Health-related quality of life outcomes in chronic myeloid leukemia patients treated with second generation tyrosine kinase inhibitors: do we know enough?

The introduction of tyrosine kinase inhibitors (TKIs) as frontline treatment for chronic myeloid leukemia (CML) has drastically changed the natural history of this disease. But since TKIs have to be continued lifelong, they have the potential to impact quality of life (QoL) in the long term. At baseline, it is now of paramount importance to consider, as potential criteria for selection, the social and psychological aspects of treatment in order to individualize a more patient-centered approach, one that will optimize treatment outcomes.

In the pivotal IRIS study, imatinib (i.e. the first targeted drug used in this population), was shown to improve health-related quality of life (HRQoL) compared to previous available therapies, such as interferon or chemotherapy¹. In the ILTE study², patients were asked to report if imatinib administered in the long term interfered with HRQoL: 52% of patients answered that the drug influenced HRQoL because of the persistence of long-term mild adverse events. In the era of TKIs, the definition of intolerance to imatinib has changed considerably: not only is there the usual occurrences of adverse events that force a patient to discontinue the drug, but there are also persistent, low-grade adverse events that allow a patient to continue therapy that may adversely impact daily activities and HRQoL³.

In a large study, that for the first time evaluated symptoms reported by patients in complete cytogenetic response (CCyR) with imatinib treated for a median time of 5 years, the symptom of fatigue was the most common side effect reported by 82% of patients. Also, one third of patients reported this symptom as moderate to severe despite the long time elapsed since diagnosis (median time of 5 years). Female patients were more prone to report side effects related to the drug, such as edema, fatigue and musculoskeletal pain. The sex effect was independent of age, education, duration of therapy, dose of imatinib and comorbidities⁴.

However, little is known about the effects of the so-called “second generation” TKIs on patients’ HRQoL^5–13: the majority of studies were conducted using different patient-reported outcome measures and addressing different research questions. For example, a cross-sectional study involving 62 patients, of whom 19 were treated with nilotinib and 9 with dasatinib, showed that, compared to healthy controls, CML patients reported significantly worse fatigue, depression, symptom burden and physical impairment⁶. Another study enrolled 303 patients, 16% treated with nilotinib and 12.5% with dasatinib: patients treated with the first drug reported missing doses more often. Treatment satisfaction was associated with improved significant HRQoL and reduced activity impairment, whereas negative medication experiences were associated with decreased HRQoL⁷.

For nilotinib as first line treatment, data stemming from the ENESTnd trial were recently presented in this journal. Adverse events were categorized into five broad categories (gastrointestinal, blood and lymphatic, general disorders, musculoskeletal, and psychiatric) and the incidence was lower for nilotinib compared to imatinib, but significantly impaired, even at low grade, QoL scores⁸. Kekale and colleagues reported the effects of adverse related events on medication adherence and perceived HRQoL in 86 patients treated with TKIs, of whom, 10.5% both with dasatinib and nilotinib, after a median time from diagnosis of 5.1 years. No relationships were found between adverse events and adherence, but there was a negative influence on daily HRQoL, in particular affecting mood, general conditions and enjoyment of life⁹. More recently, in a prospective study including 53 patients treated first line with nilotinib, Lutge and colleagues¹⁰ showed that the HRQoL of CML patients increased over time with the exception of cognitive functioning. However, the differences were not statistically significant and the authors attributed this to possibly the small sample size.

HRQoL was also evaluated in the Spirit2 trial that tested dasatinib frontline vs. imatinib: several questionnaires were used including the EQ-5D and the FACT-BRM. Broadly, no HRQoL differences were found between the two arms; however, very few details were reported on the number of patients analyzed and the type of analysis performed making it difficult, at the present time, to understand the solidity of this data¹¹.

HRQoL was also measured in patients treated with bosutinib after resistance (200 patients) or intolerance (88 patients) to imatinib. During treatment with bosutinib, the scale scores remained higher: at week 12 of treatment, significant improvement was observed in imatinib-resistant patients in physical well-being, emotional well-being, leukemia-specific subscale, FACT-leukemia total and FACT-TOI. In contrast, changes for imatinib-intolerant patients were not statistically significant at week 12, but started to be significant at week 24. At week 48, in both categories of patients, scores remained higher, suggesting improvement in HRQoL¹².

We read with interest the study reported by Whiteley et al. indicating HRQoL changes in advanced CML patients who were treated with bosutinib after imatinib failure. This study adds to the scarce data on the impact of newer TKIs on CML patients’ HRQoL. Even if the cohorts of patients were small, the study, first of its kind, indicated an improvement from baseline to week 24 in accelerated phase patients and from week 4 in blastic phase patients¹³.

Despite the availability of five TKIs, data reporting and HRQoL evaluation for all inhibitors tested in the first or second line are scarce. Most of the time, HRQoL was reported to be associated with randomized or sponsored clinical trials, therefore with highly selected entry criteria¹⁴. Moreover, several different tools were used in different trials and some of this evidence is also preliminary. Also, only a few studies assessed HRQoL in a “real-life” setting, examining and differentiating different subsets of CML patients, such as frontline treatment, second line, resistant or intolerant and advanced phase. With the availability of several drugs as front line and as a possible second line, we move towards a patient-centered approach: in this light, documenting HRQoL from a patient perspective is needed to evaluate overall treatment efficacy and tolerability. Therefore, there is need of additional research to better understand the impact of newer TKIs on the HRQoL of CML patients as it is expected that a growing number of patients will be treated with second or even third generation of TKIs in the near future. Patient reported outcomes (PROs) and evaluation of specific questionnaires created for CML patients (MDASI-CML and EORTC-CML24) should be suggested from baseline to clearly define the benefits of these drugs and to optimize treatment in case of impaired tolerance.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

F.E. has disclosed that he is a consultant to Bristol-Myers Squibb and Seattle Genetics; and has received research funding from Bristol-Myers Squibb and Lundbeck. M.B. has disclosed that he has relevant financial relationships with Novartis and Bristol-Myers Squibb.

The CMRO peer reviewer on this manuscript has no relevant financial or other relationships to disclose.