effects and inconvenience of administration. As a result, the imatinib/PEG-IFN combined arm was closed. The advent of newer tyrosine kinase inhibitors (TKIs) rendered the trial obsolete, and it was terminated early, having recruited 10 5% (258/2466) of the required number of patients. Tables I and II show the characteristics, outcomes and toxicities observed in the study. As the study was underpowered, formal statistical analyses would be unreliable but no striking outcome differences are evident. The main limiting toxicities in the imatinib/PEG-IFN arm were Grade 3/4 neutropenia, low-grade fatigue/flu-like symptoms and a small