Circulating levels of tumour DNA in plasma may help monitor treatment response and resistance in CLL
Dr Constantine Tam – Peter MacCallum Cancer Centre, Melbourne, Australia
I’m here at the iwCLL conference; I have been involved in a number of works that have been presented at this meeting, including works involving the new agents ibrutinib and Venetoclax but perhaps I’ll talk about two particular pieces of work of particular interest. The first one relates to the outcome of patients who relapse after or progress while taking ABT-199 or Venetoclax treatment. Now the background to this is that all these new drugs have really changed the way CLL is being managed but with specific reference to ibrutinib, which is the front runner in the class of these drugs, there are now reports suggesting that when people relapse or progress on ibrutinib that often they’re very hard to treat. So often they’re very resistant, they progress very quickly and that their survival may be quite short. Now, of course, the other agent that is very promising is ABT-199 or Venetoclax where there is basically no information to date on what happens when people fail Venetoclax, when they progress. So we looked at our experience at Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, together we had 70 patients on Venetoclax studies and we looked at the outcome of those who relapsed. Now, there are two patterns of relapse: some patients relapse with Richter's transformation and for Richter’s transformation, to our surprise, they actually did respond to chemotherapy, a proportion of them did respond to chemotherapy, and we were able to take four of them to transplant. In fact, after transplant three of these patients are alive, three of the Richter’s transformation; in two of the patients their disease came back but not in the form of Richter’s, it came back in CLL and we were able to restart ibrutinib in those patients and control the disease. So for once we have a situation where a patient develops a Richter’s transformation from a novel agent and we were able to salvage the situation. So that was very encouraging.
The second pattern of relapse are those who relapse with CLL, so from Venetoclax. For those patients they actually did very well and I think the reason why they did very well is because they relapsed in an age when we can give them ibrutinib therapy. So these patients were restarted on ibrutinib on the whole and they regained disease control and remain alive and well. So that’s a very different situation from those ibrutinib studies suggesting that people don’t live very long after they relapse from ibrutinib. The difference is those are older studies and when you relapsed on ibrutinib there wasn’t Venetoclax to rescue these patients. Whereas with our study, when these patients who were on Venetoclax relapsed we had ibrutinib to rescue them. So that’s the first piece of work.
The second piece of work is more translational, more scientific. Our group examined the role of plasma DNA as a way to monitor disease. Now, the background to this is that plasma DNA is a new test that’s pretty hot in solo oncology. So cancer cells shed the DNA into the blood and we can detect evidence of cancer in the blood by looking at the DNA. So we asked the question, can this test be used in CLL? You might say, well why do you want to do this in CLL? CLL is this disease that’s readily detectable in the blood. But we had several hypotheses. Our first hypothesis is that sometimes with CLL people respond in different ways, so some people get, let’s say, ibrutinib and their lymph nodes shrink but there’s a lot of disease in the bone marrow. If you get Venetoclax the bone marrow clears but there’s residual disease in the lymph node. So there’s no one test in CLL that allows us to measure the total amount of disease in the patient’s body. So we thought that maybe plasma DNA would be a way because disease at all sites of the body, regardless of whether it’s the spleen or the bone marrow or the lymph nodes, shed the DNA into the blood. So we thought that maybe plasma DNA would be a way for us to trap the disease and take a total picture of how the patient is doing on different treatments and that was true. So we actually had patients who were treated with ibrutinib or Venetoclax and we can actually track their response to their therapy very well in the blood. In fact, of all the tests that we did, blood tests, CT scans, bone marrow, the test that tracked their disease progression the best, as in how they responded, was in fact plasma DNA.
But the second thing that we found that was really exciting was in fact that we had patients who developed resistance to these drugs. When we sampled their disease at the time of resistance and we identified those genes that were potentially associated with a resistant clone we can go back to the blood and the plasma and, for many days, weeks to months before they actually develop the resistance, the plasma DNA showed the genetic changes associated with these new clones. So had we known what to look for we would have seen these clones coming several months before they relapsed clinically, suggesting that we can, in fact, use plasma DNA as a way to track multiple clones in the body and as a resistant clone emerges, suggesting that your therapy is about to fail, we can perhaps see that several months before it occurs, allowing us to intervene at a time before full resistance occurs. So this is all hypothetical, it’s all theoretical, it’s a pilot study but it excites me and I think that it’s a great introduction to trying to see if we can use plasma DNA in prospective trials to track the multiple clones.
