One of the toughest complications or progressions of CLL [chronic lymphocytic leukemia] is if a patient develops Richter syndrome. I’ll turn to Ryan to tell us a little about venetoclax-based regimens for patients who have Richter.

 Richter syndrome is a tough situation to manage in a lot of patients. Unfortunately, clinical trial data to guide us aren’t significant. We did have a poster presentation looking at the use of venetoclax in various forms to treat Richter syndrome. It had venetoclax with chemotherapy, venetoclax with BTK [Bruton tyrosine kinase], venetoclax with anti-CD20, and venetoclax monotherapy. Responses were there, but outcomes were poor overall. There were some interesting data to report. Perhaps venetoclax can help us address these difficult-to-treat patients. There’s a lot of interest in looking at venetoclax with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]in the frontline setting or R-EPOCH [rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin hydrochloride].

Not all Richter syndrome is the same. There’s some heterogeneity, but that’s something to keep our eye on. John, what do you think about venetoclax in high-risk patients defined by deletion 17p? Are there any data there?

 Yeah. As you may be aware, venetoclax had its first approval in relapsed/refractory patients with deletion 17p. This is based on a 

 paper published many years ago, I believe in 2014 or 2015, demonstrating the activity of monotherapy venetoclax in patients with this high-risk feature deletion 17p. This study has recently reported with up to 6 years of median follow-up for these patients. We now have a good sense of how patients do with high-risk features with long-term follow-up, getting monotherapy venetoclax. At the 6-year mark, this study shows that response rates are high in general. Over 80% or so of patients are responding, but most of those are PRs [partial responses]. About 20% of patients are achieving a CR [complete response]. This is in contrast to the initial report, which was under 10% of these patients.

There seems to be some deepening. Progression-free survival is about 2 years. That’s the expectation seemingly in these high-risk patients: to get progression-free survival of 2 years. But overall survival still looks very good, with a median being met around this 6-year mark. There are patients achieving MRD [minimal residual disease] negativity. Close to a third of patients achieved an MRD-negative state in peripheral blood with monotherapy. These are patients we sometimes don’t see anymore because these were 17p patients who didn’t have BTK inhibitors. In fact, most of these patients were unexposed.

That said, response rates are good. If you did get a complete remission in this study, these patients had remarkable progression-free survivals: 5-plus years. If you do have very sensitive CLL, you’re going to do phenomenally well. That said, even in patients with high-risk disease, the median mileage that we get is almost 2 years. That’s meaningful with a monotherapy approach. This put venetoclax on the map. With this study, we’ve got 6 years of follow-up. These are impressive data, and they’ve greatly informed us of how we use this drug and the expectations set forward, particularly in relapsed high-risk disease.

What about the noncovalent inhibitors for Richter syndrome? Nicole, what do you think?

 Obviously we’ve had some data presented at this meeting as well, looking at pirtobrutinib in this setting. It’s small numbers. This truly is an unmet need in CLL. All of us always try to bind together and enroll our patients in clinical trials because we need better therapies for this group. This was a study that has about 80 patients with pirtobrutinib in this setting. The overall survival was still short. It was about 13 months, but it’s a young study. The median survival of patients with Richter, when we look at older studies, is anywhere from 6 to 18 months. There were some complete remissions on this study.

It’s also a potential bridging for other therapies. That’s important. When we think about giving R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or R-EPOCH [rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin hydrochloride] to these patients, many of them are heavily pretreated, [so we have to consider the] toxicities of those chemoimmunotherapy strategies. With something like pirtobrutinib, the toxicities are relatively minor, so that’s a very good therapy. Even though it might not be a long-lasting therapy—the response durations might still be inadequate for what we’d like for patients with Richter—many of those patients were bridged. Actually, 6 of them went on to get an allogenic [stem cell] transplant, so they might be good bridging potential for other alternative therapies with much less toxicity using some of the strategies we’ve used previously for patients with Richter.

Videos

Key opinion leaders provide their perspective on the optimal management of high-risk chronic lymphocytic leukemia with novel therapeutic agents.

Novel Strategies in Managing Patients With High-Risk Chronic Lymphocytic Leukemia

Just to wrap up, is there any new novel strategy or really exciting data that we haven’t covered? Maybe since you’re very familiar with it, you want to say a word about the noncovalent inhibitors. I know the pirtobrutinib data are being updated this year at ASH [American Society of Hematology annual meeting], and also we’re going to hear data, which we haven’t heard in a long time, on what used to be the ArQule drug and is now the Merck drug. I know you were leading the charge with pirtobrutinib, and maybe we can just close with a few words about I think the excitement we all have for the noncovalent inhibitors.

Sure. Yes, it’s an exciting class or an exciting potential mechanism of action in 2 drugs that are frontrunners here. The ARQ 531 molecule, which I think is now called nemtabrutinib, that’s the new name for it. Then pirtobrutinib, which was formerly LOXO-305. Interesting molecules in that they really are targeting relapsed/refractory CLL [chronic lymphocytic leukemia], particularly in patients who’ve been exposed to a prior BTK [Bruton tyrosine kinase] inhibitor and have developed the most common mechanism of resistance, which is a cysteine 481 mutation. They have a different binding mode. They bind to a different location on BTK, and the clinical data really support the fact that these drugs are active in an unmet need patient population. In terms of the LOXO-305 [pirtobrutinib] data, which I’m more familiar with, it turns out it’s a really clean BTK inhibitor in terms of its AE [adverse event] profile, a discontinuation rate of about 1% due to adverse events, which is wonderful, but not many of the classic BTK inhibitor-associated toxicities.

It’s early days, but it’s nice to have molecules that address an unmet need that happen to be well tolerated, which from a sequencing perspective can continue remissions long term for patients. The other class, which we don’t have to go over the data because there’s not a whole lot yet, is the bispecific antibodies. They seem to be really interesting and exciting, and there are some data to be presented at the ASH meeting, at least there’s a poster presentation on one of these molecules. Those are 2 really interesting classes and many other targets that are in development as well.

It’s exciting times. Well, it’s been exciting times for a while now, but it continues to be.

Thank you, Anthony, for this really interesting conversation, and thank you, the audience. We hope you found this program informative.

Exciting novel-based treatment strategies being investigated in chronic lymphocytic leukemia.

Chronic Lymphocytic Leukemia: Novel Therapies in the Pipeline

Let’s talk a little about these exciting small molecule combinations. It seems like every large, randomized trial now being done anywhere is looking at this, but we have data from 3 trials. We have the ibrutinib, venetoclax combination from MD Anderson Cancer Center. I think that’s still the only one published. But we’ve seen multiple presentations on CAPTIVATE, which is the Pharmacyclics [LLC] trial. It has the same initial schema as the MD Anderson trial, namely a 3-month lead-in with ibrutinib, then a ramp-up of venetoclax, then 12 months of the combination. Then in the CAPTIVATE trial, of course, there were different cohorts depending on MRD [minimal residual disease] status at the end of that combination, or there was also a fixed-duration cohort, but the first 15 months were the same as the MD Anderson data. Now we have the GLOW trial, which is the first randomized trial, which compared ibrutinib and venetoclax to chlorambucil and obinutuzumab. Now we see some trials that are also throwing an antibody in there with the 2 small molecules. I know you’re familiar with these data. You can give us your thoughts on this.

I could give you my thoughts. I don’t know if I could make sense of it. It’s 2 different processes. The combination looks active. It can induce deep remission, it’s time-limited, either MRD-driven based on CAPTIVATE part 1, or fixed duration based on CAPTIVATE part 2 or the GLOW trial. What I’m still trying to get my arms around is how to determine the relative contribution of each of the components. Who should get a novel-novel combination instead of either the sequence of these drugs or venetoclax and obinutuzumab? From an MRD perspective, and even maybe a PFS [progression-free survival] perspective, they look kind of similar to me. It’s hard for me to judge the importance of the need for the combination based on the comparisons that are made. We’re joking around about chlorambucil and obinutuzumab. Everybody has been able to beat it; U2 [ublituximab, umbralisib] beat it, ibrutinib/obinutuzumab beat it, acalabrutinib/obinutuzumab, acalabrutinib monotherapy beat it, venetoclax/obinutuzumab beat it. Everybody seems to be able to beat it, but when you start putting drugs together, which individually were able to beat the control, it’s hard for me to really assess how this will impact my practice. I think it probably will be used in my practice, but probably for younger patients who have poor-risk features who want a time-limited approach. That’s kind of where I’m seeing this going at the moment.

Then you brought up the triplets. The triplets are interesting too, but I don’t have any triplet vs doublet vs mono data coming, none of us do, to decide who needs a triplet vs a doublet. So we’re starting to get into this quagmire where we have lots of active regimens, but comparisons that don’t really guide decision-making. That’s where I’m hopeful some of the newer trials, like the CLL17, at least are on the right track of asking how to judge contribution. That’s ibrutinib vs ibrutinib plus venetoclax vs venetoclax plus obinutuzumab, so really asking important questions like mono vs doublet, fixed duration vs continuous, novel-novel vs either of the individual components. That’s my take on the combinations at the moment.

I agree with you. Clearly, the patient population that stands to benefit the most are younger patients. The reason I say that is for older patients, if you think about it, the median age for diagnosis is about 71 according to SEER [Surveillance, Epidemiology, and End Results] data. Unlike this case that we presented, for the vast majority of patients you’re going to do watch and wait at the time of diagnosis. Let’s say you do a couple of years of watch and wait. Then we know from the long-term data from RESONATE-2 that at 7 years, there’s still no median PFS with the use of ibrutinib in the frontline setting, and at 6.5 years, 61% were progression free. Let me just go out in a limb and say maybe they’re going to reach a median at 8 years. You see where I’m going with this? My patient’s 71 [years old], I’ve done watch and wait, they’re 74 [years old]. They just got 8 years out of ibrutinib, so they’re 82. The MURANO trial of VEN-R [venetoclax, rituximab] was 1 prior regimen. It wasn’t ibrutinib, it was chemotherapy, but 1 prior regimen, and the median PFS was about 4.5 years.

It’s exactly what you said. If we sequence these treatments, except in very high-risk patients, and that even seems to be changing as we talked about in frontline 17p deletions. As we sequence these and consider the age of patients, do you really need the combinations? But of course, where you are really going to need them is with the hope that you can do better with the combinations and maybe even affect a cure. I don’t think anybody’s talking about that now, but certainly what we’d all like to do is get to a cure. I think MRD undetectability is essential for that, but it is not by itself enough. That may be partly because we standardly use 104 in our trials, and I think we need to be going forward, really looking at deeper levels which we can do now with these commercial assays to look at 105 or 106. We see that in a lot of these trials, they all come in at about 70% MRD undetectability at 104. What I would like to know is how do they compare at 105 or 106 because that might give us a better idea of long-term data. For younger patients, I think we still have the issue of probably not being able to cure those patients even with all the great drugs that we have without other things like CAR [chimeric antigen receptor] T-cell therapy or transplant, etc. Those are the people for whom I think the combinations are going to be really important.

Implications for treating chronic lymphocytic leukemia with small molecule combination regimens in the frontline setting.

Novel Combination Regimens for Chronic Lymphocytic Leukemia

We can talk about something else, there’s another new therapy probably coming early next year, which is a new PI3K inhibitor, umbralisib. That was combined in the UNITY-CLL trial with an anti-CD20 [monoclonal antibody] from the same company, TG Therapeutics [Inc], and that was ublituximab. That UNITY trial was presented at ASH [American Society of Hematology annual meeting] last year and has been published. That PI3K, antibody combination was significantly better than chlorambucil and obinutuzumab. That will likely lead to an FDA approval based on improved PFS [progression-free survival]. Do you have experience with that combination, Anthony, and what are your thoughts on that?

Yes, I do have experience with it. Interestingly, I’ve never given it as the U2 [ublituximab, umbralisib] combination without something added to it. I’ve given it to patients in combination with pembrolizumab on a trial. I’ve given it to patients in combination with either ibrutinib or venetoclax on a trial, but I’ve never given U2 [ublituximab, umbralisib] by itself. I think that it’s an active PI3K inhibitor. Certainly, it’s the only one that has even a potential to be approved as a frontline therapy. I think idelalisib and duvelisib have no chance at that at this particular time based on that there’s no study examining that question. What I’m grappling with a little in terms of how to interpret the UNITY-CLL data, particularly in the front-line setting is how to decide on a PI3K over the already excellent outcomes we have with ibrutinib, acalabrutinib, and venetoclax. For me, unless it’s some extreme circumstance where none of those agents were an option, the U2 [ublituximab, umbralisib] combination will still likely be a relapsed/refractory regimen for my patients.

I guess we should clarify that in that trial, there were both frontline and relapsed patients, and so we would expect the label to be both for frontline and relapsed. I certainly agree with you. I believe in the frontline setting, the median PFS was about 3 years, and that’s good, but it’s not as good as we’re getting with the BTK [Bruton tyrosine kinase] inhibitors or VEN-G [venetoclax and obinutuzumab]. So I also don’t see a clear role for that in the frontline setting and think we’re mostly talking about relapse.

The rationale for investigating and using PI3K inhibitors to treat chronic lymphocytic leukemia.

PI3K Inhibitors for Chronic Lymphocytic Leukemia

What about if this patient were, we already said, if you didn’t have a 17p, I said would you add antibody? Let me back up again and say if this patient didn’t have a 17p would you still use acalabrutinib or what would be your treatment of choice?

Then I think everything’s on the table and is an equal choice for patients. Unfortunately, we don’t have head-to-head data for any BTK [Bruton tyrosine kinase] inhibitor vs venetoclax. So I think it’s a conversation of risk-benefit, how the regimen itself will impact the lifestyle of the patient, can they make the commitment for an escalation, so on and so forth. I’m pretty comfortable, no matter what you chose in that situation, be it ibrutinib, acalabrutinib, or venetoclax, you’re going to have an excellent outcome for patients generally. So I don’t think that there is a right answer. There are several right answers.

: Does the mutation status influence you at all in the non-17p?

I feel like people are talking about that a little bit more where the BTK inhibitors seem to have similar outcomes when stratified by IGHV [immunoglobulin heavy chain] status, but the venetoclax-based curves from the CLL14 [trial] are separate, favoring the mutated patients. To me, I’m not really ready yet to make a decision for 1 targeted therapy or the other over based on IGHV status alone. But I think the right answer is probably we should be doing trials that are separate and different in those populations to try to discern that a little bit more.

I agree with you. As you said, in the venetoclax/obinutuzumab trial, the unmutated are not fairing quite as well as the mutated, but the mutated are doing fabulously. So unmutated are still doing well, I think we have reached a median PFS [progression-free survival] in that group, and it’s about 5 years. But don’t forget, that’s 4 years off therapy so that’s still a very attractive end point. Then there’s also the presumption, and I think there is data emerging to support this, that if you have stopped therapy and you have a long remission, you may be able to usethat therapy again. Which is also very attractive. I’m totally with you on that. I think the unmutated non-17p are going to have a great outcome no matter what you do. It’s hard to decide just based on the mutation status.

Let’s recast this patient with no 17p but 85 [years old]. What do you do in that setting? In other words, an older patient, let’s say he has your usual comorbidities at that age, maybe some hypertension, some hyperlipidemia. The case we have was quite young and we didn’t hear about any significant comorbidities, which is certainly possible in a 61-year-old. You may not have had any but let’s cast this patient as an older patient with standard comorbidities. Does that impact your choice of therapy?

A little bit. I feel that at least the data I have comparing the ECOG 1912 vs the ALLIANCE data set for ibrutinib suggests that the toxicities increase significantly with ibrutinib-based therapy for older patients and so I’m more likely to eliminate ibrutinib for somebody who might have underlying hypertension or some other cardiovascular risk factor and advanced age. In a world where I have a choice between ibrutinib and acalabrutinib, extrapolating data from the randomized ELEVATE-RR trial where those toxicities seem to be less for patients who are getting acalabrutinib-based therapy, I have no problem giving acalabrutinib. I have no problem giving venetoclax to an older patient, keeping in mind, you may not get to a stable dose of 400 mg before you start to get some cytopenia. I think BTK inhibitors and venetoclax are still on the table even in advanced patients in terms of age.

Susan O’Brien, MD, and Anthony Mato, MD, MSCE, describe their preferences for treating newly diagnosed chronic lymphocytic leukemia based on disease presentation and patient variables.

Individualizing Therapy for Patients With Newly Diagnosed CLL

Now, what about adding in an anti-CD20? Are you doing that when you’re using BTK [Bruton tyrosine kinase] inhibitors? And maybe you can talk about the reason I’m asking you that, which is some recent clinical trial data.

So generally not in clinical practice, although I think the data from the ELEVATE-TN trial is intriguing. Just to review, that trial was a frontline trial looking at acalabrutinib plus or minus obinutuzumab vs chlorambucil/obinutuzumab. So 1:1:1 randomization. The acalabrutinib based therapies were better. Interestingly, the acalabrutinib/obinutuzumab had a PFS [progression-free survival] advantage over the acalabrutinib monotherapy, not only at the first interim analysis at 24 months, but those curves actually widened when they took a look 2 years later. Really supporting the fact that if you add obinutuzumab to acalabrutinib, there’s an advantage in PFS. Interestingly though, I would’ve predicted it would have been in the high-risk patients like this with the deletion [del] 17p. When you look at the data, the del 17p patients were really the only group that didn’t appreciate an advantage in PFS when the obinutuzumab was added. So for this patient, for sure I would give acalabrutinib as a monotherapy. Now, if you’re thinking about use of ibrutinib, unfortunately the ibrutinib/obinutuzumab trial iLLUMINATE did not include an ibrutinib monotherapy. So I just generally don’t really understand the relative contribution for the obinutuzumab to ibrutinib, so I give ibrutinib as a monotherapy no matter what. Then of course we have randomized data from the ALLIANCE trial, an MD Anderson Cancer Center-based randomized trial in the relapse/refractory setting, suggesting no clear role for adding rituximab to ibrutinib. So short answer is most of the time just as monotherapy is probably the right answer. In a high-risk patient, it seems to be the way to go.

If this patient did not have a 17p deletion, let’s say he had no abnormality in the FISH [fluorescence in situ hybridization], what would you? Would you give the antibody with the acalabrutinib or have you done that yet, or is COVID-19 impacting your thoughts about that?

So I’m a little biased in my answer because we have a frontline trial looking at acalabrutinib/obinutuzumab as a time-limited therapy. So I think the MRD [minimal residual disease] data from now extrapolating iLLUMINATE and a little bit of the MRD data we had from ELEVATE-TN really do support that obinutuzumab deepens remission responses to ibrutinib or acalabrutinib. That opens the window to me as a time-limited therapy, but that’s not standard of care. So most of my BTK starts in my practice have been on that trial. In clinical practice, most of the time I’m just giving acalabrutinib as a monotherapy at this particular moment. Of course the pandemic does have some influence over decision-making as there is some data to suggest that an anti-CD20 will blunt, partially blunt, or completely blunt the response to vaccines, not only to COVID, but to any particular virus that we’re immunizing against.

It was unfortunate for me that there were some of my patients I wanted to give venetoclax/obinutuzumab and I deliberately waited until they had 2 COVID shots and then started their treatment. Then what happened later, this third shot was recommended. I am very worried that those patients are not going to amount much to that third shot because of the use of the antibody in that setting. So it’s definitely tricky. I agree with you. I have not given obinutuzumab with acalabrutinib, but of course when that trial was first published, there was a little over 2 years of follow-up. At that point, the acalabrutinib and the acalabrutinib/obinutuzumab curve were slightly separate, but really nothing to write home about. As you pointed out over the 2 years more follow-up that we have, and we just got this data. This was at the spring meetings, ASCO [American Society of Clinical Oncology], EHOC [Eurasian Hematology-Oncology Congress], etc. We saw the 4-year data where those curves are fairly dramatically separated. So I haven’t done it up until now, because of course up until a few months ago, we had not seen such a large separation in the curves. It definitely wasn’t there at the 2-year mark. So I’m considering it. Although, again, right now, I think the impact would kind of push me against it, that’s still the ongoing issues with COVID in that sense. So I haven’t done it yet. I might consider it moving forward.

The rationale for integrating CD20 monoclonal antibody therapy into the frontline setting of chronic lymphocytic leukemia.

Frontline Anti-CD20 Therapy in CLL

So now we have this high-risk patient. What are your thoughts in terms of what are you thinking about treatment and what are the important characteristics here that lead you to that? Is it the mutation status, the FISH [fluorescence in situ hybridization]? We did not hear about any comorbidities, and this patient is relatively young. I'm going to assume in this case, it's probably going to be more related to the disease characteristics.

I think the easiest part of the treatment decision-making is to determine what I wouldn't give this patient. For me, chemoimmunotherapy is absolutely off the table for this patient based on the IGHV [immunoglobulin heavy chain]status alone, but then add the deletion 17p and it's no longer even a standard of care consideration. I think we're having a conversation about which targeted therapy would be the best particular fit for this patient. There's 2 possible pathways, either BTK inhibitor-based therapy, and we have 2 choices. Ibrutinib and acalabrutinib or BCL2 inhibitor, which would be venetoclax with obinutuzumab. I think the general direction that the wind is blowing for a patient who has a deletion 17p is that a minimum people feel that they require continuous therapy. The BTK inhibitors have been studied in that way, and so that's generally what people are picking in this particular situation. Now, whether you choose ibrutinib or acalabrutinib, we can have that conversation, but I think venetoclax obinutuzumab, it isn't absolutely off the table, but it hasn't performed that well as a time-limited therapy in a very small number of patients with the deletion 17p. So, I would probably lean towards a BTK inhibitor for this patient. In the absence of comorbidities, either ibrutinib or acalabrutinib would be a reasonable choice. I tend to use more acalabrutinib these days based on the more favorable adverse event profile that it seems to have.

We have seen some long-term data for 17p patients with ibrutinib and not quite as long-term data, but 4 year data with venetoclax. As you were alluding to, if we look at a poster that was at ASH [American Society of Hematology annual meeting] last year, that poster combined 4 trials that included frontline patients with either 17p or p53 deletion treated with ibrutinib. And that was really important is because as we just discussed, this is an uncommon group upfront. Any given trial doesn't have that many patients. So really up until that poster at ASH, the largest series that we had was a letter to the editor from [Dr.] Adrian Wiestner’s group at the NIH [National Institutes of Health]. That was 34 frontline patients with the 17p deletion or p53 abnormality. By combining the data from the 4 trials, that cohort went up to 89. That data looked really stupendous. At 4 years, follow-up, the median and PFS [progression-free survival] had not been reached in that high-risk group. The 4 year PFS was about 78%, which is about what it was for the total population in the RESONATE-2 trial. That was the trial that compared to ibrutinib to chlorambucil and led to the approval of ibrutinib as a frontline therapy, so, really looking not so much like a high-risk group with the BTK inhibitors. With the venetoclax obinutuzumab, yes, there was a median reached at 4 years in that group. It was about 4 years, so it was pretty good data and much better than chemotherapy as you alluded to. But it didn't appear to be as good as the ibrutinib data. Now, as you also alluded to, Anthony, is it that the venetoclax is not as an effective a drug in that setting or is it simply that stopping therapy is not a good idea? I think it's hard to know, but I totally agree with you that my bias in that setting would definitely be towards a BTK inhibitor.

Frontline therapies available to treat newly diagnosed high-risk chronic lymphocytic leukemia, and the rationale for selecting a targeted therapy versus chemoimmunotherapy as initial treatment.

Frontline Targeted Therapy for Newly Diagnosed High-Risk CLL

 program on Chronic Lymphocytic Leukemia [CLL]. I’m Susan O’Brien, associate director for Clinical Science, at the Chao Family Comprehensive Cancer Center [Orange, CA]. I'm also the medical director of the Sue and Ralph Stern Center for Clinical Trials and Research at the University of California-Irvine. I’m pleased to discuss how we approach newly diagnosed CLL patient along with my colleague, Anthony Mato, MD, MSCE, who is the director of the CLL program at Memorial Sloan Kettering Cancer Center [New York, NY]. We're going to get started by looking at a patient case. The case is a 61-year-old man who presents with fatigue and left upper quadrant fullness for about 3 months. His physical exam shows his vital signs are normal, but he has cervical adenopathy at about 2.5 cm. He has a spleen palpable 5 cm below the left costal margin. Otherwise, he looks well. If we take a look at his laboratory findings, his white cell count is 157 with predominant lymphocytes. His ALC [absolute lymphocyte count] is actually 111. He's anemic with a hemoglobin of 9.6 and his platelets are ok at 120,000. He's neutropenic with an ANC [absolute neutrophil count] of 170. Flow cytometry is consistent with CLL and that it's CD5+, CD19+ and CD23+. His molecular analysis shows that his IGHV [immunoglobulin heavy chain] gene is unmutated and he also has a deletion 17p. His beta-2-microglobulin is 3.8, so it is high, and his bone marrow biopsy shows diffuse infiltration by CLL. Anthony, what’s your impression of this case? Do you think this is a typical case? Is somewhat unusual case? What’s your thoughts?

Well, I think it’s a typical case for a patient who presents with symptoms of CLL. I would say what’s unusual is the majority of patients we see are generally asymptomatic at the time of diagnosis. So, this is a patient who has I would say, less than indolent disease or less than indolent presentation. Within a few months of the diagnosis, they have advanced stage disease. To me, it's pretty clear that this patient requires CLL directed therapy based on the physical exam findings that you highlighted. The anemia, which is probably due to marrow infiltration in the absence of some other etiology. It doesn't seem like there's anything here going for hemolysis, or we would have been told that. What's a little bit unusual or atypical in terms of the molecular genetic profile is that this patient falls into the minority of patients who have deletion 17p at the time of their initial presentation.

I agree with you. I think he's somewhat unusual for both factors that you mentioned. The first factor is that he presents with very advanced disease. I would say the best majority of the patients I see have been detected because they had a routine physical, or pre-operation blood work for knee surgery, that showed a lymphocytosis. Occasionally I see patients where they've themselves will notice lymph nodes, usually quite small. But the vast majority of the patients I see are pretty much asymptomatic at diagnosis. Now, maybe this patient is more progressed because he has high risk disease. As you said, he has a 17p deletion. In particular when those patients have an unmutated IGHV gene, they tend to progress very rapidly and probably 50% to 75% need treatment within 1 year of diagnosis. The good news as you alluded to is that this abnormality is not that common at diagnosis, it probably makes up only about 5% to 7% of patients, but it's a very common clonal evolution, so we're much more likely to see this in a relapsed refractory population.

Reactions to an atypical diagnosis of high-risk chronic lymphocytic leukemia in a 61-year-old man.

Susan O’Brien, MD

Articles