Good morning. I have a friend in his 50s with aggressive unmutated IGHV. I am in my early 50s and am Trisomy 12 unmutated and recently diagnosed. Both of us have been told that we are at increased risk for Richter’s. Figuring out what this means is tough. There are top researchers who say that 5 to 10% of us will develop Richter’s each year. There are researchers that say .5 to 1%. There are researchers who say the risk has decreased due to the new drugs and researchers who say the risk is the same. The conflicting news about Richter’s is certainly the main source of my anxiety. Why is the scientific information about Richter’s so much more uncertain than it is for CLL? Is it a financial issue because there are so few patients? Is it scientific because Richter’s is so complicated?
Richter’s Anxiety: Good morning. I have a friend... - CLL Support
Richter’s Anxiety
Please remember CLL itself is considered rare. So a subset of a rare cancer (Richter's Transformation, RT) will have even less data available. Since Follicular Lymphoma patients are stated to transform at rate of 2-3%, I wonder if these figures get confounded with CLL figures occasionally.
The takeaway I have gleaned from the various discussions surrounding increased risk of RT from certain markers, is that this subset may benefit from earlier treatment. If the clones are stamped out before they can transform to the aggressive DLBCL, that may be better.
The biggest takeaway IMO is that it seems the more advanced the disease is at diagnosis, the higher the risk. "Advanced" as defined in the article below. It also talks about the various percentages you have heard & where they come from:
ncbi.nlm.nih.gov/pmc/articl...
So using myself as an example, even thought I have an aggressive fast growing CLL variant with no W&W at diagnosis, some unfavorable markers, and have had several treatments including alemtuzumab, my initial presentation staged me at 0. I am not particularly concerned about being "higher risk." If my nodes ever blow up with weight loss and shortness of breath, I'll insist on an excisional biopsy & SUV, and get a second opinion from the Mayo.
Part of the problem, I think, is that DLBCL itself is somewhat common in the realm of Non Hodgkins Lymphoma.
lymphoma.org/understanding-...
With CLL being a risk for secondary malignancy, I would make sure any DLBCL was truly a RT and not an unusual instance of DLBCL occurring.
(Updated) When I first learned about the risk of Richter's, 14 years ago, I too read 10 to 15% rate. That concerningly high figure just didn't make sense, as that was back when this community had around 1,000 members. We certainly weren't seeing a significant number of members posting about having Richter's each year!
We currently have around 4,000 to 5,000 active members and you would think that if any of the over 22,000 members developed Richter's, they would also be likely to post about it! So again, where are the expected roughly 200 posts per year (0.5% of 4,000) from people getting Richter's? (200 posts per year from someone developing Richter's, means we'd see a post announcing this about every other day!) (See SofiaDeo 's answer below about the expected annual transformation rate of 0.5% to 1.0% healthunlocked.com/cllsuppo... )
Later estimates are much, much lower than that 10 - 15% overall rate (see Skyshark 's reply below healthunlocked.com/cllsuppo... ) Also, the risk is higher with certain markers, in particular in patients with 11q del with high NOTCH-1 expression or 17p del. Complicating matters, we now have Pseudo Richter's to contend with, which can happen when people suddenly stop BTKi maintenance treatment for longer than the week or so for surgery. So I'm fairly certain that the real rate of Richter's is around the 0.5% mark or lower and mostly in those with high risk prognostic markers. It also makes sense to me, that with the move to treatments that don't rely on damaging CLL cell DNA to work, there should be a corresponding reduction in more at risk sub-clones being generated.
As to why the conflicting news, CLL is a relatively rare cancer and 0.5% is 1/200 of that number. (Again, see Skyshark 's reply.) We are reliant on large CLL research groups who keep patient databases to release studies on Richter's Transformation patients to provide us with estimates. I also suspect a further bias is because higher risk patients are more likely to make the effort to attend such centres of excellence, further inflating the estimated percentage.
Neil
Can you elaborate on the specific risks to people with 11q del please Neil?
From leukaemia.org.au/blood-canc...
For example, patients harbouring 11q and 17p chromosome deletions, un-mutated IGVH gene, NOTCH -1 mutations, shortened telomere length, elevated zeta associated protein (ZAP-70) beta 2 microglobulin (B2M) and CD38 levels and/or with advanced stage disease at first CLL diagnosis (Rai Stage III-IV with lymph nodes >3 cm) are all thought to be at a greater risk of developing RS. The exact relationship between these various factors and the actual risk of developing RS is yet to be determined and is the subject of ongoing investigation.
See also this study from Denmark, which also reports a higher risk with 11q del and 17p del. (There's a higher incidence of NOTCH-1 expression with 11q del CLL.)
ashpublications.org/blood/a...
Note:
"The incidence of RT in this unselected population was 3.3% after 5 years"
Underlining is my emphasis.
Neil
Thanks Neil – there is no mention of notch 1 in any of the literature on my diagnosis with 11q del. As you and others have said, all this data seems to be pre-targeted treatment.
Is it true that the longer we have cll the more at risk we are to develop rickters?
I'm not sure it's applicable over time, just, an overall percentage. Do you think that the longer you live, the more likely you will get hit by a car crossing the street? Statistically, X amount of people will get hit by a car crossing the street yearly. But I don't think older people who have lived longer are more likely than young children.
I know researchers are trying to see *if* and to what extent, any variables may correlate with RT. They think they have found a few, but with new genes important in CLL being found, who knows if all the factors have been discovered.
I forgot where or who said this but it was definitely a top doctor as I recall. That has stuck with me for years. Unfortunately I forgot who said this.
I think I found something addressing this you may have read:
"RS occurs in approximately 2% to 10% of CLL patients during the course of their disease, with a transformation rate of 0.5% to 1% per year"
ashpublications.org/blood/a...
This was in 2014. So back then they were taking "time one has CLL" in their equation, to include everyone throughout the decades of disease. The yearly chances of transformation appeared to be under 1%, the yearly transformation rate is really low.
The literature nowadays notes decades ago there were no rigorous definitions like we have today. With FDG PET/CT indicating the most active lymph node to biopsy, and knowing a slice is needed instead of needle, plus the newer NGS technology to type the cells, people presenting with true RT will likely be more well defined. And then statistics can be collected.
As of Jan 2024, it's still thought the yearly incidence is this 0.5-1%.
link.springer.com/article/1...
Thank you Sofia, I appreciate your reply and like it much much better😌☺️.
Sofía you always make me feel better, thank you. My eyes are watering as I type this. I’ve been doing allot better mentally but sometimes I can’t help but to break down. It still terrifies me to have this disease. I think in a way I’ve been feeling more emotional because I’m not taking as much of my antidepressants as I used to.
Cancer can be caused by inflammation. That inflammation can be due to genetics, environmental influences or long term health issues, such as chronic leukaemia. The longer you have CLL, the longer you will have inflammation. Cells can mutate into cancer at any point. This doesn't mean that you absolutely will develop a secondary issue, just that the scientific probability is higher.
My partner had CNS lymphoma in addition to CLL and they initially said it could be Richter's. Even though it turned out to be a separate cancer, it was a fair assumption as my partner had untreated symptoms for over a year prior to getting his CLL diagnosis. Leaving a condition untreated is often how some people develop cancer, but it generally takes multiple years or decades before that happens. It's an oversimplification to say inflammation causes cancer.
The important thing to note is that these studies are based on what has already happened to individuals. No one can actually predict your future outcome, doctors can only give their best guess and as we see in this thread, that guess may change over time.
I would also add that a reason people with Richter's don't discuss it on this forum is possibly because they would be too unwell to use a computer. When they thought my partner had Richter's, he was not doing well, but the doctors were skeptical that it was Richter's because he wasn't as sick as they would've expected. I did hear from one person who was taking care of their partner with Richter's on a different forum and she did manage to recover.
Neil, is there any data that you know of comparing the rate of Ricter,s after chemo vrs targeted therapies?
john
There are some studies reporting this, but I'm not confident in the findings. You really need a large group to draw meaningful results and with such a heterogeneous condition as CLL, then adding the heterogeneous prior treatment history, it's challenging to get meaningful results, more so if you can't get your specific prognostic markers measured for comparison! This is where researchers need to present the information in statistically appropriate ways, such as including 95% confidence intervals. I'd expect the confidence intervals to be fairly broad.
Neil
Neil, Sofia et al. My sense about the odds of RT has always been quite low, as you cited, for the overall population but quite high—more or less even chances of 50/50 or so—for those who have been treated already for CLL and possess certain genetic markers, like Notch 1. Is that a correct understanding? I’ve only gleaned it from reading on this and other sites. … In my case, I have been treated once successfully for CLL, found out I had Notch inadvertently along the way from a colleague of my main CLL specialist covering for him one day, and proceeded with my understanding as outlined above. Thank you for this and all your work. It’s appreciated. Bill
There are 220,000 people with CLL. 41% of us have trisomy 12, 11q or TP53 which increase risk of Richters. That is 90,000 people at higher risk for Richters. Each year, approximately 2,200 people will develop Richters. 50% seems like a really high number.
Thank you. Yes. It could be. I may have misinterpreted. Next time I see my doctor or NP, I’ll check. I actually avoid talking or thinking about this but should bite the bullet now that I’ve asked on HU. Good thoughts.
Out of 216 patients on V+O in CLL phase 3 study 1 had R-CHOP as next treatment by 72 month report, this is the indicator that they had RT.
Out of 169 patients in V+I CAPTIVATE FD phase 2 study 2 had RT by 48 month report. Both were u-CLL, TP53 wildtype with bulky disease.
In addition to u-CLL, NOTCH1 is considered to indicate an increased risk for RT.
It's a rare disease. Although CLL is the most common blood cancer it's still only 0.006% of the population that are diagnosed with it each year. RT is about 1% of that, 0.00006%.
UK 4,000 are Dx and US about 20,000 Dx with CLL each year. That's going to result in about 240 cases a year for US+UK, out a population of 400 million. But there is money being spent on trials. There are trials for adding Venetoclax or Acalabrutinib to R-CHOP, obviously the alternate trial would be selected if transformation had occurred while on one those drugs. 18 studies are recruiting (not all are drugs, some are just collecting data).
clinicaltrials.gov/search?l...
I suspect the possibility of RT gets waved at everyone that turns up late for Dx instead of having years of W&W. I had a biopsy and PET scan. The first biopsy report said DLBCL, then they looked at the PET scan sugar uptake value, it said I wasn't very sweet. So they sent the biopsy sample off for a second opinion and that came back as CLL.
There are others on HU that can tell the same story. If RT is suspected it does have to be to tested for and discounted.
PS. Lock this post to community only.
this has and will always be my biggest nightmare.😞
I don’t know anything about the prevalence of RT, but I do know that like CLL the researchers are working hard to find solutions. So even if you get it, it probably won’t be the big problem it has been in the past,
My husband had a RT in late 2022. Following treatment we can honestly say that he has been feeling better than ever.
None of us knows what the future holds. Try not to worry too much (I know that is easier said than done).
Beryl
hi Beryl, my father also has RT and currently treated by using bi-specific antibody. Do you mind sharing what treatment is your husband undergoing?
His RT was Hodgkins lymphoma and he had ABVD chemo - he finished it about a year ago.
As always, you have some great background information from everyone here on RT and its likelihood.
As I did transform (RT DLBCL), I would suggest if your doctors did bring up RT or stating you will have a ”stubborn” case of CLL due to the 17/53 del, mutations etc…. discuss having a plan and understand to act sooner than later as it will be more aggressive if it ever happens.
The medicine has come a long way to successfully treat DLBCL (mine was a bi-specific antibody & CAR-T) but as always move quickly (within the month) once the symptoms appear, I.e. night sweats start (again)…
As it is rare, just understanding what hospital in your area treats and works with other key hospitals wrt DLBCL / CLL will definitely help. Ask your CLL specialist their hypothetical plans/ expectations. Typically research or teaching facilities will be more on the latest care & collaborate.
Remember, the probabilities are in your favor and getting better as we move closer to cures of this disease.
Hello EastBayDad
I have been through possible Richter’s Transformation. I have very aggressive CLL at ALC doubling time of 2.5 months and massive bulky abdominal lymph nodes, 16cm x 18cm x 22cm from CT scan. My LDH bounced around somewhat but leveled off at m-m-m 270. High LDH is possible sign of Richter’s Transformation. LDH of 270 is not that high. PET scan was used to determine possible RT and also a target for biopsy if discovered. In my case PET scan ruled out Richter’s Transformation and did not require biopsy. From what I have heard there has been a number of CLL patients who after medical work-up, did not have Richter’s Transformation. I would not be overly concerned about statistical probability and concern more about your symptoms. Blessings.
Just to give you some hope, I am Trisomy 12 Unmutated and was diagnosed at age 53. I was watch and wait for 13 -1/2 years. I started V & O 6 months ago at age 66 and I am currently MRD negative, hopefully I stay in remission and end treatment in August. The Richter’s transformation scares me a little too, but from what I read it seems to be maybe be more prevalent after chemotherapy, which is not really used anymore, it is all immunotherapy. I hope you have a long W&W too.
In 2007, my CLL transformed to DLBCL for which I had six rounds of R-CHOP. I am trisomy12 as well. Always nervous that it will return. I had one round of BR in 2017 for the CLL and took Venetoclax in 2018 for a year.
I made it 7 months with cll TP53 deletion on calquence/acalabrutinib before my cll transformed to richters syndrome. I am now on R-chop for 18 weeks on 21 day cycles in hopes to get me to a stem cell transplant. It’s crazy how quick I went from cancer free at 38 to having cll at 39 to needing instant treatments to now having richters syndrome and being told 20% chance of survival. I wish you all the best but somethings cannot be controlled.
I had Acal and Venetoclax for 1 year (tp53 del also) before I transformed. My medicine that finally got a response and then to remission is a bispecfic antibody called EPKINLY (epicoritamab), just in case you need it.
They tried everything prior. I’m told This goes after both CLL and DLBC. After EPKINLY I did CAR-T go try and clean up the small hot spots left. Penn Med was my facility.
Stay positive and keep folks moving. I hope you find a combination that you respond towards remission.
Thanks for the information. If I may ask how are you doing now. I am currently on chemo therapy R-chop and after 6 cycles they are hoping to get me in for stem cell transplant in Calgary.
I’m doing fine and EPKINLY/CAR-T has me in remission for around 7 months now. CAR-T is becoming a go to process in the US that if successful you are off drugs and the expect remission for the active cancer. But CLL will still be there.
They tried everything with me ERCHOP ( or one of the variants) and various other immunological treatments. Etc. My body rejected several of them and I also had other issues.
I understand STEM Cell works well but has a longer isolation time after it’s implemented.
EPKINLY is an alternative to CAR-T for stubborn cases you may want to inquire about this as I believe you are young enough.
best of luck. I hope Canada allows you to have access to the emerging drugs out there as they seem to be advancing quickly.
John
I see a CLL expert. He told me he doesn’t see a lot of Richters. And remember the doctors are no longer pumping patients full of Fludarabine. Also, a lot of studies have shown that half of all Richters occurs within a few years of CLL diagnosis.
EastBayDad -
> "There are researchers who say the risk has decreased due to the new drugs and researchers who say the risk is the same. The conflicting news about Richter’s is certainly the main source of my anxiety."
I can understand the anxiety. I am Trisomy 12, unmutated IGHV with NOTCH1. I had 2 Richter scares before treatment because of an unusual swollen lymph node on my phase as well as odd cell morphology. I went through a core biopsy (the node could not be removed because of risk to facial nerves) and a PET/CT the first time. The second time just the flow cytometry. I completed a 1 year clinical trial of Pirtobrutinib, Obinutuzumab, and Venetoclax with uMRD6 on ClonoSEQ in both blood and marrow. Nevertheless, since the scares, I find that I still look over my shoulder for disaster.
I comfort myself by flipping the statistics. How many people with Trisomy 12, unmutated IGHV with NOTCH1 don't get Richter's? 99 out of 100? 99.5 out of 100? The vast majority.
> "Why is the scientific information about Richter’s so much more uncertain than it is for CLL? "
Simply because Richter's is more rare, and doctors have wished they could find some sure signs of it developing and some reliable treatment for decades. When they cite statistics, they don't cite dates, they cite papers. What we need is stats from known patient populations from known dates and therapies so we can remove the possibilities of Richter's being caused by cytotoxic chemotherapy and studies that looked only at high risk populations.
It's really hard to get a representative patient population even in studies with over 1000 people. Every study had requirements for participlation that exclude people who have kidney or liver disease, and often, heart disease to prevent skewing the study data by confounding due to their comorbidities. Yet some of those comorbidities might also represent processes that also lead to Richters.
> "Is it a financial issue because there are so few patients?"
Partly, plus the candidate patients don't like to travel or the topic scares them away.
> "Is it scientific because Richter’s is so complicated?"
Undoubtedly. There's CLL clonal-related Richter's and non-related. There's Hodgkins and non-Hodgkins. Stats that lump these together under the same name are not useful. There could be multiple mutational paths leading to the same result - just as we find with FiSH types and CLL. And even then with CLL, we don't understand the clonal changes that lead up to each FiSH type. And for Trisomy 12, we know even less.
And what would we do any differently if you could be 100% sure you will develop Richter's? You'd treat sooner with a combination of drugs. But which drugs? R-CHOP plus BTKi? EPOCH plus Venetoclax? E-CHOP plus BTKi plus Obinutuzumab? New monoclonals being tested on Richters because it's too risky to test them on someone less desperate? Old drugs being repurposed because of a promising in-vitro result?
The Brain Trust at the NCCN has been through almost all the available papers, and made some recommendations:
nccn.org/professionals/phys...
NCCN Clinical Practice GuidelinesVersion 2.2024
Create a free patient account to download that. Search for page HT-1.
You can also look for trials. I find over 200 studies mentioning "Richter", 64 that are Recruiting, some of which just happen to have someone named Richter in the record:
clinicaltrials.gov/search?t...
The naming of the syndrome is changing, BTW. They're dropping the 's. So we'll have to search on Richter from now on to be sure we get fresh info, and don't miss the recent papers that still use the old name. That was one of the changes the NCCN implemented recently to accommodate practice around the world.
If I was 100% sure of getting Richter's, I could wade through the Recruiting list with some set of additional criteria, and then register with one that would accept me at my current stage.
Another strategy might be to find the handful of researchers in the country with the most experience with Richter, and get a consult with one or more, and then go from there. You could use their name as the author on papers as some proxy for experience. You could look for YouTube videos of them and judge them by their manner.
I picked M.D. Anderson for my clinic, even though it's 350 miles from me. I picked a doctor at MDA for my consult and a trial for my then-assumed vanilla CLL. He got me accepted as a candidate for the trial, and then moved back to Australia. So I continued with a different doctor. But it's not just the doctor we pick, I found. It's the Tumor Board - the committee of doctors who do the weekly case reviews and combine their experiences. MDA has an planetary level tumor board. So do Mayo and MSK, and a few other places in the U.S. We are so profoundly fortunate.
Also examine your finances. At what level do you say, "No, that's too much. I'll make do." Trials are not cost-free. If you're lucky, the trial drug is cost-free, and they pick up some other expenses. But they never pick up the whole tab. It's really, really hard to get an estimate. MDA gave us an estimate north of $200K. In the end, it's been a tenth of that.
In the end, you turn yourself over to a team, and the ride begins. It's you and the universe and the divine. There's twists and turns. Practice breathing deeply. Many people before you took the ride. We meet up here regularly.
Best of luck, hope to hear from you soon,
=seymour=
Thanks for this helpful and informative answer. I have an excellent team at UCSF and just joined the CLL Natural History study at NIH. I have a lot of smart eyes watching me.
I found some numbers from Mayo a few days ago. 2,200 people a year on average get Richter in US. 12.3% of these people have Notch 1. 1 out of 881 people with Notch 1 as sole driver get Richter annually. Odds are in our favor. Sort of.
How long were you in W & W? My CLL started stirring in 2022. I had a bad case of COVID in August and my WBC and Lymphocytes shot up to 80. I am still Rai 0/1. Doctor thinks I have SLL. Quite a few 1 cm nodes above both collar bones. I am concerned that my stay on W & W will be short due to my Trisomy and my current lymphocyte number.
EastBayDad -
I was dignosed in January 2011, and started treatment in February, 2023. I tested as Mutated IGHV in 2013, but did not re-test that till 2022, when it came back as Unmutated - either the 1st test was wrong and I got a lucky 11 year W&W or I developed a 2nd clone in regard to IGHV.
=seymour=
EastBayDad -
If your ALC is > 5K and you have swollen lymph nodes, it's CLL. It's only SLL if you have swollen nodes and the ALC is <5K. A person can start with an SLL diagnosis, and the the ALC grows, and they're called CLL.
At some point in 2022, after talking to some fellow patients about my fatigue and mental fog, I decided to get the workup at M.D. Anderson. I think I probably could have started treatment even a year or 2 sooner. I got COVID BA.2 and a secondary staph infection in spring and summer of 2022, and my ALC went down from 75K to 56K and back up to 77K a month later. By December it was 78K, but in January 124K, then back to 92K. So ALC can change a lot. I had already agreed to treatment and had been invited to the trial before December.
So maybe ignore ALC as a specific level, despite the fact that people share and compare. It's just the single number whose change shows progression, but not severity. People here will tell you they went far, far higher before treatment. Some people wait longer for whatever reason. Some people have more CLL in the blood, and others elsewhere in the lymphatic system.
Concentrate on how you feel, and how you function. Pay attention to RBC, HgB, and platelets a lot more than ALC, because they drop when marrow gets full, and that complicates things more and gives you more comorbidities to live with like breatlessness and bleeding.
=seymour=
My red blood numbers are strong. The doc said it is in my lymph nodes. Doctor said I might need treatment this year, next year, or in 5 or 10 years. I have a 12 year old. Not needing treatment until he is at college would be awesome. 👏🏼
EastBayDad -
Sorry if I sound pendantic.
It's in your nodes, blood, spleen, and marrow. We can only count the CLL cells in blood. We can get a differential percentage of cells in marrow on a bone marrow biopsy aspiration, if needed.
So I think he's saying that your CLL is a little more in your lymph nodes than in your blood. But the ALC says it's definitely in your blood, too. Accurately measuring the lymph nodes requires a CT. The nodes can grow and shrink even before treatment - especially if there's an infection in progress. The nodes can get bigger while the ALC stays stable or vice versa. To my knowledge, that's not an indication of anything that anyone can do anything about.
But a sudden (<3mo) increase in lymph node size, or a 50% increase in ALC does signify the disease is progressing toward a phase where other things start going wrong. It's hard to size deep nodes for that without a CT, but an ultrasound can do it for shallow nodes. I used to ask every doctor I met how big they thought the lump on my face was . I got pretty different size estimates - both too large and too small, compared to the CTs.
=seymour=
Hi Seymour, is it ok to share if you used insurance to join clinical trial or self pay the cost? Did you join the trial in MD Anderson and treated in Australia? My father also has RT but his insurance is not accepted by MD Anderson.
janeychen5712 -
I live in New Orleans.
M.D.Anderson is what we call Out of Network for my insurance. So it is covered at 60% instead of the In Network rate 80%, and M.D. Anderson can bill me for the difference. But I was able to get an Out of Network Exception from my insurance so that it was covered as In Network.
International insurance is probably more complicated. You would have to contact M.D.Anderson to see what they can work out.
Also, look into grants from places like:
internationalcancerfoundati...
I'm sure there's more.
=seymour=
Transformation Confirmed - Likely Richter’s
Survival Rates
