Clinical heterogeneity under induction with different dosages of cytarabine in core binding factor acute myeloid leukaemia

Abstract

Repeated cycles of post-remission high-dose cytarabine (Ara-C) have been suggested to improve survival in core binding factor (CBF) acute myeloid leukaemia (AML). High-dose Ara-C used for induction regimens has also been reported to be associated with increased treatment-related mortality (TRM). Few data are available about intermediate-dose Ara-C serving as induction therapy. The aim of our study was to compare the tolerance and outcomes of standard- and intermediate-dose levels of Ara-C as induction in CBF AML and to analyse the clinical heterogeneity of the two AML entities under these induction settings. We retrospectively investigated the outcomes in adults with CBF AML induced with regimens based on standard-dose Ara-C at 100 to 200 mg/m² or intermediate-dose Ara-C at 1,000 mg/m². In total, 152 patients with t(8; 21) and 54 patients with inv(16) AML were administered an induction regimen containing anthracyclines plus either standard- or intermediate-dose Ara-C. After a single course of induction, the complete remission (CR) rate in the inv(16) cohort was 52/52 (100%), higher than the 127/147 (86.4%) in the t(8; 21) cohort (P = 0.005). Intermediate-dose Ara-C (HR = 9.931 [2.135-46.188], P = 0.003) and negative KITmut (HR = 0.304 [0.106-0.874], P = 0.027) independently produced an increased CR rate in the t(8; 21) cohort. Positive CD19 expression (HR = 0.133 [0.045-0.387], P = 0.000) and sex (male) (HR = 0.238 [0.085-0.667], P = 0.006) were associated with superior leukaemia-free survival (LFS) in the t(8; 21) cohort independently of KITmut status or the induction regimen. We conclude that intermediate-dose Ara-C is superior to standard-dose Ara-C for induction of remission in t(8; 21) AML, and CD19 status and sex independently confer prognostic significance for LFS. The KITmut status alone does not have an independent effect on survival in t(8; 21) AML. More intensive induction therapy is unnecessary in inv(16) AML.

Figure 1

Kaplan-Meier plots of LFS and OS according to CBF subtype. (a) The inv(16) cohort showed a trend towards superior LFS compared to the t(8; 21) cohort, with a borderline significance (P = 0.066). (b) The OS between the two CBF cohorts was not statistically different (P = 0.306).

Figure 2

Kaplan-Meier plots of LFS according to CD19 expression or patient sex in the entire t(8; 21) cohort and in both treatment arms. (a–c) According to cohort- and induction-stratified outcome analysis, patients with negative CD19 expression exhibited poorer LFS than those with positive CD19 expression in the entire t(8; 21) cohort (a), the standard-dose Ara-C arm (b), and the intermediate-dose Ara-C arm (c) (P = 0.000, 0.002 and 0.002, respectively). (d,e) Female patients exhibited poorer LFS than male patients in both the entire t(8; 21) cohort (d) and the standard-dose arm (e) (P = 0.004 and 0.019, respectively). (f) Additionally, female patients showed slightly inferior LFS compared with male patients in the intermediate-dose arm, but the difference was not significant (P = 0.132).

Figure 3

Kaplan-Meier plots of LFS according to CD19 expression combined with patient sex in the entire t(8; 21) cohort. CD19 expression in combination with patient sex led to a more obvious survival stratification for t(8; 21) AML, with male patients positive for CD19 expression having the most superior LFS and female patients negative for CD19 expression having the worst LFS (3-year LFS rate: 96% vs. 25%; median LFS duration: not reached vs. 8.6 months).