Clustered precursors in bone marrow sections predict early relapse in patients with acute myeloid leukemia within hematologic remission

Abstract

Background: Bone marrow (BM) aspiration is largely used for relapse assessment in acute myeloid leukemia (AML). It remains unclear what roles that BM trephine biopsy plays on relapse assessment.

Methods: Bone marrow (BM) sections during complete remission (CR) from 60 acute myeloid leukemia (AML) patients were retrospectively analyzed. Computer image processing technology was performed for detection of the distance between precursors and endosteum, and density of precursors was also calculated under light microscopic image. Immunohistochemistry was used to identify the immunophenotype of clustered precursors.

Results: Except for single and double precursors, there existed clustered precursors of 3-5 cells during CR. Here, we demonstrated that clustered precursors, but not single and double precursors, were useful in risk factor of relapse. Area under the receiving operator curve (ROC) was of 0.007 (CI 95%, from 0.572 to 0.851). Using a standard cut-off value of >4.0/mm² for cluster density, early relapse was detected with a sensitivity of 51.5% and a specificity of 85.7%.Multivariate Cox regression analysis revealed that clustered precursor is an independent risk factor for early relapse (Adjusted HR: 0.325, 95% CI: 0.156-0.679, p = 0.003).

Conclusions: Cumulatively, clustered precursors in BM sections during CR may serve as an independent risk factor of early relapse and poor outcome for AML patients in cluster density > 4.0/mm² in sections. Early aggressive interventions are needed to prevent hematologic relapse.

Figure 1

Distances to the endosteum among different groups of cells. (A) Representative histological section from an AML patient in CR. Solid arrows indicated single precursor, arrow head indicated double precursors, and hollow arrow indicated clustered precursor. Dashed red line highlighted the endosteal surface. Staining of sections was done by haematoxilin-giemsa acid fuchsin (HGF), and observed at × 400 magnification. (B) Single and double precursors were located near the endosteum and there was no statistical difference between the two groups. By contrast, the clustered precursors were located further from endosteum than single and double precursors.

Figure 2

ALIP-like clusters during CR in AML patients were considered the best indicator of early relapse among the three precursor group. (A) Densities of single, double, and clustered precursors were higher in the pre-relapse cases. (B) showing ROC analysis for the prediction of relapse from single, double and clustered precursors. This analysis showed that ALIP-like clusters mostly favored the prediction of relapse with AUC = 0.711. AUC: Area under curve. (C) The median time from histologic relapse to overt hematologic relapse.

Figure 3

Exceeding ALIP-like cluster density (>4/mm²) indicated poorer survival. Contrast to cases with <4/mm² of ALIP-like cluster density, cases with exceeding ALIP-like cluster density (>4/mm²) carried poorer outcome in both RFS (A) and OS (B).

Figure 4

ALIP-like clusters are of heterogeneous myeloid precursors. All ALIP-like clusters expressed MPO. Some clusters expressed both CD34 and CD117 (A). However, other clusters expressed neither CD34 nor CD117 (B). Sections were observed at × 1000 magnification. Arrows indicated ALIP-like clusters.