Molecular Responses after Switching from a Standard-Dose Twice-Daily Nilotinib Regimen to a Reduced-Dose Once-Daily Schedule in Patients with Chronic Myeloid Leukemia: A Real Life Observational Study (NILO-RED)

Introduction

Standard dosing regimen for the BCR-ABL1 tyrosine kinase inhibitor (TKI) nilotinib in chronic myeloid leukemia (CML) is 300mg twice daily (BID) in the frontline setting and 400mg BID in the 2^nd line setting or beyond. Patients (pts) are instructed to fast within 2 hours before and 1 hour after medication intake due to significant high-fat food effects on drug bioavailability. On-label dose adjustments to a lower-dose once-daily (QD) regimen are recommended solely in case of significant toxicity.

Study goal

The primary aim of our observational two-center study was to ask whether nilotinib-treated adult CML pts were able to maintain major molecular responses (MMR) within 1 year after conversion to a more convenient nilotinib QD regimen at reduced doses, regardless of reasons for tapering nilotinib. Pts with minor transcripts or a history of blast crisis or allogeneic stem cell transplantation were excluded.

Patients

Eighty one pts in chronic phase were identified and included and results from the first 67 pts with a follow-up of at least 12 months after the switch to the once-daily dose-reduced nilotinib regimen are presented. Median age at study entry was 52 years (range: 19-82). There were 25 males (37.3%) and the Sokal score was low, intermediate, high or unknown in 43.3%, 37.3%, 13.4% and 6% of pts, respectively. All pts had major-type BCR-ABL1 transcripts. Nilotinib was started as 1^st line TKI at 300mg BID in 68.6% of pts and as 2^nd or subsequent line TKI at 400 or 300 mg BID in 31.4% of pts due to intolerance, warning, resistance or absence of a deep molecular response on prior therapy. Median duration of nilotinib prior switching to a reduced QD dosing was 29 months (range: 1-94) and median duration of MMR was 25 months (range: 3-212). Primary reason for the switch to a reduced QD nilotinib dosing was non-serious adverse events in 37.3% of pts and improvement in pts convenience in 62.7% of pts. Nilotinib was reduced down to 450mg QD, 400mg QD or 300mg QD in 86.6%, 10.4% and 3% of pts, respectively. A 2^nd dose reduction from 450mg to 300mg QD was performed in 30 pts after a median time of 18 months (range: 4-37). The median duration of low-dose nilotinib QD was 24 months (5-54). No severe tolerance issues were encountered and no ischemic cardiovascular events occurred. Eleven pts stopped nilotinib due to treatment-free remission attempt (n=10) or persistent adverse event (n=1). All pts were alive at last follow-up.

Evolution of molecular responses

At baseline, the number of pts in MMR, MR4 and ≥MR4.5 was 9 (13.4%), 17 (25.4%) and 41 (61.2%), respectively and 32 pts (47.8%) had undetectable BCR-ABL1 transcripts. Median BCR-ABL1/ABL1 % IS was 0.006% (range: 0.0007-0.063) and median ABL1 copy number in pts with undetectable transcripts was 87259 (range: 36018-921339). Only 2 pts treated with 1^st line nilotinib lost MMR 4 and 6 months after QD dose reduction of nilotinib with BCR-ABL1/ABL1 % IS at 0.13 and 0.11%, respectively. Both pts spontaneously regained MMR 4 months later without any treatment modification. Kaplan-Meier analysis of survival without unconfirmed MMR loss was 97% (95% CI: 92.9-100) at 12 months and analysis by molecular response category showed that none of the pts who were at least in MR4 at baseline lost MMR (Figure 1). At last follow-up on low-dose QD nilotinib, the number of pts in MMR, MR4 and ≥MR4.5 was 4 (6.3%), 11 (16.4%) and 52 (77.6%), respectively and 37 pts had undetectable transcripts (55.2%). Median BCR-ABL1/ABL1 % IS was 0.0035% (range: 0.00025-0.058) and median ABL1 copy number in pts with undetectable transcripts was 96000 (range: 23285-472000).

Ten pts in long-lasting deep molecular response stopped nilotinib without further treatment after a median duration of TKI and of nilotinib of 60 months (range: 50-149) and 56 months (range: 42-87), respectively. Their follow-up after nilotinib discontinuation was 18 months (range: 5-33). Only 1 of them lost MMR and restarted therapy 5 months later while the others remained treatment-free.

Conclusion

Switching to a nilotinib QD regimen at reduced doses as maintenance therapy after achievement of a MMR on standard-dose nilotinib BID schedule is feasible and safe in chronic phase CML pts regardless of prior treatment history and does not compromise the anti-leukemic efficacy of nilotinib. Our results may pave the way for clinical trials aiming at systematic avoidance of overtreatment and improvement of pts convenience in treatment with nilotinib.

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