Absence of leukaemic CD34⁺ cells in acute myeloid leukaemia is of high prognostic value: a longstanding controversy deciphered

Abstract

SummaryPrimary resistance and relapses after initial successful treatment are common in acute myeloid leukaemia and therefore outcome remains poor. More accurate risk group stratification and effective personalized risk adapted treatment are necessary to improve outcome. In the last two decades, controversial results have been published concerning the prognostic relevance of CD34 expression. In this study of 706 acute myeloid leukaemia patients, we established a new flow cytometric-based CD34-definition, without use of cut-off values. We discriminated CD34-positive (n = 548) and CD34-negative (n = 158) patients by the presence or absence of neoplastic CD34+ cells, respectively. CD34-status was defined using aberrant immunophenotypes and validated using molecular phenotypes. This new definition of CD34 enables strong prediction of treatment outcome in the entire patient group and in several risk subgroups. Previously observed discrepancies in prognostic impact of CD34 protein expression using cut-offs (5-20%) can now entirely be explained by considering the number of CD34-negative cases. In the total patient group, the absence of neoplastic CD34-positive cells is paralleled by low levels of minimal residual disease, suggesting relative therapy sensitivity and explaining longer survival. Overall, we present CD34 surface expression as a relatively simple, powerful and independent predictor of clinical outcome, now warranting incorporation in acute myeloid leukaemia risk stratification.

Leukemic stem cells: identification and clinical application

“…In these cases the commonly small CD34+ (<1%) blast population does not contain leukemic cells [18,20,21]. By definition, these CD34− patients lack CD34+/CD38− or CD34+/CD38+ leukemic populations; however, a potential LSC population should be found within the remaining CD34− fraction.…”

“…About 20% [18] of AML cases are characterized by absence of neoplastic CD34+ cells [18,19]. In these cases the commonly small CD34+ (<1%) blast population does not contain leukemic cells [18,20,21].…”

“…As knowledge on the makeup of the CD34+/CD38− fraction increased, other markers and properties were included anticipating better selectivity in defining LSC as previously summarized [5,29]. In studies on the prognostic impact of CD34+/CD38− LSC on disease outcome, the prognostic influence of complete absence of this fraction was also discovered: CD34− status, characterized by the complete absence of neoplastic CD34+ cells [18], turned out to be an independent prognostic factor identifying patients with better prognosis in adult [17] and pediatric AML [39] compared to patient with high or low CD34+/ CD38− LSC frequencies.…”

“…For that reason, a broadly applicable simple one-tube approach has been developed, which can easily be implemented in routine diagnostics [6]. Additionally, screening for CD34+/CD38− LSC also enables identification of CD34− patients, who generally have a better prognosis [18]. Furthermore, as LSC-specific therapiestargeting LSC-specific surface markers-become available, individualized therapy may come in view.…”

Association of acute myeloid leukemias most immature phenotype with risk groups and outcomes

“…13 Other groups have also described heterogeneous CD34 and ALDH expression in AMLs. 8,[16][17][18][19][20] Since no leukemia subset from many patients will engraft immunodeficient mice, [5][6][7][8][9][10][11] and no leukemic CD34 + CD38 -cells can be identified in some patients, 4,13,15,16,21 other means for LSC identification are needed to allow for their study clinically.…”