Chronic myeloid leukemia (CML) is a malignant disease in which too many white blood cells belonging to the myeloid line of cells are produced in the bone marrow. CML is due to the growth and evolution of an abnormal clone of cells containing a chromosome rearrangement known as the Philadelphia chromosome (Ph+ cells). In the Ph chromosome a part of the BCR (‘breakpoint cluster region’) gene from chromosome 22 is fused with the ABL (‘Abelson leukemia virus’) gene on chromosome 9. The oncogenic BCR-ABL fusion gene encodes the BCR-ABL fusion protein. As a protein kinase it causes myeloid white blood cells to multiply uncontrollably .
Treatment of early or chronic phase Ph+ CML (CP-CML) with tyrosine kinase inhibitors (TKI) like imatinib results in very high response and survival rates . Unfortunately, a considerable number of patients does not achieve adequate response levels and is at risk for disease progression. Causes of this lack of response include the presence of point mutations in the kinase domain of the BCR-ABL protein, increased expression of the BCR-ABL fusion gene and increased drug efflux mechanisms. Pharmacokinetic factors leading to suboptimal drug plasma concentrations may also affect the treatment result . However, poor adherence to imatinib has now been recognized as the most important determinant of treatment failure [4–7]. The detrimental effect of poor adherence may be falsely interpreted as the development of resistance to TKI treatment. Reasons underlying poor adherence include the development of (serious) adverse effects, long duration of treatment and the absence of symptoms of the disease [8, 9]. Resistance to imatinib as related to BCR-ABL point mutations has been largely overcome by using the 2nd generation TKIs dasatinib and nilotinib [10, 11]. Although data on long-term treatment results are not yet available, 2nd generation TKIs, especially nilotinib, have been shown to be more effective than imatinib in first line therapy in attaining important endpoints as a complete cytogenetic response (CCyR), i.e. the absence of Ph+ cells in blood and bone marrow and a major molecular response (MMR), i.e. the near absence of BCR-ABL fusion mRNA transcripts (a reduction to ≤0.1% on the international scale) [12, 13]. The latter endpoint is strongly predictive for long-term event-free survival . First-line use of these TKI is therefore now recommended for intermediate and high risk patients [10, 11]. On average, an MMR is attained at least one year earlier with the 2nd generation TKIs as compared to imatinib [14, 15].
A better understanding of the various factors contributing to the efficacy of treatment is essential for the development of interventions to optimize CP-CML treatment with a TKI. In the present study nilotinib treatment with the standard dose (300 mg twice daily) of patients with CP-CML is monitored as recommended by the current Dutch treatment guideline . At present, treatment of CP-CML patients aims to achieve a lasting CCyR and MMR. However, on the basis of the more rapid onset of its effect than of imatinib , treatment with nilotinib could already result in a CCyR and MMR within 6 and 12 months after the start of treatment, respectively, instead of 12 and 18 months as stated in the guideline .
The present study aims to get more insight into the efficacy of treatment with nilotinib and the various aspects that govern optimal response, of which adherence is a primary endpoint. Adherence is primarily assessed by counting the daily intake of nilotinib capsules using a medication event monitoring system (MEMS). Patient experiences with drug use is assessed by means of a comprehensive questionnaire including topics on quality of life, side effects, attitude towards disease and medication, and the patients‘ appreciation of information received about the medication. Response to treatment is related to nilotinib trough plasma concentrations . In contrast to venous puncture as used to obtain sufficient blood to evaluate efficacy, the Dried Blood Spot (DBS) sampling method requires only a very small quantity of blood that is obtained by means of a finger prick. Particularly at early stages of treatment this convenient and simple method is an ideal means to detect suboptimal nilotinib plasma concentrations that may occur as a result of non-adherence to treatment or drug-drug interactions.
The primary objective of the RAND-study (Response and Adherence to Nilotinib in Daily practice) is to assess whether CP-CML patients who respond to treatment with nilotinib (MMR within 12 months of treatment) differ from the non-responders in terms of adherence. Secondary objective is to evaluate whether responders and non-responders to nilotinib (molecular response after 3, 6 and 12 months of treatment) differ with respect to their plasma levels of nilotinib. Furthermore, the study aims to identify possible predictors for response to nilotinib treatment among hypothesized predictors that include occurrence of side effects, adherence, nilotinib blood levels, quality of life, attitude towards disease, beliefs and attitude towards medicines, patients‘ appreciation of information received about the medication, percentage of dose adjustment and discontinuation of treatment.