: Let&rsquo;s talk about a 58-year-old patient with CLL [chronic lymphocytic leukemia] who was initially watched for a short period of time but then developed evidence of progressive disease. The patient is 17p deleted and unmutated

, developed an elevated white blood cell count and then subsequently anemia, thrombocytopenia, organomegaly. Required treatment, was initially given fludarabine/cyclophosphamide/rituximab, or FCR, had a complete response initially to therapy but progressed only 3 years later, requiring re-treatment.

If you think about this case, it was almost in the era pre-ibrutinib because initially, the patient is young. So, when you think about young, fit patients, fludarabine/cyclophosphamide/rituximab would not be unreasonable. Nowadays, obviously, with the novel therapies, the fact that the patient has a 17p deletion and is unmutated, I would not have given FCR in this case. Ibrutinib or a clinical trial, of course, but ibrutinib or novel-based therapy would be the approach to take. Because, again, due to the high-risk features that the patient has, we know that patients who got FCR and were 17p deleted have a short response duration to therapy. So it&rsquo;s really inferior therapy. So a patient nowadays, if they were identified as needing treatment and they have a 17p deletion, they would be selected for ibrutinib-based therapy.

In addition, The University of Texas MD Anderson Cancer Center also presented data many years ago that looked at FCR. When it was broken down by their mutational statustheir

they did not do as well for those individuals who were unmutated as opposed to those who were mutated. So, if you have somebody who has a 17p deletion and/or who is unmutated, you would probably not give them FCR-based therapy. You would put them on ibrutinib or another novel agent&mdash;ibrutinib being of course approved for untreated patients with CLL. But, certainly, you could entertain other therapies as they become approved as well.

That is one of the highlights that I think should come out about this case that&rsquo;s significant. The fact that the patient in 3 years progressed after FCR, again, just shows you the response duration to FCR in a high-risk individual who is unmutated and has a 17p deletion, this goes along with that. The response duration is short to FCR, and a novel agent would have been better.

When a patient with CLL presents, and this is always I think a little bit up for debate, do you test everything? Do you test their cytogenetics and FISH [fluorescence in situ hybridization] and their mutational status up front? What about CT [computed tomography] scans? I think there&rsquo;s two ways to look at this. I think that many of us who practice CLL routinely and are in academic centers have the ability to test and get many of these tests covered. I think if you&rsquo;re in the community and the patient doesn&rsquo;t otherwise need therapy currently, obviously you need to make the diagnosis, so you need to send flow cytometry and confirm that the patient has CLL. If the patient does not have bulky lymphadenopathy on exam nor has a big spleen or liver that you&rsquo;re concerned about, do you have to CT scan them at initial presentation? No.

If the patient though subsequently needs therapy, then the testing I think has to be done. You have to get cytogenetics and FISH because you want to know does the patient have a 17p or p53, because that will change the type of therapy you&rsquo;re giving them. And are they unmutated or they&rsquo;re mutated? Because, if they&rsquo;re unmutated, again, you&rsquo;re going to favor not chemoimmunotherapy-based therapy.

So you do need to test the patient prior to initiating therapy at the very least. Whether you test them as soon as they&rsquo;re diagnosed, I think there&rsquo;s room because many of these tests, in particular some of these blood tests, can be extremely expensive. And so if that&rsquo;s problematic for the patient, doing that up front I don&rsquo;t think is absolutely necessary if it doesn&rsquo;t change what you&rsquo;re going to do with the patient at that time.

But prior to starting therapy, yes, because having that discussion of are you going to start ibrutinib-based therapy, obviously there&rsquo;s much data that was presented at this ASH [American Society of Hematology meeting] that suggests that ibrutinib-based therapy is better regardless. But, for those individuals who you might want to still give chemoimmunotherapy, if they&rsquo;re favorable patients, mutated

, that discussion can still be had. But you need to test the patients to know that. So those testings do need to be performed prior to initiating therapy on patients with CLL.

Risk Stratification for a Patient with CLL

: Ibrutinib is frontline and has been approved for any patient previously untreated as well as relapsed and 17p deleted patients. But let&rsquo;s talk about some of the adverse effects of ibrutinib. There are also many second-generation BTK [Bruton&rsquo;s tyrosine kinase] inhibitors that are also being evaluated right now. So stay tuned for their toxicity data, and some of the head-to-head with ibrutinib will eventually be emerging.

We know that ibrutinib, when I talk to patients about initiating therapy, there is some potential short-term adverse effects of the drug as well as some potential continuous adverse effects. The most that patients and physicians are concerned about, of course, have to deal with cardiac arrhythmias, most commonly being atrial fibrillation, although they could have others, and folks who might be on anticoagulant drugs, antiplatelet agents for other reasons, whether they be cardiac reasons or other reasons.

There is a concern, because we know that ibrutinib does have a slightly increased risk of bleeding. And so then if you add ibrutinib to somebody who is already on an anticoagulant agent, there&rsquo;s concern about enhanced bleeding, or bruising, or obviously more seriously a fatal bleed. We have very good follow-up data that suggest it&rsquo;s not that you cannot not use ibrutinib with anticoagulants. I think you can. Do I think you have to be cautious? Absolutely. I think we have pretty good follow-up data even from the phase I study of ibrutinib, both in the frontline and relapsed settings, showing that major risk of hemorrhage is low, on the average, depending upon the study, somewhere between 3% and 5%. The atrial fibrillation, however, or cardiac arrhythmias probably have increased because we have longer follow up than the initial studies. The initial studies reported somewhere about 5% to 7%, with long-term follow-up data anywhere probably now from 10% to 15%. That is a real risk that you need to discuss with patients, who, when you start discussing some of the adverse effects of these medications, who will absolutely say, &ldquo;I&rsquo;m too afraid of this and I do not want that and give me something else.&rdquo; And I can&rsquo;t say that&rsquo;s unreasonable because there are many more choices now than there were ever before.

But are they manageable? Yes. I mean, we used to manage a lot of adverse effects just with chemoimmunotherapy, and so as with newer therapies, we learned to manage those adverse effects with the BTK inhibitors. We&rsquo;re hoping that some of the newer BTK inhibitors, that their adverse effect profiles will be better, so they have reduced cardiac arrhythmias and bleeding risks. That remains to be seen when the data will eventually get presented, hopefully. And, if so, that may be a game-changer for ibrutinib if there are other drugs that have fewer adverse effects and are equally efficacious.

The other adverse effect that people get concerned about with ibrutinib is hypertension. And, of course, being that our patient population is older to begin withremember the median age of CLL [chronic lymphocytic leukemia] is 70, 72&mdash;many of these patients already have comorbidities, including hypertension, diabetes, and heart disease. Many of them are on the medications to help with these other medical problems. So you do have to co-manage, potentially, adverse effects while the patient is on ibrutinib, with their internist or their cardiologist. If they&rsquo;re on antihypertensive medicines, they can be tweaked if their blood pressure gets higher. I think there is a concern for folks who don&rsquo;t have cardiac issues and then develop atrial fibrillation. If they were never on blood thinners or blood pressure medicines and then all of a sudden you tell them they&rsquo;re going to stay on them, for some individuals, if they develop atrial fibrillation, they choose not to because they really don&rsquo;t want to have to be on all these extra medications and all these cardiac medications.

So there is no doubt, with some of the toxicities that we see, you do have to have an open view with your patient whether they&rsquo;re comfortable co-managing them because they&rsquo;re all manageable. But whether the patients want to pursue and stay on ibrutinib or change to another agent always does come up and it&rsquo;s a frank discussion. But I don&rsquo;t think that if somebody is on an anticoagulant per se, ibrutinib is completely contraindicated. I think that we&rsquo;ve seen plenty of folks who are on ibrutinib and anticoagulants who are doing well. But you have to make them aware that they are at an increased risk of bleeding and obviously to stop the agents before any surgical procedures.

There are some nuances that you have to take when somebody is on ibrutinib and anticoagulants or even on ibrutinib alone. And you educate your patients, and the more familiar that oncologists become with using these novel agents, the better that they will be at managing any of the adverse effects to any of the novel agents that are coming across our path. It&rsquo;s just taking a little bit time and a little bit of education and experience. And now there are going to be many options, so certainly then I think there will be more room to pick and choose, depending upon your patients&rsquo; comorbidities.

Potential Ibrutinib Toxicities

: Let&rsquo;s re-discuss this patient who is a young, fit patient who initially received FCR [fludarabine/cyclophosphamide/rituximab] but then relapsed after 3 years. They&rsquo;re 17p deleted and they&rsquo;re unmutated. So, now at this time point, you actually have more than one option. Ibrutinib, of course, comes to mind the quickest; that&rsquo;s approved both in frontline and a relapse. Now that this patient&rsquo;s relapsed, of course, venetoclax/rituximab is another option. So, certainly, you can give either of these options to this patient. So let&rsquo;s say we gave the patient ibrutinib; then you would monitor the patient. I have to say this patient is young, so one thing to keep in mind if you have a high-risk individual with CLL [chronic lymphocytic leukemia] &hellip; I do not expect that these therapies will last indefinitely on this young patient with a 17p deletion. So transplant is still potentially an option that you need to think about. And, in fact, a person who is young in their 50s who presents with a 17p, I&rsquo;m actually HLA [human leukocyte antigen] typing them from the get-go.

It is not that I&rsquo;ve taken many patients to allogeneic stem cell transplant anymore for CLL, again, because most of our patients are older and frailer, and there&rsquo;s all these other options. And so their life is improved by these novel agents, and they&rsquo;ll be much older so they&rsquo;re not getting to transplant anyway. But a young patient, you still have to think that how are you going to strategize therapies for a young patient with high-risk features because you are trying to prolong their life, hopefully the quality of their life as well. But you have to think how to strategize, and so there&rsquo;s no doubt that even from the initial ibrutinib studies in patients with 17p, that progression-free survival curve does continue to drop off compared to the rest.

Then can you salvage with venetoclax and rituximab? Absolutely, but you&rsquo;re still going to think at some point they&rsquo;re going to relapse on that combination as well. And that&rsquo;s where a transplant might be a very good option for that person. What about CAR [chimeric antigen receptor] T cells? CAR T cells will also be an option for that person as well. And, in fact, for some folks who probably couldn&rsquo;t go to transplant if they might have been older, if they&rsquo;re relatively fit, CAR T-cell therapy actually might be an option even before transplant.

So I think that this person has several options that you&rsquo;re going to consider, and some would argue perhaps to take that person to transplant sooner because they&rsquo;re young and they&rsquo;re fit, versus waiting. Others may decide to milk these therapies as long as possible and then take the patient to transplant. And I think obviously we don&rsquo;t have the right answer. We do know that if you take patients who are transplant-eligible, and they&rsquo;re fitter, and healthier, they do obviously better if you take them sooner than waiting until they have multiple relapse and lots of disease and are frailer.

I think a strategy could be employed that you&rsquo;re closely monitoring those patients, whether they be on ibrutinib or on venetoclax, looking for relapse sooner. So you still can take them relatively healthy with very little disease burden, switching the agent, and then taking them to transplant as well. So there&rsquo;s probably more than one correct answer to the right way to go about this, depending upon the patient&rsquo;s preferences and their disease characteristics with close monitoring. But you have to realize that patients with high-risk features may eventually, not may, will likely eventually relapse, even with these novel agents.

And so you can buy a couple of years perhaps out of each subsequent novel agent, but that still only puts this patient perhaps in their mid- or late-60s, depending upon when they first started. And so you always have to think about that as well. So, certainly, we have done better with patients with 17p and high-risk features, but you&rsquo;ve still got to think long term, and certainly I would always think about transplant earlier or at least HLA type them being that she&rsquo;s in her 50s with a 17p deletion.

Treatment Options for Patients with Relapsed CLL

: If you think that this patient with high-risk features has gone through many of these novel agents, when we look at venetoclax and rituximab, given the recent MURANO data that got presented or re-presented with longer follow-up, actually 3-year follow-up, how do we look at that in the setting of a patient such as this with high-risk features? The MURANO data were very nice because, even though it was in this exact situation of relapsed/refractory patients with CLL [chronic lymphocytic leukemia], we looked at levels of minimal residual disease [MRD] in these individual patients; it was time-limited duration of therapy. The venetoclax actually was only for 2 years. What the data did provide is that looking at individuals based on their MRD level, folks who had high MRD are likely to progress sooner than folks who had undetectable minimal residual disease or even just low levels.

And so one may be able to use that information in a patient that is high-risk such as this and say, do we end it at 2 years? Should we be checking for minimal? In fact, that&rsquo;s what I would be doing, is we should be checking for minimal residual disease in a patient who&rsquo;s young with aggressive features, to think about whether they should be stopped. And so now you can actually start being more specific about how to finesse these therapies. And, even though the protocol obviously did stop individuals, at 2 years everybody stopped regardless; it was amended to allow patients who then progressed to reintroduce venetoclax therapy.

If this patient wasn&rsquo;t on that protocol, you might consider looking at the minimal residual disease. If they were undetectable, the question remains do you stop therapy because they&rsquo;re high-risk or do you be true to what we just presented with the MURANO data, stop therapy, and wait till they relapse? And I think that is one area that we still need longer term follow-up in patients who are high-risk. Is it a benefit then to stop if they have undetectable levels and wait, or should we not because eventually we know that they&rsquo;ll probably relapse, and is that good enough? Will they be sensitive again because they&rsquo;re high-risk? I think that&rsquo;s an area that we still need a lot more investigation and further follow-up and data on. I am a little nervous about stopping my 17p patients regardless. And so even if they were undetectable, I&rsquo;d be happy that they&rsquo;re undetectable, but I would likely still continue the drug.

When we look at combinations such as venetoclax, or rituximab, or some of the other combinations that are being explored, the reason some of these are being explored is everybody is very interested in how to use a short or a time-limited duration of these therapies. So, in other words, that patients won&rsquo;t be on ibrutinib indefinitely for the rest of their life or on venetoclax indefinitely for the rest of their life, both for toxicity issues that might be mounting. We&rsquo;ve been seeing, if we look at some of the real-world data sets that have been presented at these meetings, that there&rsquo;s no doubt, and I think this is not unique to CLL; I think this has to do with many disease states, whether oncology or not oncology patients. It&rsquo;s a little bit of fatigue in terms of their medications and there is a noncompliance issue that patients have.

All of these novel therapies are oralif they&rsquo;re indefinite, there is a degree of noncompliance that happens over time, even for some adverse effects that are completely manageable but are nagging to the patient. A little diarrhea here and there can be nagging. And so they just will take less. They&rsquo;ll skip some pills. I think there is an area of concern about resistance, and there&rsquo;s an area of how do we make this better for patients in the long run. And so looking at some of these strategies of time-limited duration of these therapies, deepen these responses. So by these combinations, really look at achieving deep responses so we can stop therapy and then see how long they would go until time to their next treatment. Because in chemoimmunotherapy, that&rsquo;s what we did. We could not continue FCR [fludarabine/cyclophosphamide/rituximab] or BR [bendamustine/rituximab] indefinitely because these were intense therapies. So you would give 6 cycles, you were done until you needed treatment again. Hopefully, that wouldn&rsquo;t be for years down the road, but that&rsquo;s how it was because you couldn&rsquo;t just keep that going.

Maybe now that we have deeper responses, particularly with the venetoclax combinations, deeper responses, we can shorten the time period and make an analogy like we did in the chemoimmunotherapy, although hopefully better, but that we can stop people and then reintroduce drug. That will also save on not just hopefully toxicity but cost. These medications are extremely expensive. I think this is an issue. We&rsquo;ve talked and highlighted at this American Society of Hematology meeting that there are many countries that patients don&rsquo;t have availability to these novel therapies or even in the United States. I can speak to the folks in the United States. There are some patients&rsquo; insurances that their copays are too large for even drugs like ibrutinib, which is now standard of care. I think this is going to be a problem, so if we can pursue this, it is the future of where CLL is going, if we can get deep remissions, decreased toxicity, shorter durations of therapy, cheaper, then it will be a benefit in the long run for patients.

MURANO Trial and Time-Limited Therapies

: The venetoclax combinations are obviously a highlight of the ASH [American Society of Hematology] meeting and looking at time-limited duration of therapy. We talked a little bit about some of the ibrutinib toxicities, but let&rsquo;s talk a little bit about venetoclax. One of the issues with venetoclax is that it goes through what they call a dose ramp-up phase. So the drug needs to be administered 1 week 20 mg, 50 mg, 100 mg, 200, and 400. So it&rsquo;s a 5-week ramp-up and it&rsquo;s oral. However, the reason why it&rsquo;s a ramp-up is because in some of the initial studies, there was a significant degree of what they called tumor lysis syndrome. As the patient&rsquo;s leukemia cells are dying, they can play havoc with the electrolytes and the kidney function, and, obviously, that can lead to cardiac arrhythmias and death. And so when they recommended those initial studies looking at lowering the doses and doing this much more safely, this sort of eliminated that as a possibility.

Now, how do we do this in practicality? So patients who have bulky disease, being lymph nodes or organomegaly, but lymph nodes over 5 cm, or if they have very elevated white count, those are considered high-risk individuals. So white count over 25,000, those individuals would actually have to be admitted to monitor for this tumor lysis. It&rsquo;s not that it&rsquo;s difficult to do but it&rsquo;s time consuming. And so patients with a greater degree of bulk have to be admitted to the hospital just to hydrate them and to monitor them, to give them allopurinol or rasburicase, to give them IV [intravenous] hydration and Lasix, and then they have to be monitored for a few days, depending upon what their electrolytes did in response to therapy. And you&rsquo;d have to do that every week when you dose ramped up.

That can be a little bit of a challenge for folks in the community because they&rsquo;re getting admitted to the hospital, and insurance companies, and things like that. That could be costly as well. So there have been several strategies that are not new and have been presented at this meeting and at other meetings, looking at initiating, so if you do a combination like venetoclax, there was venetoclax/obinutuzumab, presentations on ibrutinib and venetoclax. If you start the other agent first, you can debulk patients, and so their disease burden goes down. This really mitigates for profound tumor lysis, so then venetoclax is started later, and this can be done as an outpatient.

Still many of these protocols are looking at being careful, so the patient will still come as an outpatient every week to dose ramp-up, but they don&rsquo;t have to get admitted to the hospital that way. And so it makes it much more easier because then the patient comes to the clinic, they start their next dose, you check their electrolytes. Then they can be checked again the next day, making sure that they&rsquo;re OK and that they don&rsquo;t need additional hydration. But then it&rsquo;s all outpatient-driven. So I think there are ways to do this. Once they get through that 5-week ramp-up, you&rsquo;re good, and then &hellip; you don&rsquo;t have to worry about tumor lysis subsequent to that.

There are other adverse effects of venetoclax such as neutropenia and various ctyopenias, which you need to be aware of, and which can be managed quite well. It&rsquo;s the dose ramp-up phase that proves a hindrance for management, especially for patients and oncologists in the community setting, depending upon their resources, experience, and ability to respond to abnormalities quickly and effectively; this issue can certainly preclude the success of venetoclax administration. But, again, I think time and experience is important. It is not difficult to do, it is not difficult to manage this at all, but you just need to have a forum so you can do this safely for patients and make it easier for them, more convenient, but making sure you&rsquo;re not causing a problem by missing those laboratory tests. They are important to get. But there are ways by using other therapies in combination with venetoclax that  it&rsquo;s very easy then to do the rest as an outpatient.

Venetoclax/Rituximab Administration & Toxicity Management

: For a patient like this who has high-risk features and is young and fit, I think that the CLL [chronic lymphocytic leukemia] progress recently has been remarkable. And previously, when we took a young, fit patient with 17p deletion who relapsed after FCR [fludarabine/cyclophosphamide/rituximab] therapy back in the day, their overall survival was somewhere between 9 and 12 months. This is completely different. This is why drugs like ibrutinib and venetoclax have been approved. When ibrutinib got approved, all of a sudden, folks like this, their PFS [progression-free survival] was better than chemoimmunotherapy ever was for these individuals. And so we&rsquo;re prolonging the survival of patients with CLL. So it&rsquo;s a wonderful time for folks because of all the different therapies that have come out, and targeted therapies. And now we&rsquo;re tweaking them and looking at minimal residual disease, how do we get people off these therapies.

It&rsquo;s an exciting time for patients because of the availability of all these therapies. It&rsquo;s an exciting time for individuals like myself who do research in CLL, because we&rsquo;re really trying to push the field forward and at much quicker paces than in the era of chemoimmunotherapy. Do I think we have a long way to go? I do. Not a bad thing. It will be the next generation of doctors who will hopefully do this. I think what I&rsquo;m trying to say is that some of these therapies will hold patients for years, which means that for us to then change things in a meaningful time period may take us much longer, which means these therapies are doing right by the patients and prolonging their lives for much longer. And so finding some of these answers may take us a lot longer as investigators.

But I think it&rsquo;s a wonderful time, and we have lots of different areas to explore with how to combine and sequence these agents. How do we look at immunotherapies and CAR [chimeric antigen receptor] T cells, where do we move that for patients who need treatment? Given the era of all these new agents, where do you place those types of therapies? It&rsquo;s an exciting time going forward. And I think it should only highlight the fact that with patients who are going on some of these clinical trials, we can&rsquo;t thank them enough for participating, and the future of CLL is very bright.

Treatment for Relapsed Chronic Lymphocytic Leukemia

Risk Stratification for a Patient with CLL

Potential Ibrutinib Toxicities

Treatment Options for Patients with Relapsed CLL

MURANO Trial and Time-Limited Therapies

Venetoclax/Rituximab Administration & Toxicity Management

Recent Progress in Treatment of Chronic Lymphocytic Leukemia