Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study

Abstract

The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR4.5 (BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1IS)) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1IS⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6% 95% confidence interval, 44.2–58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR4.5 by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).

Budget Impact analysis of the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) adult patients

“…In recent clinical practice it has been shown that, after an adequate period of treatment and in the presence of a very deep and stable molecular response, TKI treatment can be safely discontinued, with good chance of success [7,19]. Numerous studies showed the efficacy of nilotinib in the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia adult patients [6,19,20].…”

“…In the following years, second-generation TKIs -dasatinib and nilotinib -were introduced, all showing the ability to induce molecular and cytogenetic responses in patients who had failed therapy with imatinib. Over the years, several trials demonstrated the superiority of nilotinib and dasatinib vs imatinib in the first-line treatment; these two drugs were associated to a higher rate of major molecular response (MMR) and deep molecular responses (MR 4.0 and MR 4.5 ), and to a lower percentage of progression of the chronic phase to the most advanced disease stages [6][7][8].…”

“…This possibility -not even contemplated until a few years ago -has now been accepted and officially registered for nilotinib, thanks to the results of the ENESTfreedom clinical study [7]. The aim of this study was to evaluate the potential for TFR (treatment-free remission) following frontline nilotinib treatment.…”

“…In the absence of a direct comparison between nilotinib, imatinib and dasatinib, the probability of response and progression of dasatinib was estimated through the response and progression relative risks recorded in the DASISION study (head-to-head comparison between imatinib and dasatinib) [8], applied to the transition probabilities estimated for imatinib by the ENESTnd study [6]. TRF estimates were derived from the ENESTFreedom study [7] and modeled through the support of the expert opinion. For the implementation of the model, to the original probabilities appropriate changes and adaptations were applied, that can be found in Appendix A.…”

My burning issues in TKI therapy and treatment-free remission in CML

“…Even though 2nd generation TKIs are more potent in terms of deep molecular remission (DMR) compared to imatinib [2][3][4] CP-CML patients qualify for a TKI discontinuation attempt [5]. Novel combination therapies of available TKIs together with novel drugs, such as ABL001 in patients with a lower likelihood to achieve continuous DMR should be tested [6].…”