The clinically most useful MRD test and targets are not yet determined.1 More accurate methods to measure MRD are being developed and MRD testing is now part of standard treatment regime for some diseases such as ALL and is being validated for other conditions including acute myeloid leukemia (AML). MRD is persistent disease. Current MRD techniques include first-generation flow, next generation flow cytometry, molecular PCR and molecular sequencing or NGS. There are many reports and discussions about standardization of methods used to detect MRD through tests by flow cytometry and molecular diagnostics.2
There is no FDA approved Flow Cytometric MRD (FCMRD) test, so they are all considered Laboratory Developed Tests (LDTs). Nearly 100 US labs perform FCMRD, and the International Myeloma Working Group (IMWG) has encouraged researchers and clinicians to use similar/identical methods.3 All FCMRD tests do not have the same analytical performance. This is reflected in the CAP-accreditation of the laboratories. There is no proficiency testing for MRD by flow cytometry in the US. Common approaches and common interpretation tools are needed for data comparison among labs. The European LeukemiaNet MRD Working Party has produced recommendations for sampling and interpretation because some pathology labs have questionable findings. Oncologists are recommended to send samples to reputable commercial laboratories with trained experts.4
Quantitative molecular technologies are also used for MRD testing. Some of these assays are even more specific, sensitive, technically more complex and time-consuming than FCMRD. Technology such as NGS based clonoSEQ® can detect 1 cell in a million. Sanofi is using the clonoSEQ assay to measure MRD as a clinical endpoint. Amgen and Janssen use the same technology to measure disease status and disease progression.
There is no clear consensus for measuring MRD. Some experts believe NGS may be a better approach than flow cytometry. This is why the FDA has granted De Novo designation to the clonoSEQ assay. The FDA has authorized an NGS-based test to detect very low levels of remaining cancer cells in patients with acute lymphocytic leukemia (ALL) or multiple myeloma (MM). There are many literature reports that discuss the monitoring of MRD in AML, ALL, MM and myelodysplastic syndrome (MDS) using NGS, with prospective trials currently ongoing to evaluate efficacy in this regard.5 MRD negativity using deep sequencing is a major prognostic factor in MM. In fact, MRD is being used as a surrogate endpoint in some trials to shorten evaluation times for new treatments.
The FDA news release states that ‘determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure MRD in ALL or MM patients can help providers manage their patients’ care’.6 This de novo premarket review pathway was originally developed for lower risk technology with a new regulatory classification, so copycat fast follower devices with the same intended use can go through the FDA’s 510(k) process and demonstrate equivalence. The FDA has outlined a tiered framework for the level of evidence labs would need to submit to the agency based on how certain biomarkers may be used in patient care. The regulatory framework for all in vitro clinical tests is being updated in a new draft bill called the Diagnostic Accuracy and Innovation Act.
It is interesting to note that there are over 140 clinical trials listed on the clinicaltrials.gov website that include MRD investigations, and over 80 of these are recruiting or enrolling by invitation or list as active. Nearly a third of trials that include MRD are in the USA and a smaller fraction are in Europe and China. Diaceutics has a global network of laboratories that can support market access and lab mapping activities to determine MRD testing capabilities worldwide, and to inform how labs are screening for MRD.
According to clinical trials records, Yake Biotechnology Ltd. are investigating CD19-targeted CAR-T cell therapy for MRD+ B-cell malignancies after autologous stem cell transplantation.
Pfizer is recruiting for a US based study in patients with B-cell lineage ALL with positive MRD. GSK is looking at MRD and maintenance therapy. Other biotechnology organizations investigating treatments for MRD include Ziopharm Oncology, Precigen, Inc, Bellicum Pharmaceuticals, Stemline Therapeutics, Inc and Celgene.
There is value in the measurement of MRD status. This approach could be used to adapt treatment strategies in clinical trials and after drug launch as a companion diagnostic test.7 The FDA framework for evidence review is timely, and should lead to improved outcomes and diagnostic accuracy.