John Allan, MD

 Another question that is frequently posed is, what does the future hold and where is the field of CLL going? Today, there's a lot of agents within a class. It's less about development in the frontline setting, at least the new drugs, because these drugs that we currently have are just so good. It's going to be hard to knock them off and top them.

What we're focusing on is minimizing toxicity and now potential combination approaches. We are trying to go completely infusion-free or oral chemotherapy-free approaches with ibrutinib- or venetoclax-based therapies, plus or minus anti-CD20. All of the BTK inhibitors that are FDA approved, the acalabrutinib and as well as zanubrutinib, which got approvals outside of CLL right now, have combination studies ongoing with venetoclax, as well as plus or minus anti-CD20. We'll go into this next wave of research understanding whether these oral options are just as good as sequential monotherapy options.

If we can utilize MRD [minimal residual disease] to help identify patients that we can pull back treatment on comfortably, and/or utilize MRD to identify patients that we either extend treatment on, and/or add on therapies to. I think that's where the next wave of research is going. It's a little less glamorous because it's not looking at new drugs and new mechanisms of actions, at least in that frontline setting, but it's really looking at how to optimize the drugs that we currently have. There's several clinical trials that are being done. CAPTIVATE [Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL)] is a large phase 2 study incorporating MRD results in ibrutinib-venetoclax all oral-based combination, both in a response adapted approach and a fixed-duration approach for everyone. GLOW [Phase 3 GLOW Trial of Ibrutinib and Venetoclax as First-Line CLL Therapy] was a large phase 3 study in older patients looking at ibrutinib-venetoclax, which has reported out primary end point data this past summer at EHA [European Hematology Association].

That's going to be encouraging to see what happens over time with that study. There are several other large clinical trials that are going to be reaching out with targeted agent approaches against chemoimmunotherapy approaches by the German CLL study group. I think we will know best how to do this, and in several years, from this point on and looking forward, to utilizing these potential all-oral chemotherapy-free regimens for our patients, specifically those very high-risk. I envision a combination strategy in the frontline setting, plus or minus some maintenance, depending on which potential risk factors they might have.

 I always get asked what some key takeaways are when managing your patients with CLL in the era of these targeted agents. I think education to the patient can go a long way, education about their biology, education about these drugs, and potential toxicities. Patients with CLL, for the most part, are very well-educated about their disease because they have time to read up about it. They have time to go to the chat rooms. They have time to identify other people with this disease in their community and/or at conferences and so on.

Patients with CLL get this information and talk to each other. I think we as physicians can provide them this information that they want. At the same time this prepares us for any treatment decision that may need to be made, really predicting what the future may hold, and when we need to start worrying about our patients.

I think education once you start treatment, education about side effects can go a long way. We need to be preparing patients to know what to expect, be it a rash, diarrhea, or atrial fibrillation, or when to talk to you about a palpitation that they may have had, or the headache that may occur with acalabrutinib and maybe even some of these other BTKi inhibitors. Education goes a long way in terms of that, and I think the space moves quickly. We should be looking at how to salvage some of these double-refractory patients will be an interesting looking at these new drug classes as they advance and mature in their clinical trial endeavors. We should be seeing what these outcomes are and exploring whether we can have even further small molecules to potentially offer our patients as they progress on these drugs.

A 67-year-old man presented to PCP with complaints of fatigue and night sweats

PMH: patient takes OTC antiacid tablets a few times a week for a “sensitive” stomach

PE: Enlarged mobile lymph nodes bilaterally (~1.5 cm), no palpable spleen or liver

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John Allan, MD, looks to the future of chronic lymphocytic leukemia treatments.

The Future of Chronic Lymphocytic Leukemia Treatment

One question comes up is how real-world evidence informs our use of targeted agents versus chemoimmunotherapy and patients' risk. I think real-world evidence is valuable. I do think it does mimic frequently what we see in the prospective trials. Sometimes we can get the real-world evidence before we have a prospective trial readout, and it can help predict what it might look like and/or what to expect.

Additionally, it tells us what's happening in the real-world. These are real-world patients, patients with elevated graphene, or mild liver dysfunction, whatever it might be.

Someone who's going to be excluded are now on these drugs and are being captured by real-world databases. We can identify really what are real, or potentially real, discontinuation rates, or drug dose reduction rates, and how is that progression-free survival? There are a few limitations though in real-world evidence, and that is that it's database-driven. These databases are typically not queried and curated as well as prospective clinical trials are.

Often, patients aren't scanned at specific time points to truly assess responses, so we're assuming complete remissions despite the fact that many times bone marrows aren't had and/or possibly there's no response available because of scan has never been done, despite the fact that the patient meets criteria for a partial response or even a CR, based on hematologic parameters. There are some limitations based on this, just based on how well curated the databases are and how well queried they are to really make the data nice and clean.

Although, they are valuable, they identify hypotheses generating questions, and they can lead to some preliminary evidence which gives people comfort. One would be kind of sequencing. One question that I think a lot of people became comfortable with is using a BTK inhibitor after a venetoclax-based regimen, based on some real-world evidence. There is absolute value there. I just caution you to not overinterpret the data because for some of these limitations that are typically written in the manuscripts when they are published.

A question comes up if they had other high-risk features, would it change what I would do? I think in this current day and age, where we have monotherapy, approaches in combination treatment approaches, are not currently approved, or recommended off of a clinical trial...I don't know if I would have changed anything differently.

My practice is to have high-risk patients with del17p specifically, or PPD3 [purified protein derivative 3] disruption, utilize BTK inhibitors. The caveat being there's no real strong evidence to suggest that, that is my opinion. I think any approach for them is relatively good, but I just have comfort in the long-term data, and understanding what to expect and following that classic sequence. I guess you can ask, what would you do if this patient had lower risk features?

I typically use these targeted agents for all patients. I don't really consider chemoimmunotherapy for any patient with CLL today. I really try to steer away from that. We have several clinical trials that show the benefits of targeted agents over chemoimmunotherapy, like real chemoimmunotherapy regimens, such as bendamustine or FCR, and showing PFS and even potentially modest OS [overall survival] benefits. When you look at those subgroups, the low-risk patients seem to have the same outcomes progression-free survival response rates, etc, as the chemoimmunotherapy arm. People are arguing, well you're not doing a detriment to younger or to low-risk patients.

I counter that with the potential to select chemo-resistant, high-risk clones upon relapse. FCR has immune suppressive and 5% to 10% MDS AML risks 10 years later. I think all of these benefits, even though in these low-risk patients, they may do the same long-term, I think there's value in diminishing the toxicity and having comfort knowing that these low-risk patients may not need another class of drugs if you utilize a BTK inhibitor first. I wouldn't change much about this case on the treatment approach. I agree with everything that was done, and I think for this patient, ibrutinib specifically made sense given the fact of the PPI use.

 The question comes up to speculate about how this patient is going to do in the future. I can tell you based on Resonate-2, looking at what the data says that they're going to have a great outcome. As long as they can stay on this drug, primary resistance is probably going to be pretty low. Seven years later, I would think that the patient numbers, it's still not even a coin flip; it still favors, 61% of patients are progression-free. Close to half of the patients are on drugs still at year seven. I think they're going to do fine. I have many 11q-deleted patients, very similar presentations to this that remain on the drug five to seven years out. So hopefully they won't progress, but obviously if they do, we've got great options.

The fact that they're just on monotherapy BTKi never have seen chemoimmunotherapy, they're going to respond beautifully to venetoclax, that's without a doubt. Venetoclax-based regimen, some combination, potential clinical trial would be a good option for this patient if they relapsed. A venetoclax-based option is typically the second-line standard. We just flipped the sequence. If it's a BTKi first, we utilize venetoclax second. If we utilize venetoclax first, and you'd spend that whether you treat it or just early relapse, you use the BTK inhibitor second. Our experience is growing with all these different sequences, but ultimately the data suggests, and personal anecdotal evidence suggests, that patients are salvaged with these regimens.

Once you start to truly progress and you're resistant to both BTKis and venetoclax-based treatments, you are a higher-risk patient. That's where we are thinking about clinical trials. In that setting, PI 3-Kinase [phosphoinositide 3-kinase] may have some potential role and so that's something you can consider. CAR T-cells [chimeric antigen receptor T-cells] are in clinical trials, as well as potential reversible inhibitors are options for these patients who remain resistant.

There are new classes of agents that are coming around BTK degraders, other CDK9 [cyclin-dependent kinase 9], and MCL-1 [induced myeloid leukemia cell differentiation protein Mcl-1] inhibitors to overcome potential venetoclax-based resistance. There is a lot of research being done and it's true, double refractory patients can have a very aggressive disease transform on you and/or be resistant and can be very problematic. Those patients can also be salvaged with high dose high-enough does of prednisone and some of these other types of regimens, acalabrutinib, things along those lines. Maybe we are considering allogeneic transplant, if eligible still, potentially for some of these patients.

I think the vast majority of patients are going to probably need one or two classes of drugs in their lifetime. If you're looking at the average 70-year-old patient with average risk CLL, we're probably not going to see these super-resistant patients in the near future. That's the positive thing to think about. We really need to worry about these 20% to 30% of patients with del11q or del17p p53 mutations as the ones who might be failing these drugs that we're still worrying about 10 years from now.

An expert describes various treatment approaches for patients with high-risk chronic lymphocytic leukemia.

Treatment Approaches for High-Risk Chronic Lymphocytic Leukemia

Currently, one question that comes up on everyone's mind is, “how do you differentiate between the two currently FDA-approved BTK inhibitors for CLL in the frontline setting, those being ibrutinib and acalabrutinib?” There are some features that are very different between the two. In a frontline setting, they've not been tested head-to-head to understand these differences in younger patient populations and less pretreated patients. BTK inhibitors have classic effects of side effects. Those class effects are namely bleeding, hypertension, atrial fibrillation, arthralgias, potential skin rash, and diarrhea. Those are the big class effects that we look for and tell our patients about. Ibrutinib was first in class, it is a good drug. It does have some off-target effects against the kinome. Acalabrutinib was designed to be a more selective BTK inhibitor with less off-target effects and therefore, this hypothesis that it might be a better tolerated agent was put out there, and eventually tested in a head-to-head study in the ELEVATE TN study [ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL)].

These drugs are approved both in relapsed refractory and frontline settings plus or minus anti-CD20. The BTK and Resonate-2 are the ibrutinib-based studies that put them on the map, and each respective frontline or relapsed state. The ASCEND [ASCEND: Phase 3, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia] and the ELEVATE TN study put an acalabrutinib respectively into those two places. The ASCEND study was an acalabrutinib versus idelalisib-rituximab or bendamustin-rituximab, favoring an acalabrutinib in terms of progression free survival as well as toxicity profile, and that was in relapsed refractory setting. The ELEVATE TN study was an interesting study because it was a three-arm study of acalabrutinib-obinutuzumab versus acalabrutinib monotherapy versus chlorambucil-obinutuzumab. The acalabrutinib arms beat the chlorambucil-based arms. What we saw was that for the first time, maybe there could be benefit of anti-CD20 therapy.

To this though, was not power to necessarily show a statistically significant difference. With that said, there's a modest 9% difference at the four-year follow-up, favoring the acalabrutinib-obinutuzumab arm. What's interesting is that it's mostly in the lowest risk patients; the highest risk patients don't seem to benefit as much by the addition of the anti-CD20. The number needed to treat is relatively high though it can be given.

It can, in the era of COVID-19, potentially add on to toxicity and detrimental toxicity that we don't want regarding B-cell depletion, etcetera. I think a lot of studies have shown Rituximab not to add much of ibrutinib. I think most people are comfortable utilizing monotherapy BTK inhibitors and in general, that's how I use the drugs because the anti-CD20 can complicate the regimen. It's not clear who it is that's necessarily going to benefit, and you do have to treat a lot of people in order to find that small number of patients that are going to do better than if you just gave them the monotherapy.

There is one head-to-head clinical trial in the relapsed setting ELEVATE-RR [ELEVATE-RR (NCT02477696) Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Subjects With High Risk CLL], which was looking at high-risk patients. Del17p, del11q and were randomized in relapse setting and randomized by ibrutinib or acalabrutinib. This study has finally read out over the summer with showing a primary end point of noninferiority of the acalabrutinib compared to ibrutinib. In terms of progression-free survival, with a median in this very high-risk patient population, close to 55% of patients had a del17p in this study, with a median PFS of a little over 30 months.

The secondary end points were looking at toxicity differences and ultimately showed that acalabrutinib had an AFib [atrial fibrillation] rate of 9.6% versus 16% and also showed lower rates of hypertension, arthralgias, and bleeding, and some of these other end points. It was not able to meet its specified secondary end points beyond the atrial fibrillation, which were infections is and Richter's transformation [Richter'ssyndromeorRS] because it stopped finding significance in those specific hierarchical statistical analyses end point. Acalabrutinib met its primary point of noninferiority compared to ibrutinib and a lower rate of atrial fibrillation of 9.6% versus 16%. So those things come into play when you think about using these drugs.

For this case specifically, the fact that the patient is on an acid-suppressing agent makes acalabrutinib not an ideal drug. It is probably a little less recognized relative contraindication to utilize acalabrutinib in the presence of PPIs and acid-suppressing medications. You have to modify. H2 blockers are generally not used with proton pump inhibitors, and it's discouraged as the absorption of the drug is based on an acidic environment. These little nuances help differentiate between the drugs that you want to use. Ibrutinib is once a day and acalabrutinib is twice a day. If you have patients that have issues with those types of twice-a-day dosing, again, it may not be the best ideal drug for that patient. Those are the things I think about when I'm deciding between these two FDA-approved agents and things that should be taken into consideration as you are looking to utilize these drugs for your patients.

John Allan, MD, compares the available approved BTK inhibitors for treating chronic lymphocytic leukemia.

Comparing BTK Inhibitors in CLL Treatment

In this case, ibrutinib was chosen as the frontline therapy, I do think it was appropriate for this patient. They needed treatment and had high-risk features of deletion 11q as well as an IgVH-unmutated status. Their age was a little bit older, approaching 70 years, and presumably they had this informed discussion and felt that that was an appropriate approach. I do think it's a good approach, and an approach I probably would have taken with this patient myself, honestly. There was some data in the Resonate-2 updated data as well that early on the 11q patients actually seemed like they were performing even better than those patients without an 11q when they are treated with ibrutinib and thus, flipping this whole concept of what is considered high-risk on its head. While 11q is high-risk in terms of aggressiveness of the disease before you get treatment, what Resonate-2 has shown us, which is a frontline study of ibrutinib, is that once you start treatment that high-risk feature has been overcome.

At the seven-year update now we've seen that 11q does not predict for inferior progression-free survival like it does when you use chemoimmunotherapy. While the curves have somewhat come back together, it does not seem to identify someone who's going to do better with ibrutinib. It does identify someone who's going to have the same long-term outcome as everyone else without this high-risk feature. For that reason alone, I do think ibrutinib was a good choice for this patient as well. CLL14 has not identified a certain side of genetic abnormality aside from del17p to have inferior progression-free survivals, etcetera. Ibrutinib is a great option here, it's easy to start, easy to get going and overall, a well-tolerated drug.

Resonate-2 was a large phase 3 clinical trial that was a frontline study looking at ibrutinib versus chlorambucil in patients greater than 65 years of age and/or those with comorbidities and not eligible for intensive chemoimmunotherapy. This study has put ibrutinib on the map in the frontline setting. It was a monotherapy study. It's been updated for several times and with publications behind it and has really kind of set the stage for what we expect out of our targeted agents and has been a very important landmark study. We understand the long-term toxicities of ibrutinib and BTK inhibitors in general.

We understand the long-term outcomes based on this study alone. Last year's ASH [American Society of Hematology] or ASCO [American Society of Clinical Ontology] and several other updates over the summers that we've seen now, close to six and a half years of median follow-up, with patients followed out to seven years plus. We’ve also identified, as the new standard bearer for targeted agents, what people need to meet in order to think that a newer therapy is going to have relevance. What we see here is that the response rate has deepened over time.

At the seven-year mark, 34% of patients have achieved a complete remission. This is something that's been a phenomenon across BTK inhibitors that we see deepening of response over time. At any certain time point that you look doesn't necessarily predict that a patient who hasn't gotten much of CR [complete remission] at that point is not going to achieve it. This decreases the relevance of response rate in CLL because it continuously changes over time as you stay on these drugs. What we've also noted from this study in the long-term follow up is that the progression free survival with median progression free survival has not been met yet at close to the six and a half years of follow up with a 61% of patients still progression-free at that six-and-a-half-year mark.

What's interesting half of the patients had six years or longer of drug and at that last data cut off 47% of patients remain on continuous agent ibrutinib doing very, very well. The overall survival, is around the mid-70s to highest 70% range which is a remarkable feat especially in this older patient population. Most are living normal life expectancies with this agent in this study. What we've found was that toxicities in general decreased over time. There are a few that kind of is persistent such as hypertension.

Atrial fibrillation is an issue, arthralgias, etcetera. From the five-year follow-up, we know that close to 25% of patients are developing hypertension, atrial fibrillation, arthralgias, etcetera, which results in dose reductions. From this study, we found that 23% of patients discontinued ibrutinib due to an adverse event, whereas only 12% of these patients discontinued due to progression of disease. It shows you how powerful these drugs are and if you can stay on them, that it's very unlikely that the disease will become resistant potentially with very few true progressions on drug as a cause of discontinuation. If anything, is very encouraging. I do think the side effects can be managed appropriately with those reductions and education to the patient and expectations and some familiarity with the drug. Overall, this has basically set the landmark for what we expect out of targeted agents from this study.

 One other specific finding from this long-term update was looking at the prespecified subgroups of IgHV mutational status and 11q. What we found, was that the IgHV unmutated status, which predicted four responses to chemoimmunotherapy in fear of progression-free survival year after year.

As the six and a half, seven-year mark has shown, there is no predictive capability by mutated status identifying a patient subgroup that's going to fail ibrutinib at a higher rate, or have an inferior progression-free survival. The curves overlap, and therefore this is not a real differentiating factor for the drug. It brings up this argument: if I'm going to use ibrutinib, do I have to check any of these things? While it's possibly true, you don't have to check a lot of these things. If you're going to use a drug like ibrutinib, I still find a lot of value.

I definitely recommend doing this based on who your patient is. You can talk to them about what the future may hold. Just like the findings with the unmutated status, this was also found in deletion 11q. These patients did just as well as patients without an 11q, and this was one of the first times that we're seeing this phenomenon with these targeted agents.

There used to be, seemingly, a benefit for 11q patients, but this has come back together a little bit and now these curves overlap. It completely eliminated, quote-unquote, this high-risk feature of deletion 11q, and you overcome it essentially, once you start on treatment. These patients can still present very aggressively and need treatment soon after their diagnosis, much like our patient here.

All of this identifies high-risk biology. Once you start on treatment with these targeted agents, it can be overcome and contained. One subgroup that you may be wondering about the del17p patients, it should just be noted that they were excluded from this clinical trial and therefore, we can't really analyze that patient subgroup. Patients with P53 mutations were enrolled and found to have a mutation afterwards in very small numbers in any specific group. There have been further studies looking with pooling these analyses of frontline ibrutinib studies looking at these patients, so I encourage you to look at some of that data as well that's out there.

A leukemia specialist details the Resonate-2 clinical trial studying BTK inhibitor ibrutinib.

Chronic Lymphocytic Leukemia: RESONATE-2 Trial

There are a lot of current first-line therapy options, and it's very difficult now to navigate these waters in any efficient manner with your patients. It used to be a relatively straightforward conversation when initiating treatment for a patient when there was only one targeted agent available, like ibrutinib and/or you had chemotherapy options. Now, not only do you have multiple BTK inhibitors approved in a frontline setting, that have different potential side effect profiles, but you also have different classes of drugs of targeted agents that are approved in frontline setting that also offer a fixed-duration approach. This is very different than what we do with BTK inhibitors, which is a continuous therapy treat-to-progression type of paradigm.

Getting all of this data out to the patient and having them understand this nuance and these options in the absence of any real head-to-head data of these various opportunities is a little bit of an involved discussion to have. So, it's something that I think is wise to initiate months before you are talking about treatment, so when you are needing therapy, you're not having to explain these and the patient is having to really wrap their head around it and make these decisions in a quick manner. I initiate these talks about the treatment options relatively early when I see some disease activity, despite the fact that I may have three months to a year before I think they might need treatment.

The big options would be in the frontline setting, BTK inhibitors, plus or minus anti-CD20 [B-lymphocyte antigen CD20

, and that includes rituximab or an obinutuzumab, and the two BTK inhibitors currently FDA approved in CLL and the frontline setting are ibrutinib and acalabrutinib. The other targeted agent approach is a BCL2 [B-cell lymphoma 2] venetoclax-based approach in combination with obinutuzumab, and that is a fixed-duration approach. And then, you have chemoimmunotherapy options, like bendamustine, rituximab, or even FCR [Folin's phenol reagent] for potentially young fit low-risk patients.

I've moved away from chemoimmunotherapy use, so it's really restricting patients to understanding options with targeted agents, and I've found that age is a big factor on which approach I want to use. Frequently, my older patients are not able to come in as often for the venetoclax-based ramp up, and the eight weeks when you're utilizing that the venetoclax or obinutuzumab approach that it requires of the patient.

There's a little bit of an investment of time, and a willingness and an ability, to do that. I find my younger patients are really wanting to not be on drug. If they're in their 50s or 60s they want to kind of have a treatment, get off of drugs, feel well, and are most interested in fixed-duration approaches.

I found that age is a big differentiating factor. What that age cut off is, is not necessarily clear in my head. A general guideline is around 75 years or older, I'm thinking BTK inhibitors. If they're younger than that and/or fit and/or able to come in and handle the ramp up and understand it, I'm willing to offer that to any patient. It's a difficult thing to think about; obviously, comorbidities, like atrial fibrillation, can make you steer away possibly from BTK inhibitors in general. I have many patients that have had a history of it or currently are in atrial fibrillation, and it doesn't necessarily make me shy away from using those classes of drugs if I think it's really the best for them.

The next big class, a big category that helps me differentiate which approach to use, BTK inhibitors versus venetoclax-based approaches, is risk. If you have high-risk features, like del17p or P53 mutations, I typically steer away from fixed-duration approaches without great evidence to state that there's any reason for that. Some of the data that has been demonstrated from full analyses have shown that some of the overall high-risk features have been overcome a little bit by BTA [benzotriazole

Now, what we know with venetoclax-based therapy is that medium progression-free survival for del17p patients is inferior to those without it after one year of treatment, and stopping with a medium progression-free survival of about four years. What we don't really know is how if you continue on venetoclax in these patients, would they do better? And how do they stack up comparatively to a continuous BTK inhibitor approach versus that? We don't have that data, so I think it's appropriate to use any of these approaches in these high-risk patients. I just favor the longer-term data and understanding that certainty a little bit with BTK inhibitors, and therefore that has been my go-to, but it's not wrong to utilize a fixed-duration approach for these patients.

For IgHV on mutated status, I don't typically worry too much about that in terms of thinking about my approach for the patients. We have good data from the long-term update ofRESONATE-2 [RESONATE-2 Imbruvica for frontline CLL/SLL], where IgHV mutational status does not seem to play a role in predicting someone who is going to have an inferior outcome when you use continuous inhibitor BTKs. Whereas in the CLL14 [CLL14 Trial: Fixed-Duration Chemotherapy-Free Regimen for Frail Patients with Treatment-Naïve CLL] study, we have identified those patients with an IgHV unmutated status to have an inferior progression-free survival compared to those who do not with immediate PFS [progression-free survival] of about five years. Now, five years of treatment, four of those are off of therapy, half of the patients still haven't progressed, it's still pretty good. I don't think we've gotten to a point where we identify someone with an IgHV unmutated status and say you cannot have a fixed-duration approach. Really, what's going to inform that answer is the retreatment data. How well do those patients respond to a second round? If they went four or five years, and then progress and need therapy, do they get another four or five years? And over the decade, you end up in the same place, but in that approach, you only have two years of therapy.

That remains to be seen. It's going to be a big factor on whether which way that pendulum swings. With combination therapy, it's going to be a difficult question to answer. Those are the big things that I think about: age, comorbidities, and molecular risk factors. Those are big factors that weigh in when I have these discussions about which approach is going to be best.

John Allan, MD, highlights treatment options in the first-line setting for chronic lymphocytic leukemia.

First-Line Therapy Options in CLL

 The other important aspect of this case is the workup that was done, the baseline workup of the CLL patient. And so, for the most part, the patient has had a full workup, there is a few things that are missing. The iwCLL [international workshop on chronic lymphocytic leukemia] guidelines have updated what is considered standard baseline workup for a CLL patient, and that includes for molecular prognostic factors. And that really includes three big groups of categories.

One is the FISH, the fluorescence in situ hybridization, where you have a CLL FISH panel. 80% of patients with CLL will have one of these five different abnormalities present, and each one that's present may have a different prognosis for the patient. The most common is deletion 13q, presenting in about 50% to 60% of patients of CLL that have abnormality. In this patient, they have a deletion 11q, which while at diagnosis is relatively rare, about 10% to 15% of patients, does identify somebody that might be higher-risk that associates with other high-risk features.

The other big category that should be performed, and this patient did have, is the IgHV mutational status. We've known since the late 1990s that the IgHV mutational status predicts independently an outcome for patient's time to first treatment over progression-free survival, overall survival when used with chemoimmunotherapy and fixed durations. This has identified an unmutated phenotype as a more aggressive CLL. While the aggressive feature still holds before treatment, as we will talk about later, how these new targeted agents have potentially overcome some of these features.

So, this patient had it. There can be even further nuance here by looking at the V-gene that's being used, it's not reported for this specific patient, but sometimes there are higher risk V-genes that are being used such as V3-21, V4-39, V1-69 is frequently an unmutated stereotyped receptor. So, there is a little bit of nuance that you can get with further information by looking at the V-gene that is being used. What really matters is it just mutated or unmutated, unmutated meaning it's 98% the same homology as the germline sequence of that IgHV gene.

The last part that is recommended by the iwCLL guidelines that was not done in this patient, is sequencing for P53 [tumor protein P53] mutations. It's well known that P53 mutations harbor poor outcomes when chemoimmunotherapy is used, very similar to those patients with the del17p [deletion 17p].

Now, you can find a small number of patients, less than 5% of patients, that do not have a del17p, that do have a P53 mutation, and if that mutation is present that's going to clearly steer you away from chemoimmunotherapy as an approach. We get a lot of genes frequently on these large panels that can be sent, and we get a lot of information, there are other high-risk mutations to note, NOTCH1, BIRC3 [baculoviral intra-abdominal pressure repeat-containing protein 3], SF3B1 [splicing factor 3B subunit 1], and other notch regulatory pathway mutations, these all are helpful at predicting a patient that may have more rapidly progressive disease and/or people who might transform on you and/or who are going to do poorly with chemoimmunotherapy.

The one part of this case that is not done, that I would have done. I do these three big groups of testing. I have additionally incorporated karyotyping of my CLL, the iwCLL guidelines do not routinely recommend this in clinical practice, but our cytogenetic lab is able to provide that information. I send that off as well to identify patients with complex karyotype.

One of the questions was, “should I wait on these results before initiating treatment?” I make that easy for myself because I send most of this work up in patients at diagnosis, and so I have this information ready to go and I'm not chasing after it, wondering what's going on when I need to initiate therapy for the patient.

If you are thinking about using chemoimmunotherapy, which can be argued there still may be a small role for, I do recommend that you should wait for these results before initiating treatment. If you identify some of these high-risk features, you absolutely want to steer clear of chemoimmunotherapy. If you send this stuff off and you just start treatment, and then two weeks later you identify the high-risk features but you startedtreatment, you may have done the patient a disservice.

Usually, I have the results because I already kind of know what I'm working with when the patient is requiring therapy, but before treatment you should have these results known to help guide your therapy. These results are prognostic and predictive, so they identify people, but they are now identifying patients who will absolutely do worse with chemoimmunotherapy.

A key opinion leader shares insight into testing and risk stratification for chronic lymphocytic leukemia.

John Allan, MD | Authors

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