NOVEL-1st: Interim Analysis of a Non-Interventional, Multi-Center Observational Study to Assess the Safety and Efficacy of Nilotinib in Newly Diagnosed Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) in Taiwan
Authors: Wen-Li Hwang , Han Shao-Min , Lin Shyuann-Yuh , Chang Ming-Chih , Bai Li-Yuan , Hsiao Pei-Ching , Kuo Ching-Yuan , Chen Yeu-Chin , Liu Ta-Chih , Wang Po-Nan , Gau Jyh-Pyng , Lee Yee-Ming , Ku Fan-Chen , Tang Jih-Luh 
Published: October 2019

Abstract
Background
The selective tyrosine kinase inhibitor (TKI) nilotinib has been approved for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) globally, including Taiwan. The NOVEL-1st study was conducted to examine the long-term safety and efficacy of nilotinib in this group of patients in routine clinical practice in Taiwan.
Methods
The NOVEL-1st study was a non-interventional, multi-center study. A total of 129 patients with newly diagnosed and previously untreated Ph+ CML-CP were enrolled from 11 centers across Taiwan between January 2013 and June 2016. The follow-up period was 36 months. The primary objective was to collect long-term safety data on nilotinib. Secondary objectives were to evaluate the efficacy of nilotinib by clinical response, disease progression, and survival.
Results
The median age of the enrolled patients was 49.7 (20.2-89.6) years of whom 58.3% were males. The median duration from CML diagnosis to study enrolment was 25.5 days. Of the 129 enrolled patients, 59 (45.7%) had completed the study, 29 (22.5%) had withdrawn from the study and other patients are still under follow up. The most common reasons included adverse events (AE) (n = 8), discontinuing nilotinib (n = 6), and death (n = 4). All 129 patients were included in the safety analysis, while 122 patients in whom molecular response data were collected were included in the efficacy assessment.
At the time of data cut-off, a total of 1,278 AEs were reported by 120 (93.0%) patients, of which 140 (11.0%) AEs in 41 (34.2%) patients were serious and 499 (39.0%) AEs in 40 (33.3%) patients were drug-related. Non-hematological and hematological AEs were consistent with other reports, with no new safety signal detected. Common hematological AEs (incidence ≥ 10 %) included thrombocytopenia (29.5%), anemia (19.4%), and leukopenia (14.0%). Frequent non-hematological AEs (incidence ≥ 10 %) included rash (21.7%), upper respiratory tract infection (19.4%), pruritus (18.6%), cough (17.1%), constipation (14.7%), diarrhea (12.4%), increased alanine aminotransferase (11.6%), increased bilirubin (10.1%), and insomnia (10.1%). Compared to previous studies, we observed lower rates of cardio- or cerebrovascular events (1.6%), fluid retention (2.3%), and hyperglycemia (2.3%) of all grades, but a higher rate of hepatotoxicity (20.9%) was seen in the study population. Five (3.9%) patients expired during the study of whom 2 were due to CML progression.
The efficacy outcomes were comparable to other first-line studies of nilotinib. From 3 to 36 months, the rates of clinical response increased over time, from 67.4% to 91.5% for complete hematological response (CHR), 45.0% to 86.0% for complete cytogenetic response (CCyR), 15.5% to 79.1% for major molecular response (MMR), 3.9% to 56.6% for MR4.0 (BCR-ABL ≥ 4 log reduction), and 2.3% to 38.8% for MR4.5 (BCR-ABL ≥ 4.5 log reduction). The median time to CHR, CCyR, MMR, and MR4.0 were 4, 5, 9, and 25 months, respectively (not reached for MR4.5). Early molecular response (EMR), defined as BCR-ABL ≤ 10% at Month 3, was seen in 88.7% of patients. MR4.0 and MR4.5 were significantly higher for patients with deeper EMR, confirming an association between early and long-term deep molecular response. To date, the median OS and PFS were not reached as death and disease progression were only observed in 5 and 2 patients, respectively.
Conclusions
The initial results of NOVEL-1st were comparable to other published first-line studies of nilotinib and demonstrated that nilotinib as a first-line treatment for Ph+ CML-CP patients was well-tolerated and efficacious in the real-world setting. Clinical response was observed as early as 3 months. Early molecular response is a potential predictor of long-term clinical outcome. The final analysis will be conducted when all patients have completed the study.

Disclosures
No relevant conflicts of interest to declare.