Dose Escalation Of Imatinib

If clinical resistance is modulated by an increase in the amount of BCR/ABL, it might be possible to overcome the resistance by increasing either the dose of imatinib or the ability of imatinib to bind to its target. Mutations such as T315I and E255K confer steric changes that are difficult to overcome even with higher doses of imatinib. Other mutations, such as M244V, F311L, and M351T, however, may be overcome by escalating the dose of imatinib.7 Certain other mutations, namely those in the ATP phosphate-binding loop (P loop), such as E255K, may confer a poor prognosis. In one Australian study, 12/13 patients with mutations in the P loop had a median survival of only 4.5 months.7 Mutations in the activation loop (A loop), downstream from the A loop, and in the ima-tinib-binding regions of the kinase may be at least partially sensitive to higher doses of imatinib. As these different mutations retain varying sensitivities to ima-tinib, it is rational to attempt dose escalation in such patients.

Table 21.1 Novel therapies to treat imatinib-resistant CML

Therapy

Mechanism

Developmental status

Transplantation (auto or alio)

GvL

Established therapy

Dose escalation of imatinib

Inhibition of partially resistant

Phase II/III trials ongoing

(600-800 mg)

bcr/abl mutants

0 0

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