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MONTREAL -- Absolute level of minimal residual disease (MRD) assessed by flow cytometry is an important consideration in determining remission among patients with acute lymphoblastic leukemia (ALL) who have discordance between morphology and MRD, according to a large analysis.

Based on these findings, there may be a role for flow cytometry to eventually replace morphology altogether, according to Sumit Gupta, MD, PhD, of The Hospital for Sick Children and the University of Toronto.

At the very least, the data "strongly support ... that MRD should augment the definition of morphology," Gupta said at the meeting here.

While MRD assessment, whether by flow cytometry or PCR-based methods, has become integral to risk stratification after initial therapy for ALL, and intensification of therapy in patients with high MRD has improved outcomes, remission itself is still defined by morphology, Gupta said.

For the vast majority of patients this is not problematic, because MRD and morphology are generally concordant. But in patients with discordance between these two assessments, there is a clinical dilemma.

Gupta's study included 9,350 children, adolescents, and young adults on frontline Children's Oncology Group trials with either B- or T-precursor acute lymphoblastic leukemia (B-ALL and T-ALL).

Bone marrow was assessed for remission at the end of induction therapy (Day 29). Morphologic remission was defined as M1 (<5% leukemic blast cells) versus M2 or M3 (5-25% or >25% blasts), and MRD was measured by flow cytometry.

The vast majority (97.4%) were morphology and MRD concordant, with only a few patients showing a discordance of low MRD and high M2/M3 morphology: "For example, only 2 of 84 patients with M3 morphology had low MRD," Gupta said.

However, discordance with low M1 morphology and high MRD occurred in 163 patients and was significantly more common in T-ALL than B-ALL (6.9% versus 0.9%, P<0.0001).

This type of low morphology/high MRD discordance was associated with an intermediate probability of 5-year event free survival (EFS) compared with patients concordantly in remission or not in remission.

Specifically, in B-ALL, 5-year EFS was 59.1% in discordant patients compared with 87.1% in those concordantly in remission and 39.1% in those concordantly not in remission (P<0.0001). There was a similar pattern in T-ALL disease, with a 5-year EFS of 80.3% in discordant patients versus 87.6% and 62.7% among those is concordant remission or not, respectively, although the differences were not statistically significant.

The researchers hypothesized that this intermediate response rate in discordant patients was being driven by MRD, so they compared discordant patients and patients concordantly not in remission – both groups with high MRD (5% or more), but the former with low M1 morphology and the latter with M2 morphology. They found that median MRD levels were indeed higher in patients concordant for non-remission (14.6%) versus discordant patients (8.2%).

Putting morphology and MRD into a multivariate model showed that MRD had a significant impact on EFS (P<0.0001), whereas morphology "barely meets the conventional threshold of statistical significance" at P=0.05, "suggesting that MRD is the actually driver ... more so than morphology."

In practical terms, using MRD to augment the morphological definition of remission could have "significant implications not just for clinical trial eligibility and definitions, but for our everyday clinical practice as well," he concluded. This would mean that "patients with discordance would undergo more appropriate risk stratification and therefore receive more appropriate treatment."