Editor's note: The 65th Annual Meeting of the American Society of Hematology (ASH) was held in San Diego, California, USA, from December 9 to 12, 2023. Professor Jiang Qian's team from Peking University People's Hospital was specially invited to summarize and summarize the cutting-edge content of the 2023 ASH conference for exchange.
Acute myeloid leukemia (AML) is a common hematologic malignancy characterized by the proliferation of abnormal leukemia cells in the bone marrow, affecting normal hematopoietic function. Treatments for AML include chemotherapy, targeted therapy, immunotherapy, and hematopoietic stem cell transplantation, with the goal of destroying leukemia cells and achieving complete remission (CR, less than 5% of leukemia cells in the bone marrow). However, even if CR is achieved, there is no guarantee that the leukemia cells have been completely removed, and there may be some hidden leukemia cells remaining in the body, which is MRD (measurable residual disease). MRD testing is an important part of AML treatment, which can help doctors evaluate the patient's condition, formulate an individualized treatment plan, and improve the cure rate.
Expert Profile
Prof. Qian Jiang
PI, Professor, National Center
Chief physician and doctoral supervisor
National Clinical Research Center for Hematological Diseases
Peking University People's Hospital
Institute of Hematology, Peking University
Chen Yue
National Clinical Research Center for Hematological Diseases
Peking University People's Hospital
Institute of Hematology, Peking University
Supervisor: Prof. Jiang Qian
Yu Shunjie
National Clinical Research Center for Hematological Diseases
Peking University People's Hospital
Institute of Hematology, Peking University
Supervisor: Prof. Jiang Qian
The text is as follows
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Definition of MRD
This study is a non-interventional, cross-sectional study that collects at least a complete cytogenetic response from taking tyrosine kinase inhibitors (TKIs) who visited our hospital from September 2021 to February 2023 In terms of AML, MRD (measurable residual disease, detectable residual disease) refers to patients who have undergone chemotherapy, targeted therapy, chimeric antigen receptor T cells and/ or allogeneic hematopoietic stem cell transplantation (allo-HSCT), with or without achieving a complete hematologic response, leukemia cells detectable in the body. The presence of MRD increases the risk of recurrence and affects long-term survival.
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Findings:
Currently, there are a variety of techniques that can be used for MRD detection, which fall into two main categories: immunology-based methods and molecular-based methods. The immunology-based approach uses flow cytometry to distinguish between normal and leukemia cells by detecting specific markers on the surface of leukemia cells. A molecular-based approach uses polymerase chain reaction or sequencing technology to quantify the number of leukemia cells by detecting specific genetic variants or fusion genes in leukemia cells. Each of these techniques has its own advantages and disadvantages, and it is necessary to choose the appropriate technology for testing according to the specific situation of the patient. (See Table 1)
Table 1: Advantages and disadvantages of the three MRD detection techniques
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Time point of MRD detection
During AML treatment, time points for MFC (multiparametric flow cytometry) as well as molecular biology MRD assessment included initial diagnosis, after two courses of standard induction therapy, after consolidation therapy, and after the end of treatment. For patients undergoing allo-HSCT, BM and/or PB should be taken for MRD after the end of the last dose of chemotherapy (or within 4 weeks prior to surgery). It is suggested that the center with the conditions can evaluate the MRD once after each course of induction and consolidation therapy, once a month for six months after transplantation, and every 3-6 months for six months to two years after transplantation. In addition, MRD testing is recommended at any point in time when disease recurrence is suspected in combination with clinical presentation.
MRD testing at initial diagnosis
MFC-MRD testing is required at the time of initial diagnosis to determine the patient's leukemia-associated abnormal phenotype (LAIP), and MRD testing is performed at the subsequent course of treatment using the LAIP identified at the time of initial diagnosis. LAIP refers to a combination of CD marker expression that is not found in the bone marrow of healthy individuals. LAIP can be identified in about 90% of patients with AML. However, when patients have NPM1 mutations or CBF translocations, MRD testing (eg, qPCR, digital PCR) should be performed using quantitative molecular methods.
MRD test after one treatment
Methods for detecting MRD using MFC include LAIP, which is determined at the time of initial diagnosis and used to detect MRD during subsequent treatment, and D-F-N, which can be used to detect antigen shift during treatment in patients who lack initial diagnosis of LAIP. The combination of LAIP and D-F-N is suitable both for patients lacking newly diagnosed LAIP and for detecting emerging phenotypic abnormalities or antigenic drift in LAIP.
Some scholars believe that the results of MRD testing after the first treatment of AML patients can be used to determine whether to find a bone marrow donor, because very few MRD-negative patients become MRD-positive after the second cycle of chemotherapy, and for non-responsive and MRD-positive patients, it can avoid wasting time in finding a donor. There is controversy as to whether patients at risk of adverse risk and who are MRD-positive but have CR should receive a second cycle of chemotherapy or immediately receive alloSCT (allogeneic cell transplantation).
After two courses of standard induction therapy (post-remission treatment)
The cut-off value for MFC-MRD after induction therapy is 0.1%, and the outcome has now been identified as an important factor in patient prognosis. The clinical use of MRD test results to guide further post-remission treatment strategies varies widely from place to place. Studies have shown that in favourable and intermediate-risk patients with negative MRD, no treatment with alloSCT has a negative impact on survival. That is, for both favorable and intermediate-risk patients, it may be beneficial to go for alloSCT only if the MRD result is positive.
After consolidation therapy
To further determine the role of MFC-MRD in disease surveillance, MFC-MRD should still be tested every 3 months for 2 years after consolidation therapy or alloSCT, or when there is a clinical indication for recurrence. The collection of these data in clinical trials is warranted because MFC-MRD monitoring after consolidation therapy is not yet widely available in clinical practice, but may be beneficial for early intervention protocols and early detection of recurrence.
There are several factors to consider when using MRD for post-consolidation monitoring.
First of all, the sample type is important. For MFC-MRD studies, MRD with PB had high specificity, but the sensitivity was 10-fold lower than that of BM. The molecular method MRD detection is more sensitive, so PB is considered suitable for molecular methods.
Second, the threshold of MFC-MRD positivity at follow-up and the criteria for subsequent potential clinical intervention still need to be established. A cut-off of 0.1% is a clear indication of a high risk of recurrence, but a lower cut-off may also indicate disease recurrence. The results of MRD suggest that an increase in a certain level may measure kinetics and indicate disease recurrence. For quantitative molecular methods, an increase of 1-log or more also indicates a high rate of recurrence.
Finally, the duration of monitoring needs to be clarified. Previous reports suggest that most recurrences occur within 2 years. The detection frequency of PB-MRD (4 ~ 6 weeks/1 time) was higher than that of BM (3 months/1 time). Since partial recurrence occurs quickly when a small clonal cell population gains growth dominance, MRD monitoring in PB is a better option.
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Clinical significance of MRD testing
MRD recurrence
MRD recurrence is defined as (1) a conversion from MRD negative to MRD positive, and (2) an increase in the copy number of a homogeneous sample (PB or BM) from a patient with low-level MRD by ≥1 log10 between any two positive samples. In PB or BM, the MRD transition from negative to positive should be confirmed within four weeks, and at the second serial test, it is preferable to use a BM sample.
MRD was used as an alternative endpoint to accelerate drug approval
The value of MRD in clinical practice to warn of recurrence and guide treatment selection has been well established, but more evidence is needed to use MRD as an alternative endpoint in AML clinical trials. If MRD is negative as a surrogate endpoint for survival, it is extremely helpful for the evaluation of new drugs, which may accelerate the approval of effective drugs and terminate clinical trials of drugs with poor efficacy early.
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summary
MRD refers to the leukemia cells that can still be detected in the body of AML patients after treatment, which is an important indicator of AML treatment and can reflect the prognosis and recurrence risk of patients. The detection technology of MRD is mainly divided into immunology-based flow cytometry and molecular-based polymerase chain reaction or sequencing technology, each with its own advantages and disadvantages, and it is necessary to choose the appropriate technology according to the specific situation of the patient. Time points for MRD testing include initial diagnosis, after induction therapy, after consolidation therapy, and after treatment, as well as regular monitoring after transplantation. The results of MRD tests can help doctors develop individualized treatment options, such as increasing the intensity of chemotherapy, changing the type or dose of targeted drugs, or performing hematopoietic stem cell transplantation. MRD can also be used as a surrogate endpoint for clinical trials, accelerating the approval of effective drugs and early termination of clinical trials of drugs with poor efficacy. MRD testing is an important part of the diagnosis and treatment of AML, and with the advancement of technology and the improvement of standards, MRD testing will play a greater role in the management of AML.
bibliography
1.Cloos J, Ngai LL, Heuser M. Understanding differential technologies for detection of MRD and how to incorporate into clinical practice. Hematology Am Soc Hematol Educ Program. 2023 Dec 8; 2023(1):682-690.
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