Detection of minimal residual disease in acute lymphoblastic leukemia
- Wendy Stock, MD
Wendy Stock, MD
- Professor of Medicine
- Pritzker School of Medicine of the University of Chicago
- Zeev Estrov, MD
Zeev Estrov, MD
- Professor of Medicine
- University of Texas MD Anderson Cancer Center
More than 80 percent of adults with acute lymphoblastic leukemia (ALL) achieve complete remission (CR) and up to one-half of these patients may experience prolonged disease-free survival and be "cured" of their disease. However, many will experience a recurrence and die of leukemia. Relapse is thought to result from residual leukemic cells that remain following the achievement of "complete" remission, but are below the limits of detection using conventional morphologic assessment. These subclinical levels of residual leukemia are termed "minimal residual disease" (MRD) or "measureable residual disease" and can be evaluated using more sensitive assays. The latter term emphasizes the limitations of available techniques for detecting fewer than one ALL blast in 10,000 normal cells.
MRD assays are routinely used in the clinical care of children with ALL and increasingly in adults as well. MRD measurements during and after induction therapy are highly prognostic and correlate with relapse rates.
This topic review will focus on the methods for MRD monitoring in ALL. The clinical significance of MRD detection in ALL and the use of MRD testing in acute myeloid leukemia and chronic myeloid leukemia are covered separately. (See "Clinical use of minimal residual disease detection in acute lymphoblastic leukemia" and "Remission criteria in acute myeloid leukemia and monitoring for residual disease" and "Overview of the treatment of chronic myeloid leukemia", section on 'Monitoring response'.)
DIFFICULTIES IN DEFINING COMPLETE REMISSION
The primary goal of induction therapy for ALL is achievement of an initial complete remission (CR), defined as the eradication of visible leukemia cells (at least to <5 percent blasts) from the bone marrow and blood detectable by microscopic review and the restoration of normal hematopoiesis (typically with >25 percent cellularity and normal peripheral blood counts).
While CR has historically been defined based upon morphologic criteria, an assessment of MRD can define a more stringent response that is better able to predict prognosis. This approach is supported by several observations that illustrate the difficulty in ascertaining whether a patient with ALL in morphologic CR is likely to remain disease-free:
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- DIFFICULTIES IN DEFINING COMPLETE REMISSION
- SOURCE OF CELLS
- METHODS FOR DETECTING MRD
- POLYMERASE CHAIN REACTION (PCR)
- Real-time quantitative PCR
- - Targets of RQ-PCR
- Ig and TCR gene rearrangements
- Chromosomal rearrangements
- - Advantages of RQ-PCR
- - Limitations of RQ-PCR
- Reverse transcriptase PCR
- - Advantages of RT-PCR
- - Limitations of RT-PCR
- Multiplex PCR with deep sequencing
- MULTICOLOR FLOW CYTOMETRY
- Advantages of flow
- Limitations of flow
- RESPONSE DEFINED
- INFORMATION FOR PATIENTS