According to results published in Leukemia, standardizing technical criteria for assay quality, data reporting, and data interpretation has the potential to improve the application of minimal residual disease (MRD) testing in Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL).

MRD has significant prognostic value for ALL and can be used to stratify patients and enable treatment decisions. However, its role in Ph+ ALL is less clear; variability in laboratories’ methodologies for reverse transcription real-time quantitative polymerase chain reaction (qRT-PCR), which is used to measure BCRABL1 transcript levels for MRD analysis, has given rise to considerable uncertainty. MRD measurements in Philadelphia-negative (Ph-) ALL are usually based on analysis of immunoglobulin and T-cell receptor gene rearrangements, but evidence suggests that BCRABL1 analysis may provide more accurate measurements of MRD in Ph+ disease.

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The EuroMRD Consortium was established in 2001 and comprises 57 MRD-PCR laboratories in Europe, the United States, Australia, Singapore, Japan, Israel, South America, and Australia. Its goals are to develop and assess new MRD techniques, conduct a quality-control program 2 times per year, and develop guidelines for the interpretation of qRT-PCR-based MRD data.

Of note, the EuroMRD Consortium’s standardized methods for extracting RNA, synthesis of cDNA, and cycler platforms did not further improve MRD analysis results.

Researchers assessed MRD measurements in patients with Ph+ ALL from 35 laboratories. Because laboratories used different criteria to report qRT-PCR results, especially when positive samples were at a low level, researchers developed guidelines for data interpretation similar to the guidelines for interpreting qPCR results in Ph- ALL. Notably, the guidelines for Ph+ ALL are more stringent because the assay is consistent, unlike in Ph- disease where the assay is patient-specific and highly variable.

Detailed laboratory guidelines that standardize MRD analysis included parameters for MRD quantitation, assay sensitivity, and optimal sample quality.

The authors noted that these guidelines could enable comparisons of MRD testing for Ph+ ALL across clinical trials. They stated, “[a]dhering to this standard set of recommendations will help in answering clinically unresolved questions about the prognostic and predictive value of specific BCR-ABL1 thresholds and dynamics in distinct therapeutic settings, and help resolve a number of clinical management issues that depend on accurate quantification of BCR-ABL1 transcripts.”

Reference

1.     Pfeifer H, Cazzaniga G, van der Velden VHJ, et al. Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1 [published online March 11, 2019]. Leukemia. doi: 10.1038/s41375-019-0413-0