X

*Only if negative for bcr/abl by FISH.

month following the initiation of therapy. In the absence of significant myelosuppression, the monitoring interval may be successively increased up to about every 3 months.33 35 A recommended approach to bcr/abl monitoring is provided in Table 20.4.

An assessment of treatment response should be made at 3-month intervals in the first year of therapy. Failure to tolerate imatinib or to achieve hematologic remission by 3 months is an indication for either increasing the dose of imatinib or proceeding to HSCT in appropriate patients.33 36 More than half of patients will have achieved a major cytogenetic remission with imatinib at 3 months of follow-up.20

However, a bone marrow exam should be performed annually to include standard karyotype analysis even in the setting of a CCR. The development of additional cytogenetic abnormalities to the Ph+ clone predicts for relapse and progression to accelerated-phase disease after a response to imatinib.37 Emerging results of treatment with imatinib have revealed another disturbing finding. Some patients develop clonal cytogenetic abnormalities in Philadelphia-chromosome-negative (Ph—) hematopoietic progenitors.38 Although fewer than 10% of treated patients have been identified with Ph— clonal evolution,39 the appearance of trisomy 8 and monosomy 7 among the reported abnormalities is a cause for concern. Indeed, several case reports of myelodysplasia, but not acute leukemia, have been reported in this setting.384041 Clonal evolution in a patient with chronic-phase CML should prompt a discussion of allogeneic HSCT as a viable treatment alternative.

If a patient achieves a CCR after 6-12 months of imatinib therapy, most investigators recommend ima-tinib be continued indefinitely. These patients are likely to have a relatively favorable prognosis although cure is by no means assured. The prognosis is particularly favorable if while in CCR, the level of bcr/abl transcripts becomes either undetectable or reduced more than 3-logs as determined by RT-PCR. These patients in molecular remission enjoy 100%

progression-free survival after 24 months of imatinib therapy.12

As previously discussed, patients who fail to achieve cytogenetic remission within 6 months of treatment with imatinib have a poorer prognosis, and one mechanism of imatinib resistance is mutations in bcr/abl. A second mechanism for imatinib resistance is up-regulation of bcr/abl by gene amplification, and these patients are candidates for either dose-escalation of imatinib or allo-geneic HSCT.29 42-46 Indeed, accelerated-phase CML with bcr/abl gene amplification responds better to a daily dose of 600 mg of imatinib than to a daily dose of 400 mg. Patients with chronic-phase CML resistant to 400 mg of imatinib may also achieve responses with higher doses.36 However, these responses tend not to be durable, and alternative treatments, such as HSCT, have been recommended.47 Similarly, patients who fail to achieve a major molecular remission, or have increasing titers of bcr/abl, after 9-12 months of imatinib therapy are candidates for alternative treatments including HSCT.

With regard to mechanisms of imatinib resistance, unfortunately, there is no practical widely available test that reliably distinguishes mechanisms of resistance to imatinib.

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