I am newly diagnosed. No “B symptoms”. I have probably had this for a few years already given that my lymphocytes have been sufficiently high to “qualify”. So time to play Tevye (forgive the brief intrusion by Michael Buble): On the one hand, so long as I am feelin’ good, I can continue to W&W. On the other hand, there are a lot of prognostics that can gauge the probability of Richter’s transformation and all that that implies in terms of OS. Now I have not yet had many of the more evidence-based prognostics for this purpose but let’s suppose that I did and that they pointed to a serious possibility of the transformation at some point. Seems to me that in such a circumstance if you were to start treatment to control the CLL sooner rather than later, you might head Richter’s off at the pass because, so long as you achieve remission, there would not be any cells around to become transformed. Thoughts?
Richter's topic assigned as this is an important discussion on whether early intervention is worthwhile - Admin
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Luap001
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You have asked a really good question. Watch and wait can be counterintuitive to us for so many reasons.
I have not read or heard of any data that early treatment could help those predisposed to have a Richter's transformation.
One concern with early treatment is that it could have the reverse outcome of what you want. Many types of cll treatment, particularly chemo, can "select" for the bad cells you describe. The analogy I like to use is thinking of cll cells as weeds in a yard, some shallow rooted and easy to kill and some deep rooted , thorny and herbicide resistant.
What can happen with treatment is the easy to kill weeds go away making room for the harder to kill weeds to take over your lawn.
The new non-chemo therapies seem to be better at killing the bad weeds too. It might be that new therapies might not "select" as much for bad cll cells. It might be that the watch and wait paradigm might change when they get more data and that whacking the bad cells before they transform will be the new treatment paradigm.
To my understanding, this is all vey much on the radar of top cll specialists. You could see more doctors treat early. I just do now think there is enough data now to move from watch and wait. Early treatment is not without risk.
It's still a good question. If I was in watch and wait and had Richter risk factors, I would certainly ask the question you are asking to my doctor. Will early treatment eradicate my bad cll cells or keep them under control? Or will early treatment somehow select for bad cells and make them a more dominant strain? I do not think they know the answer to that, but they could have early data from ongoing trials that is helpful in predicting the answer.
Len, the reply you included from Dr Furman in 2018 kind of sums up my understanding:
"Nothing has changed as of yet for watch and wait patients. My belief is that for 75% of patients, watching and waiting, and then starting BTK inhibitor therapy will be sufficient to provide extremely long-term disease control of their CLL. For the other 25%, we have issues with transformation and BTK inhibitor resistance. These patients do need something different. One theory of mine is that earlier initiation of treatment might be beneficial. We are currently writing a trial to test this, but for now, we are still doing it the way we always have."
As is apparent in the reply from Dr. Furman, he believes early treatment might be indicated one day for those with Richter's risk factors, but there is not enough data yet to confirm his theory.
That was in 2018. That's why I think luap is asking a very good question. worth asking one's doctors. I would be curious to know if I were considering early treatment if Dr. Furman ever got the trial off the ground he described and if the early trial results tend to confirm his theory.
Luap, it could be a moot point with you depending on the results of your prognostic testing. If you are in the 75% group Dr Furman describes who do not have aggressive disease, you and watch and wait and if you do need treatment, you could get long term control with ibrutinib or other btk drug.
Hi Jeff, I believe you are correct. Dr. Furman, Dr. Allan or Dr. Lamanna would want to see indications that the "tempo" of CLL was fast and furious. If the patient had 17p deletion or Trisomy 12 and was UnMutated then they would likely test for NOTCH-1, SF3B1, etc.
And then consider more agressive treatments.
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Here is a paper from Dr. Furman & Dr. Allan on the subject:
SNIP In this review we highlight the current landscape of molecular lesions specific to RS, review the data on historical treatment options, and look to the horizon for potential opportunities in the future.
Very interesting. The fact that people who transform to Richters before treatment do better than those who transform after treatment would seem argue for watch and wait.
But what these studies do not answer is whether early treatment would have prevented the transformation in the first place. And they do not seem to know if early treatment might accelerate a transformation.
The bottom line stills seems to be that their is not enough data showing that early treatment can delay or prevent Richters and that watch and wait is still the standard of care.
But the trick is to have reasonable confidence that you are in the 75% group. You would think that since 2018 that there may at least be some data where one might retrospectively be able to point to those prognostics that have merit; I realize still that it may be too soon but sometimes you “have to go with what you’ve got.”
At least the emergence of the non-covalent BTKi drugs such as LOXO-305 can side step at least one of the causes of resistance to Ibrutinib so perhaps such resistance will soon be less of a worry, certainly in the context of the need to consider an early start to treatment.
Somewhat of a tangent: As I have mentioned in unrelated posts, the emergence of MR1 as a possible “holy grail” target that may well be exclusively expressed by a whole host of malignant cells may emerge in the not to distant future as our best way out as it were since then it could destroy both CLL and Richter’s transformed cells if present. Perhaps CAR NK could deliver the knock out punch since there would be no need for autologous donation as there is for CAR-T. Moreover, MR1 does not vary among individuals. The prospect then would be an off the shelf product versus a customized one. That means a lower cost which in turn means greater access. And on top of that, neither the MR1 target nor NK cells as the delivery vehicle seem to solicit the cytokine storm or neurotoxicity associated with current CAR-T therapies. I have both my fingers and toes crossed regards the efforts underway at The University of Cardiff currently focused on MR1 restricted
CAR-T. Let’s all hang on long enough to see how that turns out, shall we?
This is a tricky one because the drugs are so new and the chance of Richter's is still not clearly defined although we know some markers definitely predispose but are not predictive.Patients with poor markers such as 17p del or TP53 do not necessarily progress faster in watch and wait or require treatment sooner than those without those markers.
There is a Phase 2 Early Intervention With Acalabrutinib in Patients With High Risk CLL but it is not yet recruiting.
The trial's objective is to see if early intervention in high-risk CLL can decrease the incidence of early Richter’s Transformation.
Acalabrutinib 200 mg daily continuously for five years or until treatment is discontinued for any reason. While on study, subjects will be monitored monthly for the first 3 months, then every three months thereafter until disease progression, discontinuation due to toxicity, death, or study completion.
Primary Outcome Measures :
Percentage of subjects who do not develop Richter's Transformation (RT) within 5 years of study drug administration.
Inclusion Criteria:
Subject must have high risk CLL as defined by any one of the following:
It makes sense to use a BTKi which is a non proliferation drug which will hopefully reduce the opportunity for further mutations or transformation to Richter's.
This is a relatively recent retrospective study of RT cases at the Mayo Clinic, spanning 25 years haematologica.org/article/v...
Cell of origin (by which I assume they mean de novo or clonally related) was not among the risk factors identified. I believe this is contrary to what Allan & Furman said (ref above by lankisterguy)?
Thankfully everyone seems to agree that the incidence of RT in CLL is very low.
Risk analysts start with a matrix where everything is categorized as lower or higher risk and also lower or higher consequence. So if the transformation is low risk but high consequence, I think it bears some thought as to what is the best thing to do. And you might consider your age, your general fitness, and your life circumstances in making that determination. But this does depend on whether the risk is in fact low. The fact that there is a clinical trial that aims really to determine the utility of the prognostics for this purpose is excellent and will benefit future CLL patients and the doctors who treat them. In the meantime, I believe I would focus on those prognostics selected for evaluation in that trial because those who know far more than I have selected those because they must be worthy of evaluation.
The reality is that I don’t know what the probability is. I do know that there are several prognostics. And I do know that while I haven’t had a transformation, now would be the opportunity to find out how likely it may be. And if say three or more of the prognostics point towards high probability, then it may make sense to start treatment earlier to quell the malignant cells before they can transform. This strategy, like everything else we do in life, offers no guarantees. The prognostics might indicate a low probability and you get the transformation anyway. We can only attempt to stack the odds favorably while we have the opportunity and based on the best information available. I think it is reasonable to question watch and wait in terms of whether being asymptomatic means that you should delay treatment 100% of the time. Arguably, that is an extreme position.
I suspect everyone with CLL feels the same way as you after first being diagnosed with CLL. I have very aggressive CLL, my W&W was only 14 months until I was faced with either blood transfusions or treatment. Up until 2-3 months before treatment I felt great, some night sweats, about it. When I was first diagnosed, doctors told me everything was rosy, might never need treatment with my "good" markers. All of that changed as blood tests continued to show my path. I enjoyed what little time I had of W&W before treatment, to do the things I needed to do before treatment. As my CLL was so aggressive, in the back of my mind was the possibility of Richter’s transformation. I can understand your desire to find out your possibility of Richter’s transformation and desire to deal with it now. You will be faced with the same questions when and if you need treatment for CLL and also if you need to continue treatment after reaching remission during treatment. I don't consider your position extreme, rather normal. Blessings.
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