Icon of CellsWhat is MRD?

Measurable residual disease (MRD) refers to the presence of leukemic cells below the threshold of detection when using conventional morphologic methods.1,2 While there is no consensus on a precise definition of MRD positivity, a sensitivity threshold of 10–4 has been used to predict patient outcomes.3

Complete remission (CR) is typically defined as < 5% bone marrow blasts.3 A substantial proportion of adult patients with ALL relapse despite achieving CR, with a reported relapse rate of 40%–50%.4 Furthermore, patients who achieve CR according to morphologic assessment alone may harbor some residual cancer cells in the bone marrow, with 30%–40% testing positive for MRD.5,6,*

           MRD and risk of relapse7

Chart showing MRD and risk of relapse Chart showing MRD and risk of relapse

Research continues to lead to an improved understanding of the impact of MRD on patient prognosis and outcomes.8

Icon of BellWhy is MRD
important?

A meta-analysis (Berry et al, 2017) assessed the presence of MRD after induction and consolidation therapy and concluded that MRD positivity was associated with negative outcomes regardless of treatment.8

According to the Berry meta-analysis, the presence of MRD is a strong predictor of relapse, which leads to limited treatment options and poor patient outcomes.8 Achieving MRD(–) status early in the course of treatment has been shown to give patients a reduced risk of relapse and a stronger chance for longer overall survival.8

Adult ALL and MRD

At 10 years, adult patients who achieved MRD negativity had 64% EFS (event-free survival) compared with 21% EFS for patients who were MRD(+).8,† An estimated benefit was also seen in OS with MRD negativity in adult patients.8

Impact of MRD status on EFS: adult ALL8,†

Chart Showing Impact of MRD status on EFS: Adult ALL Chart Showing Impact of MRD status on EFS: Adult ALL

Impact of MRD status on OS: adult ALL8,‡

Chart Showing Impact of MRD status on OS: Adult ALL Chart Showing Impact of MRD status on OS: Adult ALL

Pediatric ALL and MRD

MRD status has also shown to be a predictor of OS and EFS in pediatric patients with ALL.8 At 10 years, pediatric patients who achieved MRD negativity had 77% EFS compared with 32% for patients who were MRD(+).8,§ An estimated benefit was also seen in OS with MRD negativity in pediatric patients.8

Impact of MRD status on EFS: pediatric ALL8,§

Chart Showing Impact of MRD status on EFS: Pediatric ALL Chart Showing Impact of MRD status on EFS: Pediatric ALL

Impact of MRD status on OS: pediatric ALL8,**

Chart Showing Impact of MRD status on OS: Pediatric ALL Chart Showing Impact of MRD status on OS: Pediatric ALL

MRD status is a prognostic factor for post-HSCT outcomes

A study (Pulsipher et al, 2015) found that MRD negativity prior to HSCT was associated with improved 2-year OS probability in pediatric/AYA patients with B-cell precursor ALL.9,††

Post-HSCT OS probability for pediatric/AYA patients with B-cell precursor ALL9,††

Chart Showing Post HSCT Overal Survival Probability based on MRD status Chart Showing Post HSCT Overal Survival Probability based on MRD status

Additionally, a retrospective study (Logan et al, 2014) found that MRD ≥ 10-4 within 30 days prior to HSCT was significantly associated with relapse post-HSCT in adult/AYA patients with B-cell ALL.10,‡‡

Post-HSCT DFS probability for adult/AYA patients with B-cell ALL10,‡‡

Chart Showing Post HSCT Disease Free Survival Probability based on MRD status Chart Showing Post HSCT Disease Free Survival Probability based on MRD status

Watch Jae Park discuss the
prognostic value of MRD

Video Thumbnail: Physician Jae Park Discusss Prognostic Value of MRD Video Thumbnail: Physician Jae Park Discusss Prognostic Value of MRD
Jae Park, MD

Associate Attending Physician
Memorial Sloan Kettering Cancer Center

Click here for considerations for assessing when to
test for MRD, including helpful time points
throughout a treatment journey

Icon of Lightbulb Emerging concepts
in defining MRD and
its prognostic
implications in ALL

Icon of Lightbulb

Emerging concepts
in defining MRD and
its prognostic
implications in ALL

There remains ongoing research on emerging concepts of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL), including MRD cutoff levels appropriate for prognosis and treatment decisions, standardization of MRD testing methodologies, the use of peripheral blood versus bone marrow to quantify MRD, and identification of optimal time points for MRD testing. Additionally, the prognostic implications of MRD status may vary during a patient’s treatment journey (eg, in early assessment versus post-remission monitoring).11,††

Icon of patientDiscussing complex topics, like MRD, with patients: helpful perspectives

Icon of patient

Discussing complex topics, like MRD, with patients: helpful perspectives

Your patients may want to learn more about measurable residual disease (MRD). When treating patients who have achieved remission, it can be helpful to explain that a relatively small number of cancer cells remain in their body. This is called measurable residual disease, or MRD.12

As a clinician, you have most likely had the challenge of communicating the complexity of disease, potential relapse, and the rationale for your next steps in treatment in a way that puts patients at ease. In the case of MRD, you may already have an explanation established that resonates well, or you can consider explaining that MRD means that, even though they may not have signs or symptoms of cancer, there is a chance the cancer can return, which is called a relapse.12,13 If your patients test positive for MRD, it can be encouraging to tell them that there are treatment options that can help them eliminate these small traces of cancer.3 MRD positivity during treatment may also help inform important decisions, such as the role of bone marrow transplantation.12

MRD assessment is an
important prognostic tool
for treating ALL3

*Range based on 2 clinical studies in which MRD was measured at different time points.5,6

†According to a meta-analysis of 16 studies evaluating 2,065 adult patients with ALL.8

‡According to a meta-analysis of 5 studies evaluating 806 adult patients with ALL.8

§According to a meta-analysis of 20 studies evaluating 11,249 pediatric patients with ALL.8

**According to a meta-analysis of 5 studies in 2,876 pediatric patients with ALL.8

††Study analyzed MRD status determined by NGS for 41 pediatric and AYA patients aged 1–21 years with B-cell precursor ALL in CR1 and CR2 who proceeded to HSCT.9

‡‡Study retrospectively analyzed the contribution of MRD in the survival of 29 patients ages 16 to 67 years with B-cell ALL who proceeded to HSCT.10

ALL, acute lymphoblastic leukemia; AYA, adolescent and young adult; BCI, Bayesian credible intervals; CR, complete remission; CR1, first complete remission; CR2, second complete remission; DFS, disease-free survival; EFS, event-free survival; HR, hazard ratio; HSCT, allogeneic hematopoietic stem cell transplantation; MRD, measurable residual disease; NGS, next generation sequencing; OS, overall survival.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia V.2.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed November 30, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pediatric Acute Lymphoblastic Leukemia V.1.2022. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed November 30, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 3. Akabane H, Aaron AC. Clinical significance and management of MRD in adults with acute lymphoblastic leukemia. Clin Adv Hematol Oncol. 2020;18:413-422. 4. Hoelzer D. Monitoring and managing minimal residual disease in acute lymphoblastic leukemia. Am Soc Clin Oncol Educ Book. 2013;33:290-293. 5. Gökbuget N, Kneba M, Raff T, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120:1868-1876. 6. Brüggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107:1116-1123. 7. Short NJ, Jabbour E, Albitar M, et al. Recommendations for the assessment and management of measurable residual disease in adults with acute lymphoblastic leukemia: A consensus of North American experts. Am J Hematol. 2019;94:257-265. 8. 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:e170580. 9. Pulsipher MA, Carlson C, Langholz B, et al. IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients. Blood. 2015;125:3501-3508. 10. Logan AC, Vashi N, Faham M, et al. Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biol Blood Marrow Transplant. 2014;20:1307-1313. 11. Brüggemann M, Kotrova M. Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation. Blood Adv. 2017;1:2456-2466. 12. Brüggemann M, Gökbuget N, Kneba M. Acute lymphoblastic leukemia: monitoring minimal residual disease as a therapeutic principle. Semin Oncol. 2012;39:47-57. 13. National Cancer Institute. NCI Dictionary of Cancer Terms. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/relapse. Accessed November 30, 2021.

Back to top