Clinical Significance of Additional Cytogenetic Abnormalities (ACA) Acquired at the First Relapse in Adult Patients with Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL)

Background: Although cytogenetic abnormalities at diagnosis are recognized as one of the most potent prognostic factors in acute leukemia patients, they are not stable through their clinical courses. ACA, the most frequent form of cytogenetic changes, are considered as a result of genetic instability and clonal evolution of leukemia cells. Recently, we described that ACA at the first relapse was associated with the significantly low second complete remission (CR) rate and poor survival in adult AML patients. However, the clinical significance of ACA has not been elucidated in adult Ph-negative ALL patients. So, we conducted this retrospective study to address this unsolved issue. Patients and methods: Of the 144 adult patients diagnosed with Ph-negative ALL between 1990 and 2015, 48 relapsed patients whose cytogenetic abnormality data both at diagnosis and at the first relapse were available were included in this study. All these patients underwent intensive chemotherapy. Cytogenetic changes between the time of diagnosis and the first relapse were classified into four groups: (1) no change, (2) ACA was acquired at time of the first relapse, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the time of the first relapse, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the time of the first relapse. In this study, groups 2 and 4 were defined as those with ACA acquisition. Overall survival (OS) was defined as the interval from the date of the first relapse to the date of death. Fisher's exact test was used to compare binary variables. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazard model were used for multivariate analysis of prognostic factors. Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 48 patients included in this study, 33 patients were male, and 15 were female. The median age was 41 years (range, 16-75 years). According to the definition described above regarding cytogenetic changes between the time of diagnosis and the first relapse, 20 (42%), 25 (52%), 1 (2%), and 2 (4%) patients were categorized into group 1, 2, 3, and 4, respectively; thus, 27 patients (54%) acquired ACA at the first relapse. To identify the predisposing factors for ACA acquisition, age, cytogenetic abnormalities and WBC count at diagnosis, duration of the first CR, and undergoing after allogeneic stem cell transplantation (allo-SCT) in the first CR were assessed. However, none was extracted as a significant predisposing factor. The 27 patients with ACA acquisition showed a significantly lower second CR rate compared with those without ACA acquisition (14.8% vs. 76.2%, respectively; p < 0.001). Furthermore, the 1-year OS rate after the first relapse in patients with ACA acquisition was significantly poorer than that in those without ACA acquisition (55.3% vs. 25.9%, respectively; p = 0.004), and no one with ACA acquisition was alive at the time of analysis. Multivariate analysis extracted ACA acquisition as an only negative prognostic factor (hazard ratio: 2.55, p = 0.006), whereas age, cytogenetic abnormalities at diagnosis, duration of the first CR, and relapse after allo-SCT did not reach significant level. Of the 27 patients with ACA acquisition (median age: 34, range; 16-72 years), seven underwent allo-SCT after the first relapse, and all seven patients were not in remission at the time of transplant. The 1-year OS rates after the first relapse were not significantly different between patients undergoing allo-SCT after the first relapse and those treated only with chemotherapy (28.6% vs. 25.0%; p = 0.249). Conclusion: These findings suggested that ACA acquisition at the time of the first relapse was associated with chemo-refractive disease and poor prognosis in adult patients with Ph-negative ALL, just like those with AML. As no patients with ACA acquisition achieved long-term survival, even undergoing allo-SCT, innovative therapeutic strategy is warranted. Clarification of the biological background of ACA acquisition may contribute to the development of novel therapeutic strategies and improved treatment outcomes in adult Ph-negative ALL patients.