This video is intended for Medical Professionals, using Med-Speak at a rapid pace, so I have pasted the transcript below.
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Nicole Lamanna, MD: With the advent of the BTK [Bruton tyrosine kinase] inhibitors and the fact that we’ve had many individuals on ibrutinib and now even acalabrutinib for many years, there’s no doubt that we’re starting to see some patients who develop resistant mutations to the covalent BTK inhibitors. This is not so common. There have been a lot of real-world data that suggest that the majority of discontinuations, usually about 40%, may be due to toxicity and not necessarily progressive disease. We have identified resistant mutations that occur. Usually, we’ll see them somewhere between 3 to 5 years on therapy with a BTK inhibitor. They’re not so common. The development is anywhere from approximately 3% to 8%. Again, when they occur, you’ll sometimes notice that somebody’s lymph nodes might start to grow again, or maybe they’re just starting to have an elevation of their white blood cell count.
You can send off peripheral blood testing to look for the most common mutation, a C481S mutation. There’s also a PLC-gamma mutation. There are some patients for whom you cannot identify either of these. Some people have both of these. That doesn’t mean they’re not progressing, but certainly the most common mutation to identify is a C481S mutation. There are some patients for whom you might identify this early. The questions that usually come up is what’s the next step? Can you transition them to an alternative agent? Actually, some patients may have a white count that is rising but do not experience cytopenia or bulky lymphadenopathy and are asymptomatic. I could argue that you could maintain some of those individuals on their current therapy until you need to change them. This is because some of them can stay on therapy for quite some time despite their white count starting to rise, or you see a return of their disease. There are other individuals who have high-risk features in which I will advocate for a change in therapy sooner rather than later. Certainly, given the data that we have, naturally one would consider going to a BCL2 inhibitor such as venetoclax.
With the covalent BTK inhibitors, there are resistant mutations that can develop, and thankfully, there are other drugs in evaluation that can overcome the C481S mutation. These are the noncovalent BTK inhibitors. The furthest along in development and updated at a recent ASH [American Society of Hematology] meeting, was LOXO-305, or pirtobrutinib. Then, more immature data were done with MK-1026, or nemtabrutinib; now it has a name. That formerly was the ArQule drug, which also is a little more immature in data but is showing some efficacy as well. Certainly, we have some options of switching patients who develop these resistant mutations either to venetoclax, which is FDA approved, or I should say a venetoclax-based combination with a monoclonal antibody. Or, these noncovalent BTK inhibitors, particularly pirtobrutinib, will likely get FDA approved as well in the future. That will be an important consideration for a patient who develops a resistant mutation.
This transcript has been edited for clarity.
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Len
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lankisterguy
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Great summary, Len. Unhappily I learned at my last quarterly trial visit that I am progressing after 5 years on acalabrutinib. Great run for me, just not the best. I will have another CT in June. Was told there are “many great options” ahead, although only venetoclax was mentioned, which of course we are all aware of. Just wonder what else they consider “good options”. I would love to think I could get in another trial somewhere with one of the combos, a noncovalent BTK, or the new “degrader” class. Wouldnt even mind a “first in human” trial. Some folks on acala are adding veneto. As far as I know, they are not progressed on acala, hoping to ride the combo to a deep remission and stop treatment. I still don’t fully understand why my progressing on acala prevents adding something to it, letting it continue to do what it can, while hitting the resurgent resistant cells with the added drug. Anyway, interesting journey ahead. Lamanna does a nice summary of the landscape.Bud
I'm like you, only I appear to be progressing after 5.5 years on Venetoclax, so 4 weeks ago Dr. Furman added Acalabrutinib. That combination is not formally approved by FDA, so technically it is "Off Label" so many doctors and many insurance companies will back away from trying it. -
It certainly doesn’t help you to realize that a possible resistance is developing, I bet it is very stressful. But to me, getting close to starting therapy, it is very encouraging to think I might get 5.5 years! Thanks for sharing your journey, as I never get tired of repeating - the willingness of you and the other veterans to share keeps folks like me going!
Len - I am relapsing after 5 1/2 years on Ibrutinib and have started on Venetoclax, and Rituximab will be added. I am interested in pirtobrutinib for the future but my oncologist seemed to say, or I seemed to hear, that you needed to have a particular mutation for it to work. I certainly will try to clarify at my next visit, but does it sound familiar to you?
That is one of those choices that doesn’t seem to have a right or wrong answer. Add V to I while I is still working or continue on I until I fails and then go to V or better yet detour to P before V. I’m curious, what your doctors have said about your choice? CajunJeff for example decided to add V while A (in his case) was still working. Have your doctors indicated when they may have enough data to be able to determine the best choice? It seems there are plenty of doctors who recommend the drugs consecutively and others that recommend the combinations. It’s a bit puzzling. What made you stay on I alone?
Thanks Jeff very helpful. You’ve got the good 11Q marker and I’ve got the not so good Trisomy 12 marker. We both are unmutated and did well on BR frontline. I’m coming up on 3-years since starting BR. Keeping my fingers crossed.
Interesting comments on Covid in that post. I’ve had four shots and had my antibodies checked - via the Leukemia and Lymphoma project - yesterday. It will be interesting to see what comes back.
Dr. Lamanna mentioned it in the text above: You can send off peripheral blood testing to look for the most common mutation, a C481S mutation. There’s also a PLC-gamma mutation. There are some patients for whom you cannot identify either of these. Some people have both of these. That doesn’t mean they’re not progressing, but certainly the most common mutation to identify is a C481S mutation. -
I'm not certain if the trials have identified if there is yet another unknown mutation that Pirtobrutinib is not effective for. The trials are still in very early phases but I did find one comment that would negate your doctor's comment about restricting it to a specific mutation, in this:
Hi Len, This onclive series has been very enlightening. Thank you for posting.
You mentioned the complexity of your cell profile. I just saw your very nicely updated (thank you!)
description on your personal page. But WOW!
So glad you are on top of this with your knowledge and providers. I plan to redo my profile to see if it can benefit other patients when they review the page.
Questions:
May I know what the basic labs are drawn for your routine visits (FLOW & FISH basic?) and how often do you get BM and MR Lymph surveillance.
Any other labs on your BM like NGS and ctDNA from the Liquid blood Biopsy department?
Do you have your BM done in IR under light anesthesia? I requested this after reading in this forum and it was scripted for me in IR ; no pain, no anxiety.
Thank you for your frequent postings in this forum. Personally, it has given me the strength to be a very active participant in my own CLL journey. The providers resistance has been to not write for the aggressive surveillance needed to closely monitor the multiple factors in my treatment. My insurance will cover my testing. Can’t help thinking age bias and patriarchy are surfacing as I blow out more candles (76).
The most recent phrase was “rest assured - if you need a combination of drugs something will be out there to treat you” - this was after a recent 2 month drug holiday from Ibrutinib 70 mg/day.
I was not *resting assured*. I need metrics to sleep well.
A basic FLOW test is not run, but they do a MRD test ( essentially a modified FLOW test) every quarter. FISH test has only been done when I am about to start a new CLL treatment. Below is a screen shot of the tests run Jan 6 and Jan 27 - and they show what usually is done every 3 months. The Hematopathology is the MRD test. I also have frequent HHV6 tests because of a refractory infection that varies over a wild range. The screen shot also shows 2 rounds of urine tests, that is not normally done, but I was dealing with a possible infection.
Not sure but I believe that FCR is only approved for untreated CLL. I doubt you'd find a Dr to endorse it for third line over alternatives suitable for different modes of treatment failure. Having said that I seem to recall a study investigating a role for chemo immunotherapy as second line, but sorry unable to provide a link.
Thank you , I’ve never been treated. That said I’m just wondering why not do the FCR first and if you ever need to be treated again go for the BTK. I understand why people don’t want chemo and I don’t either. But if I’m understanding things correctly about the oral treatments. Please correct me if I’m wrong. The BTK works an average 5-10 years then when that stops The put you on Venetoclax that works for a while , not sure how long.
I’ve been all pumped up over the BTK as my specialist told me that if you ever need treatment it a pill and 95% effective knocking the cancer out of you longer then FCR , I’m not sure if that’s still the case. Am I misunderstanding the BTK vs FCR regarding what’s better ?
Several of the videos and papers from December ASH 2021, show that Ibrutinib gives better & longer results to the vast majority of patients. -
And among the younger (under 60 year old) del 13q Mutated, some can get a very long PFS (Progression Free Survival) from FCR, but they can also have marrow damage that results in MDS, MM or AML, and those can be much more dangerous than CLL.
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So the consensus of the CLL expert doctors seems to have now changed, that they would only consider FCR in extremely rare cases with unusual circumstances. The gold standard seems to have shifted Dec 2021. FCR is off the table.
Dana-Faber and a few other USA cancer centers reported on a combined ibrutinib FCR trial back in early 2020.
Ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) as initial therapy for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial
Fludarabine, cyclophosphamide, rituximab (FCR) can provide prolonged disease-free survival for younger, fit patients with chronic lymphocytic leukaemia (CLL) with mutated IGHV; however, patients with unmutated IGHV rarely have durable responses. Ibrutinib is highly effective for patients irrespective of IGHV mutation status but requires continuous therapy. We hypothesised that time-limited ibrutinib plus FCR (iFCR) would induce deep, durable responses in younger, fit patients with CLL.
There's a dwindling number of US CLL specialists who still consider FCR a good choice for first line IGHV mutated CLL treatment for patients under 65. That's because there's around a 55% chance of remissions lasting 20+ years. (About 45% of mutated IGHV folk see their remission last less than 7 years, but if you make it past 7 years, remissions seem to last indefinitely.)
The downside of FCR treatment is that there's around a 10% risk long term, of developing a secondary blood cancer, namely AML or MDS. CLL specialists consider that long term remissions will probably be possible for IGHV mutated folk treated with a fixed term combination targeted therapy treatment using venetoclax in combination with a BTK inhibitor and or an anti-CD20 monoclonal antibody treatment. Given clinical trials testing this only commenced around 2018, we are still waiting to see if this is true.
There's no reason FCR can't be given after relapsing from a targeted therapy. However because it's possible to switch from a covalent to non-covalent BTK inhibitor or to a BCL2 inhibitor (venetoclax, etc) along with other clinical trial options, plus by the time relapse occurs, patients are generally older than 65, the recommended cut off age for FCR, it's rare the occasion occurs.
The last part of your reply says ( There’s no reason FCR can’t be given after relapsing from a targeted therapy) so I’m clear you can take a BTK then FCR if needed ? I’m sorry I have a difficult time understanding this information.
Yes you could be treated with FCR (or BR if you are over 65) if you ran out of targeted therapy options. Only provisos are that you are not 17p del and have unmutated TP53. That's much less likely to develop in sub-clones if you aren't treated with chemo.You'd typically achieve a longer remission if you were IGHV mutated.
It's more likely you'd use a 'chemo' combination to prepare for a bone marrow transplant if CAR-T or CAR-NK wasn't available.
Just to add that some CLL specialists favour successive monotherapies, e.g. Ibrutinib followed by Venetoclax, others favour combination therapies, e.g. I + V. Each strategy has pros and cons I guess. Key clinical trials ongoing should help resolve the debate in a general sense, though there will always be exceptions for the individual patient, and perhaps the future is more personalized treatment directed by more sophisticated genetic and epigenetic analysis.
The argument that a combo for first-line would risk using up all the available treatment options faster may be weakening with the advent of more drugs in different classes, e.g. reversible BTK inhibitors to overcome a relatively common C481S resistance to Ibrutinib.
I believe most USA CLL expert doctors would try the Pi3K class (Idelalisib/Zydelig, Umbralisib, etc.) next. And hopefully the non covalently bonding BTKs (Loxo 305 / Pirtobrutinib or several similar drugs in studies) will be approved or can be accessed in a clinical trial.
I was in a zoom meeting yesterday and asked since CLL is a malignancy of memory B cells and antibody production if during Btk intake there is an improvement in quality of B cells or antibodies I don t think they consider this aspect
I don't recall any study results indicating an improvement in the quality of new non-CLL B cells, But there is data showing that Ibrutinib (and hopefully all the other BTKs) will improve the quality of your "exhausted" T cells.
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I say "other BTKs" since I recently started Acalabrutinib along side the Venetoclax I have been taking for 5.5 years, in hopes that improving my T cells will aid in reversing the trend of increasing MRD levels over 1%.
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This improvement is also being tested in clinical trials for CAR-T to see if Ibrutinib can improve the results in CLL patients, who often see inferior response to CAR-T vs. other NHLs.
Ibrutinib can enhace T cell function Acalabrutinib less and the new Btks I Don t know but improving BCell function is essential for our immunesystem otherwise we will remains vulnerable to infections and reinfections f e with EBV VZV and Cytomegalovirus
In several discussions with Dr. Furman on the subject of improving my immune system ( I have a refractory HHV6a infection, a close cousin to EBV, CMV etc.). He readily admits that the research doctors don't understand many of the aspects of our very complex immune system.
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I think his words were something like: Whenever they think they understand one aspect of the immune system they also uncover several other new curiosities they don't understand yet.
I have EBV and VZV and a mutation in the OAS3 gene which makes me vulnerable to CLL my only chance is improving my immunesystem otherwise I will relapse despite good treatment options
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BTK inhibitors for the treatment of CLL - the current state of play of 'brutinibs'
EHA 2022: Outcomes Following Treatment With a Covalent BTK and BCL2 Inhibitor
