Relapse characteristics and risk factors for central nervous system involvement in acute promyelocytic leukaemia in the oral arsenic trioxide era: a 13-year follow-up study

Abstract

BACKGROUND: Arsenic trioxide (As2O3)-based regimens are effective in inducing a remission in more than 90 percent of relapsed APL. Treatment failure following As2O3 and central nervous system (CNS) involvement is associated with a poor prognosis. The optimal post-remission therapy in relapsed APL is undetermined. Identifying the clinicopathologic characteristics and risk factors for CNS relapse will be a useful guide to stratify patients to the most optimal post-remission therapy. AIMS: The aim of this study was to prospectively evaluate the clinicopathologic characteristics and risk factors for CNS involvement in patients with relapsed APL treated with oral arsenic trioxide-based therapy. METHODS: A total of 188 patients with APL were prospectively followed for 13 years, of whom 71 patients had relapsed APL. The clinicopathologic characteristics at relapse were determined. Prognostic factors for CNS involvement at relapse were determined. RESULTS: There were 41 men and 30 women, at a median age of 43 (21–78) years. The leukemia was de novo in 68 patients (five of which were of microgranular variant morphology), and therapy-related in 3 patients. Additional karyotypic abnormalities were seen in 11 patients (15.5%). Internal tandem duplication of the fms-like tyrosine kinase 3 gene (FLT3-ITD) was detected in 13 patients. During prior first complete remission (CR1), only 15 patients (21.1%) had received oral-As2O3 based maintenance. A second complete remission (CR2) was achieved with an oral-As2O3-based re-induction in all patients in first relapse, who then received oral As2O3-based consolidation and maintenance. At relapse, the median leucocyte count and peak leucocyte count was 2.7 (0.4–94.7) x 109/L and 9.2 (0.6–130.4) x 109/L, and the median platelet count was 59 (7–281) x 109/L. APL differentiation syndrome (DS) occurred in 11 patients (15.5%) during relapse. At a median follow up of 93 (21–392) months, 28 patients (39.4%) had two or more relapses. In the whole cohort of patients, the patterns of relapses were: isolated bone marrow (BM), N=54 (76.1%); concurrent BM and CNS, N=9 (12.7%); and isolated CNS, N=8 (11.3%). In total, 22 patients relapsed during oral As2O3-based maintenance at various disease stages. On univariate analysis, factors significantly associated with CNS relapse included peak leucocyte count at diagnosis > 20 x 109/L (P=0.03), oral As2O3-based maintenance at CR1 (P=0.004), leucocyte count at R1 > 10 x 109/L (P=0.04), 2 or more relapses (P<0.001), and relapse during oral As2O3-based maintenance (P<0.001). On multivariate analysis, peak leucocyte count at diagnosis > 20 x 109/L (P=0.04) and relapse during oral As2O3-based maintenance (P=0.01) were significantly associated with CNS involvement at relapse. CNS involvement at relapse predicted worse overall survival (HR=4.19; P=0.002; 95% CI:1.72-10.19). SUMMARY: CNS involvement was associated with a poor prognosis. High peak leucocyte count at diagnosis and relapse during oral As2O3-based therapy were the main risk factors.