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Minimal residual disease negativity associated with longer survival in ALL

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May 12, 2017

Children and adults with acute lymphoblastic leukemia who achieved minimal residual disease negativity appeared more likely to be alive and disease free after 10 years, according to a meta-analysis published in JAMA Oncology.

“Having no minimal residual disease indicates substantial long-term treatment benefit in EFS and OS in both adult and pediatric ALL,” Donald A. Berry, PhD, professor of biostatistics at The University of Texas MD Anderson, told HemOnc Today. “Because this is an early readout of the treatment’s effect, it can help in the clinical management of the disease. It also paves a path in developing drugs in ALL.”

Donald A. Berry

MRD — the presence of disease in patients deemed to be in complete remission by conventional pathologic analysis — is associated with higher relapse rates in chronic myeloid leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, multiple myeloma and ALL.

To better understand the association between MRD status and EFS and OS, researchers searched PubMed, MEDLINE, and clinicaltrials.gov to perform a literature-based meta-analysis of ALL studies. The analysis included data from 39 publications comprised of 13,637 patients, including 16 adult studies (n = 2,076), 20 pediatric studies (n = 11,249) and three mixed studies (n = 312).

After 10-year follow-up, a greater proportion of children with MRD–negative ALL than MRD–positive ALL achieved 10-year EFS (77% vs. 32%; HR = 0.23; 95% Bayesian credible interval [BCI], 0.18-0.28) and OS (84% vs. 55%; HR = 0.28; 95% BCI, 0.19-0.41).

A greater proportion of adults with ALL who tested MRD negative also achieved 10-year EFS (64% vs. 21%; HR = 0.28; 95% BCI, 0.24-0.33) and OS (60% vs. 15%; HR = 0.28; 95% BCI, 0.2-0.39).

“Pediatric patients with ALL fare better than adults regardless of MRD status,” Berry said. “The most notable difference, depending on age, occurs in MRD–positive patients, especially in OS.”

Although MRD negativity led to better clinical outcomes in the studies analyzed, a new therapy might decrease the rate of MRD but not affect clinical outcomes, according to the researchers.

The improved outcomes with MRD negativity persisted across subgroups and covariates, which was unexpected.

“Although ALL is a heterogeneous disease, we could not find any disease subtypes in which achieving MRD negativity was markedly more important than it’s complement,” Berry said.

Researchers noted the next major advance in determining the association between MRD and EFS and OS in patients with ALL may be the development of more sensitive and standardized tools to assess the level of disease. Next-generation sequencing — which appears to be more sensitive than flow cytometry or polymerase chain reaction — may be easier to standardize and provide a more accurate assessment of MRD.

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“Minimal residual disease is a biomarker of disease in the powerful sense that MRD is the disease,” Berry and colleagues concluded. “However, no assay is perfect. Although MRD is a direct measure of disease burden and treatment response in ALL, there may be sanctuary sites in the body that contribute to relapse but are not measurable by conventional methods.” – by Chuck Gormley

Donald A. Berry, PhD, can be reached at Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., 4-5062 Pickens Academic Tower, Houston, TX 77030; email: dberry@mdanderson.org.

Disclosure: FNIH Biomarkers Consortium project funded this study, which in turn receives funding from AbbVie, Amgen, Genentech and Pfizer. Berry is co-owner of Berry Consultants LLC, a company that designed Bayesian and adaptive clinical trials. The other researchers report no relevant financial disclosures.