Safety and Efficacy of Nilotinib (NIL) in Patients (Pts) with Chronic Phase (CP) or Accelerated Phase (AP) Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) with Resistance or Intolerance to Imatinib Mesylate (IM): Results from the Multicenter, Observational NOVEL Study in Taiwan
Authors: Kuo Ching-Yuan , Wang Po-Nan , Hwang Wen Li , Tzeng Cheng-Hwai , Bai Li-Yuan , Tang Jih-Luh , Chang Ming-Chih , Lin Sheng-Fung , Chen Tsai-Yun , Chen Yeu-Chin , Tan Tran-Der , Hseih Chih-Yi , Lin Chinjune , Darko Miljkovic , Cheng-Shyong Chang 
Published: October 2019

Abstract

Background: The selective tyrosine kinase inhibitor (TKI) NIL is approved for the treatment of IM resistant CML-CP or CML-AP pts globally, including Taiwan. A non-interventional, multi-center observational study of N ilotinib in pts with CP or AP Philadelphia chrOmosome positiVe (Ph+) chronic myElogenous Leukemia (NOVEL) was conducted to assess the safety and efficacy of NIL in Taiwanese patients with IM intolerance or resistance.
Methods: NOVEL was an open-label, single arm, study conducted across 12 centers in Taiwan for a period of up to 2 years (y). Adult CML-CP or CML-AP pts with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to ≥1 prior CML therapy were enrolled. Also, IM resistant or intolerant pts with prior second-generation TKI therapy could be included. The primary objective was to collect long-term safety data in pts treated with NIL 400 mg twice daily. Efficacy data were collected as secondary objectives.
Results: A total of 85 pts including CML-CP (n = 76) pts and CML-AP (n = 9) were enrolled. Median age was 47 y (range, 21-85); 56.5% were males. At baseline, median duration of CML diagnosis was 20.3 (range: 1.4-287.7) months (mo). In 7 pts, confirmed BCR-ABL mutations (E450G, E543A, F317L, F486S, G250E, M244V, M351T) were found, 26 (30.6%) did not have mutations, and 52 (61.2%) did not perform BCR-ABL mutation analysis. All pts (100%) had been treated with prior IM, while 19 pts (22.4%) pts had also received dasatinib; 61 (71.8%) pts had complete hematologic response (CHR) prior to NIL initiation.
Of the 85 pts, 54 (63.5%) completed the study while 31 (36.5%) discontinued due to unsatisfactory therapeutic effect (n = 14), consent withdrawal (n = 5), adverse events (n = 4), deaths (n = 3), pregnancy (n = 1), administrative problems (n = 1), unknown (n = 1), and other reasons (n = 2).
A total of 1166 AEs were reported by 80 (94.1%) pts, of which 70 (6%) AEs in 28 (32.9%) pts were serious. Of the total AEs, 336 (28.8%) drug-related AEs were reported in 60 (70.6%) pts with the majority (87.5%) being Grade 1 or 2. Of the total drug-related AEs, 85 (25.3%) were hematological and 251 (74.7%) were non-hematological. Common hematological AEs (≥5 % of pts) were thrombocytopenia (n=18; 21.18%) and anemia (n=12; 14.1%). Frequent non-hematological AEs (≥5 % of pts) were increased alanine amino-transferase ([ALT], n = 18; 21.2%), pruritus (n = 15; 17.7%), increased bilirubin (n=12; 14.1%), rash (n = 10; 11.8%), increased aspartate transaminase ([AST], n = 7; 8.2%, and increased lipase (n = 5; 5.9%). Seven deaths were reported during the study and follow-up period, respectively due to cardiopulmonary failure (suspected to be related to study-drug), acute myelogenous leukemia, accident, exacerbation of chronic obstructive pulmonary disease, subarachnoid hemorrhage, pneumonia, and sepsis. Of the 19 pts, who switched to NIL due to known AEs with IM, AEs resolved in 16 (84.2%) pts (Table).
Cumulative CHR, major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0 (BCR-ABLIS <0.01%) and MR4.5 (BCR-ABLIS <0.0032%) rates are presented in figure. Almost 50% of pts achieved MMR by 18 mo. In pts with confirmed BCR-ABL mutations, the median time to CHR and MMR were 11.9 mo and 37.0 mo compared to 2.3 mo and 16.9 mo in other pts, respectively. In pts without CHR at baseline, median time to CHR and MMR was 3.1 mo and 15.4 mo, respectively. Statistically significant benefit on overall survival (OS) and progression-free survival (PFS) was seen in pts with CML-CP versus pts with CML-AP at screening. Median OS and PFS were not reached for CML-CP pts. In CML-AP pts, median OS was 42.3 mo (95% Confidence interval [CI], 4.4-42.3), and median PFS was 42.3 mo (95% CI, 3.3-42.3).
Conclusions: The NOVEL study demonstrates that treatment with NIL was effective in achieving cytogenetic and molecular responses in pts resistant or intolerant to IM in the real world setting. The response outcomes appeared to be influenced by BCR-ABL mutation status and CHR status at baseline, while OS and PFS were influenced by disease status (CML-CP or CML-AP) at screening. Safety profile of NIL was consistent with earlier reports. A number of AEs had lower incidences, with no incidence of peripheral arterial occlusive disorder (PAOD) reported, reflecting appropriate disease management among clinicians in Taiwan. More than 80% of AEs due to IM were resolved after switching to NIL.

Disclosures
Tang: Novartis: Consultancy, Honoraria. Chang:Novartis: Honoraria. Hseih:Novartis: Employment. Lin:Novartis: Employment. Darko:Novartis: Employment. Cheng-Shyong:Novartis: Honoraria, Speakers Bureau.