Status of minimal residual disease testing in childhood haematological malignancies

Abstract

SummaryIn children with acute leukaemia, measurements of minimal residual disease (MRD) provide unique information on treatment response and have become a crucial component of contemporary treatment protocols. In acute lymphoblastic leukaemia (ALL), the most useful MRD assays are based on polymerase chain reaction (PCR) amplification of antigenreceptor genes, and on flow cytometric detection of abnormal immunophenotypes. The latter is the only MRD assay available for most patients with acute myeloid leukaemia (AML). PCR amplification of chromosomal breakpoints and fusion transcripts can also be used to track MRD in a minority of patients with ALL or AML. Because of the strong correlation between MRD levels and risk of relapse, several ongoing regimens include treatment intensification for children with higher MRD. Treatment de-intensification for patients with early MRD clearance is also being tested. In addition to their direct clinical application, MRD measurements can be used to better understand the molecular and cellular mechanisms of drug resistance in vivo. The identification of new markers of leukaemia and the use of increasingly sophisticated technologies for detection of rare cells should further facilitate routine monitoring of MRD and elucidate the features of drug-resistant leukaemic cells.

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

“…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. HSCT provides a survival advantage over chemotherapy in the treatment of children with high-risk ALL.…”

High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia

“…[5][6][7][8][9] In addition, patients with persistent minimal residual disease (MRD) or hematologic relapse while on therapy are also considered candidates for HCT in current protocols. [10][11][12][13] As contemporary chemotherapy becomes more effective, the proportion of patients undergoing HCT is reduced. For example, patients with core-binding-factor AML or high-risk ALL are now typically treated with chemotherapy alone.…”

Confocal backscattering‐based detection of leukemic cells in flowing blood samples

“…A decrease in the sensitivity in our validation data compared to our training data suggests that further improvements in classification performance may be possible by considering larger data sets or other, slightly more complex algorithms, such as discriminant analysis based on quadratic instead of linear classification optimization or discriminant analysis with kernels (39). Nonetheless, the application of a standard classification algorithm presents improvements over the sophisticated data analysis software and personnel training needed to correlate the various parameters in multidimensional space for proper cell classification, when performing multiparameter flow cytometry (9,40). Finally, automated data analysis in combination with the capability for parallel processing in a microfluidic device offers the potential for processing times that are significantly lower than the 24-h time frame typically offered by standard PCR and flow cytometry analysis (9,41).…”

“…estimate leukemic burden after initial therapy, providing clinicians with an indication of the aggressiveness of the disease and the efficacy of treatment (9)(10)(11). Such information could be used to optimize treatment strategy, minimizing patients' risk for relapse and ultimately improving cure rates.…”

“…Advances in flow cytometry and PCR techniques have been able to improve the detection of these residual leukemic cells, which represent MRD, at neoplastic cell proportions of \1% relative to normal nucleated blood cells. A number of flow cytometry and PCR studies have shown that patients with MRD levels of 0.01-0.1% (i.e., 1 leukemic cell to 1,000-10,000 normal nucleated cells) during or after therapy have higher chances of relapse (9,(14)(15)(16). However, neither technique is applicable to all patients (17,18).…”