Nilotinib vs. nilotinib plus PEG-interferon α induction and nilotinib or PEG-interferon α maintenance therapy for newly diagnosed CML patients

In the context of a well-controlled trial, survival of chronic myeloid leukaemia patients has reached probabilities close to normal. In the TIGER study, the combination of nilotinib with pegylated interferon α was found to be associated with a higher rate of molecular responses but also impaired tolerability. Interferon maintenance proved to be feasible, but did not result in a significantly improved chance of long-term treatment-free remission.

The TIGER-study is a multicentre, randomised, phase III trial to evaluate efficacy and tolerability of nilotinib monotherapy vs. nilotinib plus pegylated interferon α2b (IFN) combination therapy with IFN maintenance as first-line treatment for patients with CML in chronic phase including success of treatment-free remission. The trial aims to improve treatment strategies in CML by improving induction and deescalating maintenance therapies using IFN as enhancer of immune-surveillance.

Study design

In total, 717 patients were recruited from 110 sites in Germany, Switzerland and the Czech Republic. A pilot phase (N= 25) validated the feasibility of the combination of nilotinib (300 mg, twice a day [BID]) and interferon (30-50 µg/week according to tolerability and commenced after more than 6 weeks nilotinib monotherapy). During the main phase of the trial, 692 patients were stratified according to EUTOS score and randomised between nilotinib (N= 353) and nilotinib plus interferon combination (N= 339) as induction therapies. Patients with a confirmed major molecular response (MRR) after more than 24 months therapy could enter the maintenance phase. Treatment-free remission (TFR) started in patients with at least 12 months persistence of MR⁴ and after more than 36 months total therapy. Quality of life was reported by patients using EORTC QLQ-C30 and CML24 questionnaires. Primary endpoints were the rate of major molecular response (MRR) at 18 months obtained with nilotinib vs. nilotinib plus interferon-α and the rate of continuous MRR 12 and 24 months after discontinuation of nilotinib and IFN (i.e. possibility for ‘cure’).

Results

The 8-year overall survival rates were 95% for patients receiving nilotinib and 94% for patients receiving nilotinib plus PEG-IFN, indicating that survival of CML patients has reached probabilities close to normal.  The 8-year PFS rates were respectively 94% and 92%. Disease progression occurred in 20 patients and 28 patients underwent allogeneic stem cell transplantation (N= 14 after progression and N= 14 in chronic phase). In total, 35 patients died, of which 9 due to CML-related deaths. The overall probability of being in MRR at 18 months was 84%, 81% for patients receiving nilotinib alone and 88% for patients receiving nilotinib plus PEG-IFN. At two years, 62% of patients in the nilotinib arm and 73% of patients in the nilotinib + PEG-IFN arm achieved MR⁴, respectively 49% and 64% achieved MR^4.5.

Out of the 279 combination therapy patients with official start of maintenance phase, 148 patients discontinued TKI and received IFN monotherapy during maintenance therapy. These 148 patients had 3 competing risks and 131 patients experienced one of 3 risk; a) >1% BCR;:ABL1 (N= 27) or death (N= 1), b) restart of TKI (N= 26) or SCT (N= 1) while still BCR;:ABL1<1% or c) start of TFR phase experienced by 76 patients.

For 313 evaluable patients, probability of MRR at 12 months after eligibility of discontinuation was 64%, 200 patients are still in MRR. Of 113 patients with failure, 111 lost MMR while 2 patients died without loss of MRR. Probability of MRR at 12 months after eligibility of discontinuation in the nilotinib arm was 60% and was 69% in the nilotinib plus PEG-IFN arm. In total, 76 patients actually started TFR after IFN maintenance. After a median observation time of 39 months, the two-year probability of maintaining MMR was 86%. Adverse events (AEs) of grade 3-5 were reported in 54% of patients in the nilotinib monotherapy arm and in 60% of patient in the nilotinib plus PEG-IFN arm. Quality of life (QoL) analyses revealed decreased cognitive function and higher rates of fatigue in male and female patients in the nilotinib plus PEG-IFN arm, particularly in patients above 40 years old.

Conclusion

In the context of a well-controlled trial, survival of CML patients has reached probabilities close to normal. The combination of nilotinib with interferon α was associated with a higher rate of molecular responses but also impaired tolerability. Interferon maintenance is feasible and may abbreviate the TKI treatment time, but did not result in a significantly improved chance of long-term TFR. Selected patients who achieved MMR after nilotinib/IFN combination therapy, achieved or maintained MR⁴ on IFN monotherapy, and discontinued IFN after at least one year in MR⁴ are likely to maintain MMR in TFR.

Reference

Hochhaus A, et al. Nilotinib vs. nilotinib plus PEG-interferon α induction and nilotinib or PEG-interferon α maintenance therapy for newly diagnosed CML patients. The Tiger trial. Presented at EHA 2023; Abstract S157.