Building a Cancer-Free World Through MRD Testing

“Cancer-free” is a wonderful phrase – but what does it really mean? For patients with leukemia, lymphoma, and myeloma, it can be a difficult phrase to trust. Why? Because even a single remaining circulating cancer cell may give rise to a relapse, triggering further rounds of treatment and their associated costs and side effects. So how can pathologists and oncologists determine which patients need ongoing treatment, which require modifications, and which may be truly cancer-free? The answer, according to Ilan “Lanny” Kirsch, Senior Vice President of Translational Medicine at Adaptive Biotechnologies, lies in minimal residual disease (MRD) testing.

What is MRD testing and how does it work?

Unlike many cancer diagnostics in use today, MRD testing is as old as oncology. We have always evaluated the extent of a patient’s disease, selected our interventions, and then looked at the impacts of those interventions on the cancer. I think “minimal residual disease” is a bit of a misnomer, though, given the sensitivity of newer technologies for detecting cancer. I prefer to use the term “measurable residual disease.”

Initially, measuring MRD involved nothing more than a physical exam; now, of course, we have additional tools available. At first, we developed technology that allowed us to perform a bone marrow aspirate, stain the slide, and evaluate the number of aberrant cells. Thereafter, conventional flow cytometry gave us the ability to phenotypically identify the clone of interest – and, for certain hematopoietic malignancies, we also gained serum paraprotein analysis, immunofixation, and serum and urine tests for immunoglobulin. All of those methods are still in practice today, but they are now complemented by more advanced approaches: next-generation sequencing (NGS), next-generation flow cytometry, more sophisticated imaging, and even mass spectroscopy techniques.

These newer methodologies offer greater standardization, accuracy, sensitivity, and specificity. “Why does greater sensitivity matter?” is a question I hear often. Many doctors dealing with intractable disease wish they were fortunate enough to worry about disease levels like one residual cancer cell per million normal cells. But as our treatments for cancers like leukemia, lymphoma, and myeloma continue to improve, our dream of controlling or even curing them is increasingly realistic. Event-free survival, previously measured in months, can now be measured in years. We now have many more treatment options, most of which can be tailored to individual patients’ genes, so the ability to closely examine MRD and consider therapeutic options is more critical than ever.

When I report MRD levels as a number of malignant cells per million, I occasionally get calls from doctors saying, “Three per million? What am I supposed to do about that?” If they’re asking whether there is still evidence of disease at that level, the answer is yes – but if they’re asking whether it’s actionable, that depends. Is the disease continuing to go down, is it plateauing, or is it going back up? Half a century ago, we assessed those things by crude methods and made our decisions based on the results. Nowadays, we do the same thing, but with much more sensitive tests.

How can tools like immunosequence-based MRD detection (e.g., clonoSEQ^®) help?

Certain tools are now more refined, more accurate, more standardized, and more sensitive than previous iterations. The outcome? A patient who would have previously been considered “in remission” by conventional methods may no longer be “in remission” with a more sensitive assay. Now, we’re able to more sensitively stratify patients who might (or might not) need aggressive therapy. Disease thresholds have previously been established to guide clinical management, but there’s nothing “magic” about, for example, falling below one malignant cell per 10,000 – that just happens to be the detection limit of conventional flow cytometry. Evidence of disease at a single time point can still have prognostic significance, and trends can yield important information about disease status. Doctors may ask, “Do I need to intervene early?”

Although this has not been proven for every malignancy, it makes sense that, in general, the earlier you spot a problem and intervene, the better your chances of gaining the upper hand. This, of course, requires that the treatments available are not riskier than the disease itself.

All data, of course, must be used with caution. It’s possible that, once a patient reaches a certain low-level disease threshold, MRD levels may be indicative of something else’s ability to exert a positive influence on the course of disease – for instance, an immune response. MRD may be a surrogate measure for control of the disease itself.

Take, for instance, standard-risk childhood acute lymphoblastic leukemia (ALL). If patients are MRD-negative as determined by NGS at the end of the induction phase of combination chemotherapy the prognosis is excellent. In fact, a 2018 study showed an overall survival rate of 100 percent for that population after eight years (1). So now we ask: do these patients need the intensive therapy they currently receive? Could we offer treatment with a lower risk of side effects or long-term sequelae? Another example might be ALL patients in need of hematopoietic cell transplantation. Some are at higher risk of relapse than others – and MRD measurements can stratify those patients so that the ones at lowest risk can receive less intensive pre-transplant myeloablation and post-transplant intervention (2).

It’s vital to determine patient needs and balance the benefits of treatment with its potential disadvantages. It’s also important from a health economic perspective. If a patient is in a deep remission and does not need additional therapy, we save time and money by finding out as soon as possible. If a patient requires intensification, early discovery of that fact can prevent downstream consequences and improve outcomes. The cost of MRD testing is trivial relative to the potential costs incurred if we don’t test.

What should pathologists and laboratory medicine professionals keep in mind when evaluating NGS MRD testing?

These technologies are here to stay. Nucleotide sequencing is not a flash in the pan, and immunosequencing – as applied to MRD or any situation in which cells of the adaptive immune response play a role – is one important way of learning about individual and population health and disease.

To develop and apply immunosequencing, three things had to happen: i) we needed to understand the origins of immune diversity, ii) DNA sequencing technology needed to become high-throughput and refined enough to scale, and iii) because the technology generates enormous databases, we needed bioinformatics to extract methods or results. All three of those things have occurred – and now, we have the power to mine the enormous resource of sequencing information. Now, it’s time for pathologists and laboratory medicine professionals to incorporate these next-generation technologies into their thinking about health and disease.

Today, an appreciation of molecular pathology is as important as an appreciation of anatomic or clinical pathology. And that’s what Adaptive Biotechnology seeks to foster – the growth of individuals as subject matter experts. The goal is for pathologists and laboratory medicine professionals to describe and interpret clonoSEQ results in tumor boards alongside imaging and histopathology, so that these results can help inform patient care. From every perspective – health economics, patient care, our overall understanding of health and disease – it makes sense for immunosequencing, and molecular pathology in general, to become a standard of care in the detection of residual disease burden for lymphoid cancers.

Adaptive Biotechnologies is the manufacturer of the clonoSEQ® Assay and provided funding for this content. The Pathologist conducted all interviews and developed all content. For technical information related to clonoSEQ®, please visit clonoSEQ.com.

clonoSEQ is available as an FDA-cleared in vitro diagnostic (IVD) test service provided by Adaptive Biotechnologies for use in B-cell acute lymphoblastic leukemia or multiple myeloma patients to detect and monitor measurable residual disease (MRD) in bone marrow samples. clonoSEQ is also available for use in other lymphoid cancers as a CLIA-regulated laboratory developed test (LDT) service provided by Adaptive Biotechnologies.