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Division of Hematology/Oncology
University of California, San Francisco
San Francisco, California
Neil P. Shah, MD, PhD, has disclosed that he has received funds for research support from Bristol-Myers Squibb.
Adherence to therapy is one of the most challenging topics to discuss with patients with chronic myeloid leukemia (CML) and their caregivers, especially as individuals are often prescribed additional drugs to treat other conditions. In this commentary, I discuss the issues with staying adherent to BCR-ABL1 inhibitor therapy for patients with CML. I also discuss why adherence is so important in patients on lifelong therapies and how the entire care team, plus the caregivers, can be involved in helping them stay adherent to their therapy.
Importance of Adherence to BCR-ABL1 Inhibitor Therapy for CML
In recent years, BCR-ABL1–targeted therapies have transformed patient outcomes in chronic-phase CML from a disease with a typical life expectancy of 5-7 years to a chronically managed condition in more than 90% of cases. Adherence is an important cornerstone in CML treatment because no drug is effective if the patient does not take it. In my experience, adherence is typically not an issue immediately following the initial diagnosis because there is a substantial amount of fear and shock about the cancer diagnosis. Patients are therefore very motivated to take their prescribed treatment. Issues with adherence tend to arise later, once patients realize that they are responding well and likely to do well, and some of that initial fear disappears. Patients can become less vigilant and miss doses here and there, or sometimes more often. I have seen several tragic cases over the years where patients, for one reason or another, stop taking their medication and stop returning for follow-up, only to return a few years later with symptomatic recurrent disease or evidence of disease progression requiring bone marrow transplantation in some cases. At every clinic visit, it is important that healthcare professionals stress the importance of treatment adherence.
Reasons for Nonadherence
Early in the management of treatment for patients with CML, it is important to inform them that treatment choices for frontline therapy vary in their dosing schedules and recommendations. For instance, nilotinib, which is taken twice per day, must be taken on an empty stomach; asciminib also requires fasting 2 hours before and 1 hour after each dose, although it can be administered either once or twice daily. Convenience of administration can be an important factor in treatment adherence, and certainly, more complicated dosing regimens can lead to long-term difficulties with adherence. It is always important to discuss adherence considerations and involve the patients in the therapy choice whenever possible. If patients feel empowered and involved in their healthcare decisions and in choosing their treatment options, they are more likely to adhere to their regimen over the long term.
At least 75% of patients with CML will require lifelong BCR-ABL1 treatment, which means that over time most patients will suffer some treatment-related adverse events (AEs). Typically, these are grade 1 or grade 2 AEs. That said, the thought of living with mild or moderate nausea, for example, every day of their lives is not very appealing for patients, and lower grade toxicities can substantially affect quality of life. Therefore, healthcare professionals should keep quality of life foremost in mind when thinking about patients who have met their treatment milestones because, in such instances, the critical need changes from control of disease to maximizing long-term survival while maximizing quality of life. Moreover, AEs are a main barrier to good adherence, and it is true that many patients will feel worse on BCR-ABL1 therapy than they felt with unmanaged disease at diagnosis. It is critical to remind patients that, to some degree, managing their disease should be thought of as riding a tiger: One cannot get off that tiger for very long and feel safe. Finding an acceptable balance between disease control and AEs can frequently be accomplished through dose reductions to improve quality of life.
It is important to note that it can be difficult to determine if a particular AE is due to CML treatment. I typically encourage patients to take a short treatment break of 2-3 weeks and track the extent to which the concerning symptoms change. I encourage patients to use a scoring system of 1 to 10 to track and rate their symptoms daily during that period. If important issues like fatigue have not substantially changed, they may be due to causes other than BCR-ABL1 treatment. By contrast, if the symptoms improve substantially, I consider either dose reduction or an alternate BCR-ABL1 therapy. Healthcare professionals can use a pocket guide and decision support tool associated with this program on the CCO website to help them assess dose reductions and potential BCR-ABL1 options to manage their patients with CML.
Cost of treatment also can affect treatment adherence. Although generic imatinib is now available, financial concerns can impede a patient’s access to second-generation or third-generation BCR-ABL1 therapies. Notwithstanding, there are financial assistance programs and grants that can help patients gain access to therapies for management of their disease. Another issue is that some patients are reluctant to take medication even after being educated on the importance of remaining adherent to their treatment. I have had some patients state that they take no more than 5 or 6 of their prescribed doses every month. In these cases, it is important for healthcare professionals to inquire about the patient’s support network and to discuss what can be done to improve adherence. Some patients with CML simply do not like the idea of having to take a pill every day for the rest of their lives.
Patient Communication Around Barriers to Adherence
Although I always do my best to ask about symptoms and adherence at every appointment, some patients will be less than forthcoming about this issue. Some may feel the physician is too busy and do not want to bother him or her with specific concerns, or some may choose to tell their physician what they believe the physician wants to hear. Sometimes, a patient’s caregivers may speak up and let you know the patient is very depressed or experiencing a lot of fatigue. Also, patients sometimes feel more comfortable discussing how they are feeling with support staff. For instance, a practice nurse may be the first to hear about AEs or to learn that the patient has not called to refill their medication when expected. Likewise, pharmacists frequently speak to patients about AEs and other concerns, particularly regarding drug–drug interactions. Hearing all of these voices enables me to recognize barriers to adherence and to promptly intervene in any way that I can to improve patient outcomes.
Patient Case Example: Treatment Discontinuation due to AEs
A 76-year-old patient received imatinib for 6 months with optimal disease control but had to stop treatment because of dyspnea associated with lung fibrosis. The patient received corticosteroids, which improved dyspnea. The patient started bosutinib 2 months later, but he again experienced worsening dyspnea and elevated liver enzymes months later. On a follow-up CT scan, lung fibrosis had worsened. Since bosutinib discontinuation, he has received no treatment for CML and his BCR-ABL1 level at 12 months is now 1%.
Expert comments regarding this patient:
Interstitial lung disease has been encountered with imatinib, and it occasionally can worsen upon treatment with an alternative BCR-ABL1 inhibitor therapy. Many other BCR-ABL1 inhibitors are available in this case, including nilotinib, dasatinib, ponatinib and asciminib. Although omacetaxine is also an option, rates of response with this agent are low and responses are not highly durable. Because this patient currently has reasonably well-controlled CML, a reduced dose of BCR-ABL1 inhibitor could be considered (eg, dasatinib 20-50 mg, nilotinib 150 mg BID, ponatinib 15 mg daily, asciminib 40 mg daily) with dose escalation as tolerated and as necessary based on molecular monitoring.
What challenges have you encountered in keeping patients with CML adherent to BCR-ABL1 inhibitor therapy? I encourage you to answer the polling question and join the conversation in the discussion box below.