A Review of Mutation Analysis In the TOPS Trial of Standard Dose Versus High Dose IM In CML Suggests That Refinements to the ELN Recommendations for Mutation Screening May Be Appropriate

BCR-ABL mutations are a major mechanism of acquired imatinib (IM) resistance in CML. Consequently, mutation analysis is recommended at milestones indicative of IM failure or suboptimal response (Baccarani JCO 2009: ELN recommendations). These criteria include lack of specified treatment responses up to 18 months of therapy, loss of response at any time, or progression to accelerated phase (AP) or blast crisis (BC). Mutation analysis was performed for patients (pts) enrolled in the TOPS trial (400 mg vs 800 mg of IM) for failure to achieve a major cytogenetic response (MCyR) by 6 months, failure to achieve a major molecular response (MMR) at 12 months, clinical evidence of resistance (including loss of any response and progression to AP/BC) and a significant rise in BCR-ABL. We determined whether the ELN recommendations for mutation screening were appropriate to optimally identify pts who acquired mutations and to limit the number of samples requiring mutation screening.

462 pts were on study for at least 3 months and were included in the analysis (median 39 months, range 3.7–54). Of the 462 pts, 280 had mutation analysis performed at least once by HPLC (high performance liquid chromatography) and/or direct sequencing. If mutation analysis was performed at a particular timepoint and no mutation was detected, then for the purposes of this analysis it was assumed the patient did not have a mutation at prior timepoints. When a mutation was detected, prior samples were tested to determine when the mutation first emerged.

Twenty-six mutations were detected in 20 pts (median 13 months, range 6–36). Multiple mutations were detected in 5/20 pts (25%). The mutations were confirmed at several timepoints in 17/20 pts, whereas mutations in the remaining 3 pts became detectable at the last sample collected before discontinuation. Sixteen of the 20 pts with mutations discontinued treatment. The frequency of mutations for the treatment arms was similar; 400 mg 6/155 (3.9%), 800 mg 14/307 (4.6%). However, the median month of mutation detection was earlier for pts treated on the 800 mg arm compared to the 400 mg arm, 10 versus 27 months, respectively. Pts treated on the 800 mg arm also had a higher frequency of the T315I mutation compared to the 400 mg arm; 6/14 pts (43%) on 800 mg compared to 1/6 pts (17%) on 400mg. In the total patient cohort, mutations were more commonly detected in those with high Sokal score (10/111 pts, 9%) compared to intermediate (6/160 pts, 3.8%) or low (4/191 pts, 2.1%). Furthermore, highly IM-resistant mutations (T315I, Y253H/F, E255V/K, L248V, G250E, F486S; Baccarani JCO 2009) were common in pts with a high or intermediate Sokal score, 9/10 (90%) and 4/6 pts (67%) respectively, compared to 0/4 with low Sokal score. Early indicators of IM failure, as recommended by the ELN, are no complete hematologic response (CHR) by 3 months and >95% Philadelphia chromosome (Ph) at 6 months. No mutations were detected in the total cohort of pts who met these failure criteria and who were tested for mutations (Table). This is consistent with previous studies indicating a low frequency of mutations in pts with primary IM resistance. However, lack of some milestone responses and loss of response were associated with mutations (Table, some pts lost more than 1 type of response). Failure to achieve an MMR by 18 months is an ELN criterion to perform mutation analysis. However, only 5% of pts in this category had a mutation and the majority of these pts also failed to achieve a CCyR. Lack of an MMR by 18 months when CCyR is achieved does not appear to be an indication for mutation analysis.

The data suggest that the ELN recommendations for performing mutation analysis that would most frequently detect mutations in IM-treated pts are failure to achieve MCyR/CCyR at 12 months, loss of any response and AP/BC. IM doses of 800 mg were associated with the earlier acquisition of mutations, including those that are highly resistant.

Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ortmann:Novartis: Employment. Duniec:Novartis: Employment. Jin:Novartis: Employment. Woodman:Novartis: Employment. Pane:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Radich:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Hughes:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria.