Frequency and Impact of Molecular Response’s with Nilotinib (Tasigna) in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP)
Authors: Daver Naval , Kantarjian Hagop M. , O'Brien Susan , Jabbour Elias , Pierce Sherry , Lim Miranda , Borthakur Gautam , Pemmaraju Naveen , Konopleva Marina , DiNardo Courtney D. , Ravandi Farhad , Garcia-Manero Guillermo , Cortes Jorge E. 
Published: October 2019

Abstract

Background: Nilotinib is a BCR-ABL tyrosine kinase inhibitor with approximately 50-fold higher inhibitory activity than imatinib in preclinical studies.
Aim: We initiated a phase II study (in 2005) to evaluate the efficacy of frontline nilotinib in pts with newly diagnosed CML-CP. The primary objective of this report was to estimate major molecular response (MMR) and complete molecular response (CMR: minimum 100,000 ABL copies) rates with prolonged follow-up, and the impact of MMR and CMR on long-term outcome.
Methods: Pts with Ph-positive or BCR-positive CML in early CML-CP [i.e., time from diagnosis 12 months] with <1 month of prior interferon-alpha and/or imatinib were eligible. Nilotinib was initiated at a dose of 400 mg twice daily. Results for CCyR and MMR are reported as intent-to-treat unless specifically annotated as response among evaluable pts (eval).
Results: 140 pts have been treated as of August 1, 2014. Herein we focus on the initial 109 pts who have a minimum follow-up of 12 months. The median (med) follow-up for these 109 pts is 52.2 months (range, 0.9 to 108.0+). The med age was 50 years (range, 17 to 86). 73% of pts had Sokal low risk. 17 (16%) had received imatinib for <1 months (med 18 days; range, 5 to 29 days).
Overall, 92% (100/109) pts achieved a complete cytogenetic response [CCyR] with a med time to CCyR of 2.9 months (range, 2.1 to 8.1+). The rates of CCyR at 3, 6, 12 and 18 months were 80% (eval:83%), 86% (eval:95%), 83% (eval:99%), and 77% (eval:100%), respectively.
Overall, MMR and CMR were achieved in 90% (98/109) and 45% (49/109) of the pts. Med time to MMR and CMR was 3.3 months (range, 2.4 to 48.0+) and 23.1 months (range, 3.2 to 86.0+), respectively. BCR-ABL/ABL at 3 months was <10% in 94% (eval:100%) and <1% in 89% (eval: 94%). BCR-ABL/ABL at 6 months was <1% in 81% (eval:89%) and <0.1% in 65% (eval:72%) in pts evaluated at these time points. MMR was observed in 65% (eval:72%) at 6 months, 71% (eval:87%) at 12 months, and 70% (eval:90%) at 18 months. CMR was observed in 9% (eval:11%) at 6 months, 14% (eval:17%) at 12 months, and 15% (eval:19%) at 18 months. We further analyzed the association between CCyR and molecular response (Table 1). For example, among the 84 pts who were in CCyR at 18 months: MMR was achieved in 90% of these pts including MR3 in 31%, MR4 in 13%, MR4.5 in 27%, and CMR in 19%.
Estimated 3-year and 5-year overall survival (OS) is 98% and 91%, respectively. Estimated 3-year and 5-year failure-free survival (FFS) is 82% and 73%, respectively. On an intent-to-treat analysis the FFS among pts who achieved CMR was superior to those who did not achieve CMR (P<0.001, respectively). On a landmark analysis, which included only those pts who received nilotinib for a minimum of 24 months (med time to CMR among pts who achieved CMR=23.1 months) the FFS among pts who achieved CMR was superior to those who did not achieve CMR (P=0.008) (Figure 1).
Dose-reductions were performed in 41 (38%) pts: 30 pts required 1 dose-reduction and 11 pts required 2 or more dose-reductions. The most frequent reasons for dose-reductions included increased liver enzymes (n=8), rash (n=5), pain/arthralgia (n=4), cardiac and QTc (n=4), fatigue (n=5), and neutropenia (n=2). The actual med dose remains 800 mg daily. 29 (27%) pts are off study due to toxicity in 8 (cardiac=3, liver enzymes=4, fatigue=1), inadequate response in 5 (3 never achieved adequate and 2 lost adequate response), progression to blast-phase in 3, death in 5 (all 5 non-CML related causes), 8 due to pt choice (financial=1, non-compliance=3, pt choice=1)
Conclusion: Nilotinib 400 mg twice daily is very effective. The cumulative rates of CCyR, MMR and CMR were 92%, 90%, and 45%, respectively. CMR rates continue to improve with long-term follow-up. Attainment of CMR is associated with improved long-term outcome.
Table 1: Molecular response rates among pts who achieve CCyR CCyR MR3 but not MR4 MR4 but not MR4.5 MR4.5 but not CMR CMR No MMR 3 months 87/105 (83%) 39/87 (45%) 5/87 (6%) 8/87 (9%) 2/87 (2%) 33/87 (38%) 6 months 94/99 (88%) 35/94 (38%) 6/94 (6%) 20/94 (21%) 10/94 (11%) 23/94 (24%) 12 months 90/91 (99%) 38/90 (42%) 3/90 (3%) 23/90 (26%) 15/90 (17%) 11/90 (12%) 18 months 84/84 (100%) 26/84 (31%) 11/84 (13%) 23/84 (27%) 16/84 (19%) 8/84 (10%)
PCyr, partial cytogenetic response; Min, mimimal; Inev, inevaluable; IM, insufficient metaphase
Figure 1: FFS CMR versus no CMR by landmark analysis for pts who received at least 24.0 months of nilotinib Figure 1:. FFS CMR versus no CMR by landmark analysis for pts who received at least 24.0 months of nilotinib

Disclosures
Daver: Novartis: Research Funding. Jabbour:Novartis: Advisory board membership Other, Research Funding. Cortes:Novartis: Advisory Board membership Other, Research Funding.