Prognostic Relevance of Genetic Abnormalities in Blastic Transformation of Chronic Myeloid Leukemia
Authors: Ochi Yotaro , Yoshida Kenichi , Huang Ying-Jung , Kuo Ming-Chung , Sasaki Ko , Hosoya Noriko , Hiramoto Nobuhiro , Bera Rabindranath , Nannya Yasuhito , Shiozawa Yusuke , Takeda June , Watatani Yosaku , Makishima Hideki , Shiraishi Yuichi , Chiba Kenichi , Tanaka Hiroko , Sanada Masashi , Ishikawa Takayuki , Takaori-Kondo Akifumi , Miyano Satoru , Mitani Kinuko , Ogawa Seishi , Shih Lee-Yung 
Published: February 2021

Background

Chronic myeloid leukemia (CML) is characterized by the BCR-ABL1 fusion gene. Despite the use of tyrosine kinase inhibitors (TKIs), a minority of chronic phase (CP) CML patients fail TKI therapies and progress to blast crisis (BC), showing dismal outcomes. Although genetic studies have revealed that CML-BC frequently carries not only ABL1 mutations but other driver mutations, our knowledge about the mechanism of TKI resistance and progression to BC is still limited by a relatively small number of patients and/or genes analyzed in each study. Moreover, it remains elusive whether mutations can predict clinical outcomes of BC patients, in which few biomarkers are known. Here, we investigated a large cohort of CML patients to reveal the landscape of genetic lesions and those predicting clinical outcomes in CML.

Methods

We performed whole-exome sequencing (WES) of paired CP and BC samples from 52 patients and targeted-capture sequencing that covered myeloid driver genes in 32 BC and 19 CP samples. Combined with public WES data for 24 BC and 77 CP, we analyzed a total of 108 BC and 148 CP samples.

Results

In WES analysis of paired CP and BC samples, an average of 5.3 nonsynonymous mutations were acquired during disease progression from CP to BC. Notably, a Poisson regression model revealed that the number of acquired mutations was positively correlated with time to progression from CP to BC (P &lt; 0.001) and negatively with TKI therapy after CP diagnosis (P = 0.0093), although the correlation of the number of driver mutations in CML-BC with time to progression was not clear. These results suggest that the use of TKI effectively reduces the size of tumor populations at risk for clonal evolution by acquiring random mutations, by which prevents BC. In CML-BC, we found frequent mutations not only in known mutational targets in other hematological malignancies, such as RUNX1, ABL1, ASXL1, BCOR/BCORL1, TP53, and WT1, but also in other genes recently reported in BC (UBE2A and SETD1B) and previously unreported mutational targets in cancer (KLC2 and NBEAL2). Deep amplicon-sequencing revealed that ASXL1 mutations were already present at the time of CP diagnosis in most cases, whereas others such as RUNX1, ABL1, and TP53 mutations were absent in CP and newly emerged during progression to BC. Some abnormalities, such as +21, +8, and ASXL1 mutations, were more enriched in myeloid than lymphoid crisis, while others, including CDKN2A/B and IKZF1 deletions, -7/del(7p), -9/del(9p), and ABL1 mutations, vice versa. By contrast, abnormalities such as RUNX1 mutations and double Ph were almost equally observed in both crises.

In univariate analysis of clinical factors for overall survival (OS) in 77 CML-BC cases for whom survival information was available, TKI-containing therapy for BC was significantly associated with a better OS, whereas genetic lesions including ASXL1 and TP53 mutations, del(17p), amp(17q), +19, and +21 had a negative impact on OS. Conspicuously, patients with TP53 mutations, del(17p), and amp(17q) showed an especially dismal outcome. We then performed a multivariate analysis using a Cox proportional hazard regression model, focusing on 36 TKI-treated patients, because TKI-containing therapy has been shown to improve OS and therefore, is a standard choice of therapy. We found that ASXL1 and BCOR mutations, complex copy-number alterations, amp(17q), and +21 were independent predictors for worse prognosis. Based on the number of these unfavorable factors, patients were classified into three subgroups showing distinct prognosis, where the 2-year OS rate was 71.8%, 15.6%, and 0% for patients with 0, 1, and ≥2 risk factors, respectively (P &lt; 0.001). Finally, we explored the genetic abnormalities and clinical outcomes in CML-CP. In CP, only ASXL1 was mutated at a frequency comparable to that in BC, while others, including TET2, KMT2D, PTPN11, RUNX1, and WT1, were mutated at much lower frequencies. Of interest, patients who later developed BC more frequently had at least one genetic abnormality, suggesting that mutations found at the time of CP might play a role in driving CML cells to BC under the pressure of TKI treatment.

Conclusion

Our study clarified a comprehensive registry of genetic lesions in BC in a large cohort of CML patients and their prognostic impact, which should provide a clue to the development of better therapy/management for patients with CML.

Disclosures

Takaori-Kondo: Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding; Thyas Co. Ltd.: Research Funding; Takeda: Research Funding; CHUGAI: Research Funding; Eisai: Research Funding; Nippon Shinyaku: Research Funding; Otsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; OHARA Pharmaceutical: Research Funding; Sanofi: Research Funding; Novartis Pharma: Honoraria; MSD: Honoraria. Mitani:CHUGAI: Research Funding; Takeda: Research Funding; KYOWA KIRIN: Consultancy, Research Funding. Ogawa:Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Eisai Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Shih:Novartis: Research Funding; Celgene: Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees.