Resistance to imatinib therapy

In evaluating relapse mechanisms, patients can be separated into two categories: those with persistent inhibition of the BCR-ABL kinase (BCR-ABL-independent) and those with reactivation of the BCR-ABL kinase (BCR-ABL-dependent) at relapse (Figure 7.5). In the largest studies of resistance or relapse, several consistent themes emerge. In patients with primary resistance, i.e. patients who do not respond to imatinib therapy, BCR-ABL-independent mechanisms are most common. In contrast, most of the patients who relapse on therapy with imatinib reactivate the BCR-ABL kinase. In these studies, more than 50% and perhaps as many as 90% of patients with hematological relapse have BCR-ABL point mutations in at least 13 different amino acids scattered throughout the ABL kinase domain (Figure 7.6). Other patients have amplification of BCR-ABL at the genomic or transcript level.

Is Bcr-Abl kinase inhibited?

Is Bcr-Abl kinase inhibited?

• Bcr-Abl amplification

• Kinase mutations

Fig. 7.5 Distinguishing between potential mechanisms of resistance to imatinib

1 Additional mutations

• Bcr-Abl amplification

• Kinase mutations

Fig. 7.5 Distinguishing between potential mechanisms of resistance to imatinib

4 22ii5

Fig. 7.6 ABL kinase domain mutations that have been identified that are associated with resistance to imatinib

The ABL kinase domain, from amino acid 240 to amino acid 500, is shown with the ATP binding domain (P), the catalytic domain ((C) and the activation loop (A). The numbers below the kinase domain are amino acids that are mutated in patients who relapsed on therapy with imatinib. The vertical lines above the kinase domain indicate the number of times each amino acid has been found to be mutated (compiled from various series).

It should be noted that the studies described above represent a minority of CML patients. Most of the patients described in the studies of resistance had advanced phase disease. In contrast, the majority of patients diagnosed with CML will be in the chronic phase, most will obtain a complete cytogenetic response with imatinib, and very few have relapsed. However, only a minority attains molecular remission. Current hypotheses for the mechanism of molecular persistence can also be divided into BCR-ABL-dependent and -independent mechanisms. For example, stem cell quiescence has been postulated as a potential BCR-ABL-independent mechanism of resistance to imatinib. BCR-ABL-dependent mechanisms of molecular persistence include the possibility that low levels of BCR-ABL kinase activity prevent cells from proliferating, but are sufficient to protect cells from apoptosis. This could be due to imatinib not being capable of completely inhibiting the BCR-ABL kinase or due to the fact that stem cells express high levels of P-glycoprotein that result in efflux of imatinib. Each of these scenarios suggests specific therapeutic interventions to overcome molecular persistence.

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