Low-Dose Second Generation TKI Is an Effective Approach to Reduce TKI Related Side Effects and Toxicity While Preserving Molecular Response in CML Patients with TKI Intolerance

Introduction:

Tyrosine Kinase Inhibitors (TKIs) are remarkably effective therapies for newly diagnosed patients with Chronic Myeloid Leukemia (CML) in chronic phase (CP). However a number of patients experience side effects with first and second generation TKIs given at standard dosage limiting their ability to continue therapy.

Second generation TKIs are more potent than imatinib thus allowing potential dose de-escalation in order to limit TKI toxicity and side effects while preserving efficacy under close molecular monitoring. We retrospectively looked at the outcome of CP-CML patients whose second generation (2G-TKI) was either dose reduced or started at a reduced dosage, in order to limit side effects.

Results:

Twenty five CP CML patients were switched to either low dose nilotinib (n=11) or bosutinib (n=14). Low dose nilotinib was defined at daily dose of 400mg or lower, while low dose bosutinib was defined as daily dose up to 400mg. Median patient age was 46 years (27-71) and disease phase at diagnosis was 24 CP and one de novo accelerated phase. Response to first line TKI at 12 months was complete cytogenetic response (CCyR) in 17 patients, major molecular response (MMR/MR3) in 4 patients while 2 patients had achieved partial cytogenetic response (PCyR) only and 2 patients achieved minor cytogenetic response. Median number of previous TKI therapy before switching to current TKI was 2 (one previous TKI n=7, two TKIs n=6, three TKIs n=8, four TKIs n=2) while two patients were started on first line nilotinib followed by dose reduction.

Before starting TKI, 3 patients had cardiac comorbidities (hypertension, ischaemic heart disease), 2 had stable auto-immune condition (raynaud's disease, psoriasis), 2 suffered from depression (treated). Reason for switch to current TKI was intolerance (n=20) or TKI resistance (n=5), while disease status before switching was MMR/MR3 (n=16) or CCyR with no MMR (n=9).

Among patients switched to nilotinib, 8 were started at a reduced dosage (150 to 200 mg once daily, n=3; 300 mg once daily, n=2; 400 mg once daily, n=3) while 3 patients received nilotinib at 300 mg twice daily and then had dose de-escalation. At last follow up, all 11 patients remained on low dose (150-200mg daily, n=5; 200-400 mg once daily, n=8) with no dose interruptions.

Among patients who were switched to Bosutinib, all 14 were initiated on reduced dose (100-200mg once daily, n=4; 300mg daily, n=10) and subsequent further dose de-escalation was done. At last follow up all 14 patients remained on low dose and 30% of patients reduced to further lower dose (150-200mg daily, n=7; 300mg once daily, n=7).

After a median follow up of 120 months (range, 30-228) since diagnosis and 21.6 months (3.2-61.1) since last TKI dose reduction, all patients achieved and sustained MMR/MR3. Patients who switched to reduced dose bosutinib achieved MR 4 (n=3) or remain in MMR/MR3 only (n=11) after a median follow up of 22.2 months (range, 4.4-80.5) and none discontinued due to intolerance. Among patients on reduced dose nilotinib, none experienced cardio-vascular side effects after a median follow up of 58.1 months (range 3.2-87.7) since starting or switching. All patients on nilotinib remained either in MR4 or better (n=8) or MMR/MR3 only (n=3).

Conclusion:

Upfront reduced dosage or subsequent dose reduction of second generation TKIs is feasible in patients who have already achieved CCyR or better. This approach may reduce side effect and TKI toxicity while preserving sustained molecular response.