CLINICAL TRIALS AND OBSERVATIONS Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib

In imatinib-treated chronic myeloid leuke-mia (CML), secondary drug resistance is often caused by mutations in the BCR-ABL kinase domain (KD). As alternative therapies are available for imatinib resis-tance, early identification of mutations may prevent disease progression. Be-cause most patients are routinely moni-tored by BCR-ABL quantitative polymer-ase chain reaction (PCR), it is important to define the optimal increase in BCR-ABL that should trigger mutation testing. Expert panels have provisionally recom-mended a 10-fold BCR-ABL increase as the trigger for mutation screening, ac-knowledging the lack of consensus. To address this question, we monitored 150 CML patients by quantitative PCR and DNA sequencing. Thirty-five different mutations were identified in 53 patients, and, during 22.5 months (median) of fol-low-up after sequencing, mutations were significantly predictive of shorter progres-sion-free survival. An unbiased receiver operating characteristic analysis identi-fied a 2.6-fold increase in BCR-ABL RNA as the optimal cutoff for predicting a con-comitant KD mutation, with a sensitivity of 77 % (94 % if including subsequent samples). The 2.6-fold threshold approximated the ana-lytic precision limit of our PCR assay. In contrast, transcript rise cutoffs of 5-fold or greater had poor diagnostic sensitivity and no significant association with mutations. We conclude that the currently recom-mended 10-fold threshold to trigger muta-tion screening is insensitive and not univer-sally applicable. (Blood. 2009;114:2598-2605