High BAALC copy numbers in peripheral blood prior to allogeneic transplantation predict early relapse in acute myeloid leukemia patients.

Madlen Jentzsch,Georg-Nikolaus Franke,Sebastian Schwind,Julia Schulz,Wolfram Pönisch,Stefanie Beinicke,Janine Häntschel,Juliane Grimm,Dietger Niederwieser,Marius Bill,Gerhard Behre,Thoralf Lange,Karoline Goldmann,Vladan Vucinic

doi:10.18632/oncotarget.21322

Abstract

High BAALC expression levels at acute myeloid leukemia diagnosis have been linked to adverse outcomes. Recent data indicate that high BAALC expression levels may also be used as marker for residual disease following acute myeloid leukemia treatment. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment for acute myeloid leukemia patients. However, disease recurrence remains a major clinical challenge and identification of high-risk patients prior to HSCT is crucial to improve outcomes. We performed absolute quantification of BAALC copy numbers in peripheral blood prior (median 7 days) to HSCT in complete remission (CR) or CR with incomplete peripheral recovery in 82 acute myeloid leukemia patients using digital droplet PCR (ddPCR) technology. An optimal cut-off of 0.14 BAALC/ABL1 copy numbers was determined and applied to define patients with high or low BAALC/ABL1 copy numbers. High pre-HSCT BAALC/ABL1 copy numbers significantly associated with higher cumulative incidence of relapse and shorter overall survival in univariable and multivariable models. Patients with high pre-HSCT BAALC/ABL1 copy numbers were more likely to experience relapse within 100 days after HSCT. Evaluation of pre-HSCT BAALC/ABL1 copy numbers in peripheral blood by ddPCR represents a feasible and rapid way to identify acute myeloid leukemia patients at high risk of early relapse after HSCT. The prognostic impact was also observed independently of other known clinical, genetic, and molecular prognosticators. In the future, prospective studies should evaluate whether acute myeloid leukemia patients with high pre-HSCT BAALC/ABL1 copy numbers benefit from additional treatment before or early intervention after HSCT.

Highlights

The identification of cytogenetic, molecular, and clinical factors impacting on outcome at acute myeloid leukemia (AML) diagnosis improved risk stratification [1, 2]
Prospective studies should evaluate whether acute myeloid leukemia patients with high preHSCT BAALC/ABL1 copy numbers benefit from additional treatment before or early intervention after hematopoietic stem cell transplantation (HSCT)
QRT-PCR measurable residual disease (MRD) monitoring is widely restricted to patients carrying specific molecular alterations [11] with the exception of Wilms' tumor gene 1 (WT1) expression [9, 12]

Summary

Introduction

The identification of cytogenetic, molecular, and clinical factors impacting on outcome at acute myeloid leukemia (AML) diagnosis improved risk stratification [1, 2]. Detection of measurable residual disease (MRD) through multiparameter flow cytometric (MFC) or quantitative real time PCR (qRT-PCR) assays may allow treatment intervention before overt relapse occurs [3,4,5]. MFC enables MRD assessment through detection of aberrant surface antigen expression in complete remission (CR) [Wormann et al, ASH 1991, 6, 7]. QRT-PCR MRD monitoring is widely restricted to patients carrying specific molecular alterations [11] with the exception of Wilms' tumor gene 1 (WT1) expression [9, 12]. Because clonal evolution can occur at disease progression and might complicate early disease detection at relapse [13], it seems reasonable to track several MRD markers per patient

Methods

Results

Conclusion