Minimal Residual Disease Test Clue to Effective Cancer Treatment
2022. 08. 12
What is MRD test?
Reaching complete remission is the ultimate goal of cancer treatment. Implementation of residual disease test to assess complete remission actually started out with monitoring the effectiveness of cancer treatment by examining the bone marrow blast through light microscopy.[1] Afterward, morphological and clinical criteria have been used to evaluate complete remission of patients after cancer therapy. However, such approach has limitations as patients relapse even though they were absent of any clinical symptoms.[2]
The technology improvement in polymerase chain reaction (PCR) and flow cytometry has changed the way to detect the residual disease.[1] By around late 1980 to early 1990s, the term minimal residual disease (MRD), generally used nowadays has been coined to distinguish from residual disease that is detected by visual examination.[1] Testing MRD, a very small number of malignant cancer cells remaining after cancer treatment, arose as a breakthrough solution to complement the examination which relied on morphology.[3] Morphologically, it may look as if patients have reached complete remission as the residual disease cannot be detected under conventional imaging methods.[3] However, implementation of MRD test has allowed the identification of unrecognized high-risk patients. MRD is distinguished from the traditional definition of residual disease and incomplete remission through two criteria. First, whether MRD is present after patients have responded fully to treatment.[4] Second, whether it can be detected by sensitive diagnostic techniques after induction chemotherapy but not by conventional imaging technique.[4]
Bone marrow is the standard source used to monitor MRD providing prognostic value in leukemia patients.[5]
For optimum results, the first volume of the bone marrow aspirate up to 3 mL is recommended.[5] There has been an effort to prove that peripheral blood is the effective source compared with bone marrow in MRD test. In the past, there were some controversies whether peripheral blood can be an alternative source to bone marrow.[6] Several studies have shown that MRD tests performed with peripheral bloods show concordant results with that of bone marrow in leukemia.[3] Both sources can be used to predict the risk of relapse after induction or consolidation therapy. In the further studies for acute lymphoblastic leukemia (ALL), it became more clear that difference exists based on the lineage of ALL. In B-lineage ALL, MRD levels were likely to be lower for peripheral blood compared to bone marrow.[7] For T-lineage ALL, detection of MRD in bone marrow was consistent with that from peripheral blood.[7] Therefore, when choosing the source, it is important to consider such differences. If one intends to serially monitor MRD, using one specific source is highly recommended for the optimum result.[4]
Accumulated evidence has proved the clinical significance of MRD test to predict relapse in leukemia patients and it has become an essential component in cancer therapy. MRD can be applied in several different ways to increase the efficacy of cancer treatment in different types of cancer. First, the primary role of MRD was conducted in curative-intent therapy to monitor the risk of relapse or effectiveness of the treatment. Second, prediction of relapse enables doctors to control the amount of treatment: stop, de-escalate, or intensify depending on the status of patients. Lastly, in pediatric patients with blood cancer, MRD test has been used to check the risk of hematopoietic stem cell transplant.
MRD test in blood cancer
Among different types of cancer, MRD test has been widely applied in blood cancer. Depending on its origin, blood cancers are divided into 3 kinds: leukemia, myeloma, and lymphoma. Different types of blood cancers hold different characteristics. Therefore, how MRD test is applied and the extent it has been investigated is different. Among these 3 types, MRD test has been most widely used in leukemia. Leukemia is a blood cancer which originates from bone marrow and blood. MRD test is well established for acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML).
a.MRD test in acute lymphoblastic leukemia
The clinical significance of MRD test has been demonstrated in both pediatric and adult ALL patients.[8] Based on several studies, 0.01% is typically used as the cut-off level to distinguish MRD positive in ALL in both PCR and flow cytometry.[9] The AIEOP-BFM ALL 2000 study was the first attempt to assess MRD quantitatively using immunoglobulin and T-cell receptor rearrangements using PCR in over 3000 pediatric patients with precursor B-ALL. MRD level was assessed in 2 time points to stratify risk in 3 different stages:standard, intermediate, and high.[10] Based on MRD risk, it was shown that MRD with standard risk show significantly higher event free survival reaching over 90% while it falls to around 50% in the high-risk group.[10]
The use of MRD tests in adult patients with ALL showed consistency. Standard-risk ALL adult patients from the GMALL 06/99 trial showed significant differences in MRD level.[11] Among 105 patients showing similar clinical features such as in sex, age, and immunophenotype, 11 patients show low or undetecable levels at day 11 and 24.[11] These patients show 100% in both 3-year disease free survival (DFS) and overall survival (OS) rates while patients classified as high MRD level showed less than 6% for 3-year DFS and around 45 % in 3-year OS rate.[11]
b. MRD test in acute myeloid leukemia
In acute myeloid leukemia (AML), there has been an effort to seek an easy and reliable way to monitor MRD by testing common mutations occuring in AML. Jongen-Lavrencic et al. investigated whether mutations related with age-related clonal hematopoiesis could provide prognostic value in AML adult patients.[12] These mutations known as DTA mutations are considered as the key mutations in AML but cannot initiate the disease.[13] 430 AML patients showing at least one mutation that may be potentially used for MRD test were included in the study. Through study, it was found that DTA mutation did not have any prognostic value to predict relapse in AML patients.[12] On the other hand, presence of non-DTA mutations correlated with higher relapse rates compared to no detection of non-DTA mutations showing that MRD provides prognostic value.[12]
In an effort to ease MRD testing, nucleophosmin (NPM1), a leukemia-specific molecular marker, has gained attention for its potential to improve prognostication in MRD test.[14] NPM1-mutated AML patients were selected and tested for MRD. From a study, it was suggested that NPM1-mutation detection after the second cycle of chemotherapy was associated with a lower overall survival rate and a greater relapse compared to MRD-negative.[14] One more promising result from the study was that NMP-1 mutations provided prognostic value independent of other risk factors.
c.MRD test in chronic leukemia
In chronic lymphocytic leukemia (CLL), the role of MRD test as an independent prognostic marker to predict overall survival and progression-free survival have been suggested as well through several studies.[15,16] In the GCLLSG CLL8 trial, MRD level has been categorized into 3 different levels: low, intermediate, and high. Low MRD level correlated with significantly longer overall survival and progression-free survival regardless of sample type either bone marrow or peripheral blood.[15] However, depending on the sample type, the level of MRD may differ as some studies have suggested the difference in MRD level between peripheral blood and bone marrow. In addition, compared with other leukemia, CLL involves not only blood but also tissue as in lymph nodes, liver and spleen thus improvement with application for tissue could extend the applicability of MRD test.[16]
Imatinib, BCR-ABL1 tyrosine kinase inhibitor, is a standard chemotherapy that can drastically improve patients with chronic myeloid leukemia (CML). According to several studies, around 40% of CML patients reach treatment-free remission after imatinib treatment.[17,18] The STIM1 study is one of the representative studies which showed that imatinib can be discontinued for those who have sustained undetectable minimal residual disease (UMRD) for a minimum of 2 years.[17] For UMRD analysis, BCR-ABL transcripts were evaluated and the absence of at least 6 transcripts were considered as UMRD. Among 100 CML patients with sustained URMD, it was shown that 38% survived without molecular recurrence-free survival at 60 months.[17] Not only STIM1 but based on other similar studies, it is clearly demonstrated that MRD test may be applied to aid making decision on cessation of chemotherapy.[17,18]
MRD test in solid tumor and its limitation
Although the MRD test has limitations depending on types of blood cancer, it can help predict relapse and complete response to cancer therapy that conventional imaging techniques cannot. Such effort has been extended to solid tumors. However, to establish MRD test in solid tumors there are hurdles that need to be overcome. As solid tumors are genetically unstable and heterogenous, it is not easy to specify certain markers from circulating tumor cells.[23] Based on large scale analysis, it was found that significant heterogeneity exists between individual tumors.[24] Overcoming such intratumor heterogeneity is essential to universally apply the MRD test, but most of the current techniques rely on single-tumor biopsy analysis to depict the overall tumor landscape.[24] Most importantly, unlike leukemias where MRD cells can be obtained from the bone marrow, for solid tumors, it is hard to identify the resection sites.[25] Even if the site is characterized, obtaining cells through invasive procedures are key hurdles that need to be overcome. As a follow-up in our next blogs, we aim to show the latest evidence and update on how the MRD test is applied in solid tumors especially in lung cancer.
Reference
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