The mean scores of PCS and MCS were 47.1 (±8.5) and 50.2 (±10.4). After adjusting for age, chest distress and shortness of breath (−2.4, P < .001 and −2.1, P = < .001) and loss of appetite (−1.6, P = .005 and −2.8, P < .001) were significantly associated with both lower PCS and MCS scores in multivariate analyses. In addition, fatigue (−2.6, P < .001), musculoskeletal pain (−1.7, P = .001), dizziness (−1.7, P = .002), and abdominal pain (−1.7, P = .007) were significantly associated with lower PCS score; anxiety-depression (−7.2, P < .001), lower MCS score (Table 4).
We interrogated prevalence and severity of patient-reported symptoms in patients with CML-CP receiving TKI-therapy. A total of 97% of the respondents reported ≥1 symptom(s) they were experiencing. The top 10 common TKI-related symptoms in our study were fatigue, periorbital or/and lower limb edema, chest distress or/and shortness of breath, memory deterioration, skin color change, alopecia, muscle cramp, weight gain, and musculoskeletal pain. Several demographic, social, and clinical variables were significantly associated with patient-reported symptoms. Female sex, foreign generic TKIs, and therapy duration 1 to 3 years were significantly associated with more frequent and more severe symptoms. Second-generation TKIs and achieving a CCyR but not a CMR correlated with less frequent and milder symptoms.
Patient-reported symptoms in our study were more common than those reported in several clinical trials.[15,18–20,22,23,27] It may due to symptoms reported by patients not assessed by physicians. We suspected some symptoms were not caused by the TKI-therapy but they were the current status of patients’ health conditions that came directly from patients, without interpretation by physicians. Efficace et al reported that patients with CML on imatinib therapy concerned more about their symptoms than physicians. Zulbaran-Rojas et al reported that nearly 90% patients on TKI-therapy experienced persistent mild symptoms by 24 months in a prospective study, which was consistent with our findings.
We found that 50% of female respondents ≤50 years reported menstrual disorder including amenorrhea, hypermenorrhea, or hypomenorrhea; hypomenorrhea was significantly associated with foreign generic TKIs; and amenorrhea was associated with age 40-50 years. These data indicate about half of females of reproductive age with CML-CP receiving TKI-therapy have menstrual disorders which were rarely reported in other studies. ABL, KIT, and platelet-derived growth factor receptor are expressed in mammalian ovaries and are important in growth and development of oocytes and follicles. Inhibition of these kinases by TKIs may cause the menstrual abnormalities and accelerate occurrence of amenorrhea in the females. In addition, the possible effects of TKIs on the menstrual bleeding (especially menorrhagia) in our study were not only the endocrinological side-effects, but also the impact of TKI on the platelet function. Because CML is diagnosed at an earlier age in Asians compared with European.[30–35] TKI-related menstrual disorders may be a greater issue in Asian female subjects than elsewhere. Also, nearly 30% of respondents reported decreased sexual desire which may lower quality of life in persons otherwise sexually active. Awareness of these potential TKI-related adverse events should help hematologists counsel patients before starting TKI-therapy.
Respondents with higher education level reported more common and more severe skin color during TKI therapy which may negatively impact their social life and daily work. This is consistent with our previous findings that higher education level was associated with more concern on TKI-therapy related issues.
We found respondents receiving Chinese generic TKIs had a similar prevalence and severity of symptoms to those receiving branded TKIs except for some symptoms such as musculoskeletal pain, anxiety-depression, and loss of appetite. However, subjects receiving foreign generic TKIs reported more frequent and more severe symptoms compared with branded TKIs. This may be the result of poor adherence and worse management. Our previous study showed use of generic TKIs was associated with less frequent molecular monitoring.
Respondents who achieved a CMR reported more frequent and more severe symptoms than those achieving only a CCyR. One interpretation of these data is once a patient achieves a CMR their attention shifts from therapy-response issues to quality of life issues. There are several implications of these data. A controversial one is CCyR and not CMR should be the target of TKI-therapy. This is based not only on more frequent reports of similar survival in persons achieving a CCyR and CMR. Another implication is that this increased symptom burden in persons with CMR may motivate physicians and patients to attempt stopping TKI-therapy.[31,37,38]
The most common patient-reported symptoms and variables correlate in our study are similar to previous reports such as fatigue was the most common symptom [21,39], female sex was associated with more frequent and more severe symptoms, and longer therapy duration and 2nd generation TKIs were associated with less frequent and milder symptoms.[15,24,40,41]
Our study has several limitations. It is impossible to know whether patient-reported symptoms associated with TKI therapy are caused by the TKI, other drugs, or other conditions, physical or psychological, or both. This can only be known with certainty in a randomized double-blind placebo controlled trial. Although the respondents were asked to report the symptoms they were experiencing, those they experienced when they received previous TKI-therapy cannot be excluded. Symptom severity was scored by respondents on a 4-point ordinal scale. Consequently, scoring was subjective and reproducibility untested. However, respondents’ perceptions of severity are a valid variable regardless of whether they are quantifiable on an objective scale. Because the survey was available on website, some respondents were self-selected. Typically, these patients are computer competent and pro-active in seeking information and resources. However, we found no substantial difference in results when these subjects were excluded in sensitivity analyses or when we compared responses in subjects completing the questionnaire in hard copy or online. It was also impossible to confirm respondents’ age, residence, diagnosis, and therapy or response state of subjects responding online. Because printed questionnaires were distributed at education meetings in large- and middle-size cities and provinces and at Peking University People's Hospital, there could be a selection bias toward respondents with an urban household registration. Response to TKI therapy was queried from respondents but not verified in the medical record. Finally, the associations and correlations we report should not be construed to imply cause-and-effect.
Our data indicate demographic and social variables, type of TKI-therapy, therapy duration, and depth of response are significantly associated with patient-reported symptoms in persons with CML-CP. Certain symptoms have adverse impact on HRQoL. This may help hematologists improve HRQoL of their patients and possibly TKI therapy outcomes.
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