Resistance and Loss of Efficacy

BCR-ABL inhibition has dramatically improved outcomes in CML and the majority of patients respond well to therapy. However, in a minority of patients, treatment yields a response that is slow, incomplete, or not durable.

It is important to note that testing for BCR-ABL mutations at baseline or in patients newly initiated on CML therapy has no established clinical value; CML treatment guidelines do not recommend mutational testing in these populations.¹

The current NCCN practice guidelines for patients in chronic phase CML state that mutational testing may be considered to provide additional information in the following circumstances:

Failure to achieve complete hematologic response at 3 months
No cytogenetic response at 6 months
Failure to achieve major cytogenetic response at 12 months
Any sign of loss of response (ie, hematologic relapse, relapse to Ph-positivitity, or an increase in BCR-ABL transcript ratio, 1 log increase, and loss of major molecular response)¹

Slow or incomplete initial response is rarely due to mutations in BCR-ABL

In de novo-treated patients with chronic CML, a slow or incomplete response is rarely due to mutations in BCR-ABL.^2,3 Factors that have been linked to poor response to BCR-ABL TKI therapy include

Low plasma concentrations of the BCR-ABL TKI, possibly due to either lack of adherence, drug interactions, or host factors⁴
Low intracellular drug levels, due to intrinsic variations in intracellular drug transport and/or high levels of P-glycoprotein^3,5,6
There are limited data showing a relationship between incomplete response and the eventual development of resistance due to BCR-ABL mutations.^5,7

Loss of response may or may not be due to mutations in BCR-ABL

A loss of response in patients who have previously achieved a hematologic or cytogenetic response may be due to a resistance-conferring mutation or to other factors. However, the existence of BCR-ABL mutations alone is not necessarily predictive of poorer clinical response or loss of response-as the following studies show:

In a large study of patients progressing on TKI treatment, 57% (82/145) were found to have mutations in BCR-ABL, while 43% (63/145) did not have any discernible mutations⁸
In another study of patients who were in complete cytogenetic response (CCR) on TKI treatment, 38% (5/13) were found to have mutations in BCR-ABL. Two of the patients with mutated BCR-ABL subsequently relapsed, while the other 3 retained CCR (follow-up, 21-30 months)⁹

National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia v.1.2009. http://www.nccn.org/professionals/physician_gls? PDF/cml/pdf. Accessed September 30, 2008.
Apperley JF. Part II: management of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8(12):1116-1128.
Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark RE. Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther. 2008;83(2):258-264.
Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109(8):3496-3499.
White DL, Saunders VA, Dang P, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood. 2007;110(12):4064-4072.
Goldman JM. How I treat chronic myeloid leukemia in the imatinib era. Blood. 2007;110(8):2828-2837.
Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol. 2005;23(18):4100-4109.
Soverini S, Colarossi S, Gnani A, et al; on behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res. 2006;12(24):7374-7379
Chu S, Xu H, Shah NP, et al. Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood. 2005;105(5):2093-2098.