Clinical Entity and Outcomes of Therapy-Related Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: Surveillance By the Chronic Myeloid Leukemia Cooperative Study Group
Authors: Iriyama Noriyoshi , Takaku Tomoiku , Sato Eriko , Ishikawa Maho , Nakazato Tomonori , Sugimoto Kei-Ji , Fujita Hiroyuki , Tokuhira Michihide , Kawaguchi Tatsuya 
Published: October 2019

Abstract
Background and Aim: Therapy-related chronic myeloid leukemia (TR-CML), which is defined as CML that developed after exposure to cytotoxic chemotherapy and/or radiotherapy, rarely exists in clinical practice, although its incidence rates are relatively lower than those of acute myeloid leukemia or myelodysplastic syndromes, accounting for 1.2-30.4% of secondary leukemias. The clinical behavior of TR-CML, including patient outcome, is reportedly not different from that of de novo CML before the era of imatinib treatment. While the recent advancement of CML treatment by the introduction of tyrosine kinase inhibitors (TKIs) has dramatically improved treatment outcomes in patients with CML, little is known about the treatment response and outcomes in patients with TR-CML treated with TKI. In this regard, we investigated the clinical entity of TR-CML in the era of TKIs, including treatment response to TKI and prognosis, in patients enrolled to the CML Cooperative Study Group.
Patients and Methods: We retrospectively reviewed the data of patients enrolled in the CML Cooperative Study to identify patients diagnosed with TR-CML. This study included patients aged >15 years who were diagnosed with CML in the chronic phase between April 2001 and January 2016, and treated with any TKIs as initial therapy and followed up for at least 3 months. The study was approved by the research ethics board of each institution and conducted in accordance with the Declaration of Helsinki. A major molecular response (MMR) was defined as ≤0.1% on the International Scale (IS) or 100 copies of the BCR-ABL1 transcript/μg RNA in a transcription-mediated amplification and hybridization protection assay. A deep molecular response (DMR) was defined ≤0.0032% in the IS. Event-free survival (EFS) was defined as the period from the date of initial treatment with TKI to the date of onset of the first adverse event (loss of treatment efficacy, progression to the accelerated or blastic phase, or any cause of death) or the last follow-up. Statistical analyses were performed by using EZR.
Results and Discussion: We identified 308 patients with newly diagnosed CML in the chronic phase, including 11 (3.6%) with TR-CML and 297 with de novo CML. Regarding the primary cancer, 2 of the 11 patients had breast cancer and the remaining 9 had prostate cancer, pharyngeal cancer, mesothelioma, lung cancer, colon cancer, ureter cancer, acute leukemia, gastric cancer, or bladder cancer, respectively. Eight cases were treated with chemotherapy, 2 were treated with radiotherapy, and the remaining case was treated with both chemotherapy and radiotherapy. The results of a cytogenetic analysis by G-banding were exclusive t(9;22)(q34;q11) in all the patients. The median time to diagnosis of CML from the initiation of chemotherapy and/or radiotherapy was 7 years (range, 1.2-33 years). No significant differences in patient age, sex, white blood cell count, hemoglobin level, platelet count, or European Treatment and Outcome Study risk were observed between the TR-CML and de novo CML groups. Among the patients whose cytogenetic and/or molecular responses were assessable, all had excellent treatment response to TKI. Seven patients unexpectedly reached MMR within 6 months after TKI initiation. Finally, 8 patients attained DMR or undetectable leukemia in the bone marrow and the remaining 3 attained MMR. The 5-year EFS of the patients in the de novo CML group was 90%. None of the patients in the TR-CML group experienced any adverse event. In conclusion, in the present study, we revealed that patients with TR-CML could attain a good clinical course with TKI therapy. Detailed investigations of TR-CML may provide new insights into the CML biology.

Disclosures
Iriyama: Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Takaku:Bristol: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Nakazato:Mundipharma KK: Research Funding. Fujita:Chugai Pharmaceutical Co.,LTD: Honoraria. Tokuhira:Bristol Myers Squibb Co., Ltd: Honoraria; Pfizer Co., Ltd: Honoraria; Eizai Co., Ltd: Honoraria. Kawaguchi:Novartis: Honoraria.