First Overall Molecular Response of the Randomized French SPIRIT Study on Behalf the Fi-LMC Group.

In September 2003, the French CML study group (Fi-LMC) activated the four armed randomized SPIRIT trial comparing imatinib 400mg with imatinib 600mg, imatinib 400mg + ara-C and imatinib 400mg + pegylated interferon in newly diagnosed CML in chronic phase. The molecular monitoring was centralized and performed, according to the EAC protocol, in duplicate on the same BCR-ABL cDNA among two French laboratories (Bordeaux and Lille). Data were expressed as BCR-ABL/ABLx100 on the new internationally agreed scale (IS) using a conversion factor of 1.33 and 0.80 for Bordeaux and Lille respectively. A good correlation between the two laboratories was observed. During the first year of follow-up the quantification was performed each three months (M0 to M12). In May 2006, 297 of the 492 enrolled pts had a follow up of more than 12 months, and 263 pts were analysed at M12. Using the IS, the median values of the BCR-ABL/ABL normalized ratios were 90%, 6,4%, 0.68%, 0.32% and 0.16% at M0, M3, M6, M9, and M12 respectively. At M12, 15%, 29%, 27%, 17% and 12% of the pts presented a BCR-ABL/ABL ratio lower than 0.01%, 0.1%, 1%, 10%, and 100% respectively. Overall, 44% of the pts reached the Major Molecular Response (MMR). Results were also expressed using individual M12/M0 ratio. At M12 13%, 29%, 28%, 17% and 13% of the pts presented a 4 log, 3 log, 2 log, 1 log and 0 log reduction respectively. Overall, 42% of the pts presented an individual 3 log reduction.

Despite very similar results between the two means of expression, the pts distribution was different due to unlike individual BCR-ABL transcript level at MO. Furthermore, the analysis of 75 paired samples before (at diagnosis) and after (at inclusion) hydroxyurea treatment (5 days to 1.2 months) revealed BCR-ABL/ABL ratios of 129% and 108% respectively, confirming the 0.2 log difference previously reported by A. Hochhaus et al.

In conclusion, expression of the data using the new IS or the individual M12/M0 ratio was very similar in our experience regarding the percentage of each subgroup but the pts distribution was different and a longer follow up would be useful to define the best method. However, the good correlation observed in the IRIS trial between MMR and progression, the influence of hydroxyurea treatment on BCR-ABL level, the good correlation observed among laboratories and the need of harmonisation of expressed results influenced our choice for the new IS. The application of this recommendation is in progress in the great majority of the molecular French laboratories.