Trial Information

The Effect of Active Adherence-Encouraging Interventions on Adherence to Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia - A Prospective Observational Multicenter Study (TAKE-IT)

The cytogenetic hallmark of chronic myeloid leukemia (CML) is the reciprocal translocation
between chromosomes 9 and 22 creating the Philadelphia (Ph(1)) chromosome. The BCRABL1
fusion gene is the result of this translocation and encodes for a constitutively active
tyrosine kinase responsible for the development of CML. Tyrosine kinase inhibitors (TKIs)
targeting the protein product of this aberrant gene, the BCRABL-1 protein, have
revolutionized the therapeutic approach to chronic myeloid leukemia (CML). Treatment with
the first FDA approved TKI, imatinib mesylate (Gleevec, Novartis), in chronic phase CML
results in a projected 8 year overall survival of 85%. Recently, two second generation TKIs,
Dasatinib and Nilotinib, have been approved for use in newly diagnosed chronic phase CML, as
a result of studies showing improved molecular and cytogenetic outcomes. Importantly, in
each of the above studies there was a substantial number of dropouts due to drug intolerance
and resistance, among other reasons. In a prospective observational study of 169 CML
patients, only 14% of patients were fully adherent with prescribed imatinib. Moreover, one
third of patients were considered to be non-adherent, which is similar to the proportion of
dropouts in the landmark studies on TKIs in CML. Thus, it is clear that there is a subgroup
of patients who do not properly adhere to treatment. This is especially significant because
the contemporary approach to CML in complete cytogenetic remission (CCyR) and major
molecular remission (MMR) necessitates long-term, chronic treatment with TKIs.

Therefore, although hematologists have the luxury of an armamentarium of highly effective
drugs, one of the most challenging aspects of treating CML is the management of
non-compliance to TKI treatment. TKI-induced adverse effects are only one of a wide spectrum
of reasons for non-adherence to TKI treatment.

Recently several studies have demonstrated the prognostic importance of adhering to imatinib
treatment. In a pivotal study of 87 chronic phase CML (CP-CML) patients in CCyR, an
adherence rate of > 90% strongly correlated with the 6 year probability of achieving MMR
(94.5% vs. 28.4% when adherence rates were ≤ 90%). Non-adherence to imatinib treatment also
adversely affects event free survival and is associated with loss of CCyR in patients on
long term treatment. These data support the intuitive concept that CML can be effectively
treated with the drugs currently available, as long as patients adhere to treatment.
Moreover, non-adherence to imatinib treatment has been associated with increased economic
burden and healthcare costs. Consequently, TKI adherence is an attractive potential target
for intervention.

Non-adherence to medication is an intricate problem that is influenced by the physician, the
healthcare system, and economic and social factors. Other medical disciplines have assessed
various modes of improving adherence to therapeutic regimens, with varying success. A recent
study assessing adherence-related behavior among CML patients, demonstrated that among a
multitude of reasons for non-adherence, patient forgetfulness and drug side effects were the
most common causes of unintentional and intentional non-adherence, respectively. Several
methods of improving adherence among patients with CML were retrospectively assessed by Moon
et al. Subjects in the intervention arm were more likely to receive prescriptions for
imatinib than those receiving standard care (98.2 ± 0.03% vs. 79.3 ± 0.16%). Although there
was no difference in adherence to prescribed treatment between the two groups, the overall
compliance, a composite endpoint of the above two outcomes, was markedly improved in the
intervention group ((93.0 ± 2.3% vs. 76.2 ± 7.4%, P = 0.001). Recently, Gater et al
conceived a conceptual model aimed at improving adherence in CML patients treated with 1st
and 2nd generation TKIs, based on a systematic review of the literature. However, there are
currently no prospective data evaluating whether adherence in CML can be influenced by
active intervention.

Study Hypothesis:

Adherence to tyrosine kinase inhibitors (TKIs) is associated with improved outcomes in
chronic myeloid leukemia (CML) patients. Hence, improved adherence might improve CML
patients' prognosis.

The investigators hypothesize that adherence-encouraging interventions improve adherence to
TKIs in CML patients.

Study Objective:

1. Primary Objective: By means of a prospective before-after study, the investigators aim
to assess whether specific adherence-encouraging interventions improve TKI adherence in
patients with CP-CML treated by these agents. The investigators will target previously
documented reasons for non-adherence 11 with interventions that were selected based on
prior experience in other medical disciplines and will evaluate their contribution to
patients' adherence to treatment.

2. To better understand non-adherence in CML and pinpoint independent risk factors for
non-adherence

3. To validate questionnaires assessing adherence, and evaluate whether they could be of
use in indentifying patients at risk for non-adherence

4. To compare adherence to second generation TKIs with adherence to imatinib

5. To assess the role of a clinical pharmacist in preventing potential drug interactions

6. To determine whether the intervention has a long term effect on adherence during one
year of post-intervention follow up

7. To estimate long term effects of adherence on clinical, cytogenetic and molecular
outcomes