Comparative Analysis Of Cytogenetic Evolution Patterns During Relapse In The Hematopoietic Stem Cell Transplantation and Chemotherapy Settings Of Patients With Acute Leukemia

Despite significant therapeutic progress, many patients with acute leukemia die from deteriorating disease after relapse. Relapse of acute leukemia has repeatedly been associated with cytogenetic clonal evolution. However, only a few studies focused on the direct comparison of cytogenetic evolution patterns during relapse of leukemia after hematopoietic stem cell transplantation (HSCT) and conventional chemotherapy. Thus, we performed comparisons of the cytogenetic patterns of patients with acute leukemia both at diagnosis and relapse after HSCT or standard chemotherapy (SC). Cytogenetic patterns with FLT3 mutational instability were also compared.

This retrospective analysis was based on a total of 516 patients. Among them, 349 were diagnosed with acute myeloid leukemia (AML) who developed relapse after HSCT (n = 125) or SC (n = 224); 167 were diagnosed with acute lymphoblastic leukemia (ALL) and developed relapse after HSCT (n = 63) or SC (n = 104). Cytogenetic analysis and FLT3 mutation detection were performed according to standard methods.

In patients with AML as shown in Table 1, differences in the karyotypes between diagnosis and relapse were more frequent in the HSCT cohort than in the SC cohort (53.2% vs. 40.1%, respectively; P = 0.035). Development of more than three new cytogenetic changes was also more frequent in the HSCT cohort than in the SC cohort (31.4% vs. 15.3%, respectively; P = 0.046). Overall, FLT3 mutation instability did not correlate to the clonal cytogenetic changes. However, restricted to patients showing FLT3 mutation instability, tyrosine kinase domain (TKD) mutation was more frequently involved in patients with cytogenetic changes compared to those without (46.2% vs. 5.0%, respectively; P = 0.008) (Table 2). Conversely, in patients with ALL, frequency and pattern of the cytogenetic alterations between diagnosis and relapse did not differ between HSCT and SC cohorts. For both types of acute leukemia, the median number of cytogenetic alterations increased from 1.0 at diagnosis to 2.0 at relapse (P < 0.001) in the HSCT cohort. The increasing number of cytogenetic alterations was also seen in the SC cohort (P = 0.011).

Higher frequencies of clonal cytogenetic changes and more complex cytogenetic patterns were observed in the HSCT cohort compared to the SC cohort. This finding may be associated with an adverse outcome for relapse patients after HSCT. FLT3 TKD mutation could have a certain role in promoting cytogenetic progression in a subset of AML patients. In addition, our data extends the findings of recent previous studies, which described patterns of clonal evolution in acute leukemia patients.

No relevant conflicts of interest to declare.