Adding Ultra-Sensitive MRD to My Treatment Toolbox
“Congratulations! Your latest MRD test was negative. Go celebrate with your wife – I’ll see you at your next appointment in 3 months.”
Nothing brings me more satisfaction than sending an email to a patient that has gone through diagnosis, sometimes multiple rounds of treatment, pre-transplant conditioning, and finally a hematopoietic stem cell transplant, to tell him that the most sensitive testing method available is unable to detect any remaining cancer cells in his body.
MRD (minimal residual disease) refers to cancer cells remaining after cancer treatment that are undetectable by traditional microscopic examination of blood or bone marrow, but are nevertheless capable of causing a relapse. In both acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), MRD testing has been shown to be a useful prognostic tool — patients who are MRD negative tend to fare better than patients who are MRD positive.
For many years the most common method for MRD testing in the United States has been a procedure called flow cytometry, in which cancer cells are detected by virtue of specific combinations of cell surface markers. Flow cytometry has its downsides though — it is not standardized from lab to lab, it is not specific to a particular patient’s cancer, and it requires fresh samples. Most importantly, it is not sensitive enough to use on blood samples — to use the test for monitoring a patient over the course of many months requires multiple painful bone marrow biopsies.
A newly available technique is molecular MRD analysis that takes advantage of the sensitivity and scalability of next-generation sequencing (NGS) technology. A unique DNA sequence is identified for each patient’s cancer and then this sequence is tracked in follow-up samples. The results are specific for each patient, but the assay itself is universal and standardized. Cancer cells can be detected at a level as low as 1 per 1 million white blood cells, allowing us to perform MRD analysis on blood samples — something patients definitely appreciate.
My colleagues and I have shown that in adult patients with either ALL or CLL who receive allogeneic (donor) hematopoietic stem cell transplants, NGS-based MRD detection using Adaptive’s clonoSEQ Process can predict relapse risk. In both ALL and CLL, MRD positivity as determined by the clonoSEQ MRD Test often precedes actual clinical relapse by several months.
Although ultra-sensitive NGS-based MRD testing is a powerful tool that allows me (and my patients) to understand disease status at the very deepest level, we don’t yet have the necessary clinical evidence telling us exactly what level of MRD should trigger a change in treatment, and what that change should be. But MRD testing is nevertheless a valuable part of my treatment toolbox.
In my practice, I use MRD testing post-transplant to help determine whether more or less aggressive follow-up treatment will be appropriate for a particular patient. During follow-up, I keep an eye on MRD levels to get a sense of whether someone is headed for relapse. If they are, I then have the opportunity to take preemptive therapeutic action while disease burden is low.
Dr. Miklos is an Assistant Professor of Medicine at Stanford University Medical Center. The views expressed here are his own and are not an endorsement of Adaptive or the clonoSEQ® Process.