Sustained Superior Long-Term Outcomes of Imatinib Therapy In Japanese Patients with Newly Diagnosed Chronic Myelogenous Leukemia In Chronic Phase: Sub-Analysis According to the Mean Daily Dose of Imatinib and the Plasma Trough Levels In JALSG CML202 Study After 66 Months Follow-up.
Authors: Nakaseko Chiaki , Ohnishi Kazunori , Takeuchi Jin , Fujisawa Shin , Nagai Tadashi , Ohtake Shigeki , Yamazaki Hirohito , Tauchi Tetsuzo , Imai Kiyotoshi , Mori Naoki , Yagasaki Fumiharu , Akiyama Hideki , Maeda Yasuhiro , Usui Noriko , Saburi Yoshio , Ishida Takashi , Kosugi Hiroshi , Miyamura Koichi , Miyazaki Yasushi , Handa Hiroshi , Yokota Akira , Matsumoto Kenji , Fujimaki Katsumichi , Matsui Toshimitsu , Kiyoi Hitoshi , Miyawaki Shuichi , Ohno Ryuzo , Naoe Tomoki 
Published: October 2019

Abstract
Abstract 3417

Background:
Now, imatinib has been established as a first line therapy for the patients with chronic myelogenous leukemia (CML) in chronic phase (CP), and a standard initial dose is 400 mg daily. Although less than 300 mg showed unsatisfactory results, 300 mg or more appears effective in some patients intolerant to standard dose. However, large studies have not yet explored the response to lower dose of imatinib. In this CML202 study, although initial dose of imatinib was scheduled to be 400 mg, many patients actually received reduced dose mainly due to adverse events. However, overall efficacy and outcomes had been comparable to other studies. We performed subgroup analysis regarding long-term survivals according to the mean daily dose during the first 6 months, 12 months, and 24 months, respectively. We also measured imatinib plasma trough concentration (Cmin) in patients receiving imatinib at a dose of 300 mg or 400 mg, and compared efficacy and survivals between them.

Methods:
The prospective multicenter study of imatinib therapy in Japanese patients with newly diagnosed CML-CP was conducted in Japan Adult Leukemia Study Group (JALSG CML202 study). The objectives of this study were to determine the efficacy, safety and long-term outcomes of imatinib therapy in patients with newly diagnosed CML-CP. Primary end point of imatinib therapy was overall survival (OS). Initial daily dose of imatinib was 400 mg. The plasma concentration of imatinib was measured using liquid chromatography-tandem mass spectrometry.

Results:
488 patients were enrolled between 2002 and 2006, and data at a median follow-up of 66 months were analyzed. The cumulative best response rates of major cytogenetic response (MCyR), complete cytogenetic response (CCyR) and major molecular response (MMR) were 99%, 98% and 81%, respectively. At 66 months, the estimated rate of overall survival (OS) was 93% (95% CI, 90 to 96), and that of survival without progression to accelerated phase (AP) or blast crisis (BC) was 97% (95% CI, 96 to 99). In the landmark analysis at 12 months or 18 months according to the cytogenetic response or the molecular response, patients who had CCyR or MMR showed significantly better event free survival (EFS) rates than those who had not, respectively. Mean daily doses of imatinib administered during the first 24 months were 400 mg or more (400 mg group) in 294 patients, less than 400mg and 300mg or more (300 mg group) in 108 patients, and less than 300 mg (200 mg group) in 86 patients. The efficacy and outcomes at 66 months were evaluated according to the mean daily dose (400, 300, 200 mg group). The estimated rates of OS were 98%, 92% (P=0.09), and 74% (P<0.0001), and those of EFS were 91%, 79% (P=0.003), and 56% (P=0.0004), respectively. The estimated rates of survival without AP/BC were 99%, 97% (P=0.20), and 90% (P=0.03), respectively. OS, EFS and survival without AP/BC in 200 mg group were significantly inferior to those in 300 mg or more groups. OS and survival without AP/BC were not significantly different between 300 mg group and 400 mg group. However, EFS was significantly different between 300 mg group and 400 mg group. The cumulative CCyR and MMR rates in 200 mg group were inferior to those in 300 mg or more groups, however, they were not significantly different between 300 mg group and 400 mg group. OS and survivals without AP/BC in both 400 mg and 300 mg groups seem better as compared with the results of the IRIS study. However, EFS in 300 mg group was inferior to that of the IRIS study. The median (range) Cmin of imatinib in patients receiving 300 mg (n=24) and 400 mg (n=26) were 1,130 ng/mL (439-2,140) and 1,035 ng/mL (710-2,420), respectively. Cmin in patients receiving 300 mg distributed toward lower concentration as compared to those with 400 mg, even though they were not significantly different.

Conclusion:
The long-term results of the JALSG CML202 study revealed almost similar to those of the European countries in spite of the relatively lower mean daily dose. Imatinib at 400 mg or more induced excellent long-term outcomes in Japanese patients, however, EFS in 300 mg group was inferior to that in 400 mg group. These results suggest that higher daily dose is associated with better outcomes, however, imatinib at least 300 mg might be acceptable for patients intolerant to dose at 400 mg. Monitoring Cmin might be useful to find the optimal dose.

Disclosures:
Ohnishi: Novartis: Research Funding. Miyazaki:Novartis: Research Funding. Kiyoi:Novartis: Research Funding. Naoe:Novartis: Research Funding.