Activity Transcript

Shirley D'Sa, MD, FRCP, FRCPath: Hello and welcome to this program entitled Next Generation BTK Inhibitors for B-cell Malignancies: Improving on the Past. I'm Shirley D'Sa, consultant hematologist and associate profess at the UCLH Center for Waldenstrom's and Related Conditions at the University College London Hospitals NHS Trust in London, UK. And joining me today are Wojciech Jurczak, professor of hematology at the Maria Sklodowska-Curie National Research Institute of Oncology in Krakow, Poland, and Emma Rowles, clinical nurse specialist in myeloma and plasma cell disorders at UCLH in London.

So I'll start by mentioning the index BTK inhibitor ibrutinib. This is the first generation BTK inhibitor. It's a small molecule drug that inhibits B-cell proliferation and survival by forming a covalent bond with a cysteine residue called Cys481, so blocking signaling through BTK inhibition. It was approved by the FDA in 2013 and the EMA in 2014 as a single agent for relapsed and refractory mantle cell lymphoma, as a single agent or in combination with rituximab and obinutuzumab for CLL, untreated, as a single agent or in combination with bendamustine and rituximab for CLL who have received at least 1 prior line of therapy, and as a single agent for the treatment of Waldenstrom macroglobulinemia who have received at least 1 prior line, or at first line for those who are unsuitable for chemo immunotherapy.

Acalabrutinib is a BTK inhibitor with improved selectivity for BTK, and fewer off target effects compared with ibrutinib. Acalabrutinib was approved in 2017 and is now approved for relapse and refractory mantle cell lymphoma and CLL/SLL. It was EMA approved in 2020 for CLL. It is not approved for the treatment of WM. Data for the ELEVATE-RR trial comparing acalabrutinib vs ibrutinib showed that acalabrutinib was non-inferior to ibrutinib in terms of progression-free survival and is associated with fewer adverse events and discontinuation events than ibrutinib.

Zanubrutinib is a highly specific next generation BTK inhibitor which binds covalently to Cys481 in the ATP binding pocket of BTK. It was approved by the FDA in August, 2021 for relapsed and refractory mantle cell lymphoma and WM, and by the EMA in November, 2021 for the treatment of Waldenstrom. Data from head-to-head studies with ibrutinib are available. The ASPEN study of zanubrutinib vs ibrutinib in symptomatic WM showed non-inferiority to ibrutinib, and a trend towards less toxicity. And in the ALPINE study of zanubrutinib vs ibrutinib in relapsed and refractory CLL, zanubrutinib was also non-inferior with improvements in response and reduced toxicity. Wojciech, I would like to ask you to talk more about the selectivity of BTK inhibitors and how this correlates with treatment emergent adverse events of special interest.

Wojciech Jurczak, MD, PhD: Shirley, thank you very much for this introduction. Before we go to compare BTK inhibitors, we have to demonstrate how selective they are. And here we have the average IC50. The smaller the IC50, the more potent the drug is. Therefore ibrutinib, an unselective but very potent drug as compared with the acalabrutinib and zanubrutinib here. Atrial fibrillation we know of seems to be due possibly to ibrutinib metabolism. However, other adverse effects like bleeding or thrombocytopenia are more likely to be connected with off target inhibition of TK kinase, while diarrhea, EGFR kinase.

The same thing happens with immunity. The inhibition of ADCC and phagocytosis is smaller compared with the first-generation drug. It means that despite a greater neutropenia, they may actually cause less infections.

Talking about target occupancy, ibrutinib, a very potent drug at 420 milligram dose has less than 80% target occupancy. It is better with acalabrutinib and zanubrutinib.

The best way to compare the drugs are head-to-head comparisons, and we had 2 in relapsing refractory chronic lymphocytic leukemia, acalabrutinib vs ibrutinib, published in JCO, and zanubrutinib vs ibrutinib, recently presented by professor Helmut at a AHA Presidential Symposium. Both studies were positive, and as you see, cardiac events, bleeding events, infections, all adverse events or special interests were much less common.

You have acalabrutinib data. Acalabrutinib have few adverse events leading to the discontinuation, 14% vs 21%, and fewer death due to adverse events, 6 vs 9.5% compared with ibrutinib. The same thing with zanubrutinib. And in here, maybe neutropenias were more common in zanubrutinib, but was not... It didn't transfer to more frequent infections for the reason I mentioned. And again, fewer adverse events leading to treatment discontinuation, 7 vs 13%. Talking about atrial fibrillation, atrial flutter, there's a considerable difference. However, before we start speaking about it, let me guide you through the data in CLL patients treated without BTK inhibitors with chlorambucil. It occurred that we can expect about 1% increase of atrial fibrillation per year in this population. And so it happens with hypertensive and hypertension and other cardiac disorders. Ibrutinib is causing atrial fibrillation flutter much more frequently. The same data comparing ibrutinib with zanubrutinib.

Talking about a hypertension, it's even more frequent, although easier to manage. Other side effects of special interest like bleeding events, diarrhea, arthralgia. They're all less common. Infections, although they are frequent, the incidence increases only in the first 2 years. Then we can quite safely use the drug for a longer time. Atrial fibrillation curve, as we expected from the randomized studies. However, we have to draw their attention to the second primary malignancies, which are important, which are increasing with time, which are more frequent than in ibrutinib, because we have a longer drug exposure. The same pooled data on zanubrutinib we published in Blood Advances. Same information, different graphs, 780 patients.

Dr D’Sa: Thank you. Wojciech. That was really excellent and very useful to summarize those data. I will briefly mention the event of interest in the WM setting from the ASPEN study. The most common AEs in the zanubrutinib patients were neutropenia, upper respiratory tract infection, diarrhea, and in the ibrutinib patients were diarrhea, upper respiratory tract infection, contusion, and muscle spasm. As Wojciech has mentioned, neutropenia appears to be higher zanu patients than ibrutinib. Same occurs in the ASPEN study. But in fact, the number of actual infections were not higher.

The incidence of all of these events of special interest were uniformly greater in the ibrutinib arm compared with zanubrutinib, including atrial fibrillation, hemorrhage, major hemorrhage, and hypertension. Likewise, the most common infection was actually pneumonia, and this was higher in the ibrutinib patients and more patients on ibrutinib required anti-infective therapies compared with zanubrutinib. Likewise, with diarrhea, there was a greater incidence of diarrhea than in the zanu patients.

Moving on to the real world data, obviously, clinical trials are much more... It's all predetermined. You have to follow protocols. There are criteria for commencing, including patients when to stop, etcetera. In a nonclinical trial setting, there is more of physician's choice that comes into being. I find that some doctors who are less familiar with BTK inhibitors will tend to be much more worried about stopping drugs than if you have a lot more experience you tend to say the course. So undoubtedly, there's more variation in real world experience, but Wojciech what would you think?

Dr Jurczak: Well, the real live data are pretty much comparable with what we observe in the clinical studies. All BTK inhibitors are safe drugs, predictable. We can agree that the discontinuation rate of second generation BTK inhibitors is considerably lower than the discontinuation rate in Ibrutinib. I still think that in a real life we can discontinue Ibrutinib and other BTK inhibitors more frequently just because we do not have to follow the protocol, just because we have other options, whether this is or it's not proven it is to be mentioned. And my experience that discontinuation rate of Ibrutinib and clinical studies is about 15% to 20% the second generation BTK inhibitors between 10% and 15% while in real life, they are, meta-analysis suggesting that it's 25 plus percent.

Dr D’Sa: Absolutely. So Emma, I was going to ask you here, in your role as a clinical nurse specialist, how do you work with patients who are on these treatments? Because you get lots of calls for people who have infections or other symptoms. What's your approach?

Emma Rowles, RN: We have a hematology help line at UCLH, and when we encourage them to use it for any query. When they call us and they're unwell complaining of some of these adverse effects from treatment, we would try and triage the call and do what we can over the phone, be it home remedies or prescription requests or things like that. And again, if they were particularly unwell, we would say, "Stop the medication, come straight to clinic for a medical review."

Dr D’Sa: So perhaps I can move on to patient related outcomes. As I understand it, the patient related outcomes from the ELEVATE-RR and ALPINE studies are yet to be reported, but the ones from ASPEN have demonstrated that most quality of life assessments, in most of them zanubrutinib trended towards a greater improvement. And this was most notable in the EQ-5D and the EORTC QLQ-C30 subscales of appetite, dyspnea, fatigue, physical and role functioning. And the symptom subscales for diarrhea trended worse for ibrutinib patients than zanu patients.

So moving on now to the key adverse event management strategies in clinical practice, I would say that as novel therapies become embedded in clinical practice, obviously further experience emerges about how they behave in real life, and of course they're effective in many ways, but there are associated challenges that for come through over the years in following up patients with CLL, mantle cell, WM.

So for example, let's illustrate it with the first case of a 60 year old man with CLL who has had no prior cardiac history. He's on ibrutinib 420 milligrams daily and has a good early clinical response. However, 2 months after beginning ibrutinib, he reports palpitations. So Wojciech, how would you manage this patient in your clinic?

Dr Jurczak: Well, it would be probably different from how you would, because acalabrutinib is not refunded in Poland, therefore we will have to go for venetoclax. But in the normal circumstances I would certainly say that over three-quarters of the patient may be safely and efficiently managed by switching them from ibrutinib to acalabrutinib without any problems. Therefore the clinical activity is sustained. We do not go to the other class or the drugs, which might be used later. And we may manage adverse pretty easily.

Dr D’Sa: Absolutely, I think there are many limitations in many countries as to what is possible in different indications, and certainly the Waldenstrom setting we don't have access to acalabrutinib, and even zanubrutinib, it's only been available in trials up to now. So I think in the other aspect, of course, is to manage the patient in a more... Assess the stroke risk... First of all, I guess, find out what do the palpitations mean? Is it truly AF? Is it intermittent? Perhaps carrying out a holter monitor, determine the stroke risk, decide whether anticoagulation is needed, and perhaps, I think... Certainly in the UK, we don't necessarily have the luxury to switch to another drug, so we try and manage the existing BTK with medical supportive therapy such as... Perhaps we may need to start a DOAC if they are deemed to need anticoagulation. You have to carry out a risk benefit analysis in that individual patient before you discard the BTK inhibitor.

Likewise, if cessation is required of the drug, question is do we... We can perhaps pause the drug, investigate the arrhythmia, move on to rate control, we've certainly done that in our practice, in conjunction with cardiology specialists and then perhaps reintroduce the drug at a lower dose and, and gradually move forward to make sure that by perhaps... Because many of them can resume the therapy, even though they have presented with some of these initial effects at the beginning. So that is certainly what we try and do. We try and hold onto the BTK inhibitor before switching. But as you say, if these strategies are not working, then either we switch to another BTK if we have the opportunity, or we have to consider non-BTK type therapy in some cases.

The next one is a case of a 68-year-old woman with CLL who's commenced on treatment with acalabrutinib, 100 mg twice a day, and within a month of starting therapy, she presents with a florid facial rash. Emma, how would you address this issue when someone rings you up with a rash who's on a BTK inhibitor?

Ms Rowles: So I think for me, because it was a new rash, I'd be thinking what's causing the rash, really. So maybe it isn't to do anything with the treatment, but I would... If a patient rang me to say they had a new rash, I would probably ask them what medication you take, what medication are you taking. And they're obviously on the acalabrutinib. With that they may have some supportive medication as well. So we often give cyclovir and cotrimoxazole to prevent infection. And maybe it's not necessarily related to the acalabrutinib, but we would be thinking what could be causing this. I'd want to know where it is. Probably bring them in for examination. And a lot of our patients during COVID are sending us photos of the rash so that we can determine does it look drug related? Is it facial flushing?

I'd be asking them, is it itchy? Have you been taking any antihistamines to help with the itch? Do you use any new creams on your face or changed your washing powder or something like that? Is this contributing to the rash? Maybe I'd then speak to the doctor and ask them if they wanted any medications stopped once they'd seen the photos, or brought them into clinic. Bit of trial and error sometimes to work out what's causing it, or is it just one of those things? And maybe sometimes we would pause medication short term to see if the rash improved and settled. Off certain medications, cotrimoxazole can be quite a common for these things. Or even sometimes if it's serious, get a dermatology review, but often it will settle with antihistamine and some cream and then restart their medication.

Dr D’Sa: Now another common side effect of BTK inhibitors is bruising and bleeding. So for example, if there was a 57-year-old man on zanubrutinib, after 8 weeks of therapy he presents with a 2-week history of easy bruising and epistaxis. So how would we deal with this? Perhaps we start with Emma first, again? What would you say when the patient calls you up and says, "Oh, I've got a nose bleed and it won't stop."

Ms Rowles: To be honest, if it won't stop, I would be thinking... And they've put pressure on it, I'd be thinking they might need to go to A&E, because they're losing blood, but also are their platelets low, are they coagulating effectively? They'll need a blood test to check that. And if it's a nosebleed and it stops after applying pressure, then I'd still want to bring them in for review for the bruising to review their medication. And is it trauma associated in terms of is the bruising associated with trauma, is it just spontaneous bruising?

I'd want to just do a set of vital signs, check the hemoglobin platelets, reassure them on the phone as well that this can be a side effect of the treatment they're on and that they're in safe hands and they'll just come to clinic for review. But in this case, because it's also a WM patient, I may also be thinking now these nose bleeds, because he's hyperviscous and the treatment isn't working as well as we would've liked. So has he got any headaches, any blurred vision? Is he having any dizzy spells, things like that? So it may as well not necessarily be an effect of the treatment, but could be his disease, and not under a good control. So that's probably where I would be thinking in my head on my assessment on the phone and then bring him in for a doctor's review.

Dr Jurczak: And perhaps we should draw to attention that grade 3 or greater bleedings are extreme rarity, but they do exist. So we cannot, especially on the phone, underestimate any of those. We have to be very meticulous. But the majority of cases where we are going to literally go into differential diagnosis or grade 1 or 2 bleeding, then the first question I would ask would be about aspirin or other innocent drugs, because in fact, most of the symptomatic bleedings were once there were some concomitant medications. Very trivial, very easy ones.

And then ask about infections, because during some infections we may have an enhanced bleeding and I would definitely ask the patients to go and have the full blood count done at the nearest area convenient, just to be sure that we are not missing something more important.

Dr D’Sa: Speaking now about another side effect that does come up from time to time, if we have a 58-year-old woman with WM who has started on ibrutinib and then 3 months later, she presents with diffuse joint pain that is preventing her from functioning at her job. How often, first of all, Wojciech, do you see this much in the CLL setting?

Dr Jurczak: We do observe them across the diseases, but perhaps not across BTK inhibitors, cause much less frequently this adverse event, it's clearly related with some sort of off target inhibition and immune function dysregulation. Now again, what we do does depend on what is the disease status of the patient. Reducing the dose is sometimes necessary, but is the last thing we want to introduce. We go for symptomatic treatment first, but there's not a single recipe for every patient, I'm afraid.

Dr D’Sa: Sure. And Emma, bringing you in here. I mean, again, people do ring you up with aches and pains, but if they do have quite rigorous joint sort of pains and so on, how do you assist them and what do you advise and how do you approach this?

Ms Rowles: Yeah, so I'd probably ask know what painkillers are you taking for it and try and manage their pain that way with simple analgesia, and just work out if any imaging of the area might be required to check if there's anything else going on. If it's somewhere particular rather than an all over body ache. If it's affecting their mobility, I might see if physio can help. So refer them to our physio team. And especially if it's affecting their work, then just discussing with them if they need any... How is it affecting their work? They need any evidence of their employer that they are struggling because of their condition and the medication they're on.

And are they coping at home with their everyday tasks, such as washing dressing. Do they need any support there or any home adaptations to help them be independent and live life well? All of these drugs are continuous and long term, so we want them to be able to have a good quality of life on them.

Dr D’Sa: I think one has to keep an open mind and have almost an individualized patient approach to these things. So moving on to other potential problems. Infections can affect these patients. And that can be due to the inherent immunocompromise that they have with their disease. It's also due to chemo immunotherapy, which they may have had before. And of course, BTK inhibitors can affect other cells of the immune system and contribute to the risk of infection. So it's often very complex in my experience.

What prior lines have they? How many prior lines? Are they hypergammaglobulinemic? Are they neutropenic? Are they on concurrent steroids? Because that increases your risk of infection. What are their comorbidities? So I think Wojciech, my understanding is that the evidence is not clear cut. Now I'm interested to know whether your practice includes prophylactic medication against PJP or viruses or even invasive fungal infections.

Dr Jurczak: Well, we begin from clinical studies where sometimes it's mandatory, but the majority of patients with simple BTK inhibitor, it is not absolutely necessary. We sometimes do it. In this case, we talk about acyclovir and Pneumocystis carinii pneumonia (PCP) prophylaxis. I find acyclovir particularly handy. The PCP prophylaxis, it does depend from the patient. Cotrimoxazole is not well tolerated by some of them. They are the skin reactions and others you already mentioned here. But I would definitely advise to go for a prophylaxis once we have the combined, treat patients with doubles or triplets. With BTK inhibitors, not that necessarily.

Dr D’Sa: Yeah. So I have made a decision in my practice for those who are on long term steroids and BTK inhibitors to seriously consider antifungal prophylaxis. Although there is the risk of interaction, the problem with the CYP3A4 interactions, et cetera. But in some cases we do it, but it's very much case by case, we discuss it with pharmacist, we discuss with the microbiologists, and we try and weigh up the pros and cons of everything.

Ms Rowles: Just to educate them on if they develop an infection to call us, be it a simple skin infection or an eye infection so that we can initiate antibiotics quickly. And if they had a temperature of over 38 degrees on this BTK inhibitors, then we would tell them to seek urgent medical attention at their local A&E, and let us know that that's just for... It probably wouldn't be an intraclinic, but you just never know. So just to be sure.

Dr D’Sa: Better safe than sorry. I think a thing that does come up quite a lot is diarrhea or bowel disturbance. Would you say that, Emma? I mean, how often do people ring you to say they've been on a ibrutinib or something and their bowel habit has changed?

Ms Rowles: Yeah, I would say that's quite common in clinic, especially in the frail patient, to be honest. And then it often... I mean, I've had one lady that couldn't suffer with it, so she actually said, "I don't want ibrutinib anymore. It was that bad for her. So she's gone down the symptom control and end of life care. But yeah, I think if someone phoned up with diarrhea, first thing you'd probably do is say, "Are you managing to drink? And you drink water and fluid to compensate for your diarrhea?" Sending off some stool samples to rule out infection and just asking them to come in for a blood test to see if it's affecting their urea and electrolytes and kidney function. We've dose reduced before because they just can't tolerate the diarrhea.

Dr D’Sa: Then there's the question of lymphocytosis. This doesn't happen in WM, but I guess in CLL, it does. Why does this happen when you start treatment?

Dr Jurczak: It's something we look forward to, we want it. It's just that you have to warn the patient because they're looking at full blood counts, sometimes done in the lab around the corner, and they might be frightened to death, they see their white blood counts high up in the sky. In reality, it's what we expect. Only you have to warn the patient about it.

Dr D’Sa: Perfect. That's great. That's good. And what about headache? I gather this seems to be unique to the acalabrutinib drug. Caffeine and paracetamol can actually help counteract this in most cases. So it's not usually a dose limiting problem. It's manageable.

Dr Jurczak: And transitory. It usually dies after the first month or 6 weeks.

Dr D’Sa: Yeah. And again, as long as patients are in the know, they can manage this, otherwise they get weighed down. Hypertension. This seems to crop up. Have you seen this, Emma? Has that been an issue in your practice when people blood pressure's going up?

Ms Rowles: It's something that we would monitor at initiation of treatment, and then not that routinely, to be honest. Not every time they come to clinic. And if there was any hypertension, I think likely we would signpost to their GP to help try and manage it with medication.

Dr D’Sa: Would you agree, Wojciech, it is manageable side effect.

Dr Jurczak: Well, it is manageable, but again, there's one good thing about treating most of your BTK inhibitor patients here in clinical studies, we do measure blood pressure on every visit.

Dr D’Sa: There are drug interactions with these agents, and there's the P-glycoprotein pathway, if you like, and then there's the CYP3A4 inhibitors. I think these are well... As far as I'm aware, it's pretty much class effect, I think, and one has to be careful about co-prescribing certain drugs. With drugs which are strong inhibitors, I think concurrent use of such drugs can be... Can it actually increase the level of ibrutinib in the system by quite a number of manyfold, isn't that right? I mean, how do you approach the use of other drugs which might affect the metabolism of BTK inhibitors, Wojciech, in your practice?

Dr Jurczak: Well, if you have a stronger CYP3A inhibitor, we just don't use it with those drugs. Most of those drugs, fortunately, are used only temporarily. Most of those drugs are used to treat infections, bacterial, fungal. Therefore just the routine where we ask the patient to stop the BTK inhibitor while on infection to allow the local physician to treat them according to his or her preferences seems to work. There are very few drugs which the patient has to take chronically.

Dr D’Sa: I mean, Emma, if someone's starting a new treatment by their GP or something, and they contact you, what would you say to them, or how do you approach that, knowing that these drugs interact?

Ms Rowles: So I'd probably speak to our pharmacist who can then decide with the help the doctor whether or not it's safe to take concurrently or stop the BTK inhibitor, which is probably the safest thing to do. Sometimes they do dose reduce whilst they're on, if it's a long term treatment. But yeah, generally I'd speak to our pharmacist to see. We do say avoid non-steroidal anti-inflammatory drugs on the whole.

Dr Jurczak: There's one group of drugs, which are unfortunately used chronically, and people tend to forget about them. The protein pump inhibitors. Simply if we have a lower acidity in the stomach, the ingestion of literally most of BTK inhibitors is slowed down. We do not have the peak concentration in the blood. We are not certain whether the target occupancy will be as required. And the easiest way to do, because ibrutinib is the most effective of those drugs, the easiest way to do is to give a break between protein pump inhibitors, which are usually taking fasting in the morning. So then let's take ibrutinib somewhere about midday. It's a very ease maneuver. Once you keep the gap long enough, there's no effect.

Dr D’Sa: Yeah. That's a really excellent tip worth remembering, and not getting too wound up with substitutions and so forth. Another important drug interaction is of antiplatelet agents, which are commonly used for AF and people who've had cardiac stents et cetera, and concurrent use of BTK inhibitors. How would you approach this for a check in your practice?

Dr Jurczak: Well, in the first place Ibrutinib, which is particularly harsh on clotting, should never be used with antiplatelet agents. And by no means it could be used with warfarin or other antivitamin K's. On the contrary, if we have a necessity for the adequate anticoagulation, we can always go for the short-acting heparins.

Dr D’Sa: I think at the end of the day, one has to make a decision based on the patient's individual risk. Some people have just had a stent put in, and they absolutely have to have an antiplatelet. So we will discuss with the cardiologist. And we occasionally, if we really feel a BTK inhibitor is necessary, we will proceed gingerly on, bearing in mind that if someone does have a severe bleed, we can stop one or other drug, give platelets for example. But yes, we take a very careful look at whether this is the right treatment for someone like that, or whether they should have more traditional chemo immunotherapies. And other things, of course that make bleeding worse or in this setting is fish oil, the vitamin E and other things like oranges, grapefruits, they are CYP3A affecting foods, so they need to be avoided and that's something that's constantly mentioned.

I'll come now to probably the final summary, which is that in essence, I think when starting with BTK inhibitors, it's really important to get a thorough review of the patient's comorbidities, concomitant therapies, and decide on how it all fits together with the introduction of the BTK inhibitors. I think that it's really vital to inform patients of the risk of the adverse events so that it's not a surprise to them, so that they can report relevant symptoms and signs to their medical team, which can then be acted upon. I think we also would encourage people to seek medical strategies to manage AEs wherever possible and not simply not use the drug, because I have seen that happen where a BTK inhibitor is dispensed with sooner than I would recommend, because it's a very important treatment for that patient before going back to other treatments, which of course are there.

And I think the other useful thing to do, and my advice would be, is seek the advice of someone who specializes in B-cell diseases. And yeah, work closely with the pharmacist and the nursing team to communicate with the patient and avert or mitigate drug-drug interactions in the setting of BTKI.

And with that, I'd like to thank you all for joining and participating in this activity. Please proceed to answer the post activity assessment questions, and receive your credit. And also please evaluate the program, because this way we can try and improve on future programs. Thank you very much, and thank you to the panel for your participation.

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