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Monitoring CLL: Determining Treatment Plan and MRD Testing

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Published on August 26, 2020

How is MRD Testing Used to Monitor My CLL and How Will I Know if My Treatment Is Working?

CLL patients want to know how experts determine if their CLL treatment is working and if they should be treated earlier. What tests are used to test minimal residual disease (MRD)? Is there a benefit of starting treatment earlier rather than being on watch and wait? Is it better to use a therapy that has a fixed duration rather than continuing to take pills for a long period of time? Host Andrew Schorr gets the answers to these questions from CLL expert Dr. Richard Furman from Weill Cornell Medicine.

This is Part 2 of a 4-part series on CLL. Watch all segments in the series below:

This program is sponsored by AbbVie, Inc., Genentech, Inc. and Adaptive Biotechnologies. These organizations have no editorial control. It is produced by Patient Power. Patient Power is solely responsible for program content.

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Transcript | Monitoring CLL: Determining Treatment Plan and MRD Testing

Monitoring CLL Treatment Effectiveness

Andrew Schorr: 

So that takes us to monitoring. For instance, how do you know if something is working, for instance, we've heard this term minimal residual disease or measurable residual disease. What testing do you do? Is it just simple blood testing or more elaborate MRD testing to say, first, how are you doing on a BTK inhibitor? Or if you're on a venetoclax (Venclexta), can you stop?  

Dr. Furman: 

So, MRD stands for minimal residual disease and you'll hear the term undetectable or negative for MRD. And that really means that you have less than what currently is 10 to the minus fourth, by flow cytometry or 10 to the minus sixth, by some of the NGS panels that are now becoming available. And what that means is, one out of 10,000 for 10 of the minus fourth or one out of 100,000 for 10 minus six cells are CLL cells. It's a way of looking at as to how few cells you have. What I really believe is most important for patients and what I think most patients also believe, is that progression free survival really is what's most important. I have patients who've been on ibrutinib (Imbruvica) for 10 years now who haven't yet achieved MRD negativity, but they're fine. They're on the drug but tolerating it well and they continue to respond. And so really progression free survival, and that translates into overall survival, is the most important endpoint. 

A drug like venetoclax, which would choose MRD negativity more quickly than ibrutinib or other BTK inhibitors doesn't necessarily afford any advantage. So what we should see with any BTK inhibitor, and this is true for any B-cell receptor antagonist, which will include the PI3 kinase inhibitors as well, is that you should initially see the lymphocytes rise in the peripheral blood as they're mobilized out of the lymph nodes, and the lymph nodes very rapidly shrink. And that's really a sign that the BTK inhibitors working. The lymphadenopathy really should be almost completely resolved by eight weeks. Now the lymphocytosis could continue on for many, many weeks and actually could last for even beyond a year. So, it doesn't necessarily mean that it's not working if a patient has a persistent lymphocyte here. 

Andrew Schorr: 

So, people are going to see their counts fluctuate as they start a medicine. And what you're looking at is the trend long term.  

Dr. Furman: 

Absolutely. 

Should CLL Patients Start Treatment Earlier?

Andrew Schorr: 

Okay. People wonder, is anything changed whether people should be treated earlier? Because I was four years watch and wait. We have a lot of people watching still and watch and wait but maybe they develop symptoms. Is there some thought with these powerful medicines to start earlier?  

Dr. Furman: 

So, it's important to remember that watch and wait was developed during the 1970s and so it was based upon one having very poor agents to use primarily chlorambucil (Leukeranand prednisone, and two actually not really being able to discern who are those people that are likely to progress from those who are not. So, I do think watch and wait is very antiquated, but it still is standard of care to not treat a patient until they meet the established criteria. Now, I do believe some patients have an idea that every day you delay treatment, it's another day you get the other end. That's not true. I think it's really important that we treat people as soon as their disease shows being active, especially because we're not using chemotherapy nowadays. And so you don't have those long term issues of damaging the bone marrow and the immune system that could really lead to long term complications.  

Overall, I think 80%, the data supports it, 80% of the patients with CLL will do extremely well with the BTK inhibitor if they are treated after a period of watch and wait and then start treatment and tolerate the treatment. And it usually is, who are the 20% that might need a little bit more? And those 20% might need a little bit more because the disease mutates and becomes very active or transforms before they need that watch and wait or before the watch and wait period is over. 

So, when a subset of people early initiation of treatment actually may be advantageous. There are some trials looking at that currently, but that's a very small subset in the vast majority of people really, we know are adequately served by watch and wait. 

Andrew Schorr: 

Okay. I just want to go back to one thing. We're in this time of the pandemic and we're also in the time of some people are losing their jobs, losing their insurance. One of the advantages of the venetoclax approach supposedly is that it would be fixed duration rather than taking pills for a long time. Where does that come into play? Like we had with FCR where people did it for six months and they stopped - where you just stop after a while and you also don't have the costs.  

Dr. Furman: 

Well, one of the big issues I think with venetoclax though, is the increased monitoring requirement really requires the patient to do so much more in person visits. So with acalabrutinib (Calquence), in essence, you can manage a patient from a distance. I can start them on therapy to get local labs every three months and just speak to them on the phone and by and large manage all the issues that might arise. Whereas when you have venetoclax, you have to worry about tumor lysis and the dose ramp up, you really end up with so much more visits to the office, visits to the lab, that you really lose a lot of the advantages. And so, I've actually been using BTK inhibitors in place of venetoclax during the COVID crisis specifically for that reason, just trying to enable patients to avoid having to leave their house.  

Andrew Schorr: 

Okay, the cost issue is not insignificant. 

Dr. Furman: 

The cost issue is not insignificant. I think obviously, a lot is dependent upon what our government's going to do. Fortunately, they met a lot of programs in place from the pharmaceutical companies to continue therapy to people have lost their jobs. 

Andrew Schorr: 

Alright. So these are individual discussions people have with their doctor to see what's right for them.  

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.


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