Identification of CD318 (CDCP1) as novel prognostic marker in AML

Abstract

Genetic and morphological markers are well-established prognostic factors in acute myeloid leukemia (AML). However, further reliable markers are urgently needed to improve risk stratification in AML. CD318 (CDCP1) is a transmembrane protein which in solid tumors promotes formation of metastasis and correlates with poor survival. Despite its broad expression on hematological precursor cells, its prognostic significance in hematological malignancies so far remains unclear. Here, we evaluated the role of CD318 as novel prognostic marker in AML by immunophenotyping of leukemic blasts. Flow cytometric evaluation of CD318 on leukemic cells in 70 AML patients revealed a substantial expression in 40/70 (57%) of all cases. CD318 surface levels were significantly correlated with overall survival in patients receiving anthracycline-based induction therapy or best available alternative therapy. Using receiver-operating characteristics, we established a cut-off value to define CD318^lo and CD318^hi expression in both cohorts. Notably, high CD318 expression correlated inversely as prognostic marker in both treatment cohorts: as poor prognostic marker in patients receiving intense therapy, whereas upon palliative care it correlated with better outcome. In conclusion, FACS-based determination of CD318 expression may serve as novel prognostic factor depending on implemented therapy in AML patients.

Keywords: AML; CD318; CDCP1; Prognosis; Risk stratification.

Fig. 1

CD318 expression on hematopoietic cells and association with clinical parameters. CD318 expression was analyzed on hematopoietic cells by flow cytometry. SFI levels above 1.5 were considered as positive expression (dotted line). a Gating strategy for two exemplary AML samples: viable (7-AAD-), singlets, mononuclear cells, blast marker (AML 1: CD13/CD33, AML 2: CD33/CD14-), and CD318 expression. b CD318 expression on blasts of AML patients (n = 70) are depicted as SFI levels and percentage of CD318 positive blasts (boxplots with min/max whiskers). c–e CD318 SFI levels according to the different FAB classifications (single values, median) (c), FAB others vs. FAB M2 (boxplots with Tukey whiskers; Mann-Whitney test) (d), primary (pAML) vs. secondary (sAML) AML (boxplots with Tukey whiskers; Mann-Whitney test) (e), and according to age < 60 and > 60 years (boxplots with Tukey whiskers; Mann-Whitney test) (f) are shown. g Distribution of CD318 expression (SFI) throughout NCCN risk group (boxplots with Tukey whiskers; Kruskal-Wallis test)

Fig. 2

Impact of CD318 expression on clinical outcome. a Overall survival (OS) in AML patients according to CD318^lo and CD318^hi expression in Kaplan-Meier analysis. b Overall survival in patients without intense therapy according to CD318^lo and CD318^hi expression in Kaplan-Meier analysis. Mean OS was reached in CD318^lo (dotted line) and CD318^hi (continuous line) after 14 or 194.5 days, respectively, and differed significantly (log-rank test). c Overall survival in patients receiving hypomethylating agents according to CD318^lo and CD318^hi expression in Kaplan-Meier analysis. d Overall survival in patients receiving anthracyclin-based induction therapy (ABIT) according to CD318^lo and CD318^hi expression in Kaplan-Meier analysis. Mean OS was only reached in CD318^hi after 572 days (dotted line; log-rank test). e Progression-free survival (PFS) according to CD318^lo and CD318^hi expression in Kaplan-Meier analysis. In CD318^hi, the mean PFS was 513 days (dotted line; log-rank test) and could not be reached in CD318^lo (continuous line)

Fig. 3

Multivariate analysis for survival in patients receiving anthracycline-based induction therapy. a Model I: all patients receiving anthracycline-based induction therapy (n = 42). b Model II: patients receiving anthracycline-based induction therapy with known cytogenetic parameters (n = 34). NCCN National Comprehensive Cancer Network; WBC white blood count; ^±reference group, dotted line: HR = 1