I'll admit that YABTKi is not a recognised CLL related acronym, (acronym lists are here healthunlocked.com/cllsuppo... ), but perhaps it should be! I've attempted in this post to keep tabs on the growing list of BTK inhibitor (BTKi) drugs on trial after ibrutinib's success, with each endeavouring to be more selective (i.e. have less side effects) and/or avoiding the known resistance development risks.
Thank you to the many contributors assisting me to keep this post current!
Not CLL specific and rather technical, with excellent information on cardiovascular side effect management with BTKi treatments. It's worth referencing this to your CLL specialist and cardiologist if you have concerns about bleeding, bruising, blood thinners, heart fibrillation, high blood pressure and so on.
Second-Generation BTK Inhibitors Hit the Treatment Bullseye With Fewer Off-Target Effects healthunlocked.com/cllsuppo...
There are recognised dermatological toxicities associated with ibrutinib, which are less of an issue with second generation BTKis.
One of the off target effects is on BTK in platelets, reducing clotting effectiveness, thereby increasing the risk of bleeding. Occasional patches of small bleeds under the skin (petechiae), and an increased tendency to bruise, are generally of no concern, but larger bleeds can be serious.
Bleeding Risk With Antiplatelets and Bruton's Tyrosine Kinase Inhibitors in Patients With Percutaneous Coronary Intervention
Pre ASH2020 presentation by three CLL specialists: Drs Ian W. Flinn, Susan M. O'Brien, and John Pagel. titled: "Addressing the Medical Need in CLL: How BTK Inhibitors Are Improving Outcomes"
Dr Furman has previously noted that the treatment naive group from the original phase II ibrutinib study has an 83% progression free survival at 7 years.
Addressing Intolerance and Resistance to BTK Inhibition Is Next Frontier in CLL Drug Development - Dr Anthony Mato
Acalabrutinib Showcases Long-Term Tolerability Across B-Cell Malignancies
Richard R. Furman, MD, discusses the findings from the analysis and highlights the differences between first and second-generation BTK inhibitors in CLL.
Here's my current List and status of BTKi drugs. How many have I missed?
1. Acalabrutinib/Calquence (covalent) Approved in USA, Australia for first and subsequent line treatments. (In mid 2021, we had about 5 years of accumulated treatment data for CLL.)
Meta-analysis: Acalabrutinib showed better PFS and OS than other frontline CLL therapies, October 7, 2020
"In this first head-to-head trial of BTKis in CLL, Aca demonstrated non-inferior PFS with less cardiotoxicity and fewer discontinuations due to AEs vs Ib"
3. Ibrutinib/Imbruvica (covalent) (First approved) Where this all started, following FDA approval for MCL in November 2013 and CLL in July 2014. (In early 2024, we have about 13 years of accumulated treatment data for CLL.)
Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies (from ASH 2019) See the visual abstract which illustrates how the adverse event profile considerably improves year by year with the exception of high blood pressure.
How I manage ibrutinib intolerance and complications in patients with CLL - Drs Debra Stephens and John Byrd
First-line treatment with ibrutinib has meaningfully improved the poor prognosis in the high-risk TP53 population (ASH2020): cancernetwork.com/view/john...
Merck has initiated the pivotal phase 3 randomized BELLWAVE-011 clinical trial (NCT06136559) evaluating nemtabrutinib versus investigator's choice of ibrutinib or acalabrutinib in patients with previously untreated CLL and SLL. Global recruitment of the trial has begun, with patients now enrolling.
Study to assess the safety and tolerability and to confirm the dose of nemtabrutinib in combination with venetoclax in participants with R/R CLL/SLL. clinicaltrials.gov/study/NC...
6. NRX0492degrades normal BTK and BTK that has become resistant to other BTK inhibitors. Human testing should have started late 2020. This may initiate a whole new class of drugs for degrading other target proteins. There is a phase 1 clinical trial for prostate cancer being done by another company. See: cllsociety.org/2020/06/ash-...
7. Orelabrutinib - ICP-022 (covalent)
InnoCare Pharma has announced that its BTK inhibitor orelabrutinib received approval from the China National Medical Products Administration (NMPA) in two indications: the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL), and the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL).
Works on patients with acquired resistance to available BTKis and Venetoclax Starting at the 50 mg QD dose, Pirtobrutinib delivered >IC90 target coverage for wild-type and C481S-mutated BTK, based on estimates from cell-based potencies
The potential of pirtobrutinib in multiple B-cell malignancies
Here, we review the pharmacologic rationale for pursuing non-covalent BTK inhibitors, the clinical need for such inhibitors, existing safety, and resistance mechanism data for pirtobrutinib, and the forthcoming clinical trials that seek to define the clinical utility of pirtobrutinib, which has the potential to fulfill multiple areas of unmet clinical need for patients with B-cell malignancies.
Jeffrey L. Jensen, Anthony R. Mato, Camila Pena, Lindsey E. Roeker, Catherine C. Coombs
TG-1701 alone and in combination with U2 (Umbralisib and Ublituximab), has an encouraging safety profile with clinical and pharmacodynamic activity at all dose levels evaluated.
UBX-303 is a Bruton’s tyrosine kinase (BTK) targeting molecule that 'has been designed to demonstrate efficacy by degrading over-expressed BTK proteins and has a different modality than current BTK inhibitors. Its distinct mechanism of action, the decomposing and removal of BTK proteins in cells, is expected to bring about overall advantages, in particular demonstrating superior efficacy, overcoming resistance, and increasing selectivity for target proteins
13. Vecabrutinib/SNS-062 (non-covalent) Phase 1b (Phase 2 is not proceeding)
Although vecabrutinib continues to exhibit an excellent safety profile, there is insufficient evidence of activity in BTK-inhibitor resistant B-cell malignancies to advance the drug into the planned Phase 2 portion of the trial.
The (USA) National Comprehensive Cancer Network (NCCN) updated their physician guidelines to recommend Zanubrutinib for first and second line treatment for CLL/SLL on 3rd December 2020
The European Medicines Agency has accepted for review 2 new indication applications for zanubrutinib as a therapeutic option for patients with chronic lymphocytic leukemia and for those with marginal zone lymphoma.
"Zanubrutinib has found a role in everyday practice, such as in patients who have continued to benefit from inhibition of the BTK pathway but have developed an intolerance to ibrutinib (Imbruvica), Ma explains. Moreover, zanubrutinib is beneficial in patients who are not candidates for acalabrutinib (Calquence), including those patients who need to remain on a proton pump inhibitor and need long-term antacid medication, Ma adds."
From the ALPINE Relapsed/Refractory trial Study:- Over 60% of patients were aged 65 years or older and around 70% were men, with no significant differences between treatment groups.
Patients were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or study withdrawal.
After a median follow-up of 15 months, the overall response rate was significantly higher with zanubrutinib than ibrutinib, at 78.3% versus 62.5% (P = .0006).
Subgroup analysis confirmed that the effect was seen regardless of age, sex, disease stage, number of prior lines of therapy, mutation status, or bulky disease.
Patients treated with zanubrutinib experienced more grade ≥ 3 adverse events than those given ibrutinib, at 55.9% versus 51.2%, although they had fewer adverse events leading to treatment discontinuation, at 7.8% versus 13.0%.
Brukinsa provides patients with CLL with improvements in response and reduced rates of atrial fibrillation or flutter compared to ibrutinib, in head to head comparison, funded by BeiGene, naturally!
At a median follow-up of 15 mo, ORR was significantly higher with zanubrutinib vs ibrutinib. ORR was higher in patients with del11q (83.6% vs 69.1%) and del17p (83.3% vs 53.8%) with zanubrutinib, as were overall 12-mo PFS (94.9% vs 84.0%, and OS rates (97.0% vs 92.7%).
The rate of atrial fibrillation/flutter, a pre-specified safety endpoint, was significantly lower with zanubrutinib vs ibrutinib.
In the Phase 3 trial SEQUOIA trial of Zanubrutinib vs Bendamustine and Rituximab in Previously Untreated CLL/SLL, zanubrutinib resulted in superior progression-free survival vs bendamustine plus rituximab.
gardening-girl has identified patents that seem to cover the properties of this new small molecule inhibitor:-
The present invention relates to a class of potent and selective Btk inhibitors which are rationally designed to not only irreversibly inhibit the WT BTK but also reversibly inhibit the C481S mutant BTK. Thus, the compounds of the present invention may be useful in treating the patients resistant/refractory to the first generation BTK inhibitors such as Ibrutinib and ACP-196(Acalabrutinib), particularly with BTK C481S mutation.
Resistance-Associated Mutations in CLL Patients Treated With Novel Agents
In 80% of patients with ibrutinib failure, acquired mutations in BTK and PLCG2 genes were detected. No common resistance-associated mutations or deregulated signaling pathways have been reported in idelalisib failure. Acquired mutations in the BCL2 gene were detected in patients who had failed on venetoclax.
Resistance-associated mutations tend to occur between the second and fourth years of treatment and may be detected several months before clinical relapse.
Also discussed is the development of next-generation agents for CLL patients who have acquired resistant mutations to current inhibitors.
16. TL-895 is a highly potent, selective, orally available, covalent inhibitor of Bruton tyrosine kinase (BTK) and bone marrow tyrosine kinase X-linked (BMX), under development for treatment of myelofibrosis and chronic lymphocytic leukemia." (added June 2023)
Adverse Events From Ibrutinib in Real-World CLL: More Research Needed
Dr Stefano Molica, MD, of Ospedaliera Pugliese-Ciaccio, Italy, and colleagues recently published data from an analysis looking at changes in glycemia, cholesterol, triglycerides, and HDL in 43 patients with CLL who received single-agent ibrutinib. This real-world analysis had several interesting outcomes.
Estimated enrollment 75 patients, commencing 22nd December 2020. MSK, New York is recruiting. The trial is also available in North Carolina and Pennsylvania.
Adding the BAFF receptor antibody Ianalumab may be another way
Kerry Rogers, MD, The Ohio State University, Columbus, OH, gives an excellent summary of the options that might be considered in this VJHemOnc ASH2021 conference interview:
Dr Woyach's take home message: "I would just say that CLL is advancing very rapidly. We have a lot of drugs that are very effective, and I think the most important thing is that we shouldn't become complacent with the success that we've had so far. We should continue to work to develop new trials to put patients on track and to continue to optimize therapy for patients with CLL."
My Perspective on 3 Questions I Am Asked on BTK Inhibitors for CLL - Dr Ian Flinn, Director, Lymphoma Research Program, Sarah Cannon Research Institute Nashville, Tennessee. Source: Addressing the Medical Need in CLL: How BTK Inhibitors Are Improving Outcomes
clinicaloptions.com/oncolog... Answers on Ibrutininb vs Acalabrutinib or Zanubrutinib, adding an anti- CD20 to BTKi treatment. Note comment on extreme lymphocytosis (very high lymphocyte count) on BTKi's:- "Lymphocytosis can occur in patients with CLL during BTK inhibitor therapy and can be extreme; some clinicians use this as a rationale for adding an anti-CD20 antibody to a patient’s CLL regimen. That said, I have only rarely seen this to be a real issue in my patients with CLL—frankly, I worry more about infusion‑related reactions that occur by administering an anti-CD20 antibody to a patient with such a high white blood cell count than I worry about the potential of lymphocytosis harming the patient. In general, I do not see lymphocytosis as a good reason to add an anti-CD20 antibody to a BTK inhibitor."
Finally, for those concerned at running out of treatment options, there's this paper published in November 2023
Taking the Next Step in Double Refractory Disease: Current and Future Treatment Strategies for CLL
From the Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
"In the pooled comparator group (n = 585), exposure-adjusted incidence rates of any grade of cardiac disorder events were approximately twice as high vs the pooled acalabrutinib group (n = 599)."
TRANSCEND CLL 004 Breyanzi Lisocabtagene Maraleucel (liso-cel) in R/R CLL/SLL
Conclusions: With longer follow-up, liso-cel continued to demonstrate durable CR/CRi, high uMRD rates, and a manageable safety profile in patients with heavily pretreated, high-risk R/R CLL/SLL. The safety results from longer follow-up were similar to those reported in the primary analysis with no new safety signals and were consistent across age groups.
Study to Compare the Efficacy and Safety of Lisocabtagene Maraleucel vs Investigator's Choice Options in Adult Participants With R/R CLL or SLL, Whose Disease Has Failed Treatment With Both BTKi and BCL2i Therapies
Slideset downloadable from Clinical Care Options 12 June 2023 TRANSCEND CLL 004: Phase I/II Trial of Lisocabtagene Maraleucel for Relapsed/Refractory CLL/SLL clinicaloptions.com/CE-CME/...
Dr Kenderian on Efficacy of Liso-Cel in R/R CLL/SLL
Phase 2, open-label, single-arm study of Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous BTKis thelancet.com/journals/lanh...
Idelalisib, duvelisib, umbralisib, zandelisib, et al, have come under a cloud due to FDA concerns about safety fda.gov/drugs/drug-safety-a...
Evidence the FDA seriously takes on its regulatory role, including withdrawing approval for previously approved drugs. However we do need options for those who have become resistant to BTKi and BCL-2i drugs.
MS-553, a protein kinase C-beta (PKCß) inhibitor, is an exciting new agent in a yet-to-be-approved class of drugs that target an area of the B-cell receptor pathway independent of Bruton tyrosine kinase (BTK) and phospholipase C gamma 2 (PLCy2) mutations which confer resistance to BTK inhibitors. This drug is demonstrating exciting promise in early-phase drug testing for treating CLL/SLL in heavily treated patient populations, potentially offering a therapeutic alternative for patients who have developed resistance to BTK inhibitor
Early treatment with lenalidomide resulted in a prolonged time to subsequent therapy in patients with high-risk chronic lymphocytic leukemia, according to extended follow-up data presented at ASH Annual Meeting and Exposition.
Kerry A Rogers, MD, Ohio State University
Lenalidomide has a long history of clinical trial studies with CLL, with hopes that it might reverse the some of the immune system damage done by CLL. Unfortunately, study after study have shown disappointing results.
I know a person using ibrutinib and other two using venteloclax for autoimmune diseases like Rheumatoid arthritis etc.?
~ Original Reply to this reply by AussieNeil~
Some CLL drugs are also used for treating auto-immune illnesses, because reducing the B-lymphocyte count reduces auto-immune antibody production, causing the challenging symptoms of these diseases. Taking these drugs has the same effect on those taking them for auto-immune disease management as it does for us - lowered immunity.
It's an astute question with a useful answer. The endings of targeted drugs medical names (not the marketing names) tell you about how the drug works. 'inib' is short for inhibitor and the 'brut' tells you that BTK is being inhibited. Likewise drug names for monoclonal antibodies end in 'mab' for monoclonal antibody.
Many thanks for the list, I've no others and you've added a couple to my list which I have to admit I had got overwhelmed trying to maintain.
To be clear to anyone reading, the scope of this list is BTK inhibitors.
Staying in the field of inhibitors (so I'm not discussing all the wonderful immunotherapy agents we also have) there are also other kinds of inhibitors e.g. ABT-199 Venetoclax which is a BCL-2 inhibitor.
There I do get a bit confused, because I have a memory of being educated that there are three kinds of inhibitors, but I've got the following on my list:
- BTK (your list above)
- BCL-2 Inhibitors e.g. ABT-199
- PI2K delta
- Syk
- Syk + JAK
So as usual I'm a little confused here . . .
P.S. To anyone wondering where the "Brutinib" name name from, I remember (from HU I think) reading about a chap called Ogden Bruton, (Somebody will have to remind me exactly how his work inspired Pharmacrylics to do their stuff and use Ogden's surname many many years later.) Neil has explained the "inib" above.
Wow! Another non-covalent BTKi that inhibits wild-type and C481-mutated BTK preclinically and in that phase 1 trial it was confirmed to work on "patients with acquired resistance to available BTKis and venetoclax".
Mutations at the Cys-481 residue cause resistance against first and second generation BTK inhibitors.3
As a third generation BTK inhibitor, pirtobrutinib does not rely on binding to Cys-481 in the active site, therefore resistance does not occur. As the body synthesizes new amounts of BTK, pirtobrutinib will remain in the body and cause constant inhibition. This is unlike other BTK inhibitors, which do not have long half-lives and cause gaps in inhibition.
:
Only 1% of patients permanently discontinued pirtobrutinib because of treatment-related AEs.4 The most common AEs included diarrhea, fatigue, and neutropenia, with hemorrhage and hypertension occurring in rare cases.
Added 3rd August 2022
Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects
963 Initial Results from a Phase 1/2 Dose Escalation and Expansion Study Evaluating MS-553, a Novel and Selective PKCβ Inhibitor, in Patients with CLL/SLL
As of June 20, 2022, a total of 45 patients (median age 69; range 38-82) have been treated with at least one dose of therapy.
:
50% (10/20) of patients exhibited a partial response and 50% stable disease with the median duration of therapy of 6.0 and 4.1 months respectively. In cohort B and C, all patients responded (B, 4/4 PRs; C, 2/3 PRs and 1/3 CR) and all remained on therapy at time of data cut. Of note, responses occurred in several ultra-high-risk patients such as those with BTK/PLCG2/TP53 triple mutations, with relapse after BTKi and venetoclax treatment, and having relapsed after both covalent and non-covalent BTKi. For the combination Cohorts B and C, all participants have shown partial or complete responses and are continuing therapy as of the data lock. While still in the dose escalation phase of the study, the median time on therapy for Cohort B is 5.6 months and for Cohort C is 6 months.
4656 Predictors of Outcomes with Venetoclax-Based Treatment in Patients with Progressive Disease or Intolerance after Covalent BTK Inhibitors (ASH 2023 Web Program)
A Phase Ia/Ib Study Exploring the Synthetic Lethality of the Orally Administered Novel BTK Inhibitor, Dtrmwxhs-12 (DTRM-12), in Combination with Everolimus and Pomalidomide in Patients with Relapsed/Refractory CLL, DLBCL or Other B-Cell Lymphomas
That gives a total of TEN BTKi drugs being used to treat CLL, either in trials or approved.
I couldn't find any information on the selectivity or resistance profile of DTRMWXHS-12 (DTRM-12), but the plots in your reference of how the blood serum concentration varied with different doses sure was interesting. At the 50mg dose, you don't maintain as high an extended blood serum level as you do at higher doses, despite the 50 to 100mg dose curves reaching the same peak - the 100mg provided a longer coverage time. I've noticed reports on half life variation with dose on other BTKi drugs and the take home message is that the half life may not be as good at lower doses.
Has anyone been on any of these drugs? I talked to one person who was on vecabrutinib (sns-062) at a 300mg dose. Curious to know if anyone has had personal experience. Seems like that drug provides some stable disease so far but not much else.
While most of our community members on BTK inhibitors are taking Ibrutinib, we have members who are collectively taking at least 3 of the other listed BTKi drugs.
Here's a recent summary, but there has been updated information provided at this month's ASH conference.
People might switch to an alternative due to either resistance developing or unacceptable side effects. I'm not sure of the split between resistance and side effect issues, but approximately 20% of those prescribed Ibrutinib discontinue taking it for either of those reasons.
No OS Benefit With Ibrutinib in Early-Stage, High-Risk CLL
— Study suggests "watch and wait" should remain standard of care
Patients with early-stage, high-risk chronic lymphocytic leukemia (CLL) failed to achieve an overall survival (OS) benefit when treated with ibrutinib (Imbruvica) compared with placebo, according to results from the randomized CLL12 trialopens in a new tab or window.
While event-free survival (EFS), progression-free survival (PFS), and time to next treatment (TTNT) were significantly longer for patients treated with ibrutinib compared with placebo, no significant difference was seen in median OS between the two groups at a median follow-up of 69.3 months (not reached in either arm, HR 0.791, 95% CI 0.358-1.748, P=0.562), reported Petra Langerbeins, MD, of the University of Cologne in Germany.
Moreover, there was no significant difference between the treatment the placebo groups and a third cohort of patients with low-risk CLL who were allocated to a "watch and wait" strategy, Langerbeins said during her presentation at the European Hematology Associationopens in a new tab or window annual congress in Frankfurt, Germany.
With a total respect for people’s privacy, and well wishes for their well being and long term health successes, if anyone would be willing to share, I would be very interested in hearing their experiences on these new BTKi drugs. Best to all.
I know this isn’t the sort of personal feedback you’re after but it may be helpful. It’s an update on the BTKi called Zanubrutinib that was just presented at ASH2019 by Dr Con Tam.
GS-4059 is in your list -- it has a name: tirabrutinib. Here's an ASH 2019 abstract reporting on it in combination with entospletinib and obinutuzumab for CLL:
Good info! Thank you! I’ve had a slight rash with 420 mg imbruvica and acid reflux issues. Also bleeding gums, nose, under the skin you name it! Dropped down to 280 mg. Much better but I had been wondering about that new drug you brought to my attention. I’m going to suggest it to my oncologist again as an alternative Incase I get the same issues back
In the paper All in the family: back-to-back kinase inhibitors for the treatment of chronic lymphocytic Leukemia, by Meghan C Thompson, Lindsey E Roeker and Anthony R Mato, haematologica.org/article/v... the authors argue that the growing range of BTK inhibitors are making it possible to switch BTKi drugs when intolerance is an issue, rather than the classic approach of switching to another drug class:- "...these studies challenge the traditional sequencing paradigm of switching drug classes in the setting of CLL therapy discontinuation for intolerance.
:
While venetoclax is an acceptable option in the setting of BTKi intolerance, CLL remains an incurable, chronic disease and there is a strong scientific rationale to maximize clinical benefit from each drug class prior to exposing patients to the selective pressures of another therapeutic class. In the case of the common problem of intolerance to ibrutinib it is best to keep the solution “all in the (BTKi) family.”
This paper gives a good explanation of how Ibrutinib and Venetoclax work differently and hence symbiotically to provide a high proportion of complete responses in time limited therapy. See the image at the end of this reply. Thanks gardening-girl .
This paper from April 29th 2021, summarises the current very promising situation with combination treatments:- Ibrutinib combinations in CLL therapy: scientific rationale and clinical resultshealthunlocked.com/cllsuppo...
'Outstanding' results from FD cohort in CAPTIVATE study of ibrutinib plus venetoclax in treatment-naive chronic lymphocytic leukemia
'... the efficacy seen with this regimen on this trial is phenomenal, with a 56% rate of complete response and 76% and 62% of patients achieving undetectable minimal residual disease (uMRD) in the blood and bone marrow, respectively, using a cutoff of 1 x 10−4 cells (see figure). At 24 months, 95% of patients remained alive and free of progression.'
Venetoclax plus Obinutuzmab approved in the UK for first treatment. (Likewise in Australia, but only when older chemo treatments won't work). For member experiences, see: healthunlocked.com/cllsuppo...
CLL: Do Anti CD20 Monoclonal Antibodies Add to Novel Agent Outcomes? by Dr Bruce Chesson (with thanks to EugeneL2 )
Conclusion: "With the increased associated cost, Novel Agent plus CD20, while approved, are not recommended outside of a clinical trial."
Anti-CD20 treatment for B-cell malignancies: current status and future directions:tandfonline.com/doi/full/10... for an overview of preclinical and clinical data, and how the pharmacodynamic properties of these newer CD20 MABs translate into clinical benefit for patients.
Obinutuzumab seems superior to rituximab for CLL treatment
"Acalabrutinib (Calquence), alone or in combination with obinutuzumab (Gazyva), demonstrated superior efficacy and an acceptable safety profile in patients with treatment-naïve chronic lymphocytic leukemia (CLL), according to long-term results from the pivotal, phase 3 ELEVATE-TN study (NCT02475681) that were presented during the 2021 Pan Pacific Lymphoma Conference".
"The use of acalabrutinib (Calquence) with obinutuzumab (Gazyva) prolonged progression-free survival (PFS) in patients with chronic lymphocytic leukemia (CLL) compared with other regimens such as ibrutinib (Imbruvica)/obinutuzumab and venetoclax (Venclexta)/obinutuzumab, according to the results of a meta-analysis published in Clinical Lymphoma, Myeloma, and Leukemia."
Phase 2 study of MRD driven time limited therapy with Zanubrutinib, Obintuzumab and Venetoclax (BOV) in untreated patients - incredible results achieved with very high rates of uMRD in this time limited treatment combination
The combination therapy of zanubrutinib (Brukinsa, BeiGene) and venetoclax was well-tolerated in treatment-naïve (TN) patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and the high-risk feature, deletion of chromosome 17p13.1 (del(17p)), according to the early results from arm D of the SEQUOIA trial presented at the 2021 American Society of Hematology Annual Meeting and Exposition. The investigators said that there were no new safety signals identified, and no reported instances of tumor lysis syndrome (TLS).
There's also an early report on the SEQUOIA an open-label, global, multicenter, phase 3 study.
Venetoclax Regimens for 'Fit' CLL Yield High Undetectable MRD Rates
— Combined with obinutuzumab, plus or minus ibrutinib, outperforms chemoimmunotherapy (from ASH2021)
Roughly nine of 10 so-called fit patients with chronic lymphocytic leukemia (CLL) achieved undetectable minimal residual disease (MRD) status after treatment with one of two venetoclax (Venclexta)-based regimens in the randomized GAIA/CLL13 trial.
In the phase III study of nearly 1,000 fit CLL patients, rates of undetectable MRD in peripheral blood were significantly improved at month 15 for those who received either venetoclax plus obinutuzumab (Gazyva) or venetoclax plus obinutuzumab and ibrutinib (Imbruvica) rather than standard chemoimmunotherapy.
The rate of CR with undetectable MRD at the start of cycle 16 was 38% (95% CI, 22-55), missing the primary end point of the study. But, notably, the CR rate increased from 14% at cycle 8% to 35% at cycle 16% and was still 38% by cycle 25. It was also notable, according to the study authors, that those who achieved a CR by cycle 8 all had IGHV-unmutated disease and 5 of them has a TP53 aberration.
- Ofatumumab/Arzerra
- Ublituximab/(TG-1101)
Primary analysis of fixed duration arm of CAPTIVATE trial of ibrutinib plus venetoclax for untreated CLL
"Fixed-duration combination treatment with ibrutinib plus venetoclax for 12 cycles provides clinically meaningful PFS and treatment-free remissions for patients with previously untreated CLL, including those with high-risk disease features; most patients remain progression-free 1 year after treatment."
CD20+CD3 Bispecific antibody Epcoritamab
These are a new experimental class of immunotherapy drugs which work by bringing your immune cells in close proximity to cancer cells. Antibodies are Y-shaped proteins. The bispecific antibody epcoritamab uses one arm of the Y to bind CD3, which is on the surface of T cells, and the other arm to bind CD20, which is on the surface of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) cells. This brings the T cell and CLL/SLL cells close together so that the T cells can better recognize and destroy the CLL/SLL cells. T cells are part of the “cellular” immune system that are modified with CAR-T therapy. The hope is that bispecific antibodies can more simply and more safely provide similar benefits to those seen with CAR-Ts.
Then we have the PI3K inhibitors, which haven't delivered on early promise and given "6 post-marketing randomized controlled trials have shown a potential detriment in overall survival (OS) and serious and potentially deadly adverse effects", future approvals for PI3K inhibitors should be approved based on randomized data instead of single-arm clinical trials: onclive.com/view/odac-unani...
PI3K inhibitors approved or in clinical trials for CLL/SLL are:-
- Idelalisib (approved for second line treatment, but from January 2022, no longer indicated for relapsed SLL cases).
- Duvelisib (also known as IPI-145)
Duvelisib May Improve Health-Related QoL in Relapsed or Refractory CLL and SLL compared with ofatumumab (Arzerra)
- Umbralisib, marketed as Ukoniq (U2 in trials, development codes RP5264 and TGR 1202) See: healthunlocked.com/cllsuppo...
- ACP-319 (also known as AMG-319)
- Zandelisib in phase 1 trials
Zandelisib/Zanubrutinib Combination in R/R CLL and B-Cell Malignancies Shows Clinical Benefit cancernetwork.com/view/zand...
Then after the success of the BCL-2 inhibitorvenetoclax/Venclexta, we have
- BeiGene's BGB-11417
- Bio-Path's BP1002
- Lupeng's LP-108
- Lisaftoclax's APG-2575
- Loxo Oncology's LOXO-338
Venetoclax is an extremely effective treatment, with clinical trial experience highlighting the risk of Tumour Lysis Syndrome (TLS) due to organs being overwhelmed by the massive die off of CLL cells. The trial was halted and restarted with a ramp up approach, with no reported TLS caused deaths since per: healthunlocked.com/cllsuppo...
Lisaftoclax (APG-2575), a novel BCL-2 inhibitor (BCL-2i), with an oral presentation of the first clinical trial being given at ASCO21. "...in a first-in-human phase 1 trial (NCT03537482).1
Twelve of 15 evaluable patients with relapsed/refractory CLL/SLL experienced a partial response (PR) to treatment with lisaftoclax, which translated to an objective response rate (ORR) of 80%. In this population, the median number of treatment cycles was 9 (range, 5-24) and the median time to response was 2 cycles (range, 2-8)."
Ianalumab (VAY736) is a human monoclonal antibody (mAb) that targets B-cell activating factor receptor BAFF-R+ B cells for elimination by antibody-dependent cell-mediated cytotoxicity (ADCC). VAY736 has anti-leukemia activity in preclinical CLL models that is superior to that of anti-CD20 mAbs
From a Phase Ib Study, "VAY736 + ibrutinib was well tolerated with an acceptable safety profile enabling dose expansion. Clinical activity was observed including multiple pts attaining uMRD status in blood and BM, allowing 6 to discontinue ibrutinib therapy for an extended period."
A First-in-Human Phase 1 Study of Oral LOXO-338, a Selective BCL2 Inhibitor, in Patients with Advanced Hematologic Malignancies (Trial in Progress)
LOXO-338 is a novel, orally bioavailable small molecule inhibitor of BCL2, designed to achieve selectivity over BCL-xL and thus avoid dose-limiting thrombocytopenia associated with BCL-xL inhibition.
Combination of ublituximab and UKONIQ® (umbralisib) referred to as U2
Update of 16th April 2022 from TG Therapeutics: "...recently updated overall survival data showed an increasing survival imbalance in favor of the control arm. Accordingly, we and our advisors determined that we should withdraw the BLA/sNDA for U2 in CLL. "
Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) with high-risk features benefited from the addition of the anti-CD20 monoclonal antibody ublituximab to ibrutinib, according to results of the phase-3 GENUINE study (ClinicalTrials.gov Identifier: NCT02301156), published in The Lancet.
The overall response rate in the intention-to-treat population of the study was significantly higher in patients treated with the combination compared with those receiving ibrutinib monotherapy (83% vs 65%; P =.020).
- Mosunetuzumab is a bispecific antibody that attaches both to the CD20 marker found on normal B cells and CLL cells and at the same time to CD3 that is found on T cells.
- When these two cells are pulled close together by mosunetuzumab, the T cells proliferate and start destroying the CD20+ cells, including the cancerous clonal cells.
Excitingly, we now have anti-ROR1 monoclonal antibody treatments on the way. With ROR1 over-expressed in CLL we may be able to eliminate our CLL tumour with less impact on our healthy B - lymophocytes and hence better maintain or even improve our adaptive immunity: pubmed.ncbi.nlm.nih.gov/222...
- Cirmtuzumab (UC-961) is the first and very promising anti-ROR1 humanised monoclonal antibody in early-stage clinical trials for various cancers including chronic lymphocytic leukemia.
Then there's CAP-100 an anti-CCR7 monoclonal antibody starting phase 2 and phase 1a clinical trials (clinicaltrials.gov #NCT04704323)
The chemokine receptor CCR7 is essential for migration of immune cells to lymphoid organs. This pivotal receptor is over-expressed in hematological malignancies with lymph node involvement, such as CLL. CAP-100 interrupts tumor cell migration to lymph nodes, strong cell killing (ADCC) and inhibition of survival of tumor cells in the lymph nodes.
For those with TP53 mutated or 17p del CLL, provided there is an intact non-benign mutant p53 protein. The APR-246 binds to the p53 protein and restores its function.
Eprenetapopt (APR-246) - a new small molecule to restore TP53 function
Then we have the exciting developments in CAR-T and CAR-NK, such as the single arm, open-label, multi-center, Phase 1 study to determine the safety and tolerability of an experimental therapy called NKX019 (allogenic CAR NK cells targeting CD19): clinicaltrials.gov/ct2/show...
Following the selection of a recommended Phase 2 dose, patients with r/r B-ALL, CLL, or other subtypes of NHL, including patients who did not achieve a durable response after treatment with a CD19 CAR T cell therapy, will be enrolled in the dose-expansion portion of the trial. pipelinereview.com/index.ph...
Two of the three CLL patients in the first CAR-T trial achieved 10 year remissions in early 2022.
These patients had exhausted all approved lines of therapy. Phase 1 trials of ibrutinib, the first BTK inhibitor had also recently commenced at the time.
Or MB-106, a CD20-targeted, autologous CAR T cell therapy, with Phase 1/2 data to be presented to the February 2022 Tandem Meetings I Transplantation & Cellular Therapy Meetings of the American Society of Transplantation and Cellular Therapy and Center for International Blood & Marrow Transplant Research. MB-106 is being developed in a collaboration between Mustang and Fred Hutchinson Cancer Research Center (“Fred Hutch”).
Bispecific T-Cell Engagers (BiTEs) in Phase 1/2 first-in-human study
Bi-specific antibodies have been described as an ‘off the shelf’ type of CAR-T treatment which has the potential to be more accessible to a wider group of CLL patients because more readily availability and cost.
NVG-111 is a humanised, tandem ROR1 and anti CD3 bispecific antibody previously shown to produce potent killing of tumour cells in both vitro and in vivo by engaging a membrane-proximal epitope in a domain of ROR1 and directing T cell activity via the CD3 to kill the CLL cells. NVG-111 has now progressed to a Phase 1/2 first-in-human study in patients with debulked, relapsed/refractory CLL (and mantle cell lymphoma) with the drug given as add-on to ≥2nd line therapy with a BTK inhibitor or venetoclax
Finally, Good news about targeted therapies and autoimmune cytopenias
'Ibrutinib, idelalisib and venetoclax have a beneficial impact on preexisting AICs associated with CLL and Treatment-emergent AICs are more frequent, though easily manageable, during treatment with venetoclax than with ibrutinib or idelalisib.'
Last updated on 8th April 2002 to add report on effectiveness of Tumour Lysis Syndrome (TLS) Prevention procedures with Venetoclax treatments - no deaths from TLS
Updated 4th June 2022, noting outstanding results from CAPTIVATE study of ibrutinib plus venetoclax in treatment-naive CLL
Updated 21st June 2022 to include reference to post on Durable Remissions in CLL With Fixed-Duration Triplet (Gazyva, Imbruvica, Venclexta) at 4 Years
Updated 24th June 2022 to reference post on high response rates achieved with repeated venetoclax treatment.
Updated 29th June to add anti-ROR-1 study results
1st July 2022 relapsed/refractory options
24th July 2022 added evidence that obinutuzumab seems superior to rituximab
Neil
Tumor cell dynamics under ibrutinib or venetoclax treatment.
Exportin-1 (XPO1) selinexor (Phase 1 trial in combination with ibrutinib for relaxed/refractory CLL - not yet recruiting)
Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells.
Bio-Path Holdings has completed the first dose cohort of the dose escalation portion of its Phase I clinical trial of BP1002 to treat refractory/relapsed lymphoma and chronic lymphocytic leukaemia (CLL).
In the ongoing Phase I trial, patients with r/r CLL who are unresponsive or relapsed following venetoclax-based frontline therapy will also be enrolled.
A liposomal Bcl-2 nanoparticle antisense therapy, BP1002 targets the Bcl-2 protein, a key player in cell survival in various cancer types.
Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of BTK with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies
ZE50-0134 is a highly effective BCL2 inhibitor with substantially less impact on the normal immune cells responsible for both anti-tumor and anti-infectious immunity. The pharmacology of this agent makes it an ideal therapeutic to optimize tumor BCL2 dependence and avoid untoward toxicity that occurs through continuous BCL2 targeting. This data supports the further clinical development of ZE50-0134 in both B cell malignancies and AML.
ZE50-0134 binds the P2 pocket of BCL2, thereby increasing selectivity toward BCL-2, ZE50-0134 showed a 4600-fold greater selectivity for BCL2 over BCL-xL compared to venetoclax with only an 84-fold greater selectivity.
Combination Treatment with Sonrotoclax, a 2nd-Gen BCL2i and Zanubrutinib, a BTKi, Well Tolerated and Achieves Deep Responses in Patients with TN-CLL/SLL: Data from an Ongoing Phase 1/2 Study
Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia
CLL patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib.
:
While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up.
A Phase 1b/2, Open-Label, Safety and Efficacy Study of Epcoritamab (GEN3013; DuoBody®-CD3 X CD20) in Relapsed/Refractory Chronic Lymphocytic Leukemia and
Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results
"At a median follow-up of 41 months, median PFS has not been reached in previously treated CLL patients on the BTK inhibitor acalabrutinib.
:
Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status)."
Sorry, we have a challenging enough time keeping up with new CLL drugs! Quite a few are used to also treat MCL, but dosage and treatment protocol may differ. Side effects would largely overlap however.
Richard R. Furman, MD, discusses the findings from the analysis and highlights the differences between first- and second-generation BTK inhibitors in CLL.
The second-generation BTK inhibitor acalabrutinib (Calquence) demonstrated favorable long-term tolerability in patients with B-cell malignancies, according to a pooled analysis spanning several hematologic malignancies, explained Richard R. Furman, MD, who underscored the importance of having a continuous, well-tolerated treatment.
:
Only 9% of patients discontinued acalabrutinib due to treatment-related adverse effects (AEs).
The most common AEs, which were headache (35%) and diarrhea (26%), were mostly grade 1/2 and occurred within the first 6 months of treatment. Secondary primary malignancies, atrial fibrillation, and hypertension were infrequent and of low grade.
:
Because of differences in specificity, you see fewer off-target effects with acalabrutinib and zanubrutinib than we do with ibrutinib. As such, we see different AE profiles. Also, because of the differences in how drugs are metabolized, we see differences in their interactions with other drugs.
“Although vecabrutinib continues to exhibit an excellent safety profile, there is insufficient evidence of activity in BTK-inhibitor resistant B-cell malignancies to advance the drug into the planned Phase 2 portion of the trial. One partial remission was observed after 11 treatment cycles in a CLL patient treated in Cohort 5 (300 mg BID) and a number of patients treated across the dose range explored (25 mg to 500 mg BID) saw stable disease; however, no other remissions have been observed,” said Dayton Misfeldt, Interim Chief Executive Officer of Sunesis. “We will complete the Phase 1b and evaluate the best path forward for vecabrutinib. We are grateful for the patients and their families who participated in this trial, as well as the investigators and research staff at our trial sites.”
ASH 2020 abstract for orelabrutinib, looks promising.
1320 Updated Results from the Phase II Study of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Cell Leukemia
"So, orelabrutinib showed a significant higher CR rate comparing to other BTK inhibitors at a similar treatment period and we anticipate a further increase of CR rate with longer duration of treatment."
Some possibly encouraging news for those intolerant of Ibrutinib or Acalabrutinib treatment and for those in the USA with this challenge, the possibility to join a clinical trial at one of 30 sites, to see if Zanubrutinib/Brukinsa resolves intolerance. Zanubrutinib appears to have a lower adverse effect profile than the approved BTKi drugs Acalabrutinib and Ibrutinib. The trial results will be eagerly awaited by those that do well on the former, but struggle with adverse effects.
At the 2020 ASCO Virtual Scientific Program, Flinn presented a poster showcasing the ongoing phase 2 BGB-3111-215 trial (NCT04116437) evaluating zanubrutinib in patients with previously treated B-cell malignancies intolerant to prior ibrutinib or acalabrutinib.
Investigators plan to enroll approximately 60 patients with CLL, small lymphocytic lymphoma, Waldenström macroglobulinemia, mantle cell lymphoma, or marginal zone lymphoma intolerant of prior BTK inhibition whose treatment-emergent adverse effects (TRAEs) resolve to grade 1 or lower prior to initiating treatment with zanubrutinib.
The primary end point of the study is the recurrence and change in severity of TRAEs with zanubrutinib compared with ibrutinib and/or acalabrutinib, according to Flinn.
Enrollment, which is currently underway, will span across 30 primary community medical centers from across the United States.
Dr Jeff Sharman's clinical thoughts on the use of non-covalent bonding BTK inhibitors to overcome resistance developing in patients treated with the covalent bonding inhibitors Acalabrutibib, Ibrutinib and Zanubrutinib.
This is potentially very good news. While it is rare for covalent BTKi resistance to occur, being able to switch to a non-covalent BTKi could enable patients doing well on this form of targeted therapy to remain on BTKi treatment for well over a decade before needing to switch to another targeted therapy, despite developing resistance!
"AstraZeneca’s Calquence (acalabrutinib), a next-generation selective Bruton’s tyrosine kinase (BTK) inhibitor, has been approved in the European Union (EU) for the treatment of adult patients with chronic lymphocytic leukaemia (CLL), the most common type of leukaemia in adults.
The approval by the European Commission was based on positive results from two Phase III clinical trials, ELEVATE-TN in patients with previously untreated CLL and ASCEND in patients with relapsed or refractory CLL.1,2 This follows a recommendation for approval by the Committee for Medicinal Products for Human Use of the European Medicines Agency in July 2020."
Clinical Care Options (CCO) has just uploaded an excellent webcast that was recorded pre ASH2020 and is titled: "Addressing the Medical Need in CLL: How BTK Inhibitors Are Improving Outcomes"
It is presented by three CLL specialists: Drs Ian W. Flinn, Susan M. O'Brien, and John Pagel.
It's a 2 hour webcast so not for the time poor but it's divided into sections for Treatment Naive and Relapsed/Refractory patients and is a really excellent discussion of the role BTK inhibitors currently play in the provision of CLL treatment.
When I started on Ibrutinib it was the new non chemo treatment. My doctor pointed to a lot of research happening with new treatments for CLL. Because patients live for a long time research on treatments are quite well funded. It is nice to see that many of the treatments developed also prove to be useful for other diseases.
A new interview in Targeted Oncology with Jennifer A. Woyach, MD, associate professor of hematology at The Ohio State University in Columbus, Ohio, ‘shares insights about the role of the first-generation agent ibrutinib and the BTK class more generally’.
‘BTK inhibitors have changed the treatment paradigm in CLL.’
‘ ... ibrutinib, and potentially this class of BTK inhibitors, can overcome the negative prognostic value of a TP53 abnormality—at least in the short to intermediate term.’
‘The biggest question right now is whether BTK inhibitors are best administered alone or in combination with other agents, such as venetoclax. There are studies that are designed to answer that question, but it’s going to take a long time to get those results because these drugs work so well. However, this is something that is going to be very important to tease out because it has many implications on toxicity—especially chronic toxicity—as well as financial implications since a combination comes with an upfront increase in cost; it may be more economical in the long-term if a long treatment-free interval can be experienced.’
Dear Neal, I missed this post the first go around. In view of the above, what should we think of a haematologist who says to a treatment naive, fit CLLer, unmutated, T-12, that if treatment becomes necessary, they will recommend ibrutinib? Aren't some of the second generation BTK inhibitors performing better than ibrutinib with better tolerability? Or is there still the idea to leave "room" to choose another BTK-I if one fails on ibrutinib?
We now have about 10 years of patient data for Ibrutinib. Acalabrutinib is, like Ibrutinib a covalently bonding drug, so resistance development is probably the same. Acalabrutinib's lower side effect profile is the main advantage over Ibrutinib. Ibrutinib has the advantages of being easier to reduce the dosage and being able to shift when in the day you take it (it is taken once per day vs twice per day), plus it doesn't have the requirement to go off PPI drugs used to control acid reflux/ gastroesophageal reflux disease (GERD).
So, given the above, it's arguably more about matching what would best suit the patient, given both appear to be equally effective against CLL. I would say that the main reason to question being prescribed Ibrutinib, is when you have high blood pressure and/or atrial fibrillation, or are considered at risk of developing these, or are concerned about Ibrutinib's higher side effect profile. That is after all, a significant reason for discontinuing Ibrutinib treatment. At least now we can switch to Acalabrutinib, Zanubritinib, etc.
Worth noting is that it includes information about a couple of non-covalent BTK inhibitors which have not progressed for use in CLL: Fenebrutinib (GDC-0853) and Vecabrutinib (SNS-062).
However, it does contain information about non-covalent BTK inhibitors in general and about Pirtobrutinib (LOXO-305) and MK-1026 (formerly ARQ-531) specifically.
Acalabrutinib/Obinutuzumab Prolongs PFS vs Ibrutinib and Venetoclax Combos in CLL, Meta-Analysis Sayscancernetwork.com/view/acal...
From this meta-analysis of the ELEVATE-TN, ILLUMINATE and CLL14 clinical trials, "In all instances the Relative Risk did not exceed the 1.0 value, translating to a lack of notable difference in PFS for ibrutinib/obinutuzumab, venetoclax/obinutuzumab, and acalabrutinib. However, the combination of acalabrutinib and obinutuzumab was found to improve PFS vs other regimens such as ibrutinib/obinutuzumab (RR, 0.43; 95% CI, 0.22-0.87) and venetoclax/obinutuzumab (RR, 0.29; 95% CI, 0.15-0.56)."
Much more in the brief article, including "Patients who had a TP53 mutation or 11q deletion did not have an improvement in PFS with after being treated with venetoclax/obinutuzumab or ibrutinib/obinutuzumab. However, it was found that those with unmutated IGHV had a better PFS with acalabrutinib/obinutuzumab than venetoclax/obinutuzumab (RR, 0.36; 95% CI, 0.15-0.90)."
October 2023 update: Matching-Adjusted Analysis Shows Acalabrutinib/Obinutuzumab Offers PFS Benefit Vs Zanubrutinib in CLL/SLL Without 17p Deletions
Post-matching, patients in ELEVATE-TN who received acalabrutinib plus obinutuzumab (effective sample size [ESS] = 124) achieved an investigator-assessed 36-month progression-free survival (PFS) rate of 95% (95% CI, 90%-97%) compared with 84% (95% CI, 79%-88%) among patients who received zanubrutinib in SEQUOIA (n = 241; HR, 0.41; 95% CI, 0.23-0.74). Notably, patients who were treated with acalabrutinib monotherapy (ESS = 105) did not achieve a significant difference in terms of investigator-assessed 36-month PFS rate compared with those who received zanubrutinib, at 86% (95% CI, 78%-91%) vs 84% (95% CI, 79%-88%), respectively (HR, 0.91; 95% CI, 0.53-1.56).
“Currently, we have 2 second-generation BTK inhibitors that are [FDA] approved for the treatment of CLL: acalabrutinib and zanubrutinib,” Adam S. Kittai, MD, assistant professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center–James in Columbus, said during the presentation. “There is no phase 3 clinical trial planned that will compare these 2 drugs. Ultimately, when you don't have a phase 3 clinical trial planned, it's difficult to know what drug to use, especially when these 2 drugs have such a similar mechanism of action. The point of this project was to do a comparison between these 2 drugs to help inform providers when the appropriate use of these drugs might be, how the toxicity differs between them, and whether efficacy differs between them.”
Thanks for all of the continuing work you do on this! One question I have is related to BTK drug resistance due to a PCLG2 mutation. It appears that latest generation BTK inhibitors are able to get around the BTK (C4819s) mutation but I can find little or nothing about their effectiveness against the PCLG2 mutations, which is what I developed after 6 years on Ibrutinib. Because of the PCLG2, I have switched to Venetoclax but am wondering if I might, if needed, be able to go back to a BTK drug if/when I eventually relapse from Venetoclax or even before? I have had CLL for 20 years and have eventually relapsed from every therapy so I am always looking ahead...
gardening-girl may be better able to answer your question. I hope that you can continue to stay ahead of your CLL, a task that has definitely become easier recently.
Katinlr, the short answer is that a BTK inhibitor will not be able to bypass your PCLG2 mutation.
Take a look at the figure I've given the link to below, and find the BTK and PCLG2 enzymes. They are linked in a pathway from the B cell receptor (BCR) to the expression of genes that contribute to the survival and proliferation of CLL cells. For whatever reason the BCR in CLL cells is constantly sending an "on signal" to the downstream LYN which passes the signal on to SYK which passes it to BTK which passes it to PCLG2, etc. BTK inhibitors like ibrutinib inactivate BTK such that it can't send the signal to PCLG2 which leads to inactivation of the whole pathway, which is good because the pathway is allowing the CLL cells to survive and proliferate.
The problem with your PCLG2 mutation is that it causes the PCLG2 enzyme to be active all of the time, regardless of whether is gets a signal from BTK. That means that inhibiting BTK with some new inhibitor would have no effect on your runaway PCLG2 mutant enzyme. It doesn't need BTK to be active so blocking BTK's activity will have no effect.
Please let me know if that makes any sense to you or if you have any other questions about it.
Thanks. That is a good explanation and diagram is very helpful. It doesn't appear then that there can be any BTK drug which will mitigate the PCLG2 mutation which is disappointing as my 6+ years on Ibrutinib were probably the best years I had on my 20 year CLL journey.
No Viability in Adding Chemotherapy to Novel Regimens in CLL
Adding bendamustine to venetoclax (Venclexta) plus rituximab (Rituxan), or Ven-BR, appeared to increase toxicity in patients with chronic lymphocytic leukemia (CLL) and did not show efficacy benefit when compared with venetoclax plus bendamustine and obinutuzumab (Gazyva), or Ven-BG, according to results from a phase 1b study published in Haematologica.
Over the past decade, survival outcomes for patients with CLL have greatly improved. This improvement is mainly due to the expansion of the treatment landscape to include agents that targeted the B-cell receptor signaling pathway as well as other pathways involved in CLL cell proliferation. BCL-2 inhibitors have also become standard treatment options for the patient population.
Stilgenbauer S, Morschhauser F, Wendtner CM, et al. Venetoclax plus bendamustine-rituximab or bendamustine-obinutuzumab in chronic lymphocytic leukemia: final results of a phase Ib study (GO28440). Haematologic. 2021;106(11): 2831-2844. doi: 10.3324/haematol.2020.261107
Sorry to hear your update and I've amended my entry accordingly. I hope venetoclax works well for you this time. Thanks for keeping a record of your treatment history in your profile, which should also be updated healthunlocked/profile/edit
The FDA has accepted for review a supplemental new drug application for zanubrutinib for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.
Under the Prescription Drug User Fee Act, the regulatory agency will decide on the application by October 22, 2022.
Meanwhile, zanubrutinib/Brukinsa can be prescribed off label, as it is FDA approved for Mantle Cell Lymphoma. The USA NCCN Guidelines also already recommend it for CLL late last year.
A report published this week in Haematologica 'characterizes pooled CV [cardiovascular] adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: NCT02029443, NCT02475681, NCT02970318 and NCT02337829).'
'Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL).'
In order to further explore cardiac and hypertension-related effects of acalabrutinib in patients with CLL, we conducted a retrospective pooled analysis of data from all clinical studies of acalabrutinib (from phase I to III) in CLL containing an acalabrutinib monotherapy arm and characterized CV adverse events (AE).
The report concludes that 'based on the results of this pooled analysis, the incidence of cardiac AE with acalabrutinib treatment is relatively low in patients with CLL. The results from our analysis also suggest an intriguing difference in atrial fibrillation and hypertension rates with acalabrutinib compared with ibrutinib. Our findings are supported by the recently reported results from the head-to-head ELEVATE-RR trial (ACE-CL-006; clinicaltrials gov. Identifier: NCT02477696), which demonstrated a statistically lower incidence of any-grade atrial fibrillation and hypertension with acalabrutinib versus ibrutinib in patients with previously treated CLL'.
Brown JR, Byrd JC, Ghia P, Sharman JP, Hillmen P, Stephens DM, Sun C, Jurczak W, Pagel JM, Ferrajoli A, Patel P, Tao L, Kuptsova-Clarkson N, Moslehi J, Furman RR. Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients. Haematologica 2021;107(6):1335-1346; doi.org/10.3324/haematol.20...
An excellent overview of the continuing improvements in BTK inhibitors for B cell malignancies, highlighting the promise of one of the newer, non-covalent bonding BTKi drugs, pirtobrutinib. The review details how acalabrutinib, zanubrutinib and now pirtobrutinib are improving discontinuation rates over ibrutinib, where nearly half of time, patients stopped taking ibrutinib because of adverse events, not because ibrutinib stopped working.
The potential of pirtobrutinib in multiple B-cell malignancies
Here, we review the pharmacologic rationale for pursuing non-covalent BTK inhibitors, the clinical need for such inhibitors, existing safety, and resistance mechanism data for pirtobrutinib, and the forthcoming clinical trials that seek to define the clinical utility of pirtobrutinib, which has the potential to fulfill multiple areas of unmet clinical need for patients with B-cell malignancies.
Jeffrey L. Jensen, Anthony R. Mato, Camila Pena, Lindsey E. Roeker, Catherine C. Coombs
Covalent BTK inhibitors are commonly discontinued in real-world practice because of toxicities and disease progression. In a series of 616 CLL patients treated with ibrutinib, 41% of patients had discontinued ibrutinib within a median follow-up time of 17 months. Among those discontinuations, nearly half were secondary to adverse events including atrial fibrillation, infectious complications, and cytopenias. Disease progression accounted for approximately 20% of discontinuations and RT accounted for approximately 5% of discontinuations.
wow that is alt of reading. I didn't read the whole thing because im falling asleep 😄. But will come back to this very interesting post. Thankyou to all.
An early access copy of a report published in ejHaem on 23 Jan 2023 confirms what we've already learned about the cardiovascular risk of ibrutinib. Written by Anthony Mato et al, it "adds to existing literature by simultaneously investigating the correlation between pre-existing CV risk factors and the relative cardiotoxicity of ibrutinib vs other therapies in CLL/small lymphocytic lymphoma (SLL).
Note that one of the limitations of this study is that "while other BTK inhibitors were available for treatment at the time of writing, there were not enough patients treated with them in this dataset to conduct the same analysis, so only ibrutinib was investigated in this study. In the future, it will be useful to conduct similar studies of CV toxicity with other BTK inhibitors."
Nevertheless, the results of this study suggest that "clinical caution should be taken when selecting ibrutinib for patients with CLL/SLL, especially in those with high baseline CV risk."
"Using a real-world database, the risk of subsequent CVAEs (any CVAE, atrial fibrillation [AF], or hypertension) were compared among patients who received 1L ibrutinib monotherapy or another type of non-ibrutinib therapy, grouped as intensive (IT) or non-intensive therapy (NIT).
Each patient's baseline CV risk was estimated using the Framingham risk score. Inverse probability treatment weighting was incorporated into a logistic regression model to reduce baseline imbalance.
Results showed ibrutinib was significantly associated with higher risk of CVAEs regardless of baseline CV risk.
Compared with IT, odds ratios of any CVAE, hypertension, or AF were 2.61, 3.66, and 3.02, respectively vs 1.88, 2.13, and 2.46, respectively, with NIT.
Sensitivity analyses confirmed the findings were robust."
Here's YABTKi to add the the growing list of BTK inhibitors:
TL-895 is being studied in patients with CLL(NCT02825836) and, for the first time for a BTK inhibitor, in a clinical trial for myelofibrosis (MF).
"TL-895 is a highly potent, selective, orally available, covalent inhibitor of Bruton tyrosine kinase (BTK) and bone marrow tyrosine kinase X-linked (BMX), under development for treatment of myelofibrosis and chronic lymphocytic leukemia."
Three poster presentations and three publications about TL-895, across both CLL and MF, were released at the recent EHA conference including:
Abstract #P1006 "Characterization of TL-895: A Novel Bruton Tyrosine Kinase Inhibitor (BTKI) in Clinical Development for Chronic Lymphocytic Leukemia (CLL) and Myelofibrosis (MF)"
"TL-895, a highly selective, novel BTKi demonstrated potent inhibition of cell activation, proinflammatory signaling,migration and cytokine production in lymphoid and myeloid cells. In pts with CLL and MF, the 150mg BID dose achieved complete and sustained BTK occupancy throughout the dosing interval, despite faster BTK resynthesis in myeloid cells. TL-895 holds therapeutic promise by modulating key signaling nodes of cell activation, reducing stromal support, and downregulating proinflammatory cytokines in pts with CLL and MF."
Abstract #PB2205"A Mechanistic Absorption and Pharmacokinetic model of covalent BTK inhibitor TL-895: Influence of Food and Acid Reducing Agents"
"Physiological factors underlying higher exposure of TL-895 with fed administration were inferred from a MA-PBPK model. Simulations revealed dose linear increases in exposure with fed administration were aided by higher intestinal bile salt concentrations under fed conditions. Absorption was precipitation-limited under fasted conditions.Model parameters indicated that lower TL-895 exposure when given with omeprazole in a fed state involves longer stomach transit time and decreased intestinal bile salt secretion. Staggered famotidine administration with food did not decrease TL-895 exposure and provides an alternative to proton pump inhibitors in patients that require an ARA."
Abstract PB2200 "Food and Acid Reducing Agent Effects on Pharmacokinetics (PK) and Pharmacodynamics (PD) of the Covalent Bruton Tyrosine Kinase Inhibitor (BTKI) TL-895 in Healthy Subjects"
"TL-895 had appropriate PK for a covalent BTKI, with a short t, long PD effect, and dose-proportional PK. Food increased AUC* and decreased PK variability, regardless of meal type, TL-895 is given with food. At 300 mg TL-895,BTK occupancy was similar in fed vs fasted states, with saturable maximum BTK occupancy only incrementally higher than 150 mg. Staggered H2 antagonist dosing at 150 mg TL-895 did not affect TL-895 PK. Omeprazole(PPI) administration with 150 mg TL-895 decreased exposure enough to delay and decrease maximum BTK occupancy, and to decrease the duration of target coverage TEGT"
A multi-site comparison using an unanchored matching-adjusted indirect comparison (MAIC) was performed on R/R (Relapsed/Refractory) CLL/SLL patients for two of the BTKi contenders from China - zanubrutinib and orelabrutinib. The abstract from this paper Indirect comparisons of efficacy of zanubrutinib versus orelabrutinib in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma or relapsed or refractory mantle cell lymphomapubmed.ncbi.nlm.nih.gov/374... notes:-
In R/R CLL/SLL patients, after matching, IRC-assessed ORR (Overall Rate of Response) was comparable (86.6% vs. 92.5%; risk difference, -5.9% [95% CI: -15.8%-3.8%]); IRC-assessed PFS (Progression Free Survival) was similar with a favorable trend in zanubrutinib over orelabrutinib (HR, 0.74 [95% CI: 0.37-1.47]) and the 18-month PFS rate was numerically higher in zanubrutinib (82.9% vs. 78.7%).
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MAIC result showed zanubrutinib demonstrated favorable PFS over orelabrutinib for R/R CLL/SLL patients.
The third generation of BTKi, which noncovalently or reversibly inhibits BTK, has shown promising results in early phase trials and are being evaluated in the phase 3 setting. These drugs could be an effective treatment option in patients with either resistance and intolerance to cBTKi. The most recent development in therapeutic agents targeting BTK is the development of BTK degraders. By removing BTK, as opposed to inhibiting it, these drugs could remain efficacious irrespective of BTK resistance mutations, however clinical data are limited at this time. This review summarizes the evolution and ongoing development of newer BTKi and BTK degraders in the management of CLL, with a focus of future directions in this field, including how emerging clinical data could inform therapeutic sequencing in CLL management.
I've listed whether the BTKi drugs bond covalently or non-covalently in the parent post. The currently approved BTKi treatments for CLL, acalabrutinib, ibrutinib and zanubrutinib all bond covalently. Pirtobrutinib, the non-covalent BTKi closest to FDA approval for CLL, can be prescribed off label in the USA, because it was approved for Mantle Cell Lymphoma in January 2023
U.S. FDA Approves Jaypirca™ (pirtobrutinib), the First and Only Non-Covalent (Reversible) BTK Inhibitor, for Adult Patients with Relapsed or Refractory Mantle Cell Lymphoma After at Least Two Lines of Systemic Therapy, Including a BTK Inhibitor (January 27, 2023)
Pirtobrutinib (Jaypirca), as well as other noncovalent BTK inhibitors in development, may play a role in earlier treatment settings for patients with mantle cell lymphoma (MCL) and/or chronic lymphocytic leukemia (CLL), although further research is needed to confirm the efficacy of this agent in the frontline setting or after progression on a prior covalent BTK inhibitor, according to Prioty Islam, MD, MSc.
On January 27, 2023, the FDA approved pirtobrutinib for adult patients with relapsed/refractory MCL who have received at least 2 prior lines of systemic therapy...
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In an interview with OncLive®, Islam discussed findings from the BRUIN trial, highlighted the potential benefits of using noncovalent BTK inhibitors instead of or before covalent BTK inhibitors in patients with MCL or CLL, and previewed ongoing clinical trials investigating this class of agents in earlier treatment lines in these populations.
Islam is an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.
With the number of new drug and clinical trial developments, I keep hitting the 7,000 character limit in my replies to this post. Hence I've begun this reply which I'll maintain specifically about BTKi degraders. My co-admin CLLerinOz , has provided an excellent summary of the current situation (February 2024) with respect to the use of BTK degrader treatments for CLL in this reply; healthunlocked.com/cllsuppo...
Covalent BTK Inhibitors: Which One is Best, and When Can I Switch?
- Many patients want to know which covalent BTK inhibitor is the best treatment for CLL. Unfortunately, not even experts can answer this question.
“There is no data available, which would say that one of the three covalent BTK inhibitors is the best,” said Jennifer Woyach, MD, a hematologist-oncologist at Ohio State University Comprehensive Cancer Center (OSUCCC) in Columbus, Ohio.
- What Did the Comparison Trials Show?
- When Can I Switch Between Them?
“If you take one of them until your CLL is resistant, the others aren't really going to work,” Dr. Rogers said.
If you want to switch from one covalent BTK inhibitor to another because of intolerable side effects, however, that is safe, Dr. Rogers added. “For anyone doing great on [ibrutinib] with no side effects, I've recommended against switching just because you risk the minor side effects of the other drug[s],” she said. However, if a patient is not tolerating one covalent BTK inhibitor, switching to another “works very well,” she said.
One exception to this rule of thumb: If a patient experienced particularly worrisome symptoms, such as atrial fibrillation, while taking a covalent BTK inhibitor, Dr. Rogers said she would try to avoid a different covalent BTK inhibitor to reduce the chances of the symptoms recurring.
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New drug: MS-553 inhibitor for CLL/SLL who develop resistance to BTK inhibitors
