Second-Generation TKIs Can Be Stopped in Many CML Patients

February 26, 2017

Cessation of second-generation TKIs yielded good treatment-free remission rates in patients with chronic myeloid leukemia who had sustained deep molecular responses.

Cessation of second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib yielded good treatment-free remission (TFR) rates in patients with chronic myeloid leukemia (CML) who had sustained deep molecular responses while on therapy. Suboptimal prior response was associated with the risk of relapse.

“The notion that TKIs may never be stopped was successfully challenged in imatinib-treated patients with deep and sustained molecular responses,” wrote study authors led by Delphine Rea, MD, PhD, of Hôpital Saint-Louis in Paris. Second-generation TKIs induce higher rates of deep responses and a more rapid decline in BCR-ABL1 transcript levels compared with imatinib in newly diagnosed patients. “These data suggest that the use of dasatinib or nilotinib may increase opportunities to attempt treatment cessation in comparison with imatinib.”

This study included 60 patients who received either dasatinib or nilotinib as a first-line or subsequent therapy for CML. All patients had received the therapy for at least 3 years, and had a molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years. Patients were followed for a median of 47 months; results were published in Blood.

Eight patients had received first-line nilotinib or dasatinib (13.3%), while 40 patients (66.7%) received those agents as a second-line therapy; 12 patients (20%) received them as third-line therapy. A majority of patients (65%) had a history of intolerance to imatinib, and 13 patients (21.7%) had a prior suboptimal response or resistance to imatinib.

In total, 26 patients (43.3%) experienced a molecular relapse after treatment cessation, with a median time to relapse of 4 months. Most relapsing patients (80.8%) lost major molecular response (MMR) within 12 months. The cumulative incidence rate of molecular relapse was 35% by 12 months, and 44.76% by 48 months; the TFR rate at 12 months was 63.33%, and was 53.57% at 48 months.

Of the 26 relapsing patients, 25 resumed therapy. All patients remained in hematologic response throughout, with no progressions toward advanced-phase CML. All patients who restarted therapy remained sensitive to the treatment, with one exception in a patient who died before evaluation due to complications from Alzheimer’s disease. Patients regained MMR after a median of 2 months, and MR4.5 after a median of 3 months. On a univariate analysis, prior intolerance or resistance to TKI therapy was significantly associated with the risk of relapse (P = .00233).

Seven patients underwent a second treatment discontinuation after restarting therapy; of these patients, 5 failed to remain treatment-free and again lost MMR, a finding that has been previously reported in imatinib cessation studies as well.

“The definition of optimal conditions for [second-generation TKI] cessation, namely those offering the best chances of remaining treatment-free, will need further clarification before widespread practice of TFR in routine patient care, especially in the first-line setting,” the authors concluded.