Quality of Life Improvements in Patients With Chronic Myeloid Leukemia After Stopping Long-Term Therapy: Who Can Benefit the Most?

Outstanding advances have been made in the treatment of chronic myeloid leukemia (CML) over the last few decades, and patients with this disease now have a life expectancy similar to the general population (1). However, patients with CML are to remain on lifelong therapy with tyrosine kinase inhibitors (TKIs), which negatively affect various aspects of their health-related quality of life (HRQoL) (2).

Treatment-free remission (TFR) describes the condition of a patient who is clinically well, with minimal detectable or even undetectable residual disease by real-time quantitative polymerase chain reaction, and remains in that condition after discontinuation of TKIs (3). Therefore, TFR may be seen as a sort of “clinical cure,” and this is a further triumph of most recent CML research. Discontinuation may only be attempted, after several years of TKI treatment and at least 2 years of stable deep-molecular response (DMR) (BCR-ABL1 ≤ 0.01% on the International Scale), in approximately 40% of patients, but only approximately 50% of them remain in TFR; 50% undergo a molecular relapse without any clinical effect because they go back to DMR on retreatment (3).

Patients in TFR do not live longer than patients on chronic TKI therapy but may enjoy several benefits, both physical, such as freedom from TKI side effects, and psychological, such as freedom from leukemia, that could potentially translate into a better HRQoL. However, the patient in DMR who discontinues treatment must undergo more clinical and laboratory examinations and may be afraid of leukemia recurrence and become anxious, although recurrence is always controlled restarting the TKI. Some patients may also suffer of a syndrome of muscle and joint pain (withdrawal syndrome) (4). Therefore, there are many good reasons to investigate HRQoL of CML patients in TFR.

In this issue of the Journal, Schoenbeck and colleagues (5) provide robust evidence-based data on this research topic by documenting functional outcomes in a sample of 172 CML patients after stopping long-term TKI therapy (ie, 3 or more years) with imatinib, dasatinib, nilotinib, or bosutinib, from the Life After Stopping TKIs (LAST) Study (NCT02269267).

Using the well-validated Patient-Reported Outcomes Measurement Information System (PROMIS) measures and conducting thorough statistical analyses, the authors investigated key functional domains, including ability to participate in social roles and activities, social isolation, physical function, cognitive function, satisfaction with sex life, and interest in sexual activity. As summarized here in Table 1 for the purpose of this editorial, the highest percentages of patients with clinically relevant improvements were observed in the ability to participate in social roles and activities (92.0%) and in the social isolation (71.4%) scales at 12 months after treatment stop. These percentages were lower (ie, 72.1% and 19.4%, respectively) when the authors considered changes at 6 months. In any case, less than 10% of patients reported clinically meaningful improvements at 12 months in the remaining functional domains investigated, including physical function (3.6%), which is now regarded as one of the core patient-reported outcomes (PROs) to be considered in cancer clinical trials (6).

Table 1.

Percentage of chronic myeloid leukemia patients with clinically meaningful improvements in functional and symptom domains at 12 months after stopping tyrosine kinase inhibitors

PROMIS domains investigated	Patients with clinically meaningful improvements at 12 mo, %
Functional domainsa
Ability to participate in social roles and activities	92.0
Social isolation	71.4
Sexual satisfaction	9.8
Physical function	3.6
Cognitive function	0.0
Interest in sexual activity	0.0
Symptom domainsb
Diarrhea	87.5
Fatigue	80.4
Depression	34.8
Sleep disturbance	21.4
Pain interference	4.5

^aData extracted from Schoenbeck et al. (5) with regard to clinically meaningful improvements (ie, ≥3 points in the scale) observed at 12 months.

^bData extracted from Atallah et al. (7) with regard to clinically meaningful improvements (ie, ≥3 points in the scale) observed at 12 months.

To better put into context current findings (5), data from the authors’ previous report documenting patient-reported symptoms of these patients (7) should also be considered. They earlier observed (7) a substantial proportion of patients with clinically relevant improvements at 12 months for diarrhea and fatigue but a relatively modest percentage of patients with clinically relevant less depression, sleep disturbance, and pain interference (see Table 1). Taken together, these 2 reports (5,7) from the LAST Study represent 1 of the most comprehensive and detailed evidence-based sources of information currently available on HRQoL of CML patients in TFR.

Overall, despite valuable improvements with regard to social-related aspects, diarrhea, and fatigue for a substantial proportion of patients, which is of course an important achievement, modest or no improvements were observed for many patients with regard to other HRQoL aspects. Should we have expected more patients to benefit from stopping CML therapy across other key functional and symptom domains? Considering the chronic nature of TKI therapy and the fact that even low-grade adverse events may substantially affect the HRQoL of these patients, the answer is probably yes. However, results from the sparse evidence in this area indicated rather modest HRQoL improvements in patients who stopped imatinib (8) or nilotinib therapy (9). Although several explanations may account for the lack of more substantial changes in patients who discontinue therapy, some of which have been discussed by Schoenbeck and colleagues (5), a timely question is: where do we go from here?

The investigation of PROs after TKI discontinuation is a novel area of research, and several questions are yet to be answered. For example, future studies could include the assessment of patient-reported symptomatic adverse events associated with the specific toxic profile of TKIs used prediscontinuation. In this respect, the PRO-CTCAE Item library (10) may be a valuable source of information to capture most relevant symptoms for the specific CML population being studied. In addition, research efforts should now also be directed to identify the profile of patients who are most likely to obtain HRQoL improvements after treatment discontinuation. For example, can we expect greater changes in female patients or younger patients?

Already in the pivotal IRIS trial (11), which led to the approval of the first TKI used in CML (ie, imatinib), it was observed that the average of HRQoL scores of males was larger than that of females, independent of treatment effects. Subsequent studies also reported worse HRQoL outcomes in female patients compared with males in the setting of CML therapy with TKIs (12-15). Also, one of the earlier studies in CML responding patients (ie, at least in CCyR ) receiving long-term imatinib therapy found that the HRQoL profile of younger CML patients (ie, 18-59 years) was lower than that of their peers from the general population, and this was particularly evident with regard to physical health–related aspects. Conversely, the HRQoL profile of CML patients aged 60 years or older was very similar to that of their peers in the general population (15). Therefore, it would be interesting to explore in future adequately powered analyses whether younger patients (ie, <60 years old) are those who can benefit the most, in terms of HRQoL improvements, from treatment discontinuation.

In conclusion, the LAST Study Research Team should be commended for having provided the hematology community with such high-quality data on the HRQoL of CML patients in TFR, and we hope their findings will stimulate further initiatives in this important area of research.

Funding

None.

Notes

Role of the funder: Not applicable.

Disclosures: FE: Consultancy for: Abbvie, Amgen, Janssen, Takeda, and Grants from Amgen and Abbvie (to his Institution), outside the submitted work. MB: Board Membership and consultancy for Novartis, outside the submitted work.

Author contributions: Conceptualization: FE, MB. Formal analysis: FE, MB. Writing—original draft: FE, MB. Writing—reviewing and editing: FE, MB.

Data Availability

All data underlying this editorial are presented in the editorial itself or cited references.