Discussion
nausea, diarrhea, CML-CP, fatigue, cancer, CML, vomiting, Fatigue
ADVERSE EVENTS, CANCER, CML
PRO assessments were pre-specified exploratory endpoints in ASCEMBL and, as such, were not powered to demonstrate significance; therefore, interpreting changes in PRO scores over time as well as differences in mean scores between treatment arms requires consideration of clinically meaningful thresholds. The MDASI User Guide describes that several MIDs have been reported in the literature; the user guide tentatively proposes a guide for MIDs to range from 0.98 to 1.21 [ref. [In ASCEMBL, mean baseline PRO scores indicated a low impact of CML on symptoms and HRQOL, with mean MDASI-CML baseline scores of around 2 on a scale ranging from 0 to 10 (where higher scores indicate greater severity/interference). Fatigue was the most severe symptom reported at baseline; impact on work, mood, and general activity contributed most to overall symptom distress. At baseline, general HRQOL as assessed by the EQ-5D-5L VAS in this CML-CP population (72.2) was slightly better than a cancer population normative value (68 points for the United States) [During 48 weeks of treatment, symptoms of CML decreased in severity after treatment with asciminib, particularly for fatigue, which started to improve soon after treatment initiation. In contrast, patients treated with bosutinib reported an increase in severity of diarrhea, nausea, and vomiting, with the increase in diarrhea severity observed as early as week 4 and reaching a clinically meaningful threshold overall. These findings are consistent with the 24-week analysis of HRQOL from ASCEMBL [Although LS mean changes from baseline were small and improvements did not meet the clinically meaningful threshold for most items, there is a trend for more improvement in all MDASI-CML symptom and interference items and EQ-5D-5L VAS after treatment with asciminib relative to bosutinib. A larger proportion of patients treated with asciminib compared to bosutinib reported improvement on the PGIC-CML after 48 weeks of treatment. This trend for more improvement in PRO scores for patients treated with asciminib compared to bosutinib is consistent with the 48-week clinical data previously presented, which support better safety and tolerability of asciminib, likely due to its specific mechanism of action. In particular, rates of adverse events leading to discontinuation at week 48 were < 1/3 of those in patients treated with asciminib (7.1%) compared to bosutinib (25.0%) [ref. [By week 48, the number of patients in the bosutinib arm who were ongoing and expected to complete PRO assessments had dropped to 22, and this small sample size limits our interpretation of treatment comparison data between the two arms. Furthermore, the small proportion of patients who were employed at baseline (asciminib: 46%; bosutinib: 36%) limits our interpretation of the impact of treatment on work productivity, with only 27 and 8 employed patients on asciminib and bosutinib, respectively, responding to WPAI items at week 48. As a result, no clear differences between treatment arms were observed in impact on work as assessed by the WPAI-CML.In a targeted literature review conducted in 2022, a survey of CML patients on TKIs who completed the MDASI-CML reported that the most commonly prevailing symptom was fatigue (reported by 72.4% of patients) [