MDR1 Expression and Pre-Treatment Tumor Load Predict Molecular Response in CML Patients On Nilotinib Therapy After Imatinib Failure.

The majority of patients with chronic myeloid leukemia (CML) in chronic phase achieve and maintain complete cytogenetic remission after frontline therapy with imatinib mesylate. In case of resistance or intolerance to imatinib, a switch to second generation tyrosine kinase inhibitors, such as nilotinib or dasatinib, is recommended. Mutations in the BCR-ABL kinase domain and various BCR-ABL independent mechanisms, e.g. clonal evolution and pathways bypassing BCR-ABL are considered as leading causes of resistance. Efficacy of imatinib and nilotinib depends on intracellular drug levels, which are influenced by the activity of the efflux transporter protein multidrug resistance 1 (MDR1, ABCB1 or P-gp). MDR1 involvement in the pathogenesis of resistance to nilotinib was postulated (Mahon et al., Cancer Res 2008).

Hence, we evaluated the predictive impact of MDR1 expression levels as well as pre-treatment BCR-ABL load from imatinib resistant CML patients on molecular responses during second line therapy with nilotinib.

Imatinib resistant patients in chronic phase CML treated with nilotinib (n=94) were investigated. Baseline BCR-ABL mutations were detected by D-HPLC and direct sequencing. MDR1 and BCR-ABL mRNA expression levels were determined by quantitative reverse transcription PCR (qRT-PCR) using LightCycler™ technology, normalized against beta-glucuronidase (GUS) expression and standardized according to the international scale (IS). Log-rank tests were performed to analyze and compare the time to achieve major (MMR, BCR-ABL IS ≤0.1%) or good molecular response (BCR-ABL IS ≤1%).

Within 12 or 24 months of nilotinib therapy, 22% and 27% of patients achieved MMR, and 37% and 41% of patients attained good molecular response, respectively. After 12 or 24 months, patients with MDR1/GUS ratios ≥2.5 (60%) achieved MMR in an estimated rate of 45% and 53%, whereas those with initial MDR1/GUS ratios <2.5 (40%) showed MMR in 14% and 14%, respectively (p=0.034). Good molecular response was attained in 52% vs 49% and 63% vs 66% after 12 and 24 months (ns). Further, BCR-ABL load prior to nilotinib revealed a significant impact on consecutive molecular response. BCR-ABL IS <28% separated best concerning prediction of MMR after 12 and 24 months (53% vs 25% and 53% vs 34%, p=0.002) and good molecular response (62% vs 44% and 85% vs 51%, p=0.004). Combining the two methods implied the definition of a low risk group (20%; pre-treatment BCR-ABL IS <28% and MDR1/GUS ratios ≥2.5) in contrast to a high risk group (27%; pre-treatment BCR-ABL IS ≥28% and MDR1/GUS <2.5) achieving MMR in 67% vs 6% of the patients after 24 months (p=0.0004). No relevant differences were found looking at subgroups of patients bearing BCR-ABL mutations.

Pre-treatment expression levels of MDR1 and BCR-ABL tumor load predicts molecular responses of imatinib resistant chronic phase CML patients within the first two years of treatment with nilotinib.

Woodman:Novartis Oncology: Employment. Hochhaus:Novartis : Research Funding.