TOPLINE:

In patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML), combining the TKI nilotinib with pegylated interferon alfa-2a (Peg-IFN alfa-2a) was associated with higher rates of initial deep molecular response than nilotinib alone, but this advantage did not persist over the longer term. Additionally, the combination did not significantly improve treatment-free remission and was associated with additional toxicities.

METHODOLOGY:

• Second-generation TKIs have improved chronic-phase CML outcomes, but durable treatment-free remission requires deeper molecular responses. Phase 2 studies have suggested that adding Peg-IFN to nilotinib may help, but larger, randomized trials are needed to confirm a benefit.
• To determine whether adding Peg-IFN to frontline nilotinib increases deep molecular responses, researchers conducted an open-label, randomized, multicenter, phase 3 trial (PETALs) involving 200 patients (median age at diagnosis, 45 years; 65% male) with newly diagnosed Philadelphia chromosome-positive chronic-phase CML between August 2014 and September 2016.
• Patients were randomly assigned to receive either oral nilotinib 300 mg twice daily alone (n = 99) or oral nilotinib 300 mg twice daily combined with subcutaneous Peg-IFN for 2 years (n = 101).
• The primary endpoint was the cumulative rate of molecular response 4.5 at 12 months of treatment, indicating a deep molecular response. Follow-up was a median of 67 months.
• Secondary endpoints included kinetics of response, sustained MR4.5 rates, treatment-free remission rates, molecular relapse rates, tolerability of both drugs, overall survival, progression-free survival, and event-free survival.

TAKEAWAY:

• The MR4.5 rate at 12 months was higher in the combination group than in the nilotinib monotherapy group (24% vs 15%; P = .048). However, MR4.5 rates at 2 years (29% vs 29%) and 5 years (55% vs 54%) were similar between the groups, indicating that the early advantage did not persist in the long term.
• Sustained MR4.5, defined as MR4.5 for 2 consecutive years, was similar between the groups during long-term follow-up (27% with nilotinib alone vs 31% with nilotinib plus Peg-IFN); treatment-free remission was numerically greater with combination therapy than nilotinib monotherapy (19% vs 12%), but this difference was not statistically significant.
• Among patients who discontinued therapy, molecular relapse — defined as the loss of major molecular response — occurred in 8 of 27 patients (30%) in the combination group and 9 of 22 patients (41%) in the nilotinib monotherapy group. The 6-year overall survival rate was identical in both groups (99% vs 99%); progression-free survival (99% vs 94%) and event-free survival (68.8% vs 69.8%) were also similar.
• Female sex (odds ratio [OR], 2.85; P = .007) and the cumulative dose of Peg-IFN delivered during the first 9 months (OR, 3.04; P = .011) were significant factors affecting the rate of MR4.5 at 12 months.
• Grade 1-2 adverse events were more common with combination therapy than with monotherapy (91% vs 57%), though the number of grade 3-4 hematologic events was similar (14 events in each arm). Psychiatric adverse events were more common with combination therapy, particularly grade 1-2 events (28% vs 15%); grade 3-4 psychiatric events were not common in either group (6% vs 5%), though suicide attempts occurred in three patients receiving combination therapy and one patient receiving nilotinib alone.

IN PRACTICE:

The combination therapy “induced higher initial rates of deep molecular response” but “did not significantly improve treatment-free remission rates,” the study authors wrote, adding that these findings may diminish interest in using Peg-IFN plus TKIs.

SOURCE:

The study, led by Franck E. Nicolini, MD, Haematology Department, Centre Léon Bérard, Lyon, France, was published online in The Lancet Haematology.

LIMITATIONS:

The trial was open-label and was not originally powered for the treatment-free remission endpoint. The upper age limit of 65 years and the exclusion of patients with significant comorbidities limited generalizability to older or higher-risk real-world populations. Additionally, the study could not explain why combining nilotinib and Peg-IFN, despite their differing mechanisms, did not significantly improve treatment-free remission.

DISCLOSURES:

The study was funded by Novartis Pharma. Nicolini disclosed serving as a consultant for Novartis, Incyte Biosciences, and Kumquat Biosciences; receiving institutional grants from Novartis and Incyte Biosciences Europe; and serving as a speaker and advisor during meetings and boards for Novartis, Incyte Biosciences, Ascentage Pharma, and GSK. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.