Real-world efficacy and safety outcomes of imatinib treatment in patients with chronic myeloid leukemia: An Australian experience

Abstract

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of chronic myeloid leukemia (CML), but patients still experience treatment-limiting toxicities or therapeutic failure. To investigate the real-world use and outcomes of imatinib in patients with CML in Australia, a retrospective cohort study of patients with CML commencing imatinib (2001-2018) was conducted across two sites. Prescribing patterns, tolerability outcomes, and survival and molecular response were evaluated. 86 patients received 89 imatinib treatments. Dose modifications were frequently observed (12-month rate of 58%). At last follow-up, 62 patients (5-year rate of 55%) had permanently discontinued imatinib treatment, of which 44 switched to another TKI (5-year rate of 46%). Within 3 months of starting imatinib, 43% (95% CI, 32%-53%) of patients experienced imatinib-related grade ≥3 adverse drug reactions (ADRs). Higher comorbidity score, lower body weight, higher imatinib starting dose, and Middle Eastern or North African ancestry were associated with a higher risk of grade ≥3 ADR occurrence on multivariable analysis (MVA). Estimated overall survival and event-free survival rates at 3 years were 97% (95% CI, 92%-100%) and 81% (95% CI, 72%-92%), respectively. Cumulative incidence of major molecular response (MMR) at 3 years was 63% (95% CI, 50%-73%). On MVA, imatinib starting dose, ELTS score, BCR-ABL1 transcript type, pre-existing pulmonary disease, and potential drug-drug interactions were predictive of MMR. In conclusion, imatinib induced deep molecular responses that translated to good survival outcomes in a real-world setting, but was associated with a higher incidence of ADRs, dose modifications and treatment discontinuations than in clinical trials.

Keywords: anticancer drugs; chronic myeloid leukemia; imatinib; pharmacoepidemiology; precision medicine; real-world evidence; tyrosine kinase inhibitors.

FIGURE 1

Kaplan–Meier estimated time to first imatinib dose modification (any type, dose reduction or treatment interruption, and dose escalation), time to imatinib discontinuation and time to next treatment.

FIGURE 2

Cumulative incidence of imatinib‐related adverse drug reactions (ADRs) Cumulative incidence of imatinib‐related ADRs by 3 years (95% confidence intervals) calculated using the cumulative incidence competing risk method.

FIGURE 3

Cumulative incidence of major molecular response (MMR), deep molecular response (DMR) and sustained DMR (sDMR) in patients treated with imatinib. Cumulative incidence of molecular response at certain time points are presented with their associated 95% confidence intervals. Cumulative incidence was calculated using the cumulative incidence competing risk method.

FIGURE 4

Kaplan–Meier estimated overall survival (OS), progression‐free survival (PFS) and event free survival (EFS) in patients receiving imatinib treatment.

FIGURE 5

Cumulative incidence of (A) major molecular response (MMR), (B) deep molecular response (DMR) and (C) sustained DMR (sDMR) in patients treated with imatinib, by likely eligibility for the ENESTnd and DASISION trials. The unadjusted subdistribution hazard ratios (SHRs) and associated 95% confidence intervals (CIs) are reported, with Gray's weighted log‐rank test used to compare groups.

FIGURE 6

Cumulative incidence of imatinib‐related adverse drug reactions (ADRs) by likely eligibility for the ENESTnd and DASISION trials; (A) ADRs of any grade, (B) grade ≥3 ADRs and (C) ADRs resulting in hospitalizationThe unadjusted subdistribution hazard ratios (SHRs) and associated 95% confidence intervals (CIs) are reported, with Gray's weighted log‐rank test used to compare groups.

FIGURE 7

Kaplan–Meier estimated overall survival (OS), progression‐free survival (PFS), and event‐free survival (EFS) in imatinib‐treated patients by likely eligibility for the ENESTnd and DASISION trials. The unadjusted hazard ratios (HRs) and associated 95% confidence intervals (CIs) are reported, with a log‐rank test used to compare groups. 48 treatments likely ineligible for the ENESTnd and DASISION trials (dashed lines) and 41 likely eligible (solid lines).