Chronic Myeloid Leukemia: Choosing A TKI

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Clinical trial data regarding deep molecular response outcomes suggest that dasatinib and nilotinib are superior to the first-generation TKI, imatinib.
Clinical trial data regarding deep molecular response outcomes suggest that dasatinib and nilotinib are superior to the first-generation TKI, imatinib.

The BCR-ABL tyrosine kinase inhibitors (TKIs) were an early example of a successful targeted cancer treatment and have dramatically improved outcomes for patients diagnosed with chronic myeloid leukemia (CML) — and advances in TKI treatment continue to accumulate.1-4

Imatinib, dasatinib, and nilotinib are now US Food and Drug Administration (FDA)-approved for the first-line treatment of chronic-phase CML (CML-CP); bosutinib and ponatinib are FDA-approved for patients with disease refractory to the former TKIs.3

Designers of the ongoing multinational phase 3 BFORE trial (ClinicalTrials.gov Identifier: NCT02130557) recently reported in the Journal of Clinical Oncology that bosutinib outperformed imatinib among patients with Philadelphia chromosome–positive CML-CP, offering significantly improved major molecular response and complete cytogenic response rates.4 It is too soon, however, to determine whether overall survival outcomes will be similarly improved.

Clinical trial data regarding deep molecular response outcomes suggest that dasatinib and nilotinib are superior to the first-generation TKI, imatinib.5,6 Treatment decision-making should, however, involve conversations with patients about different agents' toxicity profiles, drug resistance, unknown long-term risks for newer drugs, and drug costs, experts caution.

The TKI treatment era has, furthermore, led to a sharp decline in stem cell transplantation rates for patients with CML. And since the introduction of imatinib, subsequent generations of TKI agents have offered increasingly improved molecular outcomes for patients.

Monitoring molecular responses can allow for the prediction and detection of refractory disease and guide treatment for patients with CML-CP.7-10 The National Comprehensive Cancer Network (NCCN) recommends molecular response monitoring of BCR-ABL1 messenger RNA levels with real-time polymerase chain reaction (PCR).8 NCCN guidelines define major molecular response (MMR) as BCR-ABL1 levels ≤ 0.1% or ≥ 3-log reduction in BCR-ABL1 mRNA from baseline, and recommend measurement at diagnosis for baseline values, every 3 months after initiating treatment until MMR is reached, every 3 months for 2 years after this point, and every 3 to 6 months thereafter.

PCR methodology and molecular monitoring are, however, insufficiently standardized across labs, and recommendations are not consistently followed in real-world clinical practice, researchers have found — complicating assessments of clinical response rates outside of clinical trial settings.7,9,11 The failure to implement NCCN recommendations is, furthermore, likely to affect patients' long-term outcomes.

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