Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology

Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology
This was a retrospective study that analyzed MRD samples of patients treated for childhood Philadelphia-positive ALL or CML in Australia and the Czech Republic. The study was run by a group that has previously shown discrepancies between Ig/TCR-based and BCR-ABL1 transcript based MRD testing for patients with Philadelphia-positive ALL. This study further details the concordance of the MRD methods and looks at related outcomes.
Samples from 48 patients with BCR-ABL1 positive childhood ALL and 3 with CML in blast crisis were analyzed. Each sample had MRD measured by fusion transcript quantification and by clonal Ig/TCR rearrangement. BCR-ABL1 breakpoints were defined by genomic means as opposed to the more standard method of measuring the fusion transcript.
The majority of patients showed good correlation of MRD levels with the different technologies. Genomic (as opposed to transcriptomic) MRD testing also showed differences from Ig/TCR but was consistent with MRD using the BCR-ABL1 fusion-transcript.
Only ALL blasts were BCR-ABL1 positive in patients with concordant MRD. However, in patients with discordant MRD, cell sorting showed the presence of non-blast B-, T- and myeloid cells harbouring the BCR-ABL1 fusion. No significant difference in outcome between patients with concordant and discordant MRD were seen.
Patients were treated on several different trials. The study used a small sample size to compare outcomes. They were unable to identify the genomic breakpoint in 20% of patients.
Different MRD tests yield different results - as expected, PCR-based MRD has a higher sensitivity than flow cytometry-based MRD. The presence of multi-lineage BCR-ABL1 positive cells in patients with discordant MRD suggests that a multipotent hematopoetic progenitor cell is affected similar to CML-like disease. Although different MRD methods yield different results, the clinical significance of this is unclear.