Best Practices in MRD Quantification: The Importance of the First Bone Marrow Pull

Measurable residual disease (MRD, formerly known as minimal residual disease) has been defined as the quantity of residual leukemic cells remaining in the bone marrow or peripheral blood following treatment. The achievement of MRD negativity at the threshold of 10-4 (0.01%) leukemia cells has been shown to be the single most important factor in predicting the risk of relapse for patients with acute lymphoblastic leukemia (ALL). Accurate measurement of MRD relies on the retrieval of a high-quality specimen of the patient’s bone marrow.

Aaron Logan, MD, PhD, associate professor of hematology and blood and marrow transplantation at the University of California, San Francisco, spoke with Nucleus about the crucial importance of accurate MRD measurement and his involvement in efforts to educate the diverse community of health care professionals who perform bone marrow aspiration about best practices in MRD measurement. Dr. Logan is the senior author of a review article on the clinical significance and management of MRD in adults with ALL that was published in July in Clinical Advances in Hematology & Oncology.

A meta-analysis published in JAMA Oncology in 2017 showed that patients with ALL who were MRD-negative early in the course of therapy were substantially more likely to remain in remission than those who were MRD-positive. The findings were consistent across therapies, methods and times of MRD assessment, MRD cutoff levels, and disease subtypes.

Dr. Logan identified three key messages for health care professionals concerning MRD and its quantification in patients with ALL:

  • MRD quantification should “absolutely” be considered the standard of care in the management of patients of all ages with ALL.
  • MRD negativity does not guarantee continued remission. To ensure that any disease progression is detected as early as possible and therapy adjusted accordingly, MRD assessment should occur serially as patients proceed through therapy.
  • The optimal way to assess MRD is via an initial pull of no more than 3 mL of bone marrow aspirate to avoid hemodilution of the specimen.

Why is it so important to use aspirate from the first bone marrow pull to assess MRD? Clinicians may order many tests to be performed on bone marrow aspirate in the course of management and follow-up of patients with ALL, Dr. Logan said.

“It’s not unusual for a patient to have 20 mL aspirated in a single draw,” he said. “But when you take a large volume of material from the bone marrow all at once, the aspirate will be diluted by peripheral blood.” In one recently reported study, out of 410 analyzed bone marrow specimens, 30% had clinically significant hemodilution.

MRD quantification is highly sensitive to hemodilution because it is reported as the number of leukemia cells divided by the total number of cells in the sample. If the sample is hemodiluted, the reported proportion of leukemia cells may be artifactually low.

“Let’s say, for example, that a patient with ALL has a residual disease burden of 0.2%,” Dr. Logan said. “If the sample sent for MRD assessment is significantly hemodiluted, their disease burden might be inaccurately assessed at only 0.05%.”

This matters because the MRD threshold approved by the U.S. Food and Drug Administration (FDA) for treatment with the bispecific T-cell engager blinatumomab – the first and as yet only drug approved to treat patients with B-ALL who are in their first or second remission and have detectable MRD – is 0.1%.        

“A disease burden of 0.05% does not meet the FDA-approved criteria for treatment with blinatumomab, which could result in the patient receiving inferior care because of inaccurate MRD quantification based on a hemodiluted bone marrow sample,” Dr. Logan said.

Other important decisions, such as whether to pursue allogeneic hematopoietic cell transplantation, are based on achievement of undetectable MRD at the 0.01% threshold, Dr. Logan pointed out. “Optimal patient care may be compromised if such decisions are based on inaccurate assessments caused by MRD quantification in hemodiluted bone marrow aspirates,” he said.

The best way to ensure that the sample for MRD quantification is not hemodiluted is to limit it to no more than 3 mL from the first bone marrow pull, he said. “Hand that syringe off immediately for processing of the sample. Then use a fresh syringe to pull whatever you need for other tests, which are less likely to be adversely affected by hemodilution.”

Dr. Logan is working with other hematologists on an effort to educate providers who perform bone marrow aspiration about the optimal way to perform it for MRD quantification. In many centers, he noted, bone marrow aspiration may be performed by an interventional radiologist, a nurse practitioner, or a physician assistant, rather than by a hematologist or oncologist. The group would also like to reach out to community oncologists who may occasionally find themselves treating a patient with ALL so that they are aware of the importance of accurate MRD quantification.

“ALL is a very rare disease,” he said. “About 6,000 people in the United States are diagnosed with it every year, and slightly more than half of them are under the age of 18. So it’s rare for adult oncologists working in the community to see a patient with ALL. They might see at most one or two patients with ALL in a year, and they may be less familiar than academic hematologists are with concerns about hemodilution of bone marrow specimens intended for MRD quantification.”

Citations for linked articles

[review article] Akabane H, Logan AC. Clinical Significance and Management of MRD in Adults With Acute Lymphoblastic Leukemia. Clin Adv Hematol Oncol. 2020 July;18(7): 413–422.

[meta-analysis] Berry DA, Zhou S, Higley H, et al. Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis. JAMA Oncol. 2017;3(7):e170580. doi:10.1001/jamaoncol.2017.0580  

[one recently reported study] Shalabi H, Yuan C, Kulshreshtha A, et al. Disease Detection Methodologies in Acute Lymphoblastic Leukemia (ALL): Opportunities for Improvement. Biol Blood Marrow Transplant. 2019 March;25(3):S108–109. https://doi.org/10.1016/j.bbmt.2018.12.383