Pei Lin, MD Pei Lin, MD Department of Hematopathology Department of Hematopathology UT M.D. Anderson Cancer Center, Houston, UT M.D. Anderson Cancer Center, Houston, TX TX Monitoring of Minimal Monitoring of Minimal Residual Disease Principles Residual Disease Principles and Applications and Applications
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Pei Lin, MD Department of Hematopathology UT M.D. Anderson Cancer Center, Houston, TX Monitoring of Minimal Residual Disease Principles and Applications.
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Pei Lin, MDPei Lin, MD
Department of Hematopathology Department of Hematopathology
UT M.D. Anderson Cancer Center, Houston, TXUT M.D. Anderson Cancer Center, Houston, TX
Monitoring of Minimal Residual Disease Monitoring of Minimal Residual Disease Principles and ApplicationsPrinciples and Applications
MRD studies in AML: Potential MRD studies in AML: Potential UtilityUtility
• Time points of testing: post induction, post Time points of testing: post induction, post consolidation, pre-transplant, during CR consolidation, pre-transplant, during CR
• Prognostic in most studiesPrognostic in most studies
• Effectiveness of therapy: quantitative, kineticsEffectiveness of therapy: quantitative, kinetics
• Guidance for risk adjusted therapyGuidance for risk adjusted therapy
• Distinguish early recovery from persistent AMLDistinguish early recovery from persistent AML
• Predicting early relapsePredicting early relapse
• Aberrant levels of normally expressed antigens Aberrant levels of normally expressed antigens ((↓,↑ ↓,↑ CD38, CD34…)CD38, CD34…)
• Coexpression of early and later antigens Coexpression of early and later antigens (CD34++CD15++)(CD34++CD15++)
• Altered forward and side scatterAltered forward and side scatter
Approaches• Must know the patterns of Must know the patterns of normalnormal and and
recoveringrecovering bone marrow bone marrow
• If available, compare MRD to the original If available, compare MRD to the original phenotypephenotype
• Need detailed description of antigen Need detailed description of antigen expression or dot-plotsexpression or dot-plots
• Rely on “LAIP” or deviation form normal Rely on “LAIP” or deviation form normal to identify leukemic cellsto identify leukemic cells
Criteria for Dx and SensitivityCriteria for Dx and Sensitivity
• LAIP vs “different-from normal” approachLAIP vs “different-from normal” approach
• A: LAIP approach: A: LAIP approach:
• Find aberrant clusters of at least 20 cells, Find aberrant clusters of at least 20 cells, showing abnormal expression of at least 2 showing abnormal expression of at least 2 markers in the LAIP boxmarkers in the LAIP box
• Many Many ““LAIPLAIP” ” have a low frequency in have a low frequency in normal BMnormal BM
• To yield sensitivity of 0.01%, collect at To yield sensitivity of 0.01%, collect at least 200K cells per tube (20/200K = 1 least 200K cells per tube (20/200K = 1 in 10in 104 4 = 0.01%)= 0.01%)
• Sensitivity may be limited due to Sensitivity may be limited due to background normal cells, 0.1% or higher background normal cells, 0.1% or higher
• * 0.1% is commonly used threshold in the * 0.1% is commonly used threshold in the literatureliterature
Detection of MRD by Flow Detection of MRD by Flow CytometryCytometry
• Advantages: Advantages:
• Widely applicable (90- 95% of cases) Widely applicable (90- 95% of cases)
• Relatively rapid turn around timeRelatively rapid turn around time
• Disadvantages: Disadvantages:
• Interpretation often challenging, requires Interpretation often challenging, requires experienceexperience
• Can be expensiveCan be expensive
• Lack of standardization Lack of standardization
Potential challenges• LAIPs may not cover all leukemic blasts, partial LAIPs may not cover all leukemic blasts, partial
overlap with normaloverlap with normal
• Antigen shift resulting from Antigen shift resulting from selection/emergence of subclones selection/emergence of subclones
• A complete change in LAIPs in about 20% of A complete change in LAIPs in about 20% of AML, with 80% having at least one LAIP AML, with 80% having at least one LAIP similar to the original (Voskova et al)similar to the original (Voskova et al)
• Post therapy hypocellular samplePost therapy hypocellular sample
• Use a comprehensive panel of antibodies to Use a comprehensive panel of antibodies to establish baselineestablish baseline
Summary
• MRD detection by FCM or/and PCR are promising MRD detection by FCM or/and PCR are promising tools to guide therapy and to improve outcomestools to guide therapy and to improve outcomes
• Each method has pros and consEach method has pros and cons
• More studies are underway to better incorporate More studies are underway to better incorporate the data into clinical decision making (dose the data into clinical decision making (dose intensification and/or ASCT)intensification and/or ASCT)
• Timing of MRD testing by FCM and the cut off Timing of MRD testing by FCM and the cut off levels for each time point that are significant are levels for each time point that are significant are being refinedbeing refined