What is the importance of adherence to Tyrosine Kinase Inhibitors (TKIs) in Chronic Myeloid Leukemia (CML) management?

Adherence as a Critical Prognostic Factor in CML Management

Poor adherence to tyrosine kinase inhibitor (TKI) therapy is the most important factor contributing to cytogenetic relapse and treatment failure in chronic myeloid leukemia (CML) patients. 1

Impact of Adherence on Clinical Outcomes

Adherence to TKI therapy directly impacts survival and treatment response in CML:

• Survival impact: Patients with low medication possession ratio (MPR <0.68) have 11.6 times higher mortality risk compared to highly adherent patients, while those with moderate adherence (MPR 0.68-0.95) have a 4.9 times higher mortality risk 2

• Cytogenetic response: Poor adherence (≤85%) increases the probability of losing complete cytogenetic response (CCyR) at 2 years to 27% compared to just 2% in patients with adherence >85% 1

• Molecular response: Adherence to TKI therapy has been identified as the only independent predictor for achieving complete molecular response on standard-dose imatinib 1

• Disease progression: Consistent TKI use is associated with significantly lower rates of disease progression to accelerated or blast phase 3

Factors Associated with Non-Adherence

Several factors predict poor adherence to TKI therapy:

• Demographic factors:

  • Age (both younger patients and those >70 years) 2, 4
  • Female sex 4
  • Lower educational level 5
  • Lower income status 2, 6
  • Employment status 5

• Treatment-related factors:

  • Type of TKI (adherence to dasatinib was lowest compared to imatinib or nilotinib) 2
  • Higher starting dose 4
  • Greater monthly financial burden 4
  • Longer duration from diagnosis to treatment initiation 4
  • Treatment-related side effects, particularly gastrointestinal 1

• Healthcare system factors:

  • Suboptimal molecular monitoring 6
  • Lower socioeconomic status of residential area 6

Monitoring Adherence

Regular monitoring is essential to identify and address non-adherence early:

• Molecular monitoring: Frequent molecular monitoring with qPCR (IS) every 3 months is recommended for all patients after initiating TKI therapy 1

• Early identification: Unexplained fluctuations in BCR-ABL1 levels may indicate non-adherence and should prompt discussion 1

• Plasma level testing: Monitoring imatinib plasma levels may be useful in determining patient adherence, though not widely available 1

• Optimal monitoring frequency: After CCyR has been achieved, molecular monitoring is recommended every 3 months for 2 years and every 3-6 months thereafter 1

Strategies to Improve Adherence

To optimize outcomes in CML patients:

• Patient education: Thoroughly explain the benefits of regular use and risks of non-adherence at diagnosis and reinforce during follow-up visits 1

• Side effect management: Adequate and appropriate management of side effects can improve adherence 1

  • Short interruptions or dose reductions when medically necessary may not negatively impact disease control 1

• Regular follow-up: Schedule appropriate follow-up visits to review side effects and adherence 1

• Targeted interventions: Implement personalized monitoring and intervention strategies for individuals identified as likely to be non-adherent based on risk factors 4

• Medication level monitoring: Consider plasma level measurement as an objective compliance assessment tool 1

Common Pitfalls and Caveats

• Underestimation of impact: Physicians often underestimate the severity of non-adherence and its impact on treatment outcomes 1

• Changing adherence patterns: Adherence is not static - patients may follow different trajectories (never adherent, initially non-adherent becoming adherent, initially adherent becoming non-adherent, or stable adherent) 4

• Comorbidities and polypharmacy: Patients with fewer comorbidities and fewer concomitant medications may paradoxically be at higher risk for non-adherence 4

• Monitoring gaps: Older patients (≥66 years) often receive suboptimal molecular monitoring, which is associated with decreased TKI adherence and worse survival 6

• Drug interactions: Interactions between TKIs and commonly used drugs may affect plasma levels and efficacy, potentially impacting adherence due to side effects 1

In conclusion, adherence to TKI therapy is the cornerstone of successful CML management, with direct impact on molecular response, cytogenetic stability, disease progression, and overall survival. Regular monitoring and targeted interventions to improve adherence should be integral components of CML care.