Understanding MRD Status & Testing
MRD Testing Can Uncover Leukemic Progenitor Cells
in Patients With a Hematologic Complete Response
Evaluation of bone marrow by microscopic morphological testing cannot identify
the presence of leukemic cells if there are fewer than 5% (1 in 20) in the total
- A substantial proportion of persistent MRD has been reported to consist of slowly
dividing progenitor cells that may be resistant to certain therapies.4,5
- Relapse is a result of the continued presence of MRD in patients who have achieved a hematologic CR.6
MRD Testing Methods Encompass Different Techniques and Sensitivities, but All Can Be Used to Detect MRD Response6-12
Flow cytometry detects abnormal combinations of cell surface markers on leukemic cells using immunologic methods and has a routine sensitivity of 1 in 10,000 (10-4).6-8,13
Polymerase chain reaction (PCR)
PCR is a highly accurate and sensitive technique enabling genetic abnormalities in B-ALL cells to be detected with a sensitivity of 1 leukemic blast out of 100,000 normal cells (10-5 or 0.001%).6-8 PCR tests detect either the junctional regions of rearranged immunoglobulin and T-cell receptor genes or leukemia-specific gene fusions, such as bcr-abl.1,6
Next-generation sequencing (NGS)
NGS is a newer technology that allows the possibility of simultaneous detection of all the genetic variants existing in a cancer genome at a single-base resolution, with a limit of detection of 1 in 1,000,000 normal cells (10-6 or 0.0001%).9,10,14
Patients Testing Negative for MRD Are Said to Have Achieved an MRD Response
and <1 in 10,000 (10-4 or 0.01%) Residual Leukemic Cells.2,15,16
MRD response is also known as MRD-negative status, molecular CR, complete MRD response, or MRD negativity.2,11,16
All of the methods mentioned here can detect leukemic cells at a sensitivity of at least 10-4, the value needed to declare MRD negativity.2,15,16
Highly sensitive methods for detection of MRD may help inform risk
assessment and treatment.12
Hypothetical Relationship Between MRD Levels and Outcome Over Time9,12
Image derived from a hypothetical graph showing the kinetics of leukemic decrease and re-growth in 2 ALL patients with moderate MRD clearance (intermediate‑risk group).
Derived from Hoelzer D, et al. Hematology Am Soc Hematol Educ Program. 2002.
Loss of MRD response represents an early warning of subsequent clinical relapse.11
Median times from molecular relapse to clinical relapse range from 4 months to 9.5 months depending on the MRD
Prognostic Value of MRD
MRD Detection Informs Risk of Relapse
MRD Response Achieved After Induction Therapy Is an Important Independent Prognostic Factor for Relapse-Free Survival (RFS), Disease-Free Survival (DFS), and Overall Survival (OS).6,11,15
Patients achieving a MRD response are less likely to relapse; only 20% to 30% of patients achieving a MRD response will experience relapse.15
Conversely, the presence of persistent MRD is almost always associated with relapse.17
Both the Speed at Which Molecular Response Is Achieved and the Depth of MRD Eradication Have Prognostic Value3,17
A Study of 3-Year Outcomes by MRD Status Using Current Standard Treatments18
Table derived from a GMALL 06/99 study of 148 evaluable patients 15 to 65 years of age with standard-risk disease defined as absence of t(4;11) MLL translocation or t(9;22) BCR-ABL translocation; WBC count less than 30x109/L for B-cell lineage ALL or less than 100x109/L for T-cell lineage ALL; and achievement of CR after phase I of induction treatment.
MRD Status at Time of HSCT Is an Indicator of Outcomes2,11,19
Patients who have an MRD response at the time of undergoing HSCT have better outcomes than those who still have MRD.2,11,19
However, patients with MRD can still benefit from HSCT.11,20
MRD Testing Can Help Physicians Plan and Personalize Treatment for Patients With This Aggressive Disease11,19,20
References: 1. Campana D. Am J Clin Pathol. 2004;122(suppl 1):S47-S57.
2. Gökbuget N, Kneba M, Raff T, et al. Blood. 2012;120:1868-1876.
3. Campana D, Pui CH. Blood. 1995;85:1416-1434.
4. Dick JE. Blood. 2008;112:4793-4807.
5. Zhou Y, You MJ, Young KH, et al. Hum Pathol. 2012;43:1347-1362.
6. Brüggemann M, Raff T, Kneba M. Blood. 2012;120:4470-4481.
7. Schrappe M. Hematology Am Soc Hematol Educ Program. 2012:137-142.
8. Campana D. Hematology Am Soc Hematol Educ Program. 2010:7-12.
9. Thol F, Kölking B, Damm F, et al. Genes Chromosomes Cancer. 2012;51:689-695.
10. Faham M, Willis T, Moorhead M, Carlton V, Zheng J, Campana D. Blood. 2011;118:Abstract 2450. http://abstracts.hematologylibrary.org/cgi/content/abstract/118/21/2540?sid=c0a66678-1a1d-4960-b7dc-f59f3974de20. Accessed July 8, 2014.
11. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia V.1.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed July 8, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
12. Hoelzer D, Gökbuget N, Ottmann O, et al. Hematology Am Soc Hematol Educ Program. 2002;162-192.
13. Peters JM, Ansari MQ. Arch Pathol Lab Med. 2011;135:44-54.
14. Riva L, Luzi L, Pelicci PG. Front Oncol. 2012;2:40. doi:10.3389/fonc.2012.00040.
15. Hoelzer D. Am Soc Clin Oncol Educ Book. 2013:290-293. doi: 10.1200/EdBook_AM.2013.33.290.
16. Brüggemann M, Schrauder A, Raff T, et al. Leukemia. 2010;24:521-535.
17. Bassan R, Spinelli O, Oldani E, et al. Blood. 2009;113:4153-4162.
18. Brüggemann M, Raff T, Flohr T, et al. Blood. 2006;107:1116-1123. http://www.bloodjournal.org/content/bloodjournal/107/3/1116.full.pdf. Accessed August 5, 2014.
19. Spinelli O, Peruta B, Tosi M, et al. Haematologica. 2007;92:612-618.
20. Bassan R, Hoelzer D. J Clin Oncol. 2011;29:532-543.