MRD may more accurately assess remission than morphology in ALL

Issue: February 10, 2017

SAN DIEGO — Discordance between traditional morphologic measures of remission and assessment of minimal residual disease was associated with inferior outcomes among children with acute lymphoblastic leukemia, according to study results presented at the ASH Annual Meeting and Exposition.

Perspective from Rebecca A. Gardner, MD

Based on these findings, minimal residual disease (MRD) should replace morphology in defining remission in patients with ALL, according to Sumit Gupta, MD, staff oncologist and clinician investigator in hematology/oncology at The Hospital for Sick Children, as well as assistant professor in the department of pediatrics at University of Toronto in Canada, and colleagues.

Although MRD is used to determine depth of remission in patients with ALL, remission is still defined — in clinical practice and in clinical trials — according to morphological assessment.

Thus, Gupta and colleagues evaluated outcomes of children, adolescents and young adults who had discordant assessments of remission by morphology compared with MRD. The goal was to identify the extent to which morphologic assessment of remission can aid the risk assessment process in these patients.

The analysis included 9,350 patients enrolled in frontline Children’s Oncology Group trials. This cohort included 7,857 patients with B-ALL — 5,049 of whom were standard risk and 2,808 of whom were high risk — and 1,493 patients with T-ALL.

The researchers used traditional criteria to determine M1 (< 5% leukemic blasts; remission), M2 (5% to 25% leukemic blasts) and M3 (> 25% leukemic blasts) morphology, and they determined MRD status by flow cytometry. The primary outcome was to assess EFS in discordant vs. concordant morphology and MRD remission assessments.

Overall, the rate of discordance was low. Few patients with M2 or M3 marrows had discordant low MRD values. For example, only two (2.4%) of 84 patients with M3 morphology had MRD less than 5%. Of 202 patients with M2 or M3 morphology, 23 (11.4%) had MRD less than 1% and 9 (4.5%) had MRD less than 0.1%.

“We found that 97% of children are morphology–flow concordant,” Gupta said. “Analyses of discordance were restricted to patients with M1 morphology but with flow cytometry consistent with failure to achieve remission (MRD 5%).”

Within this category, the rate of discordance was 0.9% among patients with B-ALL. However, among patients with T-ALL, the discordance was 6.9% (P < .0001).

Predictors of discordance in multivariable analysis included age 10 years or older (OR = 1.7; 95% CI, 1.1-2.8), white blood cell counts of 50,000/microliter or higher (OR = 2.1; 95% CI, 1.3-3.6) and unfavorable compared with favorable cytogenetics (OR = 31; 95% CI, 8.9-109).

“The variables that are traditionally associated with poor response also predicted discordance,” Gupta said.

Among children with B-ALL, those with M1 morphology but discordant MRD had slightly higher 5-year EFS than those with M2 morphology and discordant MRD (59.1% ± 6.5% vs. 39.1% ± 7.9%; P = .03).

However, children with M1 morphology and concordant MRD — defined as less than 5% — had significantly higher 5-year EFS than those with M1 morphology but discordant MRD (87.1% ± 0.4% vs. 59.1% ± 6.5%; P < .0001).

Five-year EFS outcomes were similar among patients with T-ALL who had discordant M1 morphology and MRD compared with those with M2 morphology and MRD of 5% or higher.

“These results suggest that, in addition to measuring depth of remission, MRD should replace morphology in defining remission in subjects with ALL, with consequent implications for risk stratification, treatment assignment and eligibility for experimental agents,” Gupta concluded. – by Rob Volansky

Reference :

Gupta S, et al. Abstract 758. Presented at: The ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

Disclosures: Gupta reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

Rebecca A. Gardner, MD

Ever since minimal residual disease (MRD) testing came out, people have been excited about how we’re now better able to prognosticate how patients do with acute lymphoblastic leukemia, but one thing that has stood out is that we still base patients’ remission status on their morphologic remission. This is the first time researchers have really looked and said that MRD is, in fact, superior to morphologic assessment of remission status. Researchers retrospectively looked at patients with pre-B and T-cell ALL who were in morphologic remission and evaluated whether their MRD rate was concordant or discordant with their morphologic remission. They found that, among patients who had discordant MRD results, MRD actually was more prognostic than morphologic remission. Moving forward, we need to rethink how to define endpoints in trials and how to stratify patients. If, in fact, MRD is a better modality going forward, trials will have to adapt to that and rely on MRD rather than morphological remission.

Rebecca A. Gardner, MD

Seattle Children’s Hospital

Disclosures: Gardner reports no relevant financial disclosures.