I often thought about posting my view on MRD testing, however, I have chosen to present possible considerations through medical research publications. Well today is the day I come out of the closet.
Dr. Brian Koffman provided his eloquence and credibility in stating his view of uMrd testing in which I am most not in argument with.
In this publication where he addresses "NGS testing with clonoSEQ for uMRD Status",He provides the pre-emptive words "One might argue I could have continued blissfully unaware".
I am interested to learn more about uMRD as a surrogate endpoint for drug approval in CLL.
It seems to me that the duration of uMRD would matter more than reaching it. If you reach it but start rising above it a month after compared to two years of uMRD.
In the end it will always come down to how aggressive the individual’s cancer biology is.
Frankly, it seems to me there are enough youngish people with CLL that trials could be developed to be powered for Overall Survival and quality of life. The only two things that really matter.
There recently was consideration by the FDA for uMRD in multiple myeloma. I believe it was granted. During public comment I only recall one dissenting voice from a biostatistician who argued approvals are already very permissive.
I think where things get difficult is that patients are emotionally involved since we want more more more drugs. The drug companies want approval ASAP to finally cash in. But, if the statistics are questionable and if it turns out to not be a great surrogate endpoint then we are left with more questions and another expensive drug that might have needed more scrutiny.
Fortunately, in CLL it seems we have great scientists doing great work compared to the train wreck of multiple myeloma. There are interesting discussion with Dr. Aaron Goodman from UC San Diego on the MM topic on YouTube.
We also appear to have good comparator arms. For example, S+Z vs V+O instead of chemo. We need to keep pressure on the companies to always compare to standard of care now.
Hopefully, the CLL Society will be willing to shake their fists if we get straw man comparators.
Dr. Anthony Mato commented on this in the past. By the way, why did he move to Ithaca, NY? He dropped off the radar in conference coverage too….
My CLL Specialist would agree with you. He would like to see new medications tested against the best ones approved so far - not the first BTK on the market
Part of the problem is they have to test against standard of care when the trial started not when it ends 5 or 7 years later. Trials are being overtaken by the rapid introduction of new drugs or new restrictions in applicable standard of care.
When FLAIR, GLOW, SEQUOIA, GAIA and many other trials started the standard of care was FCR/BR with TP53/17p excluded from the trial. FCR as the SOC further restricted trials to fit patients under 65 years old. If they had started a few years later IgHV unmutated would have been excluded as well.
For the unfit it was obinutuzumab+chlorambucil, which was the comparator arm for ELEVATE TN and CLL14. In part this unfit cohort was selected as it still allowed the full range of genetics without limitations presented by FCR/BR.
While other trials such as CAPTIVATE FD/MRD have been run at phase 2 without comparator to fill in the blanks that the exclusions create.
For R/R trials were run with patients that had mainly had prior CIT. Trials for R/R using novel drugs after novel drugs are still underway. The more recent approval of V+O, V+I, 2nd gen cBTKi will feed R/R trials with a cohort that didn't have meaningful durations of response (<3 years).
FYI the Majic trial has a clonoSEQ screening to see if you fit the trial then compare at cycle 15 (60 weeks)to see the changes. Not only B cell counts but changes in chromosomes etc.
Interesting and point worth thinking about, the first 70%. I'm not arguing against the last 30%, I just do not believe the pressure angle is going to keep business/gov't from moving the goal lines anymore, that ship has sailed.
Well, the article was interesting, sadly as was written, "It is my N of 1 and... It is based on a little data and more conjecture", so props on full disclosure.
However, it is not scalable. We're talking about a well connected person with a history of access to experimental treatments and experimental testing, such that they can use the testing in unconventional an way as a personal compass to treatments, with great results. Which, I wouldn't take away from him.
While the middle of the spectrum is waging a test before treatment campaign, learning about what I feel most would never be able to do is sort of moot ( in this specific sense: deprived of practical significance : made abstract or purely academic - merriam-webster.com/diction.... Perhaps not forever, will this topic be estimated this way, but certainly is at this point in time.
Interesting article. When he says he tracked his disease by MRD testing - which showed disease progression when flow and cbc tests did not- what exactly was the MRD testing he was doing? is it blood marrow tests or a specific MRD blood test? thanks
Brian's trial was using ClonoSEQ "Next Generation Sequencing" tests every 6 months on both bone marrow and peripheral blood. Starting with a baseline "training" sample before the CAR-T trial.
With uMRD6 (undetectable, one in a million) for 2 years until dMRD6 (detected), it took 2 years for him to progress to dMRD4 (one in 10,000). Then a further year to have detectable rise in lymph count.
For most people the cheaper uMRD4 or uMRD5 test by flow cytometry will suffice but this failed to detect progression for Brian.
To all - Great conversations, and I appreciate the feedback.
I have no argument to make pro or con because in my view the science has not yet focused on any aspect of uMrd other than it being a measure of efficacy for stopping treatment in certain circumstances.
I do however share Dr. Koffman's measure as a work in process according to his own experience which is considerably notable and presented consistently credible. And as I assume he would, I would adjust the definition accurately as new data becomes available and my personal outcomes reveals more absolute.
I doubt that the uMrd questions that we propose with each other will soon be answered, as we all know - Answers cost money and take time. uMrd appears to be low on the list of observations being funded.
For now, I like very much to be told by my doctor that I have no observable cll cells in a sample of a million cells. What does this mean to research and the goals of treating cll overall.
Let us not forget that the cancerous B cells are not distributed uniformly throughout the bone marrow, perfipheral blood or lymphnodes for that matter. Seeing the counts increase in time after showing MRD-6 negative means to me a lot were put out of action since my oringinal BM test showed 92.7% cacnerous B cells. I am fully aware there are likely other B cells that were not collected and they will multiply and eventually end remission. This is the definition of a chronic disease. I prefer to end taking A and V when the B cells numbers go down to less the MRD-6 and resume with newer targeted therapies yet to be discovered when I need them. Soldier on!
PS - my BM clonoSEQ, CT and peripheral blood tests will be taken in 2 weeks after about 1 year on the Majic trial. The lower the count the better for me.
And we also don't know at what "level" any cells are enough to "become active/affect systems".
I know I am "out of remission" because my ClonoSEQ rose from something around 11-12 per million in blood, to 64. This definitely isn't a "4 month doubling time" which my CLL has, in the past, done at lymphocytes values much higher. When I came out of my almost 5 year remission, I "felt sick" and went to the doctor. discovering lymphs were above normal. Every end of remission since that lengthy one, had me feeling ill/lymphs doubling about every 4 months.
Yet the 3 month test after that level of 64 per million, had my lymph count slightly lower. My specialist commented he had expected it to rise. I am feeling "off" a bit, waking up with a light sheen of sweat instead of drenching, as well as several times during the night, but not what I would consider "my usual". It will be interesting to see what my lymphs show next month. My specialist merely did another 3 month appointment; I didn't appear to have really active CLL which he monitors more closely.
So I wonder if/how the fluctuations, as well as the actual numbers of uMRD, will play out. Since that bit of blood they tested may have had an unusually high "clump" to give that 64 value.
This is something that never leaves my thoughts totally. Ever since diagnosis my brain defaults to cll as the cause for any sense of being sub-par. As a result, I have developed a state of anticipation to see my routine blood labs showing no progression. Now that I am at the five year threshold of relapse expectation, the anticipation is at times more of an anxiety.
Regardless of uMrd, this disease still presents an unpleasant authority over conscious thought such as Sepsure would describe to be the sword of Damocles.
We don't know how repeatable the clonoSEQ measurement is given the same blood sample. We do know the distribution of B cells is not uniform so it could just be sampling variabilities that your numbers went down.
It seems that the USofA for R/R V+O they can use a hybrid dosing scheme. V+O for first line is 8 doses of Obinutuzumab and 11.25 cycles of Ven, with a total of 12 cycles from start of Obin. R/R approved VenR is 24 cycles of Ven and 6 doses of Rituxan.
For R/R V+O they use 24 cycles Ven from VenR and 8 doses of Obin from 1st line V+O.
The hybrid Rituximab/Obinutuzumab dosing is a new one I haven't seen before. But since both drugs are FDA approved, they can mix and match, perhaps. Or is it that they saw you did FCR, started Rituximab monotherapy, and then decided to change to V&O?
For second or third line therapy, the NCCN says:
"Preferred Regimens
...
Venetoclax f,h + rituximab (category 1)
...
Useful in Certain Circumstances"
...
Venetoclaxf,h ± anti-CD20 mAb (venetoclax + obinutuzumab preferred)
..."
Footnotes f and h relate to package instructions for dosing and TLS avoidance.
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Dr. John Allan - Chronic Lymphocytic Leukemia (CLL) Patients @Undetectable Measurable Residual Disease (MRD) after Ibrutinib Plus Venetoclax
What happens to the body if you are MRD negative and keep taking imbruvica?
Blood Negative MRD
Update: I/V CAPTIVATE Fixed Cohort Trial - 4 years later
