First-line nilotinib may induce treatment-free remission in chronic myeloid leukaemia
Nilotinib demonstrates potential in the first-line treatment of patients with chronic myeloid leukaemia, yielding sustained deep molecular response (DMR) in a clinically significant percentage of patients, according to the results of the phase II ENESTfreedom trial. Importantly, nilotinib-treated patients may remain in treatment-free remission (TFR) for up to 48 weeks after stopping nilotinib.
The study population comprised 215 patients with chronic myeloid leukaemia who had been treated with frontline nilotinib for ≥2 years and achieved molecular response (MR)4.5. All patients continued treatment for up to 52 weeks in the consolidation phase of the trial and were assessed every 12 weeks using real-time quantitative polymerase chain reaction (RQ-PCR).
Of the patients, 190 (median age 55 years; 50.5 percent male) achieved sustained DMR and entered the TFR phase and discontinued treatment. Sustained DMR was defined as MR4.5 in the last assessment, no assessment worse than MR4, and ≤2 assessments between MR4 and MR4.5. [Leukemia 2017;31:1525–1531]
Patients in the TFR phase received nilotinib for a median duration of 43.5 months before stopping treatment. The primary endpoint of sustained major MR (MMR; defined as BCR-ABL1 ≤0.1 percent on the International Scale) without reinitiation of treatment at week 48 of the TFR phase was reported in more than half (51.6 percent or n=98) of the patients.
On the other hand, of the 86 patients who lost MMR and subsequently reinitiated nilotinib, 98.8 and 88.4 percent, respectively, achieved MMR and MR4.5 by the data cutoff date.
In terms of safety, musculoskeletal pain-related events occurred in 16.3 percent of patients in the consolidation phase compared with 24.7 percent in the TFR phase. Most were grade 1/2, and none resulted in study withdrawal.
“The observed TFR rate of 51.6 percent is a clinically important outcome, particularly when considering the relatively short duration of prior nilotinib therapy (3.6 years) among patients in the study and the association between duration of tyrosine kinase inhibitor (TKI) therapy and TFR probability in prior studies,” the authors noted. [Haematologica 2016;101:22–23;717–723]
They said the loss of MMR within 6 months of stopping nilotinib in the group of patients who reinitiated nilotinib underscores the importance of frequent monitoring of patients who stop TKI therapy to ensure timely retreatment.
While frontline nilotinib therapy is known to yield rapid and high rates of DMR, which is a key prerequisite for TFR, several factors must be considered when selecting a TKI for frontline therapy, the authors pointed out. [Leukemia 2016;30:57–64;1044–1054]
“[I]n addition to the efficacy and safety profiles of each available treatment option, treatment cost can be an important consideration, particularly with the introduction of generic imatinib; now, the increased potential for TFR eligibility with nilotinib (and the potential cost savings through treatment discontinuation) may be additional factors to consider for some patients when selecting a frontline TKI,” they continued. [Blood 2013;122:abstracts 255, 654, 787]
The aforementioned long-term considerations are increasingly important, as the authors noted, because patients with chronic myeloid leukaemia now have a life expectancy comparable to that of the general population. [J Clin Oncol 2016;34:2851–2857]
“The results from ENESTfreedom, together with the results from ENESTnd showing higher rates of DMR and sustained DMR with nilotinib vs imatinib, suggest that more patients may become eligible to stop treatment and sustain remission following frontline nilotinib therapy than following imatinib therapy,” the authors concluded. [Leukemia 2016;30:1044–1054; Blood 2015;126:abstract 2781]
“Additional follow-up and analyses of TFR data in ENESTfreedom and other TFR studies will be needed to further evaluate the patient, disease and treatment characteristics before stopping treatment that may be associated with maintaining TFR, as well as the long-term durability of TFR,” they added.