The Depth Of In Vivo Kinase Inhibition Achieved Over The First Month Of Nilotinib Therapy Predicts For Subsequent Molecular Response, and Is Closely Related To Nilotinib Plasma Levels

We have previously demonstrated that the degree of in vivo kinase inhibition achieved over the first month of imatinib therapy in newly diagnosed, chronic phase chronic myeloid leukaemia (CP-CML) patients, is an excellent predictor of subsequent molecular response. Patients achieving >50% in vivo kinase inhibition all achieved major molecular response (MMR; ≤0.1% BCR-ABL1 (IS)) by 24 months compared to 56% of patients with <50% in vivo kinase inhibition (p<0.001). (White et alJCO 2007). To date, no biomarker which accurately predicts response to nilotinib has been reported.

Achievement of <10% BCR-ABL1 by 3 months (EMR) is predictive of subsequent molecular outcome in imatinib treated patients. Only 1 of the 70 CP-CML recipients of first-line nilotinib (300mg bid) monitored in Adelaide failed to achieve <10% by 3 months, and this patient withdrew from treatment due to toxicity 7 months after the start of nilotinib therapy. Failure to achieve <1% BCR-ABL1 (EMR 1%) by 3 months was strongly associated with a significantly lower rate of MMR by 12 months when compared to patients achieving <1% BCR-ABL in the 65 of 70 patients with molecular response data examinable at 12 months. (55% MMR (n=11) vs 93% MMR (n=54) p=0.002).

The degree of in vivo kinase inhibition was measured by calculating the % reduction in the p-Crkl level of mononuclear cells collected at days 7 and 29 after the start of nilotinib therapy. A significantly higher proportion of nilotinib treated patients achieved 50% or greater in vivo kinase inhibition over the first month of treatment compared to our historical cohort of imatinib treated patients (75% vs 45% of patients. p<0.001). Dividing patients into those with low and those with high in vivo kinase inhibition revealed a significantly higher proportion of nilotinib treated patients with high in vivo kinase inhibition achieved EMR1% (p=0.012) and MMR by 12 months when compared to patients with low in vivo kinase inhibition (p<0.001)Table 1.

Correlating drug levels achieved over the first month of therapy, with in vivo kinase inhibition revealed a strong correlation for nilotinib (p<0.001), but not imatinib (p>0.05), suggesting that early dose intensity may be the key factor for nilotinib response. In contrast, while dose is clearly important for imatinib other factors, such as variable drug influx also play a pivotal role. Previous studies have demonstrated that the pharmacokinetics of nilotinib are similar to that of imatinib, and that trough plasma levels of imatinib >1000ng/ml are associated with a higher rate of MMR. Grouping patients into those <1000ng/ml by day 29 and those >1000ng/ml revealed that early trough nilotinib plasma levels were also strongly predictive of the achievement of MMR by 12 mo (<1000ng/ml – 79% (n=38) versus >1000ng/ml – 96% (n=25). p=0.009). Of note two patients have developed kinase domain mutations and both patients failed to achieve high in vivo kinase inhibition or drug levels >1000ng/ml.

Preliminary analysis of this cohort of nilotinib treated patients strongly suggests that the in vivo kinase inhibition achieved is significantly higher than observed with imatinib at equivalent timepoints, and is a significant factor for subsequent molecular response. Importantly the plasma levels achieved over the first month of nilotinib therapy appear to be a key factor in the achievement of both early in vivo kinase inhibition and subsequent molecular response.