Correlation between deletion of the CDKN2 gene and tyrosine kinase inhibitor resistance in adult Philadelphia chromosome-positive acute lymphoblastic leukemia

Xu et al. Journal of Hematology & Oncology Correlation between deletion of the CDKN2 gene and tyrosine kinase inhibitor resistance in adult Philadelphia chromosome-positive acute lymphoblastic leukemia Na Xu 0 1 Yu-ling Li 0 1 Xuan Li 1 Xuan Zhou 1 Rui Cao 1 Huan Li 1 Lin Li 1 Zi-yuan Lu 1 Ji-xian Huang 1 Zhi-ping Fan 1 Fen Huang 1 Hong-sheng Zhou 1 Song Zhang 3 Zhi Liu 2 Hong-qian Zhu 4 Qi-fa Liu 1 Xiao-li Liu 1 0 Equal contributors 1 Department of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou 510515 , China 2 Department of Hematology, The Second People's Hospital of Guangdong Province , Guangzhou 510317 , China 3 Guangzhou Air Force Headquarters Hospital , No. 475, Huanshi East Road, Yuexiu District, Guangzhou 510071 , China 4 Department of Hematology, Hospital of Guizhou Province , Guizhou 550002 , China Background: Frequency relapses are common in Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) following tyrosine kinase inhibitors (TKIs). CDKN2A/B is believed to contribute to this chemotherapy resistance. Methods: To further investigate the association between CDKN2 status and TKI resistance, the prevalence of CDKN2 deletions and its correlation with a variety of clinical features was assessed in 135 Ph-positive ALL patients using interphase fluorescence in situ hybridization (I-FISH). Results: Results showed that no difference occurred between patients with CDKN2 deletion (44/135) and wild-type patients in sex, age, and complete remission (CR) rate following induction chemotherapy combined with tyrosine kinase inhibitors (TKIs). However, CDKN2 deletion carriers demonstrated higher white blood cell (WBC) count, enhanced rates of hepatosplenomegaly (P = 0.006), and upregulation of CD20 expression (P = 0.001). Moreover, deletions of CDKN2 resulted in lower rates of complete molecular response (undetectable BCR/ABL), increased cumulative incidence of relapse, short overall survival (OS), and disease-free survival (DFS) time (P < 0.05) even though these patients received chemotherapy plus TKIs followed by allogenic hematopoietic stem cell transplantation (Allo-HSCT). In the case of 44 patients who presented with CDKN2 deletion, 18 patients were treated with dasatinib treatment, and another 26 patients were treated with imatinib therapy, and our study found that there were no differences associated with OS (P = 0.508) and DFS (P = 0.555) between the two groups. Conclusions: CDKN2 deletion is frequently acquired during Ph-positive ALL progression and serves as a poor prognostic marker of long-term outcome in Ph-positive ALL patients with CDKN2 deletion even after the second-generation tyrosine kinase inhibitor treatment. CDKN2; Acute lymphoblastic leukemia; CD20; Philadelphia chromosome; Tyrosine kinase inhibitors; Deletion Background Tyrosine kinase inhibitors (TKIs) were currently used as front line chemotherapy agents in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) patients. Although favorable clinical outcome and complete remission (CR) has been reported, TKI resistance demonstrates a higher relapse rate and short survival time. Development of resistance is a continuous clinical challenge [ 1 ]. Therefore, exploration of TKI resistance mechanism and its associated new prognostic markers becomes a model of therapy for particular subgroups of patients who have showed no significant benefit from TKI therapeutic trials [ 2 ]. CDKN2A/B deletions including tumor suppressor genes INK4A, INK4B, and/or ARF commonly occur in all types of lymphoid malignancies and account for approximately 55 % of adult T-ALL and 30 % of BCP-ALL [ 3 ]. Our previous research reported the unfavorable prognostic role of CDKN2 gene deletion in long-term leukemia outcomes [ 4 ]. Especially, an association study between CDKN2 deletion and clinical outcomes suggested CDKN2 as a poor prognostic marker, and this has been observed in 29 % of BCR-ABL-positive ALL [ 5 ]. Previous studies failed to demonstrate this phenomenon as they were limited by a small sample size and were unable to investigate the correlation between CDKN2 deletion and immunophenotypic or molecular characteristics. Our current study enrolled 135 newly diagnosed patients who were Ph-positive ALL patients in multi-cancer centers, and the prognostic value of the deletion of CDKN2 gene was assessed. Methods Patient information From January 2008 to December 2014, 135 de novo patients diagnosed with Ph-positive ALL at the Nanfang Hospital of Southern Medical University, Guangzhou Air Force Headquarters Hospital, the Second People’s Hospital of Guangdong province, and the Hospital of Guizhou Province following standard bone marrow morphologic, cytochemical, immunophenotypic criteria and cytogenetics were included in our study. All patients received the systematic treatment. Furthermore, we assessed factors that may affect the prognosis of the patients such as age, perip (...truncated)