What is the role of minimal residual disease studies in the workup of pediatric acute lymphoblastic leukemia (ALL)?

Updated: Jan 03, 2019
  • Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP; Chief Editor: Jennifer Reikes Willert, MD  more...
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Answer

Historically, the response to leukemia treatment was assessed morphologically, which can be challenging when looking for small numbers of leukemic cells, especially in bone marrow specimens recovering from chemotherapy or after transplantation.

Studies of minimal residual disease (MRD) may be based on the detection of chimeric transcripts generated by fusion genes, the detection of clonal TCR or immunoglobulin heavy-chain (IgH) gene rearrangements, or the identification of a immunophenotype specific to the leukemic blasts. [2] All of the methods for detecting MRD have a much higher sensitivity than that of morphology, and all studies using MRD techniques have shown significant correlations between end-of-induction leukemia burden and outcome. [12] As a result, current treatment protocols use MRD measurements for acute lymphoblastic leukemia risk assignment. [13]

For B-lineage ALL patients, the significance of MRD was quantitatively different among genetic subgroups and NCI risk groups, with the time point for measurement varying between studies:

  • On COG P9904/5/6 clinical trials, multivariate analysis found Day 29 (end of induction) bone marrow (BM) MRD measured by flow cytometry with a cut-off of 0.01% was the most significant predictor of outcome in patients with B-ALL. The  These studies also found that Day 8 peripheral blood MRD level was an independent predictor of outcome in multivariate analysis.

  • The UK ALL 2003 clinical trial also confirmed MRD as the single most important predictor of relapse, and patients with day 29 BM MRD ≥ 0.01% had a threefold higher relapse rate (5-year EFS 79%) compared with low-risk patients (5-year EFS 94-95%).

  • The St Jude Total XV trials confirmed that BM MRD on Day 19 and Day 46 of induction therapy were important predictors of relapse with Day 19 BM MRD of < 1% detecting a favorable risk group (10-year EFS 95-100%) and day 19 BM MRD of >1% who still had >0.01% at day 46 having poor outcomes (10-year EFS 25-69%)

For T-lineage ALL patients:

  • The Italian Association of Pediatric Haematology-Oncology (AIEOP)-Berlin-Frankfurt-Muenster (BFM) 2000 study used PCR to measure MRD on Day 33 (end induction) and Day 78 (end of consolidation, EOC) and found EOC MRD a better predictor of adverse outcome in T-lineage ALL. Regardless of Day 33 MRD, patients who had EOC MRD < .01% had a 7-year EFS of at least 80%, in contrast to patients with EOC MRD >.01% who had a7-year EFS of 49%.


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