I've had FCR (2010) BR (2015) Ibrutinib (2017) and now Venetoclax for the past 18 months.
My consultant says I'm no longer responding to Venetoclax - I was hospitalised in February and March 2023 with neutropenic sepsis, pneumonia, covid and Norovirus and lost 2 stone in weight, dropping down to below 6 stone (38 kilos).
Several times I had asked to reduce Venetoclax from 400mg daily to 200mg, as I was feeling increasingly nauseous, losing weight and very tired, but was refused, so in Feb, I finally did it anyway. My consultant meanwhile requested an urgent PET CT scan which I had the following week, by which time I was so emaciated and literally dying that I was hospitalised. My neutrophils were zero, and the doctor told me to stop Venetoclax immediately. When I finally came back home, at my next oncology appointment I was told to resume Venetoclax at the full 400mg dose. My consultant also told me that my PET CT scan showed masses in my abdomen, so my CLL had clearly become aggressive and turned to non-Hodgkins lymphoma or else Richter's Transformation.
She wanted me to start R-CHOP immediately and when I refused she said I would die. I kept asking how she could be so sure that my CLL had transformed, because I'd had masses in my abdomen that were larger than the current ones before starting Venetoclax, so perhaps these were the same ones but smaller now? I asked for a biopsy and in the meantime she contacted the local hospice and sent me home to die.
I resumed Venetoclax 200mg daily, but was hospitalised again 3 days later and my neutrophils had again dropped to zero. This time I didn't return home for 10 days. At my next oncology appointment the results of my bone marrow biopsy and CT guided biopsy of the masses in my abdomen had both come back without any evidence of non-Hodgkins lymphoma or RT. The consultant didn't have the grace or humility to apologise for all the pain and anguish she had caused me and my family for saying I would die. Instead she said I was failing on Venetoclax and needed to join a new drug trial in Oxford.
I asked for an MRD blood test to be done first because all my bloods have been very stable and within normal ranges since leaving hospital 6 weeks ago and I've been feeling a lot better and gaining weight. She had advised me in mid-March to resume Venetoclax at least at a reduced dose of 200 mg daily, but I've been taking just 100mg daily as I didn't want to kill my neutrophils again, and it seems to have worked.
The consultant says that my CT guided biopsy includes the MRD under the heading flow (see the chart above), and the fact that it shows CLL/SLL is confirmation enough that my CLL is active again.
But my question is how active? Is there 1% CLL disease in the MRD or is there 99% CLL disease present. How can I tell from this chart? Or is an MRD blood test a more accurate way of measuring the amount of disease present?
I'm sorry to be so long-winded but I really don't want to embark on a new drug trial whilst there is even a tiny chance that I'm still responding to Venetoclax - the biopsy results above were from a CT guided biopsy 6 weeks ago, before I resumed 100mg Venetoclax daily, which as I say I'm feeling really well on.
Thanks for any advice, or light you can shed on the above biopsy results.
Ruhi9
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Ruhi9
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My, you've had a very rough time lately, but you are definitely a survivor! I'm sorry to hear that you've not had appropriate support during your very traumatic recent experiences. I admire how you have self advocated to get to this point where you have achieved a marked improvement in your health, coming to a working compromise with your venetoclax dose.
With that abdominal mass of CLL cells present, which is not responding as expected to venetoclax, the normal uMRD checks of blood and bone marrow aren't relevant. To me, all that report is showing, is that you have CLL cells present in that abdominal mass (much better than the suspected alternatives), which have developed resistance to the currently approved BTKi treatments. Thankfully there are now other options available in the UK when CLL becomes resistant to the standard approved treatments, such as that Oxford trial.
Jm954 /Jackie would be much better able to comment on those options. Meanwhile, as your consultant has advised, it is important to stay on what venetoclax dose you can tolerate, so you are best situated to enter clinical trials available to you.
Thanks for your reply. I've been in touch with the Oxford team and they're going to phone me this week to arrange my first appointment.
I was reluctant to start on a new drug trial with all its accompanying risks, whilst there was even the slightest chance that I was still responding to Venetoclax, even at the reduced dose of 100mg daily. My 24 months on Venetoclax was due to end this October, and I had hoped to hold out until then, but perhaps I'm being too optimistic...
It's great to see that you have been provided with some helpful information from other community members. I'm also encouraged to hear that you are exploring the Oxford team's nemtabrutinib trial. Nemtabrutinib is a third generation BTKi drug that bonds non-covalently. The CLL Society provided this information about it back in 2020:cllsociety.org/2020/06/ash-...
Please take note ofJm954 's suggestion about nemtabrutinib probably best being considered a bridging therapy. You've now made some good contacts and most importantly, time to consolidate your hard won efforts towards much better health. Please keep us informed of how you are going, as you explore future treatment options towards a cure. Your experiences will be of particular interest to others who find that their CLL is becoming resistant to ibrutinib and venetoclax.
Yes, community members have all been very kind in helping to clarify my biopsy results and options going forward.
The Oxford team contacted me today and my appointment is this Friday for signing of consent forms (if I’m accepted for the trial), followed by medical tests and a CT scan. I'll keep you posted.
Your results show that 14 in every 100 cells are CLL cells which is a significant amount although probably not clinically important.
7% of the CLL cells have developed a BTKi mutation and are resistant to Ibrutinib.
6% of your CLL cells have the TP 53 mutation.
You haven’t mentioned anaemia but the M:E ratio is reversed and your marrow is frantically trying to make red cells. It would be worth checking for a haemolytic anaemia using a test called a direct anti globulin test or DAT.
We don’t have any measurements of your abdominal LNs and one set of results on its own like this can not determine if you’re still responding to venetoclax. It may be that the venetoclax is only holding your disease and now is the time to investigate possible new drug trials.
I would listen to your consultant and look at the trial in Oxford. The benefit of that would also be the opportunity to have an assessment of your disease by a CLL expert and that could be very valuable.
Thanks for taking the time to write such a detailed response.
Unfortunately a CT scan was carried out in Oct 2021 prior to my starting on Venetoclax/Rituximab, but no further CT scans were done until I became ill in Feb 2023. So there is no knowing if these current masses are the original ones which have become smaller in size, or if the original ones were completely wiped out, and these are now new masses growing on the site of the old ones.
As I mentioned to Neil, I'm now waiting to hear back from the Oxford team with a date for my first appointment there. I'll keep you all posted.
I've attached the full reports to my BMB and needle biopsy in reply to Seymour. For some reason I couldn't send more than one attachment per post, so the reports ended up across 5 posts. I'd be grateful if you could let me know whether they shed any more light on my MRD / the progress of my CLL.
I’ve read all those reports and although there is more detail, they all say essentially the same as the first. (I used to prepare and read this type of report when I was at work so I understand the terminology).
Headline results are: No Richters, proliferative and relapsing CLL showing up to 30% in the trephine biopsy, low level TP53 disruption, erythropoeisis is increased relative to myeloid cells ( they also suggest DAT as I did) but that ratio could be due suppression of myeloid cells by the Venetoclax.
This is a very thorough set of investigations done by your Dr who is to be applauded for that as not many would do NGS as she has. The decision to refer you to Oxford at this time is also a good one, your Dr doesn’t want this relapse to gain too much momentum before a decision on your next treatment, especially as you are taking a reduced dose of venetoclax
I think she’s a good doctor and is certainly acting in your best interests at this time. Hopefully there’s a suitable trial for you as options for those, like you, who are heavily pretreated and double refractory to both BTK and BCL2 inhibitors are limited. New drugs are coming along and Oxford is a centre of excellence for CLL (Anna Schuh is there) so if anywhere will have something for you it will be them.
Wishing you all the best, please let us know what you decide
It’s incredibly kind of you to take the time and effort to go through my biopsy results and give me such detailed feedback. Thank you!
The Oxford team contacted me today and my appointment is this Friday for signing of consent forms (if I’m accepted for the trial), followed by medical tests and a CT scan.
Feeling nervous, but hopeful. I’ll keep you posted.
The Oxford trial is called: MK-1026 (nemtabrutinib) and is a targeted Bruton Tyrosine Kinase inhibitor (BTKi), which is a specific treatment for CLL, SLL and RT.
Maybe I missed something here, but, the mention of possible Richter's and offering RCHOP?
From what I read in the post, it is my view that the first line of defense is a competent diagnosis of Richter's, especially when the attending physician states that "you will die"!
Understanding the stress and effect of what your going through and how it affects your ability to advocate for yourself, I hope that you have someone attending who will aid in the conversation of asking the right questions and following through to the outcome.
Competent diagnostics are imperative in decision making.
We aren't privy to the exact conversation, but IME when these things happen the docs are always *jumping* to rule out RT/treat what they think is an aggressive, acute leukemia. IMO depending on their experience, they push the R-CHOP because they've been taught that acute leukemias need aggressive therapy if a patient is to survive.
Which is why IMO it's so important to get CLL specialists input. When I was having the pseudo-RT thing, the local hem-onc woke me up early in the AM, urging me to go directly to the hospital, that I needed to start chemo *immediately*, that day. Another CLL patient, in a study but not directly being treated by who I consider top docs, with top labs, was thought to have RT but insisted the Mayo Clinic give a second opinion, and Mayo thought it wasn't. It *was* fast growing, just not RT.
So depending on the doc, they urge us to go to the hospital *right now*. It's awful that some use language like "you're going to die if you don't do as I say Right Now." I am sorry to hear about this, and all the problems. I hope you can find a treatment that works, soon.
I thought my haematology oncologist was a CLL specialist. She appears to know about all the latest treatments and drug trials, etc.
I just think she needs a course in empathy, compassion and how to be less brutal when breaking bad news. At the very least she should have had the diagnostic facts in front of her and not assumed that I had RT.
Yes, I'm really hoping the Oxford trial will work🙏
I apologize, I wasn't very clear. My definition of "experienced doc" is one who has also developed a decent bedside manner, and doesn't upset patients needlessly! One can be the best technician in the world, and a brilliant diagnostician, but like the TV Dr. House, I'd still call them crappy/inexperienced. If you aren't scoring high on "all" parameters related to being a good doctor. Like many, many professions, "soft skills" can be very important.
I agree it was a huge shock that I was first given what sounded like an ultimatum, and then when I refused to take that path, it quickly became a death sentence.
Thankfully my son has flown back to the UK to attend subsequent appointments with me. He has a clear head and is a good negotiator/mediator, and is good at advocating on my behalf. He will also attend the Oxford appointments with me as my husband isn't well enough.
hello Ruhi9, your strength and courage facing an aggressive CLL are remarkable. I've had a very similar journey--PCR, BR, ibrutinib and venetoclax--and am currently uMRD, but i know several CLL patients who have developed resistance to V and/or I. In at least one case in my area (Boston) the patient had failed nine prior therapies and was warned she was near death. Then she found a clinical trial for pirtobrutinib. It also is a BTKi, but very different. My friend, and others in the pirto clinical trial are doing quite well now.
If that "oxford" trial you mention includes pirto, you should definitely consider it. Pirto already is approved in the U.S. for a related blood cancer (MCL) and my docs here in the U.S. say it will be the gold standard once it's approved for refractory/relapsed CLL patients.
here is a link to the u.s. government's listing for the pirto clinical trial, so you have some background:
The Oxford trial is called: MK-1026 (nemtabrutinib) and is a targeted Bruton Tyrosine Kinase inhibitor (BTKi), which is a specific treatment for CLL, SLL and RT.
My consultant did mention Pirtobrutinib, but unfortunately it's not readily available in the UK. She said the only way she might be able to get it is if the Oxford trial doesn't work out, and then on compassionate grounds I might qualify for Pirtobrutinib.
You're welcome, Ruhi9. As it turns out, nema...is a close relative of Pirtobrutinib. They have the same structure and are different in key ways from the traditional BTKs. Nema may have a slightly more challenging side effect profile than pirto, but that's not clear and i suspect not that big a deal compared to the other stuff.
check out the Q&A about the two drugs in this link:
The thing about side effect profiles as they change with "each generation" is that "fewer effects" isn't always the case. As the docs learn more about the drugs, and exactly where they work, they look at 3D models of receptors thought to be involved in a process. And they attempt to design molecules to affect certain parts of other molecules. Like the "spike protein" we've all read about on the Covid virus. The thing is, there's generally no way to 100% predict how a particular human body will react. One example I have personal experience with, are the cephalosporin drugs. I've taken cephalexin, a 1st generation cephalosporin, in the past no problem. At one point I was prescribed cefpodoxime, a 3rd generation one, when trying to get my recurrent sinus infections under control. My body had intolerable side effects to that. There's no way to predict who will get a SE or not. So I am happy to see various BTK's getting tested, as well as newer BCL agents, and other mechanisms of action. The more options we have, the better.
Very very rough situation & I am so so sorry. It sounds like you & your present team aren’t on the same page. I just believe that it is not always what you say but how you say it & fighting with your doctor is a no go, who got energy for that? If not the new trial, still get a new doctor with some compassion 🤦🏽♀️
I'm really hoping the Oxford team will be more approachable and willing to address any questions and concerns I may have without any arrogance or impatience on their part. As you say it's so important to be on the same page.
I don't blame you at all for your skepticism of your consultant's analysis. It's good to be skeptical until you can get to a position of trust.
While I see the usual covalent BTK resistant marker, Cys481Arg (C481A), I don't see anything indicating resistance to Venetoclax. Some of the research on Venetoclax resistance is recent, and may not be commonly available.
Although I see at least part of the CLL Flow Cytometry report you posted here, I don't see an MRD report. The Flow simply shows the markers tested and their relative brightness, and would be what I would expect to see to confirm a CLL/SLL diagnosis. There are no counts listed next to Flow.
Could the MRD report be cut off, or on Page 2, or in another report?
MRD can be done on peripheral blood or bone marrow aspirate. I suppose it could also be done on a lymph node aspirate, too.
The aspirate listed on your post was not clearly marked bone marrow or lymph node. I would think it would be a lymph node, since Richter's normally presents in a node or other lump. But then, I would expect to see the Richter's markers tested by Flow Cytometry. Perhaps they ruled out Richter's based on the lack of blasts (immature cells) in the aspirate.
The counts for the aspirate are simply a differential. No total cell count is listed on what you're provided, so we cannot convert the percentages to actual values. In my own marrow reports, I believe that they only looked at 200 cells or so. MRD normally looks at a tube of about 1-2M cells to find 10,000 cells from which the MRD is actually done.
I don't think that the report that you presented explains your symptoms well.
Have you had a PET/CT or just a CT?
I am by no means a doctor. I'm an American CLL patient who has had a Richters scare recently. What triggered my scare was 65% abnormally large lymphocytes in a sample of 100 cells. They did flow cytometry of my blood to check 26 different CD markers to preclude DLBCL and I think Hodgkins Lymphoma (HL). Previously, they did flow cytometry on a core biopsy of a lump on my face to preclude a parotid gland tumor.
I'm in a pirtobrutinib/venetoclax/obinutuzumab trial at M.D. Anderson in Houston, and doing well so far on blood tests.
The letters and numbers make very little sense to me. My son and I agreed that we could see no counts listed next to Flow. I also had a PET CT scan right at the start 2 months ago.
I wanted to attach pages 1, 2 and 3 of the BMB in this post, but it won't allow me to, I'll send pages 2 and 3 separately.
Even though it says "Type: Bone Marrow Aspirate; Bone Marrow Trephine" at the top, the Diagnostic Review comments on the retroperitoneal biopsy. So this is all commentary provided for the ultimate review of the BMB, I think.
The Note comment on the retriperitoneal biopsy seems hopeful:
"diffuse chronic lymphocytic leukemia with larger cells with a high-proliferation rate, but not amounting to high-grade transformation. These are similar to those described in 2017."
This should be a relief, I would think. Since Richter's creates a lymphoma lump, this comment seems to preclude it.
FISH - "FiSH showed no evidence of a TP53 deletion."
Note that FiSH is a visual diagnostic that can detect only major shape changes of the chromosome. They look for missing arms on the chromosomes, as well as missing stripes that chromosomes usually have. A deletion of an entire arm or entire gene is a pretty large change. A deletion of a single base pair of DNA can have the same disease effect, though. Hence, the Molecular Oncology that does PCR sequencing of selected genes.
Variant Allele Frequency (VAF) - I'm still getting myself educated on my own molecular results. My current understanding is that a VAF percentage of 40-60% is considered germline - i.e. inherited - since we have normally have 2 copies of each gene due to having 2 copies of each chromosome. The percentages that you have reflect the fact that your cells do not have those mutatations or variants in abundance.
I’m really sorry for being so preoccupied with my own health concerns that I forgot to ask about your recent Richters scare and the subsequent drug trial that you’re now on.
How awful that must have been at the time. I’m pleased to hear you’re doing well on the drug trial and hope you continue to do so for many more years!
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Diagnosed with Richters
Update for followers 
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