MRD determination in bone marrow at the end of induction (EOI) and end of consolidation (EOC)

Source: Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 21, 2025 · Captured 2026-09-09.

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Context: Risk-Based Treatment Assignment / Prognostic Factors Affecting Risk-Based Treatment / Response to initial treatment

Morphological assessment of residual leukemia in blood or bone marrow is often difficult and is relatively insensitive. Traditionally, a cutoff of 5% blasts in the bone marrow (detected by light microscopy) has been used to determine remission status. This corresponds to a level of 1 in 20 malignant cells. To detect lower levels of leukemic cells in either blood or marrow, specialized techniques are required. Such techniques include polymerase chain reaction (PCR) assays, which determine unique Ig/T-cell receptor gene rearrangements and fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes. With these techniques, detection of as few as 1 leukemia cell in 100,000 normal cells is possible, and MRD at the level of 1 in 10,000 cells (1 × 10-4 or 0.01%) can be detected routinely.[130] Newer techniques involving high-throughput sequencing (HTS) of Ig/T-cell receptor gene rearrangements can increase sensitivity of MRD detection to 1 in 1 million cells (1 × 10-6 or 0.0001%).[131]

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Multiple studies have demonstrated that EOI MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[132-134] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities.[135] In general, patients with higher levels of EOI MRD have a poorer prognosis than do those with lower or undetectable levels.[130,132-134] However, the absolute risk of relapse associated with specific MRD levels varies by genetic subtype. For example, at any given level of detectable EOI MRD, patients with favorable cytogenetics, such as ETV6::RUNX1 or high hyperdiploidy, have a lower absolute risk of subsequent relapse than do other patients, while patients with high-risk cytogenetics have a higher absolute risk of subsequent relapse than do other patients.[136] This observation may have important implications when MRD is used to develop risk classification plans.

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EOI MRD is used by almost all groups as a factor in determining the intensity of postinduction treatment. Patients found to have higher EOI MRD levels (typically >0.1% to 0.01%) are allocated to more intensive therapies.[130,133,137]; [138][Level of evidence B4]

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A study of 619 children with ALL compared the prognostic utility of MRD by flow cytometry with the more sensitive HTS assay. Using an EOI MRD cut point level of 0.01%, HTS identified approximately 30% more cases as positive (i.e., >0.01%). Patients identified as positive by HTS but negative by flow cytometry had an intermediate prognosis, compared with patients categorized as either positive or negative by both methods. Patients meeting the criteria for standard-risk ALL with undetectable MRD by HTS had an especially good prognosis (5-year EFS rate, 98.1%).[131]

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MRD levels obtained 10 to 12 weeks after the start of treatment (EOC) have also been shown to be prognostically important. Patients with high levels of EOC MRD have a significantly inferior EFS compared with other patients.[134,135,139] In one study by the Dutch Children's Oncology Group, patients with low but detectable EOC MRD (<0.05%, assessed by Ig/TR PCR assay) fared as well as those with nondetectable MRD at this time point, if their subsequent MRD assessments were negative. However, these patients did poorly if their subsequent MRD assessments remained detectable by the PCR assay.[140]

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B-ALL. For patients with B-ALL, evaluating MRD at two time points (EOI and EOC) can identify the following three prognostically distinct patient subsets:[135]

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B-ALL. For patients with B-ALL, evaluating MRD at two time points (EOI and EOC) can identify the following three prognostically distinct patient subsets:[135]

Low or undetectable EOI MRD: Best prognosis.

B-ALL. For patients with B-ALL, evaluating MRD at two time points (EOI and EOC) can identify the following three prognostically distinct patient subsets:[135]

High EOI MRD but low or negative EOC MRD: Intermediate prognosis.

B-ALL. For patients with B-ALL, evaluating MRD at two time points (EOI and EOC) can identify the following three prognostically distinct patient subsets:[135]

High EOC MRD (week 10–12 of therapy): Worst prognosis. The prognostic impact of EOC MRD is modulated by NCI risk criteria. NCI high-risk patients with high EOC MRD have DFS rates lower than NCI standard-risk patients who have similar MRD levels at this time point.[139]

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T-ALL. There are fewer studies documenting the prognostic significance of MRD in patients with T-ALL. The United Kingdom Acute Lymphoblastic Leukaemia (UKALL) group reported that T-ALL patients with nondetectable EOI MRD had excellent outcomes, while those with very high MRD levels (>5%) at EOI had a poor prognosis. However, for all other T-ALL patients, an association between EOI MRD level and relapse risk was not found.[136] The DFCI ALL consortium also reported that T-ALL patients with very low EOI MRD (<10-4) had a very favorable outcome.[45] In the COG AALL0434 trial, high EOI MRD (>0.1%) was an independent predictor of inferior EFS and OS for patients with T-ALL on multivariable analysis.[46] In this trial, high EOI MRD was associated with inferior EFS in patients with non-ETP and near-ETP T-ALL, but not in those meeting the immunophenotypic definition of ETP.[46]Another study also indicated that MRD at a later time point may be more prognostically significant in T-ALL.[141] In the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) ALL-BFM-2000 (NCT00430118) trial, MRD status at day 78 (week 12) was the most important predictor for relapse in patients with T-ALL.[141] Patients with detectable MRD at EOI who had negative MRD by day 78 generally had a favorable prognosis, similar to that of patients who achieved MRD-negativity at the earlier EOI time point.[141] In the COG AALL0434 trial, EOC MRD was evaluated in patients with T-ALL who had very high EOI MRD (>1%). High EOC MRD was associated with a markedly inferior outcome.[46] The COG AALL1231 study confirmed the prognostic significance of EOC marrow MRD for patients with T-ALL.[142]

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MRD measurements, in conjunction with other presenting features, have also been used to identify subsets of patients with an extremely low risk of relapse. The COG reported a very favorable prognosis (5-year EFS rate, 97% ± 1%) for patients with precursor B-cell phenotype, NCI standard risk age/leukocyte count, CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the ETV6::RUNX1 fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood) and EOI (from bone marrow).[133] The excellent outcomes in patients with low MRD at the EOI were sustained for more than 10 years from diagnosis.[143]

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Modifying therapy on the basis of MRD determination has been shown to improve outcome.

The UKALL2003 (NCT00222612) study demonstrated that reduction of therapy (i.e., one rather than two courses of delayed intensification) did not adversely impact outcome in non-high–risk patients with favorable EOI MRD.[22][Level of evidence B1] In a randomized controlled trial, the UKALL2003 study also demonstrated improved EFS for standard-risk and intermediate-risk patients who received augmented therapy if EOI MRD was greater than 0.01% (5-year EFS rates, 89.6% for augmented therapy vs. 82.8% for standard therapy).[144]

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The Dutch ALL10 trial stratified patients into the following three risk groups on the basis of MRD after the first month of treatment and after the second cycle of chemotherapy:[145][Level of evidence B4] Compared with previous trials conducted by the same group, therapy was less intensive for standard-risk patients but more intensive for moderate-risk and high-risk patients. The overall 5-year EFS rate (87%) and OS rate (92%) were superior to the previous Dutch studies.

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Standard risk (low MRD after the first month of treatment).

Moderate risk (high MRD after the first month of treatment, low MRD after the second cycle of chemotherapy).

High risk (high MRD after the second cycle of chemotherapy).

In the DFCI ALL Consortium 05-001 trial, B-ALL patients with high EOI MRD (defined as ≥1 × 10-3) were classified as very high risk regardless of other presenting characteristics. These patients received an intensified cytotoxic chemotherapy backbone. The 5-year DFS rate for these patients was 77%, significantly better than outcome for such patients on previous trials, when EOI MRD was not used to stratify therapy.[8]

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