Detection and management of minimal residual disease in acute lymphoblastic leukemia

Abstract

The detection of minimal residual disease (MRD) has become part of the state-of-the-art diagnostics to guide treatment both in pediatric and adult acute lymphoblastic leukemia (ALL). This applies to the treatment of de novo and recurrent ALL. In high-risk ALL, MRD detection is considered an important tool to adjust therapy before and after hematopoietic stem cell transplantation. Precise quantification and quality control is instrumental to avoid false treatment assignment. A new methodological approach to analyzing MRD has become available and is based on next-generation sequencing. In principle, this technique will be able to detect a large number of leukemic subclones at a much higher speed than before. Carefully designed prospective studies need to demonstrate concordance or even superiority compared with those techniques in use right now: detection of aberrant expression of leukemia-specific antigens by flow cytometry of blood or bone marrow, or detection of specific rearrangements of the T-cell receptor or immunoglobulin genes by real-time quantitative polymerase chain reaction using DNA of leukemic cells. In some cases with known fusion genes, such as BCR/ABL, reverse transcriptase-polymerase chain reaction has been used as additional method to identify leukemic cells by analyzing RNA in patient samples. MRD detection may be used to modulate treatment intensity once it has been demonstrated at well-defined informative checkpoints that certain levels of MRD can reliably predict the risk of relapse. In addition, MRD is used as end point to determine the activity of a given agent or treatment protocol. If activity translates into antileukemic efficacy, MRD may be considered a surrogate clinical end point. Learning Objectives

Assessment of Minimal Residual Disease in Standard-Risk AML

“…The assessment of minimal residual disease may capture some of this individual variation but to date is established for use only in acute promyelocytic leukemia and childhood acute lymphoblastic leukemia. 15,37,38 We therefore investigated the prognostic value of assessment of minimal residual disease in the most common molecular subtype of AML. 2,7 Molecular profiling highlighted the molecular heterogeneity of AML, with 223 patients categorized into more than 150 subgroups.…”

Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia

“…Resistance against chemotherapy is closely related to dormancy as chemotherapy mainly targets proliferation-associated processes that are inactive in dormant cells (Clevers, 2011, Zhou et al., 2009). Dormant cells, by definition, do not divide or divide very slowly over prolonged periods of time, might survive chemotherapy, persist in minimal residual disease (MRD), and give rise to relapse (Schillert et al., 2013, Schrappe, 2014). Indeed, an increased frequency of non-dividing tumor cells has been described in patients after chemotherapy for defined subtypes of ALL (Lutz et al., 2013).…”

Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia

“…To date, the prognosis of B-ALL patients has focused mainly on clinical, haematological and genetic factors, such as age, leukocyte count at diagnosis, percentage of blast in peripheral blood, immunophenotype, central nervous system involvement, cytogenetic and molecular alterations and the presence of minimal residual disease (MRD), the latter two characteristics being most strongly associated with prognosis (Izraeli, 2010; Pui et al , 2011; Salari et al , 2014; Schrappe, 2014). However, ∼30% of pediatric and 50% of adult ALL patients lack defined genetic hallmarks of biological and clinical significance (Bungaro et al , 2009; Dawson et al , 2011; Forero-Castro et al , 2016a; Forero-Castro et al , 2016b).…”