Why and how to quantify minimal residual disease in acute lymphoblastic leukemia?

Abstract

Several studies have demonstrated that monitoring of minimal residual disease (MRD) in childhood and adult acute lymphoblastic leukemia (ALL) significantly correlates with clinical outcome. MRD detection is particularly useful for evaluation of early treatment response and consequently for improved front-line therapy stratification. MRD information is also significant for children undergoing allogeneic hematopoietic stem cell transplantation and those with relapsed ALL. Currently, three highly specific and sensitive methodologies for MRD detection are available, namely multiparameter flow cytometric immunophenotyping, real-time quantitative polymerase chain reaction (RQ-PCR)-based detection of fusion gene transcripts or breakpoints, and RQ-PCR-based detection of clonal immunoglobulin and T-cell receptor gene rearrangements. In this review, characteristics, pitfalls, advantages and disadvantages of each MRD technique are critically discussed. The special emphasis is put on interlaboratory standardization, especially in view of the results obtained within the European collaborative BIOMED-1, BIOMED-2, and Europe Against Cancer projects and recent developments by European Study Group on MRD detection in ALL and EuroFlow Consortium. Standardized MRD techniques form the basis for stratification of patients into the risk groups in new treatment protocols mainly in childhood ALL. Only the results of these studies can answer the question whether MRD-based treatment intervention is associated with improved outcome. Leukemia ( The rationale for detection of MRD in ALL The concept of minimal residual disease (MRD) detection in acute lymphoblastic leukemias (ALL) is inherently associated with the progress in treatment of these malignancies. 1 More than 80% of childhood and 35% of adult ALL patients can be cured with modern chemotherapy supplemented with hematopoietic stem cell transplantation (HSCT) in high risk patients (reviewed by Hoelzer et al. 2 ). Still, a substantial number of ALL patients relapse and the prediction of relapse with conventional prognostic factors such as age, blast count at diagnosis, immunophenotype at diagnosis, presence of chromosome aberrations, response to steroid prophase and classical clinical risk group assignment is far from optimal. Also microarray-based gene expression profiling could not identify gene signatures, typically associated with high risk of relapse. Tracing residual leukemic cells during early phases of treatment provides prognostic information superior to all known classical prognostic factors. Several prospective studies in childhood ALL demonstrated that the most relevant information comes from detection of MRD in bone marrow at the early phases of treatment, particularly at the end of induction treatment (reviewed by Szczepań ski et al. 3 and Cazzaniga and Biondi 4 ). Children with undetectable MRD at the end of induction have an excellent prognosis and are good candidates for treatment de-intensification or at least should not be subjected to further treatment intensificat...

Relationship between minimal residual disease measured by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation and outcome in children with acute lymphoblastic leukemia

“…Current MRD assays are based on polymerase chain reaction amplification of antigen-receptor genes and detection of abnormal immunophenotypes by multiparametric flow cytometry. 7,16,17 Multiparametric flow cytometry-based assays are rapid, readily available and provide accurate MRD quantification while simultaneously yielding information on normal hematopoietic status. 9 Multiparametric flow cytometry and polymerase chain reaction amplification of the genes encoding immunoglobulin and T-cell receptor proteins estimate similar levels of MRD in most remission samples obtained from children with ALL, 8,[18][19][20] when the level of MRD is 0.01% or greater.…”

Cytotoxic effect of trans-cinnamaldehyde on human leukemia K562 cells

“…Thus, with the exception of graft-versus-leukemia (GVL) effect, there are not many treatment options available today to eradicate residual malignant cells. However, GVL effect is mediated by GVHD, a potentially dangerous and usually mortal condition often developed by patients following HSCT [22] . Therefore, it is necessary to develop new strategies to treat patients post-HSCT.…”

Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring

“…[20][21][22][23] In Ph-positive (Ph þ ) ALL cases, quantitative detection of the BCR/ABL fusion transcript provides an alternative option for follow-up. MRD monitoring based on fusion transcript detection possesses some disadvantages, 24 but the substantial advantage of this method is the opportunity to use a universal system for fusion transcript identification and monitoring, which makes this method relatively easier, faster and cheaper than the Ig/TCR approach. We have previously shown that in TEL/AML1-positive childhood ALL, fusion transcript-based MRD monitoring is clinically relevant and closely correlates with the Ig/TCR approach.…”