BTK inhibitors for the treatment of CLL - the current state of play of 'brutinibs'

[CLLerinOz]

In just a short time, in many places, BTK inhibitors (BTKi) have largely replaced chemoimmunotherapy (CIT) for treatment naive CLL patients, while also playing an important role in relapsed/refractory CLL.

For a detailed list of the many BTK inhibitors in the pipeline, check out @AussieNeil’s post YABTKi (Yet Another BTKi): healthunlocked.com/cllsuppo...

For some of the most recent BTKi trial results, see these posts which also contain references to trials incorporating other therapies:

healthunlocked.com/cllsuppo...

healthunlocked.com/cllsuppo...

One of the great things about BTK inhibitors is that they “are effective across all molecular subtypes of CLL” and even provide a good treatment option for those patients who previously did poorly with CIT - patients with a 17p deletion or TP53 mutation.

Another advantage is that they are 'easy to administer and easy to take' and, on the whole, any 'side effects are mostly manageable', especially in an era of second and third generation BTK inhibitors. Supportive care medications, dose alterations and moving to an alternative BTKi can help to mitigate adverse reactions. A big bonus is that 'most patients start to feel much better when they’re taking a BTKi'.

A recent study has also shown that targeted therapies, including BTK Inhibitors can have a beneficial impact on pre-existing Auto-immune cytopenias associated with CLL.

healthunlocked.com/cllsuppo...

Since Ibrutinib first started to transform CLL treatment, a number of later, more targeted BTK inhibitors have been developed with Acalabrutinib and Zanubrutinib being the most well known.

Being more targeted, they have fewer off target side effects and have shown encouraging signs that they can reduce the risk of atrial fibrillation and hypertension which can affect some patients on Ibrutinib.

Later BTK inhibitors like Orelabrutinib and TG-1701 were reported on at the 2021 midyear conferences. So, too, has the new reversible BTK inhibitor, Pirtobrutinib, (LOXO-305) which has shown some great results for relapsed/refractory patients, including in the setting of Richter’s Transformation.

The downside of BTK inhibitors is that, when used as a monotherapy, they require ongoing, continuous therapy and this raises the toxicity risk and the risk of resistance.

In July 2022, an “International Consensus Statement on the Management of Cardiovascular Risk of Bruton's Tyrosine Kinase Inhibitors in CLL” A summary of those recommendations and a link to the full statement can be found here:

healthunlocked.com/cllsuppo...

In the not too distant future, trials will answer questions about:

- treatment sequencing

- the appropriateness of monotherapy Vs combination therapy for different patient groups

- the benefit or otherwise of adding a CD20 medication

- pausing, stopping, restarting therapy

- resistance mechanisms

- dose alterations

A recently published Phase III trial (ELEVATE - NCT02477696) compared Ibrutinib Vs Acalabrutinib in previously treated high risk CLL patients. After this year’s ASCO meeting, John C Byrd, MD, then professor of hematology at The Ohio State University (now at University of Cincinnati) said, “Acalabrutinib is a more selective inhibitor of [Bruton tyrosine kinase (BTK)] and has been known to have less adverse events (AEs) when compared across trials. [Until] today, no clinical trial has directly compared ibrutinib to acalabrutinib in previously treated CLL. Our trial presented here does this.”

cancernetwork.com/view/acal...

Another study, the ALPINE study, compares Ibrutinib vs Zanubrutinib in Patients With Relapsed/Refractory CLL. Interim analysis shows that zanubrutinib could improve clinical benefit vs ibrutinib.

Preliminary data from a Phase 2 study of Zanubrutinib in patients with B-cell malignancies intolerant to Ibrutinib/Acalabrutinib showed that zanubrutinib may provide a therapeutic option in patients intolerant to other BTK inhibitors.

Another very important trial is the CLL17 trial which compares Ibrutinib based therapy Vs Venetoclax based therapy Vs Ibrutinib + Venetoclax based therapy.

A summary of a recent presentation at the 16th International Conference on Malignant Lymphoma by Michael Hallek, Director of Germany’s Center for Integrated Oncology, presents a snapshot of the past, present and future of CLL continuous monotherapy vs fixed duration combination therapy.

'Therefore, one of the most important questions regarding CLL therapy is the comparison of two different treatment concepts, fixed duration therapy aimed at achieving maximal response (undetectable MRD) versus long-term disease control with single agent BTK inhibitors. The CLL17 protocol that has just opened recruitment will address this important question.'

healthunlocked.com/cllsuppo...

We’re also seeing some evidence that BTK inhibitors could be useful for patients who have progressed after Venetoclax treatment and that the Venetoclax treatment may be able to be continued again after a course of BTKi.

ashpublications.org/blood/a...

To get a good sense of the current state of play regarding BTK inhibitors and CLL, an excellent resource is provided by Clinical Care Options which produces resources designed for medical professionals.

The resources include a series of slidesets based on information presented at the recent EHA 2021 and ICML 2021 conferences. Topics covered include:

Evolving Strategies Using BTK Inhibitors in CLL: A Selective Approach to Improve Patient Outcomes

EHA/ICML 2021: The Current Role of BTK Inhibitors in CLL

EHA/ICML 2021: A Focus on Safety of BTK Inhibitors in the Management of CLL

EHA/ICML 2021: BTK Inhibitor-Based Combinations in Frontline CLL

A 2 hour webcast (FF is your friend!) is coming soon.

clinicaloptions.com/oncolog...

Clinical Care Options now has some 2022 resources about BTK inhibitors including this podcast:

clinicaloptions.com/oncolog...

It also has a great interactive decision making tool designed to help manage adverse events (AEs) associated with BTK inhibitors in haematological malignancies, including CLL.

clinicaloptions.com/oncolog...

You may need to register for access to the CCO site if you wish to view these resources.

An earlier article about managing toxicities associated with BTK Inhibitors appeared in the December 2020 Hematology ASH Education Program:

ashpublications.org/hematol...

For a review and summary about the different frontline treatments that might be considered for CLL in 2021, visit the following post:

healthunlocked.com/cllsuppo...

Previously pinned posts about BTK Inhibitors on this forum include:

Ibrutinib and the possibility of tumour flare / pseudo Richters Transformation when temporarily halting therapy:

healthunlocked.com/cllsuppo...

Ibrutinib cost

healthunlocked.com/cllsuppo...

Single-Agent Ibrutinib in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia: A 5-Year Experience (from 3 year’s ago)

healthunlocked.com/cllsuppo...

MUST READ for those on Ibrutinib/Imbruvica - concerning advice in pilot study on lower dosing - incl. danger of starting with a lower dose

healthunlocked.com/cllsuppo...

Hypertension & CV events on Ibrutinib

healthunlocked.com/cllsuppo...

Two references about Imbruvica (ibrutinib) and drug interactions

healthunlocked.com/cllsuppo....

High biotin doses may interfere with some SERUM blood tests, e.g. thyroid, anaemia. Those on Ibrutinib please note!

healthunlocked.com/cllsuppo...

UPDATE 27 October 2021:

BTK updates from the Lymphoma, Leukemia & Myeloma Congress 2021

Neil Kay, MD, Mayo Clinic, Rochester, MN, discusses

* MRD (measurable or minimal residual disease) in

* BTK combinations for CLL

* BTKi discontinuation in CLL - intolerance and disease progression

* Treating CLL intolerance or disease progression on BTKi

vjhemonc.com/video/v1ma7-h0...

These videos are also available on VJHemOnc's YouTube channel

UPDATE 31 October 2021:

The resistance mechanisms and treatment strategies of BTK inhibitors in B-cell lymphoma

onlinelibrary.wiley.com/doi...

UPDATE 11 November 2021: ‘This publication reviews the role of Bruton tyrosine kinase inhibitors, particularly when treating patients with agents that are to be taken continually and for an indefinite period of time, for the treatment of chronic lymphocytic leukemia/small lymphocytic leukemia, recapping key insights from a scientific interchange & workshop.’

onclive.com/view/updates-in...

(cdn.sanity.io/files/0vv8moc...

Image: From Clinical Care Options slideset - 'A Focus on Safety of BTK Inhibitors in the Management of CLL' clinicaloptions.com/oncolog...

UPDATE 18 November 2021: Targeting BTK in CLL: Expert Guidance on Selecting Single-Agent and Combination Therapy

This group of resources includes slide sets covering these topics:

- The Current Role of BTK inhibitors in CLL and

- Targeting BTK in CLL: Expert Guidance on Selecting Single-Agent and Combination Therapy

- An on demand webcast will be added soon

clinicaloptions.com/oncolog...

UPDATE 12 Dec 2021: Options for CLL patients who progress after BTK inhibitor therapy - ASH2021

youtu.be/vAMccDJKtjI(Not working as expected?) or vjhemonc.com/video/vamccdjk...

The video is produced by VJHemOnc and shows an interview with Kerry Rogers, MD, The Ohio State University, Columbus, OH, at the recent ASH2021 conference. It is an excellent summary of the options that might be considered by a CLL patient who progresses on a BTK inhibitor.

In it, Dr Rogers discusses Venetoclax but highlights that it may not offer a durable response. Instead, she says, patients could consider clinical trial options for reversible BTK inhibitors, BTK degraders or drugs with a completely novel mechanism that are in development. She also suggests CAR-T treatment as a suitable alternative for some patients.

Knowing what mutations are associated with a patient’s disease progression is important. She explains that patients with a BTK (C481S) mutation might choose a reversible BTK inhibitor like pirtobrutinib (Loxo 305) but that those with a PCLG2 mutation would be better advised to consider options that don’t target BTK.

UPDATE 21 Dec 2021: 'BTK Inhibitors in the Presence of 17p Deletions or TP53 Mutation in CLL'

Susan M. O’Brien, MD in a recent video for CancerNetwork says: 'There’s 1 group [of patients for whom I] always use BTK inhibitors, and those would be the patients who have a 17p deletion or a TP53 mutation.’

'Clearly, patients with 17p deletion have remissions that appear to be lasting longer than they would with venetoclax. What we don’t know is [whether or not] ibrutinib is just a better drug than venetoclax for that subset or is finite therapy not a good idea in that subset. If I felt like there was a patient for [whom] I didn’t want to give a BTK inhibitor—and I’ve already stated that I can hardly think of what that setting would be—but if I did give them venetoclax-obinutuzumab, I’m not sure I would stop at 1 year. I might leave them on continuous therapy. But if I’m going to use the regimen as it’s FDA approved, then in that setting, I’m definitely going to go with my BTK inhibitors because the data are better.'

cancernetwork.com/view/btk-...

In a Clinical care Options article, Jennifer Woyach, MD explains this further:

‘Patients with high-risk disease, such as those with abnormal TP53, might be more strongly considered for BTK inhibitor–based therapy based on available data. Specific patient health factors can also potentially direct treatment. For example, someone who is receiving warfarin should not receive a BTK inhibitor and would be better suited for treatment with a BCL2 inhibitor–based regimen. Similarly, patients who have a history of hypertension that is difficult to control might not be optimal candidates for ibrutinib but may do very well with other BTK inhibitors or with venetoclax.’

clinicaloptions.com/oncolog...

UPDATE 16 Jan 2022: CLL12 Trial does not justify changing the current standard of “watch and wait": healthunlocked.com/cllsuppo...

UPDATE 19 Jan 2022: Choosing between a BTKi based therapy and a BCL2i based therapy for frontline CLL - healthunlocked.com/cllsuppo...

UPDATE 29 Jan 2022: BTKi sequencing and the role of 1st, 2nd and 3rd line BTKis youtu.be/S2xnjFkxY70(Not working as expected?)

UPDATE 11 Feb 2022: See the following linked post by lankisterguy - a video of Dr Nicole Lamanna discussing some of the challenges associated with BTK inhibitors.

healthunlocked.com/cllsuppo...

UPDATE 25 Feb 2022: Understanding mechanisms of resistance to Pirtobrutinib in Chronic Lymphocytic Leukaemia healthunlocked.com/cllsuppo...

UPDATE 22 March 2022: The British Society of Haematology updated guideline document for the treatment of CLL: healthunlocked.com/cllsuppo...

(my emphasis)

*** PLEASE NOTE: This is an UNLOCKED reference post. If you wish to ask any questions, please do so in a separate post, not by replying here ***

How to write a post:

support.healthunlocked.com/...

Update 7 May 2022: A systematic review and meta-analysis has highlighted dermatologic toxicities associated with ibrutinib - healthunlocked.com/cllsuppo...

Update 12 May 2022: A short summary of the role of zanubrutinib in the treatment of CLL, highlighting its role for patients who take a Proton Pump inhibitor while requiring BTKi treatment:

onclive.com/view/dr-ma-on-u...

Also, a short summary about the ALPINE trial of zanubrutinib and ibrutinib -

onclive.com/view/dr-heyman-...

Post Updated 7 July 2022

[Name-1]

In Serbia no! Sorry.

[CLLerinOz Administrator in reply to Name-1]

In his presentation, Michael Hallek concluded '... most importantly, we need to make sure that these novel therapies will become available to all patients with CLL world-wide.' (my emphasis)

[PaulaS Volunteer in reply to Name-1]

I'm sorry it's not the case for you in Serbia, Olga. I hope the Rituxamab you are having is continuing to work for you,

Big hug,

Paula xx

[annmcgowan]

Hi CLLerinOz thank you for this very thorough update. Much appreciated.Ann

[Newdawn Administrator]

Excellent summation. Well presented! 😊

Newdawn

[Tupelomojo in reply to Newdawn]

I agree. Two

👍👍

[Jm954 Administrator]

Great post setting out the current state of play with BTKi's

Thank you for this 😊

Jackie

[Philelliott04]

My new dr. Is changing my treatment to venetoclax and obinutuzumab replacing imbruvica. Is this a good idea?

[AussieNeil Partner Administrator in reply to Philelliott04]

What reasons did your doctor give for changing? I note from your profile (thanks!), that you've had skin issues and joint pain on Ibrutinib and acalabrutinib, so you'll hopefully not have those issues on V+O, plus you can look forward to a treatment drug holiday.

Neil

PS, I've corrected your spelling of V+O.

[Philelliott04]

Thank you, i have not started yet on the combo treatment. I actually sought out another dr. For this treatment. My previous dr. Seemed to be experimenting to me. Try this, oops, maybe this is better. 2 strikes and he was out. New doc has all new approach. The O+V combo. More aggressive but i feel yhe afministration of the drugs is better monitored. Hopeful.

[unairdefamille]

Thank you so much for all this information. Can you tell me the difference between Acabrutinib and Venetoclax? My hemato doc also is experimenting with different dosages of Ibrutinib because it caused Atrial Fib and changing me to Acabrutinib. 🤔

[AussieNeil Partner Administrator in reply to unairdefamille]

Acalabrutinib is a BTK inhibitor, whereas venetoclax is a BCL-2 inhibitor. These are independent ways of controlling CLL.

Neil

[unairdefamille in reply to AussieNeil]

Thanks Neil. I guess I'm not familiar with HOW each one is supposed to work and what difference does it make in practical terms on the patient. If you have any idea, thanks for your help 🙏

[AussieNeil Partner Administrator in reply to unairdefamille]

In brief, BTK inhibitors block the signalling that B-cells receive through their B Cell Receptor, the part of the B-Cell which normally responds to antigens (viruses, bacteria, fungi, etc), but in CLL tends to signal anyway, keeping the CLL cell alive. With that signalling blocked, the CLL cells lose their adhesion that normally keeps them in the propagation centres in the nodes and spleen and move into the blood stream, where they eventually die. This is a gradual process. In an early trial, only about 10% achieved uMRD after 4 years on Ibrutinib.

Venetoclax works far more rapidly on CLL cells in the blood than BTK inhibitors. So much so, that the dose needs to be ramped up slowly to avoid Tumour Lysis Syndrome, where dying CLL cells can overwhelm our body's ability to deal with the released cell content. It works by targeting BCL-2 in the cell mitochondria which normally blocks apoptosis signalling. It's much easier to achieve uMRD with venetoclax. When used in combination with a BTK inhibitor or anti-CD20 targeted therapy (obinutuzumab, rituximab, etc), 80% or more achieve uMRD in about year of treatment.

Neil

[unairdefamille in reply to AussieNeil]

Thank you Neil. One question remains in my mind, since Venetoclax seems to work so well. I wonder why doctors prescribe Ibrutinib or Acabrutinib first. Could it be a question of cost?

[AussieNeil Partner Administrator in reply to unairdefamille]

We have approaching 10 years of experience with BTK inhibitors, but only about half that with venetoclax. I suspect that's why the usual monotherapy approach is to start with a BTKi and then switch to venetoclax later if needed. If a patient either has atrial fibrillation (AF) or is at risk of developing AF, then it's appropriate to consider venetoclax or maybe one of the later generation BTKi drugs. Cost shouldn't be a factor, though I appreciate it may be in the USA, depending on insurance cover.

[Zia2]

Thank you. So much information and I’m not sure WHICH to read so if anyone can direct me I’d appreciate it. May offer me hope PS I don’t feel better after treatment began (Ibrutinib or Acalabrutinib) and the side effects aren’t mostly manageable for me.

I see CLL doc in six weeks.

[AussieNeil Partner Administrator in reply to Zia2]

Thanks for updating your profile so extensively. You fall into the group that find it difficult to continue with Ibrutinib due to intolerable side effects and you are also finding acalabrutinib challenging. If you don't find the side effects reducing to what is tolerable (most do), then when your CLL tumour is considered sufficiently reduced, you should explore with your specialist the option of reducing your acalabrutinib dose to see if management of your CLL is maintainable while hopefully experiencing a better quality of life from reduced side effects. I presume you've explored taking your acalabrutinib before, during and after food. You won't be able to explore taking it morning vs before bed until you go to a half dose if your specialist approves this.

If the above approach isn't considered appropriate by your specialist, you might be able to switch to another BTK inhibitor by joining a clinical trial. Alternatively, explore the options of either adding venetoclax to try and achieve uMRD, switching to venetoclax or idelalisib or entering another clinical trial for other treatment options. Hopefully you'll soon experience improving tolerability of acalabrutinib.

Neil

[Zia2 in reply to AussieNeil]

Thanks Neil. I don’t understand why my muscles, joints and bones hurt (pressing on my shin hurts) still. My leg muscles cramp too. Perhaps it takes more than four months. Waking with headaches has returned as well so I’m up quickly for coffee and taking Tylenol again but it doesn’t help really. I have tried Acala with food, without, before and after. I find myself skipping breakfast often now. Something I’ve never done before. I wonder if most that tolerate it ok are retired….. I am hoping she’ll reduce the dose.

[CLLerinOz Administrator]

See this separate post for information about the issues that come into play when deciding between a BTKi based therapy or a BCL2i based one for frontline treatment in patients with CLL: healthunlocked.com/cllsuppo...

[CLLerinOz Administrator]

This week, The Lancet Oncology printed an article about the phase 3 SEQUOIA trial comparing zanubrutinib with bendamustine-rituximab (BR) in treatment-naive CLL.

'Zanubrutinib significantly improved progression-free survival versus bendamustine–rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL.' (my emphasis)

This trial was 'an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0–2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine–rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib.'

The full article is paywalled but a summary, including key data, is available:

Constantine S Tam, Jennifer R Brown, Brad S Kahl, Paolo Ghia, Krzysztof Giannopoulos, Wojciech Jurczak, Martin Šimkovič, Mazyar Shadman, Anders Österborg, Luca Laurenti, Patricia Walker, Stephen Opat, Henry Chan, Hanna Ciepluch, Richard Greil, Monica Tani, Marek Trněný, Danielle M Brander, Ian W Flinn, Sebastian Grosicki, Emma Verner, Alessandra Tedeschi, Jianyong Li, Tian Tian, Lei Zhou, Carol Marimpietri, Jason C Paik, Aileen Cohen, Jane Huang, Tadeusz Robak, Peter Hillmen, Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial, The Lancet Oncology, 2022, ISSN 1470-2045, doi.org/10.1016/S1470-2045(... (sciencedirect.com/science/a...

An earlier article about the same trial appeared in OncLive in January after interim findings from cohort 1 were presented at the ASH 2021 conference in December last year: onclive.com/view/zanubrutin...

[AussieNeil Partner Administrator in reply to CLLerinOz]

So other than availability or cost, are there any reasons for treatment by Bendamustine + Rituximab (BR) nowadays? (This was a very large trial for CLL, with well over 500 patients enrolled.) Unlike FCR, there's no chance of a very long remission if you are IGHV mutated, plus rituximab dramatically reduces your chances of developing antibodies to an infection or vaccination for up to a year or so after your last infusion.

I'd be asking for a second opinion if BR was recommended as a treatment, or at least ask why it would be preferable in my specific circumstances.

Neil

[CLLerinOz Administrator in reply to AussieNeil]

Similarly, the long-term outcomes of the E1912 trial have been released and they demonstrate the superiority of the BTK inhibitor treatment IR over FCR. The report appeared in the journal Blood Advances this week.

'Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial' demonstrated:

"After a median follow-up of 6 years, IR led to superior PFS relative to FCR in patients with both IGHV muted and IGHV unmutated CLL.

Among ibrutinib-treated patients who discontinued treatment for a reason other than progression, median PFS was 25 months."

"In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients."

Tait D. Shanafelt, Xin Victoria Wang, Curtis A. Hanson, Elisabeth M. Paietta, Susan O’Brien, Jacqueline Barrientos, Diane F. Jelinek, Esteban Braggio, Jose F. Leis, Cong Christine Zhang, Steven E. Coutre, Paul M. Barr, Amanda F. Cashen, Anthony R. Mato, Avina K. Singh, Michael P. Mullane, Richard F. Little, Harry Erba, Richard M. Stone, Mark Litzow, Martin Tallman, Neil E. Kay; Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood 2022; 140 (2): 112–120.

doi: doi.org/10.1182/blood.20210...

A related article was also published: 'Ibrutinib frontline in young patients with CLL'

"Altogether, the update of the E1912 study confirmed that the safe and very efficacious administration of IR in younger patients with CLL is superior to FCR, independent of IGHV status. How continuous therapy compares to time-limited targeted therapies such as venetoclax plus obinutuzumab or venetoclax plus BTK inhibitor will be shown by currently ongoing phase 3 trials."

Barbara Eichhorst; Ibrutinib frontline in young patients with CLL. Blood 2022; 140 (2): 80–81. doi: doi.org/10.1182/blood.20220...

Long-term outcomes IR Vs FCR

[CLLerinOz Administrator]

This week Advances in Therapy published long-term outcomes of zanubrutinib monotherapy in treatment-naive (TN) and relapsed/refractory (R/R) CLL patients.

The post hoc analysis pooled 211 patients from three phase 1/2 studies: BGB-3111-1002, BGB-3111-AU-003, BGB-3111-205.

The abstract provides overall response rates (ORR) across different patient groups, "The ORR was 95.4% and significantly higher in the TN group than in the R/R group (100 vs. 91.0%, p < 0.0001)." The ORR was higher in the group of R/R patients with 1 previous line of therapy than in the group with more than 1 previous line of therapy.

"The median follow-up times were 50.1, 35.7, and 45.9 months for TN, R/R and all cohorts, respectively. "

"Efficacy was similar regardless of the presence of genomic aberrations."

"Most frequent grade ≥ 3 adverse events were infections (41.7%), neutropenia (34.1%), and thrombocytopenia (9.4%). "

"Atrial fibrillation occurred in only 1.9% of patients."

Conclusions: With extended follow-up, zanubrutinib yielded long-term benefits and demonstrated a favorable safety profile for patients with TN or RR CLL/SLL. Earlier utilization of zanubrutinib was associated with better outcomes. (my emphasis)

Xu W, Yang S, Tam CS, Seymour JF, Zhou K, Opat S, Qiu L, Sun M, Wang T, Trotman J, Pan L, Gao S, Zhou J, Zhou D, Zhu J, Song Y, Hu J, Feng R, Huang H, Su D, Shi M, Li J. Zanubrutinib Monotherapy for Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies. Adv Ther. 2022 Jul 28. doi.org/10.1007/s12325-022-.... Epub ahead of print. PMID: 35900694.

[JerrysGirl3 in reply to CLLerinOz]

So my doc was right ! Since all my numbers were right in the green zone, I was a candidate because of 5 cm node in my chest that was growing and multiple nodes in my neck / throat. I guess being in the right place at the right time is fitting for me 😊. Thanks for the great info !!

[CLLerinOz Administrator]

This review article, submitted in March 2022 and accepted for publication in July 2022, provides an overview of the current use of BTK inhibitors in the treatment of CLL:

St-Pierre F, Ma S. Use of BTK Inhibitors in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Practical Guidance. Blood Lymphat Cancer. 2022 Jul 22;12:81-98. doi: 10.2147/BLCTT.S326627. PMID: 35911566; PMCID: PMC9325877.

doi.org/10.2147/BLCTT.S326627

The authors 'discuss the role of BTK inhibitors in treatment of CLL/SLL, review the data that led to approval of BTK inhibitors in CLL/SLL, outline the toxicity profile of each approved BTK inhibitor and management, and give practical guidance on how to select the most appropriate agent for treatment.'

'BTK inhibitors have become an important treatment option in the frontline and R/R setting in CLL/SLL. Determining which patients will benefit most from BTK inhibitors and selecting the most appropriate agent in an individualized manner requires careful considerations of disease and patient comorbidities. Monitoring and management of potential adverse effects isimportant for the safe long-term use of BTK inhibitors. Resistance to covalent BTK inhibitors might be overcome by noncovalent novel BTK inhibitors. Novel combinations of BTK inhibitors + venetoclax +/- anti-CD20 mAb are currently under investigation and may further expand the role of BTK inhibitors in the treatment of CLL/SLL in the future.78–80'

[CLLerinOz Administrator]

Over the past week, OncLive has been releasing some short videos with up-to-date information about the role of BTK inhibitors in CLL.

The first is an interview between Anthony R. Mato, MD, MSCE, Catherine C. Coombs, MD, Alexey V. Danilov, MD, PhD, and Matthew S. Davids, MD, MMSc. It provides a review of treatment for patients with high risk or relapsed/refractory disease

On the role of BTK inhibitors in the front-line treatment for patients with a TP-53 mutation, Dr Danilov says:

" . . . the data with ibrutinib and P53-aberrant disease is highly encouraging. We have data from a single-arm study where, at 5 years, PFS was about 75% in patients with CLL, which, for a single agent, is much better than chemotherapy. Recent data suggests that patients with P53 aberrations do not perform [as] well with bendamustine/rituximab as we expected. It seems that these patients perform just as well as P53 wild-type patients when they are treated with either ibrutinib or ibrutinib/rituximab combinations. Overall, the data is very encouraging, which really positions BTK inhibitors well as the best frontline strategy for patients with TP53-aberrant CLL."

They also discuss the complex and somewhat still unanswered question of what role obinutuzumab might have combined with ibrutinib. Dr Davids observes:

"We did recently see longer-term follow-up published on the iLLUMINATE study, which continues to look very good for ibrutinib/obinutuzumab, but as we compare it across to other frontline datasets for ibrutinib monotherapy, I don't think there are clear differences that have emerged there."

In the relapsed/refractory setting " . . . we don't know for sure that obinutuzumab is adding benefit."

"In the frontline setting with acalabrutinib, we have seen that obinutuzumab does seem to have some benefit in terms of PFS and maybe even eventually OS (overall survival). I think it is intriguing to wonder whether we should be studying ibrutinib with obinutuzumab further, and it would be great to eventually have a randomized study against ibrutinib monotherapy."

onclive.com/view/treatment-...

[CLLerinOz Administrator in reply to CLLerinOz]

The second video in this OncLive series is with Anthony R. Mato, MD, MSCE, Catherine C. Coombs, MD and Brian T. Hill, MD, PhD. They look more closely at the question of acalabtutinib plus obinutuzumab in the frontline setting and discuss the latest data from the ELEVATE TN trial and ASCEND trial.

Catherine Coombes says a "really exciting thing from the 5-year update is that there's starting to look like a survival advantage to the acalabrutinib plus obinutuzumab regimen, and I think that's really changing my mind on whether to offer obinutuzumab to patients. Early on when I thought it was just a PFS advantage, I had concerns about the potential added toxicity of obinutuzumab. However, what we're seeing now with this further follow-up is that the acalabrutinib plus obinutuzumab patients have the highest rate of OS at 5 years, specifically 90% compared to 82% for the chlorambucil plus obinutuzumab patients. Though there may be added toxicities with obinutuzumab compared to just doing acalabrutinib by itself, this may be paying off in dividends with respect to survival, which may become more pronounced with further years of follow-up. We will have to see."

onclive.com/view/acalabruti...

[CLLerinOz Administrator in reply to CLLerinOz]

The third video in the series is with Anthony R. Mato, MD, MSCE, Catherine C. Coombs, MD and Alexey V. Danilov, MD, PhD, who look at Zanubrutinib and the ALPINE trial.

Catherine Coombs observes that, in the ALPINE trial, "zanubrutinib had a superior overall response rate as compared with ibrutinib. It also looks like there may be improved progression-free survival; however, the caveat is that the follow-up on this trial is very short. It's a little over 1 year."

"One of the exciting things about zanubrutinib is that it has, so far, very low rates of atrial fibrillation [and] flutter. [In] that trial, it was 2.5% compared with ibrutinib's 10%, so we'll see what happens with longer-term follow-up. As far as other toxicities go, zanubrutinib has very similar rates of hypertension as compared with ibrutinib. They both were about 16% in each arm. There is a little bit more neutropenia with the zanubrutinib, although I'll say in my own practice, I don't think it's usually very clinically significant. Overall, a favorable look at zanubrutinib, but it had a short follow-up, so we'll need a few more years before making any firm conclusions on that one."

onclive.com/view/zanubrutin...

[CLLerinOz Administrator in reply to CLLerinOz]

In the fourth video, Anthony R. Mato, MD, MSCE, Brian T. Hill, MD, PhD, Alexey V. Danilov, MD, PhD, Matthew S. Davids, MD, MMSc, Michael Wang, MD discuss "Treatment Decision-making Among Second-generation BTKis in CLL"

They note the need for more time to be able to adequately compare across the ELEVATE RR and ALPINE studies. On the question of choosing between ibrutinib, acalabrutinib and zanubrutinib, Dr Hill says:

"For CLL (chronic lymphocytic leukemia), I think you really have very strong head-to-head evidence that acalabrutinib is at least as effective and safer than ibrutinib, so that tends to be where the field has moved for frontline and relapsed treatment. Zanubrutinib data is very compelling. I think a lot of us just want to see a little more follow-up. Sometimes some of the AEs (adverse events) creep up over time, but barring any severe headache or drug-drug interaction with a PPI (proton pump inhibitor), I think most people do very well with acalabrutinib."

On the question of whether zanubrutinib might replace ibrutinib as standard of care in CLL in a year or so, Dr Danilov says: "I think that question [is] really difficult to answer. I think we will have to analyze why the PFS curve separation is occurring. It seems to be that ibrutinib may be somewhat underperforming in that study, and I don't quite understand why as the discontinuation rates seem to still be relatively low. I will say, however, that all of us have switched to second-generation BTK inhibitors and favor acalabrutinib, at least as it is approved, over ibrutinib. I think the field has already been slowly—at a glacial pace—moving in the direction of these drugs over ibrutinib. I think the standard of care is changing already. Looking at all of these studies together, in some, I would probably say that, ultimately [the] use of second-generation BTK inhibitors is preferable to ibrutinib at this stage."

On the question of hypertension, Dr Davids says:

'I think one of the unique aspects of hypertension—and this is probably best characterized with ibrutinib—is that it is a risk that continues beyond the first year or 2. You see hypertension popping up in longer-term follow-up of patients [after] 4, 5, or 6 years on ibrutinib. The cardiovascular risks are real. This can lead to increased risks of stroke, MI (myocardial infarction), and other cardiovascular complications, so it is something I watch closely in my patients on ibrutinib. In the past, I've been aggressive about blood pressure control and antihypertensives. If a patient's struggling with hypertension on ibrutinib, I’m now more inclined to switch them to acalabrutinib, where we know the risk of hypertension is less."

"We have prospective trial data from Kerry A. Rogers, MD, at The Ohio State University Comprehensive Cancer Center and others suggesting that it's an effective strategy to switch from ibrutinib to acalabrutinib specifically for hypertension."

onclive.com/view/treatment-...

[CLLerinOz Administrator]

This week, on 12 October 2022, BeiGene announced that "BRUKINSA® (zanubrutinib) achieved superior Progression-Free Survival (PFS) versus IMBRUVICA® (ibrutinib) in a final analysis of the Phase 3 ALPINE trial, as assessed by an independent review committee (IRC) and investigator. BRUKINSA was generally well tolerated; safety findings at the final PFS analysis were consistent with prior reports."

“This positive result adds to the growing body of evidence underpinning our belief in the potential for BRUKINSA to provide new hope for CLL patients facing this intractable disease. With this final PFS analysis, BRUKINSA has achieved superior progression free survival, as well as superiority in overall response rate versus ibrutinib,” said Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology at BeiGene. “We look forward to sharing the full results with the medical and patient communities and will submit for presentation at a medical congress and for publication.”

Stay tuned for the details when they're released. ir.beigene.com/news/beigene...

[CLLerinOz Administrator]

"Current and Emerging BTK Inhibitors for Chronic Lymphocytic Leukemia"

An article with that title by Tori Rodriguez, MA, LPC, AHC, was published by Hematology Advisor on 11 November 2022. It provides a good summary of where we are currently situated with the 'brutinibs', nearly eighteen months since this post on that topic first appeared.

It focusses on ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, also mentioning some of the other third-generation BTK inhibitors with less impressive results to date than pirtobrutinib.

In the second part of the article, Jennifer A. Woyach, MD, Hematologist-oncologist at The Ohio State University (OSU) Comprehensive Cancer Center – The James and Professor in the Division of Hematology at the OSU Wexner Medical Center, answers a number of questions:

1. What are currently the most promising BTK inhibitors for CLL treatment?

2. How might these therapies be used to tailor treatment to individual patients?

3. What are other key takeaways for clinicians regarding this topic?

hematologyadvisor.com/home/...

It's worth highlighting here again that  AussieNeil manages a post that provides a comprehensive list of BTK inhibitors: healthunlocked.com/cllsuppo...

He has also recently shared a 1hr video presentation about BTK inhibitors.

healthunlocked.com/cllsuppo...

[CLLerinOz Administrator]

Clinical Care Options has recently updated its excellent resources about BTK inhibitors to include two slide sets, a webinar and now a podcast about the Evolving Role of BTK Inhibitors in CLL: Sequencing, Combinations, and Novel Agents

clinicaloptions.com/oncolog...

The 20 minute podcast features Farrukh T Awan MD and Nicole Lamanna MD who answer questions about the evolving role of BTK inhibitors in CLL.

clinicaloptions.com/oncolog...

The resources on Clinical Care Options are designed for health practitioners and provided by Medical Learning Institute, Inc. in partnership with Clinical Care Options, LLC. However, many patients find their resources both accessible and helpful.

CCO also has a valuable Treatment Tool that is part of a suite of resources with patients in mind that is grouped under the heading "Smarter. Stronger. Together. Progressing Toward Optimal CLL Care Through Healthcare Professional and Patient Education".

clinicaloptions.com/oncolog...

We've linked to it before but it's worth mentioning it again. The tool is available for use by health practitioners and patients and enables you to compare your choice of therapy with those of 5 renowned CLL experts. It provides information across a range of CLL treatments that may or may not be available to you as standard treatment, depending on where in the world you are located.

clinicaloptions.com/oncolog...

It was last updated in Sept 2022 so doesn't yet include zanubrutinib which has recently been granted approval in the EU for CLL. It does, however, include the other covalent BTK inhibitors which could serve as a comparison.

healthunlocked.com/cllsuppo...

[CLLerinOz Administrator]

Cardiotoxicity information relating to acalabrutinib appeared in the journal Blood on 17 November 2022. See this post for the details:

healthunlocked.com/cllsuppo...

[CLLerinOz Administrator]

“How are advances in Bruton’s tyrosine kinase targeted therapies continuing to change how chronic lymphocytic leukemia (CLL) is treated?”

What is Bruton’s tyrosine kinase (BTK) and why is it an important treatment target in CLL?

1st and 2nd generation Bruton’s tyrosine kinase inhibitors (BTKi), how different are they?

How have side effect profiles and outcomes changed with BTKi advances?

Non-covalent BTKi, how do they differ from existing BTKi in use today?

What does covalent, non-covalent and reversible mean?

Emerging technologies, such as BTK degraders, what are they and how do they work?

How are BTK targeted therapies continuing to change the chronic lymphocytic leukemia (CLL) treatment landscape?

clladvocates.net/cllan-webi...

Thanks to Lavinia-Blue for sharing the link to the CLL Advocates Network (CLLAN) podcast.

[CLLerinOz Administrator]

Comparison of the different BTK inhibitors available & under investigation in frontline and R/R CLL" is a VJHemOnc video with Toby Eyre, MBChB (Hons), DipMedEd, MRCP (UK), FRCPath (UK), MD, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

In this video, Dr Eyre "discusses advances in the field of BTK inhibitors for both frontline and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), commenting on the safety and efficacy of first and second-generation BTK inhibitors and non-covalent BTK inhibitors, and highlighting the results of various clinical trials evaluating these agents . . . "

youtu.be/K-b2JB_iMak(Not working as expected?)

In a second video, Dr Eyre discusses "Ongoing trials investigating the efficacy of pirtobrutinib in CLL"

youtu.be/fp3EYZ9NpHM(Not working as expected?)

And, in the third, he talks about the "impact of comorbidity burden on treatment decisions in CLL".

youtu.be/D-nBT7J3KwM(Not working as expected?)

Update 6th December 2023 - AussieNeil

"The FDA expanded the label of pirtobrutinib (Jaypirca) to include the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) following two prior lines of therapy, the agency announced on Friday.

An oral, non-covalent Bruton's tyrosine kinase (BTK) inhibitor, pirtobrutinib was granted accelerated approval for adults who have previously received both a BCL-2 inhibitor and a covalent BTK inhibitor, such as ibrutinib (Imbruvica), acalabrutinib (Calquence), or zanubrutinib (Brukinsa).

"Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL-2 inhibitor therapies, treatments are limited and outcomes can be poor, making the approval of Jaypirca a meaningful advance and much-needed new treatment option for these patients," said William Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, in a statementopens in a new tab or window from drugmaker Eli Lilly.

Pirtobrutinib "offers a new treatment option and different approach to targeting BTK, providing clinical benefit for a high proportion of patients with CLL or SLL," added Wierda."

medpagetoday.com/hematology...

Also see: healthunlocked.com/cllsuppo...

[CLLerinOz Administrator]

Update March 2024:

A 2024 review article about BTK inhibitor therapy was published in the journal Blood Advances in March 2024. More information about that can be found in the following post: healthunlocked.com/cllsuppo...

CLLerinOz