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Molecular Response to Imatinib in Chronic Phase CML

Our results suggest that major (i.e., BCR-ABL/ABL <0.05%) or complete molecular remissions (i.e., undetectable BCR-ABL) were associated with more durable cytogenetic remissions. Only 5% of patients who have achieved a major molecular response and 4% of those reaching undetectable levels of BCR- ABL/ABL have lost their complete cytogenetic remission, compared with 37% of patients not reaching these degrees of response (P < 0.0001). This difference is not due to a lead-time bias as patients in both groups were followed for a similar period of time. A similar trend was reported in a smaller series by Rosti et al. (23). One of 18 patients who had a 2- log reduction in BCR-ABL/B2M ratio (6%) lost a complete cytogenetic remission, compared with 3 of 9 patients who had a <2-log reduction.

The importance of achieving an early molecular response was first reported from the IRIS trial. Among patients who achieved a complete cytogenetic remission after 12 months of therapy, those with at least a 3-log reduction in BCR-ABL transcript levels had a significantly better progression-free survival compared with those with less than a 3-log reduction (16). Other smaller series’ and subsets of the larger IRIS cohort have reported that early declines in transcript levels are associated with achievement of cytogenetic response (24–26). In our series, patients who achieved a major molecular re- mission by 12 months after the start of therapy had an im- proved probability of a sustained complete cytogenetic remission. A similar trend was seen at earlier time points (i.e., 3 and 6 months) but it was not statistically significant, probably because of the relatively small number of patients who reach these levels at earlier time points. However, if patients are divided by quartiles of BCR-ABL transcript levels at 3 months, those with the lowest levels (i.e., <0.0847) have a significantly better probability of a sustained cytogenetic remission. Branford et al. (27) reported similar results for patients reaching a 2-log reduction at 6 months. Patients with greater than a 1-log reduction (our series) or 2-log reduction

(27) at 3 months have an improved probability of later achieving a molecular response. These results emphasize the need for frequent and early molecular monitoring of patients treated with imatinib, and the importance of achieving the best response as early as possible.

There is little available data on the durability of molecular responses. In our study, major molecular responses have been sustained in 72% of patients, whereas complete responses have been sustained in nearly half of the patients. In nearly a third of these patients, the cause for loss of response was treatment interruption. Despite the loss of molecular responses, this has not translated into loss of cytogenetic remissions in most patients. An important question then is the significance of increasing levels of BCR-ABL transcripts during therapy. Our results suggest that there is a high risk of loss of cytogenetic remission with greater increases of measurable molecular disease (i.e., >2-log increase or an absolute increase >1), but the risk is particularly high for patients who did not achieve a major molecular remission. However, it is possible that patients that achieved lower transcript levels will only require longer times to show a loss of their cytogenetic response. Continued follow-up will answer this question. Different treatment strategies, such as adding other agents to imatinib, should be investigated in these cases of increasing molecular disease.

In summary, molecular monitoring provides valuable infor- mation for the follow-up of patients with CML in chronic phase treated with imatinib. Achieving a major molecular response correlated with an improved probability of a durable cytoge- netic remission, particularly when achieved early during the course of therapy. Most major molecular remissions have been durable, and increases in BCR-ABL transcripts have not translated in loss of cytogenetic remission for most patients with molecular response. Thus, a major goal of therapy with imatinib should be to achieve an early major molecular response.

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