Insights From: Michael J. Mauro, MD Memorial Sloan Kettering Cancer Center
Michael J. Mauro, MD: We’ve clearly come a long way in the treatment of lymphoid malignancies: ALL, myeloma, CLL. There has been an explosion of therapies across the board. But really, the principle is we need better tools or we have to use our best tools to monitor a response. There’s definitely a link, a connection, between our therapies and our MRD, or minimal residual disease, testing.
We have our historic tests of changes in blood counts; bone marrow studies looking at morphologic remission; classic genetic tests like cytogenetics; and classic, additional cytogenic testing like fluorescent in situ hybridization, or FISH. These have been workhorses for decades. But clearly, as we try to make decisions about what the best path is for a patient with a higher-grade lymphoid malignancy, or even a lower-grade lymphoid malignancy, MRD testing has become the king.
There are multiple techniques we can use, but what we’re looking to do is judge whether patients had medications very early and rapid responses to therapy, which predict for certain paths in many treatment plans. This has been pioneered in pediatrics, and I think it’s the case in adults. We want to understand the effective therapy to get patients to a deep enough remission to consider whether transplantation—that is, allogeneic stem cell transplantation—is the right choice or not. And this holds true for both myeloid and lymphoid malignancies. Lastly, of course, monitoring a patient who has been treated to track any early evidence of relapse is another scenario where MRD testing has become important.
So, it has become engrained in the culture of treating a higher-grade, or even a lower-grade, lymphoid malignancy patient. MRD testing shows you how well you’ve done, what the text step might be, and when it’s potentially time to think about an alternate step or return to therapy.
As we dig deeper in lymphoid malignancies, we clearly have better tools available. I mentioned that cytogenetics and FISH have been workhorses for decades. Flow cytometry is probably the next thing to discuss, and that really has become increasingly important in detecting MRD with as good as detail as we can. I think we can clearly look at cellular subsets much more carefully than we used to with more complex flow cytometry that’s available. That being said, I think we’ve learned a lot about the molecular underpinnings of ALL, and that’s become perhaps even more important.
One area to highlight would be the fact that some cases of ALL really behave like other molecularly driven diseases, where there’s a molecular target. Philadelphia chromosome-like ALL is one example. That’s a case where MRD testing may be driven by molecular parameters, where we look for PCR [polymerase chain reaction], standard PCR, or newer techniques to follow a molecular driver.
Molecular testing across the board has become important to look at. What are the biologic, but more molecular, underpinnings of a disease? How complex is it? What’s driving it? It may not be something that is trackable and shows disease response, but it will point us towards therapy choices and help us assess the risk and behavior of leukemia. So, next generation sequencing is a platform where we can look at very low levels of molecular markers that we either expect or may not expect as the disease is first diagnosed or treated that may evolve. There are other techniques to look at very small levels and very minute changes, single-based pair changes, techniques such as allele-specific oligonucleotide PCR, with which you can look at a single nucleotide change and a single strand of DNA.
All these tools are available to help us first and foremost choose treatment, understand response, track a patient who’s in deep remission, and make decisions about their proper path. But they also help us understand the disease better, expand our treatment choices into the realm of targeted therapy, and really help us better cure these diseases.