Targeted Literature Review of Patient Reported Outcomes (PROs) in Chronic Myeloid Leukemia (CML) Patients Receiving Second and Later Lines of Treatment

Background: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic CML in the last several years; however, the failure rates associated with TKIs still remain high in second line (50%) and later lines (75%-80%) treatment. Also, patients often experience adverse events associated with these TKIs, but are often left with no alternative treatment in real world practice which might result in TKI cycling. There is a need to understand the quality of life (QoL) and symptom burden among these patients, in order to better manage their disease and also to explore new treatments. The objectives of this study were to summarize the PROs among patients with CML receiving 2^nd/3^rd/4^th line (2L/3L/4L) treatment, and the instruments used for QoL and symptom burden assessment in clinical trials and real world studies.

Methods: Embase, MEDLINE, and the Cochrane Library were searched using pre-defined search terms to identify studies published from 1/1/2010 to 6/15/2020. Following the title/abstract and full-text screening based on the inclusion/exclusion criteria (see Table), one reviewer independently extracted all relevant data with random quality check (~20% of the sample) by a 2^nd reviewer. Included studies reported QoL, symptom burden, or any PROs of adult CML patients who received 2L/3L/4L treatment. Only clinical trials and observational studies published in English were included, including conference abstracts.

Results: Database search identified 1,377 records, which were screened to identify 20 studies (5 observational studies and 15 clinical trial-based studies) that met eligibility criteria (see Figure). Of the included studies, 16 targeted chronic phase CML patients only. More than half of the studies (n=14) focused on patients receiving 2L treatment (bosutinib, dasatinib, or nilotinib) only, and six reported QoL data on patients receiving 2L/3L/4L treatment, out of which four studies reported results by line of therapy. Out of 15 studies reporting a follow-up period, 13 observed patients ≥ 12 months with a maximum of 24 months. The duration between observations were usually 12 weeks for observational studies; while shorter duration was observed in clinical trials. Six clinical trial-based studies were associated with one trial (NCT00261846).

Instruments used to assess QoL included four generic instruments [Functional Assessment of Cancer Therapy - General (FACT-G), EuroQol 5 dimension (EQ-5D), 36-Item Short Form Survey (SF-36), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)], three disease specific instruments [Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu), MD Anderson Symptom Inventory chronic myeloid leukemia (MDASI-CML), Comprehensive Symptom Profile in Chronic Myeloid Leukemia Patients (CSP Leuk-CML)], one Work Productivity and Activity Impairment (WPAI) questionnaire, and two additional general questions on QoL. Ten studies applied both generic and disease specific instruments altogether to evaluate patients' QoL and symptom burden.

For 2L TKI treatment, studies have shown improvement in QoL following treatment; however, one study indicated that although patients were content with their QoL, they reported poor symptom scores on mobility, usual activities, and pain/discomfort. Among four studies examining PROs by line of therapy, only one study reported results on the 4L cohort individually, which showed lowest baseline FACT-G and FACT-Leu score in the 4L cohort compared to other cohorts, especially in terms of the physical and emotional well-being domain. Discrepancies existed in QoL between 2L- and 3L cohorts. Two studies found QoL to be similar between the 2L- and 3L cohorts, while the other two observed the QoL was lower in the 3L cohorts. In addition, three reported that QoL scores remained stable throughout observation period regardless of the line of therapy, but one study demonstrated the utility score got improved in the 2L but not the 3L cohort.

Conclusions: Evidence on PROs in CML patients receiving 3L/4L treatment is very limited, especially real-world data. Existing research indicates patients with CML receiving later lines of treatment may have poor quality of life. Robust real-world studies with longer follow-up period are needed to provide evidence on later lines treatment management among CML patients.

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