The Philadelphia chromosome in CML results from a swap of genetic information between chromosomes 9 and 22. This results in fusing BCR to ABL - one of a family of proteins called tyrosine kinases, which are important in regulating cell division in normal cells. The resulting BCR-ABL protein has increased activity and results in uncontrolled cell growth and division. Glivec, [Imatinib or STI571] is a drug that inhibits BCR-ABL, and has been shown to be very effective in CML in returning the bone marrow back to normal with minimal side effects. The effect of Glivec depends very much on the stage of the disease that it is used in. Relapse on therapy is due to bypassing of  Glivec’s inhibition of BCR-ABL. This may be because the cell makes more of the BCR-ABL and overwhelms the drug. The most common reason though, is as a result of new mutations in the BCR-ABL molecule that affect the ability of Glivec to bind to ABL.

Most patients with CML who are on Glivec are in chronic phase and will achieve a complete cytogenetic response. Few of these have relapsed so far. However, using very sensitive tests, there always remains evidence of CML and it may be that more patients may relapse from this low level of disease over time. It is possible that ensuring an adequate dose or combining Glivec with other chemotherapy drugs may prevent this. Other inhibitors of ABL are being developed which would allow combination therapy or the targeting of a drug to a patient’s particular resistance mechanism.  There is also evidence that increasing the dose may overcome resistance to Imatinib or a failure to respond initially.

Discuss your concerns with your specialist who can explain the current understanding on Glivec resistance. Imatinib is a very new drug and we are still learning about its strengths and its weaknesses.