Case Study: CLL Diagnosis, Prognostication, and Treatment

Sanam Loghavi:

Great to be here with you. And let’s discuss our patient. So our patient is a 74-year-old man who presents with lymphocytosis, absolute lymphocytosis of 52,000. And I would like to know as the diagnostician who’s working up this patient, so I have a peripheral blood sample, what is the minimum information you need from me in order to make an informed decision, in terms of how you’re going to treat the patient?

Matt Davids:

So of course we make the diagnosis of CLL by flow cytometry on the peripheral blood. So we want to see an absolute B cell count of greater than 5,000 with the characteristic immuno-phenotype, namely CD19, CD20 positive. Often the CD20 is dim.

Sanam Loghavi:

Yes.

Matt Davids:

As you know. CD5 is also positive. So when we see that, it’s usually CLL, but occasionally it can be mantle cell lymphoma. So we also like to send fish to look for an 11;14…

Sanam Loghavi:

Absolutely.

Matt Davids:

… translocation and rule that out. But as long as that’s the case, then we don’t usually need a bone marrow biopsy or a lymph node biopsy to make the diagnosis of CLL.

Sanam Loghavi:

That’s fantastic. So maybe for the trainees a little bit, when we talk about a typical CLL phenotype, it’s a B-cell lymphoma, and like you said, CD20, typically dim. CLL tends to be like a very polite neoplasm, everything’s very DIM. 20 DIM 79 B dim, light chain restricted, DIM, 22 dim. But there is actually an atypical variant of CLL, which is immuno phenotypically atypical. So there are variations to the immuno-phenotype. Most characteristically it’s lack of CD23 expression, which is very common for CLL or bright expression of CD20, surface light chains, or CD79B. So when we deal with that, especially when you have an atypical phenotype, you want to make sure that you’re not dealing with another B-cell lymphoma such as mantle cell lymphoma. But be mindful that CLL with trisomy 12, for example, can have any typical phenotype. So it doesn’t necessarily exclude the diagnosis, but you have to be a little bit more careful.

Matt Davids:

Yeah. I’m curious also, do you rely on other markers like CD200, left one?

Sanam Loghavi:

Yes. Actually CD200, very much. The only caveat with CD200 is… So CLL almost always is uniformly bright for CD200. The only caveat in that, is, and that’s where you should… The main differential diagnosis is non-nodal leukemic mantle cell lymphoma. And in that case there can actually be overlap. So mantle cell lymphoma typically is negative for CD200, except for when it’s the non-nodal leukemic variant. So it can be, but it’s never as bright as CLL or as uniform as CLL. And then left one, tissue based, yes. But not necessarily. But we have 200 in our flow panel, and so we definitely consider that. And then in terms of ancillary studies, so obviously for prognostication and then for choice of therapy, we do ancillary studies, including fish, next generation sequencing. You want to know the mutation, or mutated or non mutated status of the IGHV. So how do you use this information to make a treatment decision?

Matt Davids:

Yeah, so those are the key factors. And really just to emphasize that in addition to fish, to look for deletion 17P. You do have to also sequence for TP53…

Sanam Loghavi:

Absolutely.

Matt Davids:

… mutation, and that can be done through an NGS panel or it can be done by other methods, Sanger sequencing, et cetera. And we know that even very low VAF clones of TP53 mutant can be aggressive.

Sanam Loghavi:

Absolutely.

Matt Davids:

And so when we see that, it is important clinically, and it actually helps direct our treatment. IGHV status is also very fundamental to the biology of CLL. Affects even things for me, in terms of the threshold of when I treat. So if I have a patient who has more aggressive genetics, I still wait until they meet the treatment criteria, but I’m a little more proactive about getting them started. I have patients with mutated IGHV and low genetic risk otherwise, where I really drag my feet a little bit more, and wait until they really need treatment, because some of those patients can go so many years on observation without the risks of treatment.

Sanam Loghavi:

Yeah, so this is very important, what we’re alluding to, in terms of the subclonal maybe populations with TP53 mutation. Why do we care about these? So diagnostically, it’s important that if you’re using a variant color that may filter out anything less than two or 3%, you have to be very mindful if you’re dealing with a case of CLL. Because let’s say if you have 20% circulating CLL cells, and only a small fraction of them harbor this TP53 mutation that falls below the threshold of what your variant color would call, you may actually miss the mutation. So it’s really important to not filter aggressively when you’re looking at CLL cases, for molecular pathologists. And then also to mention in the report, because what happens is TP53 mutated clones tend to be resistant to chemotherapy. And so if you treat the patient, what happens is that TP53 wild type clone may go away, but the TP53 mutated clone may actually expand upon therapy.

So that’s very important to mention. So let’s talk about our patient now. So we have a 74-year-old patient who’s presented with lymphocytosis. And we want to make a treatment decision. So the information I have for you at this point is this patient has a TP53 deletion, they have actually a TP53 mutation, as well as a deletion.

Matt Davids:

Which is very common to have bot, right?

Sanam Loghavi:

Which is very common of course. And then they also have an unmutated IGHV status. So what would be the first… Well, first of all, when do you decide to treat? Right?

Matt Davids:

Right.

Sanam Loghavi:

What is the threshold for count? What is the-

Matt Davids:

Yeah, so that’s always the first really important decision. And we have recent randomized data, again confirming prior studies that early intervention strategies, even with targeted agents, are not helpful for patients if they don’t meet these treatment criteria. So the standard iwCLL treatment criteria includes cytopenias, and we typically start to watch the hemoglobin more closely when it’s less than 11, particularly less than 10. Platelets as they’re less than 100. When those lines are both down, I do usually like to do a bone marrow biopsy before treating, and actually just recently had a case of MDS…

Sanam Loghavi:

That’s [inaudible 00:05:59].

Matt Davids:

… that was diagnosed…

Sanam Loghavi:

Of course.

Matt Davids:

… in a patient with CL., and so that’s important, you want to rule that out. But usually it’s going to be CLL extensive infiltration that’s causing the cytopenias. If you have that, that’s enough to start treatment. Some patients may not have cytopenias, but they might develop bulky lymphadenopathy or spinal magaly. And if that’s becoming symptomatic or starting to threaten organs…

Sanam Loghavi:

Of course.

Matt Davids:

… that’s a time to treat. And then usually in the context of these clinical features, also patients can have symptoms, constitutional symptoms like unintentional weight loss, fatigue, night sweats, these sorts of things. So it’s a complex picture. All these factors are there, and then also the genetics, as I said. Again, if it’s a low risk patient, I may drag my feet a little bit. If it’s a high genetic risk patient who’s starting to have these symptoms, I don’t want to wait for them to get too sick, and I might start treatment a little sooner.

Sanam Loghavi:

Okay, fantastic. So based on the characteristics that our patient has now, what would be the best choice of frontline therapy for this patient?

Matt Davids:

So assuming this patient meets the iwCLL treatment criteria, then we still can consider a couple different options. So standard for the TP53 abberant patients would be a BTK inhibitor given continuously. We have three covalent BTK inhibitors approved in CLL now, ibrutinib, acalabrutinib, and zanubrutinib. We tend to use acalabrutinib and zanubrutinib now more than ibrutinib, based on the improved safety profile of these newer drugs. So that’s one option that would be a continuous treatment, and that’s usually how we treat patients with high risk disease. The other option is venetoclax with obinutuzumab, which is a time limited treatment regimen, which is nice. But we’ve seen from now randomized studies that patients who have TP53 abberant disease do have a shorter progression-free survival with venetoclax plus obinutuzumab, compared to patients who have wild type TP53. So that’s why we tend to lean toward the continuous BTK inhibitor based therapies for most patients. Although I understand this patient has some other unique medical issues.

Sanam Loghavi:

They do. So this patient has significant cardiovascular disease. So would that affect your decision?

Matt Davids:

Yeah. So one of the major side effects of BTK inhibitors is cardiovascular complications. Atrial fibrillation, hypertension, and also bleeding risks. So particularly if you have a patient who has AFib and needs to go on anticoagulation, and they need to be on a BTK inhibitor, that can be problematic, and those patients are at risk for major bleeding issues.

Sanam Loghavi:

Well, it’s good to know that they have other options.

Matt Davids:

Yeah. So Venetoclax plus obinutuzumab would probably be my choice for our patient, because although he has the TP53 mutation and deletion, he also has these cardiovascular risk factors. And so I know that I can probably get a median of about four years of progression-free survival, with one year of venetoclax plus obinutuzumab. Which is not bad. It’s not as long as we’d expect with the BTK inhibitors, which might be more like six to seven years, median PFS. But one of the nice things about venetoclax is the potential for re-treatment. And we don’t have prospective data yet on the re-treatment question, but we have some accumulating retrospective data suggesting that venetoclax may work a second time in patients who previously had venetoclax. So if we imagine about four years of initial PFS, but then we treat with venetoclax again, maybe we get another two to three years, and then actually maybe it ends up looking pretty similar to the BTK inhibitor, but without all those cardiovascular risks.

Sanam Loghavi:

Of course, that’s pretty encouraging. Can you tell me how you dose the venetoclax?

Matt Davids:

Yeah, so the venetoclax obinutuzumab regimen starts with the obinutuzumab antibody infusions. Days one, two, eight, and 15. So you load the antibody, and then you start the venetoclax at 20 milligrams, and you do the five-week ramp up all the way up to 400 milligrams. And then you complete the year of therapy with the initial six months being the obinutuzumab combination.

Sanam Loghavi:

That’s fantastic. And then while you’re giving the patient treatment or they’re on this course, how do you monitor the response and their disease? What is the role of MRD? And I’m going to talk a little bit before I let you answer that question, is that we now have two established methods of doing MRD. One actually I think may die out very soon if it has not already. But essentially we use flow cytometry that has a sensitivity of 10 to the minus four if you have a good sample. And then we also use sequencing. ClonoSEQ is one of the methods that’s being used right now, that has a much higher sensitivity. It looks for the sequence of the clonal IGH, and that has a sensitivity of 10 to the minus six. And so because of the superior sensitivity, what’s being used now in practice in a lot of especially academic settings, I think, and private probably too, is flow cytometry and ClonoSEQ. So how often do you monitor for MRD, and how do you use that information?

Matt Davids:

So I don’t think flow cytometry is totally dead yet. And part of that is because…

Sanam Loghavi:

Yeah. We’re doing it, yeah.

Matt Davids:

… in order to do ClonoSEQ, you have to remember to send an identification sample…

Sanam Loghavi:

Absolutely.

Matt Davids:

… before the patient starts treatment. And so sometimes even we forget to do that, even though we’re at an academic center. Usually we have bank samples available for our patients, but in practice that might not be the case.

Sanam Loghavi:

Of course.

Matt Davids:

Flow cytometry is always great if you don’t have an identification sample. But I do agree if you have the ID sample and you send it, ClonoSEQ gives much better level of detection, so that is what we’ve tended to use more often. I usually don’t check before six months. So sort of in that six month range is my first test, I send from the peripheral blood, you don’t need to do a bone marrow biopsy. I like to start checking it every three months in that second half of therapy, because I like to see what the trend is in the MRD. And I’ve run into patients who’ve had issues with neutropenia later in the course. And if they’re already undetectable for MRD or they have a nice downward trajectory, I might not necessarily complete the full 12 months, if they’re really struggling with neutropenia.

So it’s a little bit helpful in that early setting. And then I like to check it about three months after the completion of the year of therapy. That aligns with the data point in a lot of the studies that they looked at, to understand how that’s going to correlate with eventual PFS and NOS. And then after that, in patients on longer term follow up, I’m still checking MRD every six to 12 months, depending on the patient. If it’s a low genetic risk patient, probably just every 12 months. If it’s a high risk patient, maybe every six months. And that can serve as an early warning system. If they’re starting to show MRD relapse, you might want to watch them a little more closely and think about what the next line of therapy is. But I think an important message is, right now we don’t intervene based on detectable MRD. We wouldn’t restart treatment just based on that.

Sanam Loghavi:

Okay, that’s good to know. But I think again, really important to know that we have to accumulate sufficient data to be able to change management and change therapeutic decision making for these patients, which I think is happening as we speak.

Matt Davids:

I agree.

Sanam Loghavi:

So with that, thank you so much. This was a great discussion, and we hope that the audience enjoyed it too.

Matt Davids:

Thanks so much.