Health-Related Quality of Life of CML Patients Under 2nd or 3rd Line Bosutinib Is Not Impaired Significantly By Gastrointestinal Toxicity (GI Tox) but Influenced By Sex - Results from a Subanalysis of the Bosutinib Dose Optimization (BODO) Study (CML-VII) Trial of the German CML Study Group

Introduction: Patient-reported outcome measures (PROMs) are an important tool to assess the impact of disease and their treatments on daily living and thereby on Health-related quality of life (HrQoL). Impact of side effects and gender-specific differences have been partly been addressed in Chronic myeloid leukemia (CML) in the past. The "Bosutinib Dose Optimization (BODO) Study" is a multicenter, open-label single arm phase II study testing tolerability and efficacy of 2nd&3rd line bosutinib step-in dosing (i.e. starting with 300 mg QD) in chronic phase CML patients (pts) intolerant and/or refractory to previous imatinib, and/or nilotinib, and/or dasatinib therapy with the ultimate goal to decrease GI toxicity rates. PROMs were assessed via the EORTC-QLQ-C30 and EORTC-CML24 questionnaires to correlate HrQoL changes with the rate and severity of GI toxicity and gender.

Methods: The BODO Study (NCT02577926) had to be terminated prematurely after 57 of 127 projected pts due to delayed recruitment but included detailed analysis of PROMs reported here. Summary statistics of the HrQoL questionnaires were calculated at baseline (BL), month 3, and month 6. Depending on the observed distribution of differences of a score (component), comparisons between groups (e.g., males vs. females) were performed using methods based on the normal distribution assumption (t test) or a non-parametric test (Mann-Whitney U test or Wilcoxon signed rank test).

Results: 57 pts with a median age of 51 years (median duration of pretreatment: 19.8 months) were included in the BODO trial. Even though 74%, 53% and 26% of pts suffered from any grade of GI-toxicity (e.g., diarrhea, nausea and vomiting) during the study, GI toxicity triggered treatment discontinuation in only one patient. Median duration of GI toxicity was 15 days (range: 1-1281) and was self-limiting in most pts. Median time to first onset of diarrhea was 23 days, and the median duration of any grade diarrhea was 14 days (range: 1-960). HrQoL-results were available for 51, 44 and 35 pts at baseline, end of month 3 and end of months 6 visits, respectively (for median scores over time see figure 1A-C). PROM results were analyzed according to occurrence of GI toxicity: The only symptom reported to be aggravated in the 15 pts without vs. the 42 with diarrhea during the first 6 months was the insomnia symptom scale (52 vs. 23, p=0.02). Nausea and vomiting did not significantly impact symptom burden. As most of the AEs have an early onset, the 3 month visit was assessed. Again, no significant differences in HrQoL could be detected between pts with or without GI toxicity at 3 months.

At baseline, women seemed to be more affected by necessity of treatment change than males: there were statistically significant differences in physical (87 vs. 72, p=0.0055) and role functioning (82 vs. 60, p=0.0043). Higher functional scores were reported in male pts. Regarding symptoms, statistically significant differences were found for fatigue (31 vs. 51, p=0.01) and insomnia (24 vs. 42, p=0.04). Female pts reported higher symptom burden. In addition, the impact on daily life was found to be lower in male pts than in females (24 vs. 34, p=0.04). At 3 months, emotional (79 vs. 57, p=0.003) and cognitive functioning (88 vs. 68, p=0.008), insomnia (17 vs. 39, p<0.05) and symptom burden (19 vs. 26, p=0.03) differed. Male pts reported higher functional scores and lower symptom burden than female pts. At 6 months, male pts reported statistically significantly higher scores in emotional functioning (75 vs. 56, p=0.04) than female pts. Regarding the CML-24 questionnaire, symptom burden showed a statistically significant increase from BL to month 6 (25 vs. 26, p=0.02) with no statistically significant difference in any scale between month 3 and 6.

Conclusion: Although the analysis is limited by relatively small number of pts in the respective subgroups and by the pre-selected time points of PROM assessment, the data suggests that HrQoL from pts with chronic phase CML treated with bosutinib within the BODO trial is not significantly impaired by the presence of GI toxicity and that there are significant differences in HrQoL and symptom burden between male and female pts which should be addressed in future trials.

Isfort:Hexal: Other: e.g. travel support; Roche: Other: e.g. travel support; Mundipharma: Other: e.g. travel support; Alexion: Other: e.g. travel support; BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support. Wolf:BMS/Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; MSD: Honoraria, Research Funding; GEMOAB: Honoraria. Teichmann:Boehringer-Ingelheim: Honoraria; BMS: Consultancy, Honoraria; Astellas: Consultancy; AOP: Honoraria; Sobi: Consultancy, Honoraria; Pfizer: Consultancy; BeiGene: Other; Gilead: Other: n. Crysandt:Pfizer: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria. Burchert:Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AOP Health: Honoraria, Research Funding. Hochhaus:Incyte: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Saussele:Incyte: Honoraria, Research Funding; Roche: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Kiani:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Göthert:Proteros Biostructures: Honoraria; zr pharma&: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Membership on an entity's Board of Directors or advisory committees; Imago Bioscience: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees. Schafhausen:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Merck Serono: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; AOP Orphan: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: e.g. travel support. Brummendorf:Pfizer Inc: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodation, Expenses; Merck: Consultancy, Other: Travel, Accommodation, Expenses.

Bosutinib - approved in Europe as second or later line drug only if imatinib, nilotinib or dasatinib are not applicable. In the study it was used as second or third line therapy regardless of treatment alternatives.