ACA Rearrangement is Associated with the Prognosis of CML in the Era of TKI

Research Article

Ann Hematol Oncol. 2019; 6(6): 1252.

ACA Rearrangement is Associated with the Prognosis of CML in the Era of TKI

Sisi Cai¹, Zhaodong Zhong¹, Xiang Li², Li Wang², Hongxiang Wang², Yong You¹ and Min Zhang¹*

¹Institution of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, China

²Institution of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science & Technology

*Corresponding author: Min Zhang, Institution of Hematology, Union Hospital, Huazhong University of Science & Technology. Jiefang Road 1277#, Jianghan District, Wuhan, Hubei Province 430022, China

Received: April 15, 2019; Accepted: May 07, 2019;Published: May 14, 2019


Approximately 9-13% of CML patients Acquire Additional Chromosomal Aberrations (ACAs) in chronic phase and blast crisis. Major route ACAs emergence indicates an increased risk of progression and shorter survival. We analyzed the chromosome data of 280 CML patients from Department of Hematology, Union Hospital, Tongji Medical College, affiliated to Huazhong University of Science and Technology, and ACA were detected in 19 patients of them. Bone Marrow (BM) morphology, molecular biology and cytogenetics of 19 CML patients with ACA were monitored. Our data displayed that no significant difference in Complete Cytogenetic Remission (CCR) or Major Molecular Remission (MMR) was existed between CML patients with minor route ACA or major route ACA (P>0.05), which may be due to the small sample size in our study. However, we found that patients with well-responsive chromosomes to Imatinib had a higher probability of acquiring CCyR or MMR. Our data implied that chromosomes could be used for prognosis stratification of CML, which may be critical for formulations of treatment strategies during CML therapy.

Keywords: Chronic myelogenous leukemia; Major route; Minor route


IM: Imatinib Mesylate; ACAs: Additional Chromosomal Abnormalities


Chronic Myelogenous Leukemia (CML) is characterized by the Philadelphia chromosome (Ph), which originated by reciprocal translocation t(9;22) (q34;q11.2) [1]. Current evidence indicates that acquired genetic instability was a consequence of the Philadelphia (Ph) translocation and the resulting BCR-ABL fusion causes the continuous acquisition of Additional Chromosomal Aberrations (ACAs) and mutations, and thereby progression to the Accelerated Phase (AP) and/or Blast Crisis (BC) of CML [2]. Cytogenetic clonal evolution occurred in approximately 50-80% of patients with BC of CML and was associated with poor prognosis [1,2]. However, CAs (chromosomal abnormalities) other than the standard Ph are described in less than 10% of cases with Chronic Phase (CP) CML at diagnosis [3,4]. The study of Lee et al reflected the relevance of cytogenetic evolution to CML course [3]. In the era of IM (Imatinib Mesylate) therapy, the prognostic implications of ACAs in CP CML still remain to be found. Several studies have indicated that ACAs occurring in CP patients treated with IM were associated with poor prognosis, especially with poor OS and Poor PFS [3-6]. However, other studies have indicated that in CP, ACAs could be transient [4], presence of ACAs are not associated with the possibility of achieving MCyR (Major Cytogenetic Remission) and CCyR (Complete Cytogenetic Remission), even with the long term of cytogenetic and molecular remission or OS [7-9]. Johansson et al has suggested that aberrations occurring in >5% of CML with secondary changes, which include +8(34% of cases with additional changes), +Ph(30%), i(17q)(20%), +19(13%), -Y(8% of males), +21(7%), +17(5%) and monosomy 7(5%), should be denoted major route ACAs [4], while the other ACAs belong to minor route ACAs such as -17, +13, +4, t(5;13), t(3;21) and so on. Alice Fabarius et al., has indicated that in patients with major-route ACAs, times to achieve CCyR and MMR (Major Molecular Remission) were longer and PFS and OS were shorter (P< .001) than in patients with standard Ph [2]. In addition, major route ACAs at diagnosis have a negative impact on survival and signify progression to the AP or BC, no difference in the cumulative incidence of CCyR or MMR was seen among patients with standard Ph, variant translocation, -Y (not shown), and minor route ACAs [2]. Additionally, according to the treatment recommendations of European Leukemia Net (ELN) for CML, the expert panel has brought the emergence of major route, not minor route, cytogenetic changes into the criterion for AP [10]. Although major route ACAs in CP has been considered as not only negative factors for achieving CCyR or MMR but also association with poor prognosis, significance of minor route ACAs in CP is not clear yet. To testify the importance of minor route ACAs, we investigated the effects of additional chromosomal abnormalities besides the standard Ph in CP on the clinical outcome of CML. Here, we detected the occurrence of ACAs, especially minor route ACAs in 19 patients with CP-CML before or during IM treatment, and then analyzed their characteristics and effects on treatment responses to TKI and their prognosis.

Materials and Methods

Patients and response analyses

From July 2003 to April 2013, 280 newly-diagnosed CML patients were analyzed, 147 of them were only treated with IM, while 133 of them were administrated with interferon before the initiation of IM treatment. ACAs were detected in 19 of 280 patients with CML, their Bone Marrow (BM) morphology, molecular biology and cytogenetics were monitored every 3 months during the therapy.


Clinical phase and clinical outcome were defined according to recent criteria [11]. Cytogenetic alterations and clonality were defined according to the International System for Human Cytogenetic Nomenclature [12]. ACAs were displayed as additional or variant cytogenetic alterations in Ph positive cells. The patients with majorroute were referred to those with the karyotypes of major route ACAs (with or without minor route ACAs). The patients with minor route ACAs were referred to those only with the karyotypes of minor route (without major route ACAs).


The characteristics of ACAs in 280 patients.

ACAs were detected in 19 CML patients with a median age of 44 years (range 19-56y), 7 of 19 patients had major route ACAs [13-20], other 12 patients had minor route ACAs, the rare atypical transcript type of bcr-abl1 gene was detected in one patient with minor route ACAs. No significant differences were found between two groups with major route or minor route ACAs in terms of Age, Sex, and the presence of ACAs (Table 1). The commonest ACAs were shown on chromosome 22(n=6), 7(n=2), 8(n=2), C(n=2), Y(n=2). The partial polyploidy were detected in two patients and complex karyotype in five patients. Complex karyotype was also detected in one patient with variant Ph [21-26].