Still strange that it is thought differently worldwide.
s the combination of chemo- and immune therapy outdated?
'In my eyes, and now also that of the directive committee, certainly not! Targeted drugs, the 'new' drugs, are ingenious and good. But the question was, are they better than the 'old' medicines? To answer that question, you need to look at studies that compare chemo-immune therapy with targeted agents. Those studies were designed with the expectation that chemo-immune therapy would cause more side effects and that the duration of response would be longer with these new, targeted drugs. When the research results were well studied, there was no, to almost no, difference in noticeable serious side effects.'
'What the final life expectancy will be when chemo-immune therapy is skipped in the first line, we don't know. After all, we know little to nothing about the effectiveness of the treatments now available after a first-line treatment with a targeted remedy. While we do have long-term experience when chemo- immune therapy is started and only then the targeted resources are used.'
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this is the whole article from the Dutch magazine.
I,am almost ready with my FCR, still one to go.
I’am unmutated, 11 atm del. Had no other option to go for.
The choice of treatment order for someone with CLL varies by patient. What does this mean for people who hear they have CLL? We asked Michel van Gelder, a hematologist at Maastricht UMC.
CLL is a disease that requires repeated treatment. Over the past year, a substantive discussion has been held among hematologists about the treatment order at CLL, to which Hematon advocates have also made an important contribution. An article about this was published in the Dutch Journal of Hematology that is called the 'ice shot approach' by doctors. We ask 5 questions about this treatment to hematologist Michel van Gelder.
Why did a discussion arose about the treatment order of drugs?
'The discussion arose because new drugs have come; the targeted drugs. These are, for example, ibrutinib or venetoclax with obinutuzumab. Because of those new drugs against CLL, we received a discussion within the CLL guideline committee about the pros and cons of a first treatment option with targeted drugs compared to the 'old' chemo- and immunotherapy. 'New' sounds almost the same as 'better'.'
Is the combination of chemo- and immune therapy outdated?
'In my eyes, and now also that of the directive committee, certainly not! Targeted drugs, the 'new' drugs, are ingenious and good. But the question was, are they better than the 'old' medicines? To answer that question, you need to look at studies that compare chemo-immune therapy with targeted agents. Those studies were designed with the expectation that chemo-immune therapy would cause more side effects and that the duration of response would be longer with these new, targeted drugs. When the research results were well studied, there was no, to almost no, difference in noticeable serious side effects.'
'What the final life expectancy will be when chemo-immune therapy is skipped in the first line, we don't know. After all, we know little to nothing about the effectiveness of the treatments now available after a first-line treatment with a targeted remedy. While we do have long-term experience when chemo- immune therapy is started and only then the targeted resources are used.'
Where did that name ice shot approach come from?
'Due to the discussions within the CLL directive committee, Eddy Out (formerly a representative at Hematon) presented the image of the ice floes. This image is based on the idea that CLL's main treatment goal is not only to respond well to the first treatment, but also to which treatments are then possible if the disease starts to play up again.'
'He said he saw his further life journey with CLL as if he wanted to do everything not to drown in the ocean, having always had solid ground under his feet as a healthy person. He hoped that there would be enough large ice floes on which he could walk through life for as long as possible. Each ice floe symbolizes the time you get when undergoing treatment.'
So, does chemo-immune therapy remain an option?
'Yes. We have a lot of knowledge and experience about the expected life time when a patient starts chemo-immunotherapy. That lifetime is a lot and long. We don't know about the new targeted resources yet. Simply because these resources were only recently developed. From that limited experience, we also don't know what works next from those other resources. And that question is crucial for many people with CLL.'
Effectiveness is important, but so is order?
'This ice cream model clearly showed us what can be important for many patients, namely the question with which treatment order they have the most certainty to live as long as possible with comparable quality of life. So it is not only important which first treatment is the longest effective, but especially which treatment order gives the most certainty to be able to live as long as possible. In other words: after each ice floe, are there enough other ice floes that you can jump on?'
This is something we have been grappling with here in Aotearoa NZ. Within our CLL Advocacy group there are those who still see chemo to have a place as a first line treatment in those with ‘good’ markers. At the moment we have no choice as no other treatment is funded as first line. I have been advocating long and hard to try to get at least ibrutinib and venetoclax funded so that we can have some choice. I thought that chemo wasn’t advisable for those over 65 but a retired haematologist who is a part of our group says she wouldn’t hestitate to use it in an older person who is otherwise fit and well. Her reasoning is pretty much along the same lines as those propounded in the above article.
I note from your earlier post healthunlocked.com/cllsuppo... that you responded well to your first few FCR cycles, but they later deferred the rituximab, due to you developing neutropenia (which, for the record, is not unusual on any CLL treatment). You must be relieved that you are nearly finished treatment. FCR does have the advantage over the new combination targeted therapy treatments that treatment is over in just under 6 months, rather than a year.
With respect to the article (and thanks for sharing the full, translated version), it's not unusual to see FCR defended, as it has been the gold standard for a decade or more. Unfortunately, as you would know from reading posts to this community, where targeted therapies have been approved, the use of FCR has only been recommended as a treatment for possible consideration only for those with mutated IGHV.
The article is correct in that you have one, additional "ice floe" on your treatment path than if you had started on a targeted therapy treatment, but with unmutated IGHV and 11 del, atm del, this "ice floe" is likely to only give you a small step along your treatment path. You've have age on your side for this first "ice floe", but what will be your next "ice floe", when you will hopefully be older than 65?
That's true too, Neil, and it's the way it goes. but that's why I also want to keep you informed. I also have more confidence in the new method, but I just don't have a choice. to be continued. Rene
I read every piece of research I could before I started treatment early this year (O&V). At one stage, prior to getting approval to this treatment, it looked like FCR might be my only choice. I am age 69. Everything I read pointed to FCR being less effective at an older age plus the chances of Richter's transformation or transformation to AML were too high for my comfort - 10-15 to percent in some studies. One study strongly recommended against FCR from age 70, preferring BR if new treatments were not available. Even FCR light was not much better.
I just don't understand that there are worldwide studies/trials with the associated outcomes, but that there are different treatment guidelines. JUST A FINANCIAL ISSUE.
"For patients who have del(17p) or mutated TP53, first-line therapy is with a Bruton tyrosine kinase (BTK) inhibitor; CIT is contraindicated for these patients."
"Patients who are older than 65 years and those with comorbidities do not tolerate the most effective chemotherapy regimen,"
"Long-term follow-up data from MD Anderson, the German CLL study group, and an Italian multi-institutional analysis showed that treatment with FCR among patients who are young and fit and who have mutated IGHV leads to a PFS exceeding 10 years in approximately 55%. This group of patients might be considered cured. Therefore, I recommend first-line FCR for patients who are fit, have no comorbidities, do not have del(17p) or mutated TP53, and have a mutated IGHV gene."
Mutated IgHV + TP53 wildtype and under 65 is a very small number of patients presenting for first treatment. About 30% are mutated IgHV + TP53 wildtype. Median age is about 65, so it's down to 15%. Only 55% achieve a long remission, so that's just 8% that are considered "cured". But they can't tell who will be in that 8%. Nearly 20% have cytopenia that may preclude some 2nd line treatments.
Then it has other ways to kill you, 8% "cured" is now 5%. Kill or cure? Chemo is derived from mustard gas.
32% of those treated with FCR develop other malignancies.
"A risk-benefit assessment is warranted when counseling patients, balancing potential functional cure with the risk of late relapses and serious secondary malignancies."
Got CLL? You have already been dealt a bad hand and chances of getting lucky are slim, think I'd dodge that.
Pretty tough view for the many of us in countries that have to do FCR first. Just adding that I just had a great weekend, enjoying the CLL break that FCR has given me. This post was like a punch to the gut, reading it on the train home. It is important to remember that many of us don’t have the choice of what treatments we get first line, particularly if young (relatively) and mutated (marginally mutated in my case). If I had a choice I would have picked a newer treatment, but I didn’t.
I know that in the CLL8 study almost half of the secondary cancers with FCR were skin cancer, hopefully that makes up a large chunk of your 32%. Also, since the follow up extends to 19 years in the referenced study, I assume some decent chunk of those are just ‘normal’ cancer rates.
I hope anyway, since I was stuck with FCR and am trying to stay positive that it wasn’t hastening my demise.
Thank you for posting this. I have been grappling with next steps and am relying on research scientists coming with effective newer alternatives to treat MY CLL.
This portion of your post resonated with me the most: Effectiveness is important, but so is order
'This ice cream model clearly showed us what can be important for many patients, namely the question with which treatment order they have the most certainty to live as long as possible with comparable quality of life. So it is not only important which first treatment is the longest effective, but especially which treatment order gives the most certainty to be able to live as long as possible. In other words: after each ice floe, are there enough other ice floes that you can jump on?'
I was very ill and hospitalized when I started therapy in Sept 2022. I have paroxysmal A-Fib so the BTKi inhibitors weren't seen as initial option. My neutrophils were hovering near zero and my hemoglobin was marching down towards 6.0. Richard Furman put me on venetoclax monotherapy with a standard ramp-up. I couldn't tolerate the 400mg QD so I landed on 300mg QD. What happened in the next 8 weeks was nothing short of miraculous. At this point, my CBC and metabolic chemistries are (with minimal exception) outstanding. But.....the question remains: for how long?
I'm going to ride this treatment 'horse' for as long as I can and discuss next steps when the time comes. While I will always wonder if there was another path we could have taken to maximize known therapies, I balance that concern with the fact that, right now, I'm VERY well and lead a normal.
> "When the research results were well studied, there was no, to almost no, difference in noticeable serious side effects."
I've only seen evidence to the contrary on this. We cannot lump all side effects (Adverse Effects or AE's) together as if they are equal, even for a given AE level. Certainly, more research is needed to try to forecast who is likely to experience which AE. Did he cite any particular studies?
> "'What the final life expectancy will be when chemo-immune therapy is skipped in the first line, we don't know. After all, we know little to nothing about the effectiveness of the treatments now available after a first-line treatment with a targeted remedy."
The argument that we do not have life expectancy data for young CLL patients is specious, in my opinion. Young, fit patients almost always have longer survival no matter which therapy simply due to constitutional factors. New therapies are in constant development. Existing combo therapies may yet prove to be a cure - it takes a decade or so to justify claiming a cure.
The argument that targeted therapies have known or unknown adverse effects long after therapies is a fantasy for the recent therapies. Show me the papers about long term effects of the current frontline therapies - Acalabrutinib, Zanubrutinib, or Venetoclax plus Obinutuzumab. The existing BTKi monotherapies may have some effects that last as long as the therapy lasts - that's why limited duration regimens are so popular in research now. But there are perhaps many thousands of people who started with Ibrutinib, and then stopped for various reasons, and have yet to experience additional effects.
I could not find a link to the original article in Dutch. I don't speak Dutch, so I used Google Translate. I also searched the site for Michel van Gelder. I did find this video that touches on most of his topics and sounds identical to the article you cite:
Characteristics and Clinical Outcomes of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Receiving Ibrutinib for ≥5 Years in the RESONATE-2 Study
Published online 2023 Jan 13.
I've been where you are recently - well, a year ago. I'm not young - I'm 68. I started a trial in February, 2023. I don't know what your markers are. So I'll address how I searched for treatments.
It's particularly annoying to people who are considering first time (first line) treatment alternatives that so many trials are either for relapsed/refractory, or compare odd combination therapies that are not yet approved (ibrutinib+obinutuzumab, Cyclophosphamide+Obinutuzumab) instead of what many experts view as the standard therapies (BTKi monotherapy, V&O, BR, FCR).
The EU, UK, US, and other countries have differing approved therapies and rules for bending the rules. For example, in the US, we can get any therapy that is approved by the FDA, whether it was approved for CLL or not, but our insurance or Medicare may decline payment of some drugs - no 2 insurance companies are alike. So, Financial Toxicity is an issue in the U.S.
Another annoying thing is trials (or studies based on trials) that either specifically require High Risk vs trials that specifically exclude High Risk. But they may define High Risk differently. Older trials may specifically mention del17q/TP53, but some trials started to include del11q/ATM, and now we see both of those included with unumutated IGHV in the term High Risk. The older chemo-immunotherapy studies generally only considered del17q/TP53, from what I recall in my reading.
A final annoying thing is papers behind paywalls. There are illegal ways to get around this, but sometimes there are webinar videos and other papers that comment on the studies, too.
I tried to make a spreadsheet to track the trials and their requirements, and results, but it's an awesome task, and I finally picked a US trial on my own, and am now in it. I never made it to filling in the result columns, because I realized that my situation is not well covered in papers - Trisomy 12, unmutated IGHV, with NOTCH1. The more the markers, the less we find in papers about trials.
Failing completion of that spreadsheet for time reasons (I still have it, and am still trying to update it - a learning experience), I would recommend looking at:
Sadly, the slides are almost all pasted graphics instead of searchable text. So, I started to make notes about each slide to extract the study citation and find URLs, but got only about half way through. I'd be happy to share what I have so far, but I suspect a similar PeerView presentation will come up in a few months.
My takeaway is that the latest targeted therapies are almost always better than CIT (cytotoxic chemo-immunotherapy - FCR and BR). I don't think there's any guaranteed advantage at all to doing CIT first, and there are some concerns as others have noted. As time goes on, results regarding relapse and life expectancy appear better and better for the targeted therapies. The only issue that I see is the hemo/oncos struggle to keep up, and may not understand things like MRD and resistance gene testing.
In particular, I would say that if you can get a combination of BTKi plus BCL2 (Venetoclax) that's turning out better for most people.
As René, shared earlier, healthunlocked.com/cllsuppo... , the article begins, "The choice of treatment order for someone with CLL differs per patient. What does this mean for people who hear they have CLL? We asked Michel van Gelder, hematologist in Maastricht UMC.
Keeping on with the ice flow analogy, starting with any alkylating agent, which for CLL are the drugs, cyclophosphamide (the C in FCR), bendamustine, the B in BR, or chlorambucil, will select for tougher to treat clones with mutated or missing TP53, (i.e.17p del), or mutated or missing ATM. There's also the increased risk of developing AML (Acute Myeloid Leukaemia) or a Myelodypslastic Syndrome MDS), reducing your choice of ice flows for your ongoing journey. Wikipedia has a good summary of alkylating agents, which the Merriam Webster dictionary describes as "a substance that causes replacement of hydrogen by an alkyl group especially in a biologically important molecule specifically : one with mutagenic activity that inhibits cell division and growth and is used to treat some cancers."
This is why now that we have the additional choice of targeted therapies to treat CLL, countries with universal health care initially only allowed access to these more expensive therapies after treatment with a chemoimmunotherapy first line treatment (BR, FCR, or perhaps chlorambucil with obinutuzumab) unless the patient had 17p del, or mutated/missing TP53 or ATM, where access to targeted therapies was granted. Per the growing amount evidence such as you have referenced, chemoimmunotherapy treatments are gradually being abandoned in favour of targeted therapies for all front line (first) treatments in countries with universal health care. Meanwhile, per BobbyFour 's reply to Skyshark it's "Pretty tough view for the many of us in countries that have to do FCR first.", but that's unfortunately the reality that most of us outside of the USA face, unless we can get into a clinical trial. Even then, we usually face the risk of being assigned the chemoimmunotherapy comparison arm, as was the case with the FLAIR trial in the UK.
Addendum: It wasn't that long ago that US patients trying to gain access to targeted therapies, first had to have an initial approved 'chemo' treatment. I can remember people mentioning just having one cycle of chemoimmunotherapy so that they could qualify for ibrutinib or idelalisib, or CLL specialists advising patients to whom they had prescribed chlorambucil and obinutuzumab to "just lose the chlorambucil pills".
Can FCR be considered as last recourse for those who are mutated? Or is it not an option once you have gone down the path of BCL or BTKi treatment?
Also, I have read here and elsewhere that FCR has a small percentage chance of later leading to other cancers or transformation to a more serious kind of leukemia. Does this risk also exist with BTKi and BCL forms of treatments?
In theory, there's no reason why you can't have FCR after BCL-2 or BTKi (targeted) therapy, but I don't recall anyone having done this.
Unlike FCR, BCL-2 and BTKi therapies don't change cell DNA, so, they can't cause cancer. However, because CLL and treatment reduces our immunity, unfortunately we are still at increased risk of secondary cancers.
I'm no expert on all this - AussieNeil is the gold standard there - so can only give a personal perspective. The one thing I have picked up on is that since CLL is a very heterogeneous condition, what works for one person won't necessarily work for another.
I was diagnosed in 2011 and in 2012 was treated with four rounds of BR chemo... first round, I had neutropenia and spent a night in A&E. I also had a very nasty skin rash after each round, and my skin has been a little 'sensitive' ever since - especially in a squamous cell cancer which took three long surgical procedures to resolve (2013). So, as I have only had one type of treatment, I can only guess what might have happened later with more choices... but I am still in remission 11 years on. So:
Side effects and neutropenia - would these have been different with modern treatments?
Skin cancer - is the risk less with modern treatments?
Death as a result of treatment - is this a smaller risk with modern treatments?
Remission - can this be as long with modern treatments?
The answer to all of these is: "Don't know". I daresay research is ongoing into such questions.
Would I do it again if I could go back in time? Yes, of course - but I would say that, wouldn't I, as it worked for me.
Would I do it now, when there are more choices? Everyone must do their research and take the best advice available. I didn't know much about it when it happened to me, and had no time for research as it progressed so rapidly.
Last word: it's not a death sentence any more for many of us. With any luck, you will pull through. But... we all die eventually, of something. I'd prefer to be knocked over with CLL or some other physical illness than go into dementia, as has happened to family members. People seem to forget, sometimes, that 'beating' a cancer does not mean you end up living for ever!
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