Did a search on this, not a lot of recent discussion, and it's a topic where the findings are changing rapidly. What's the current experience / thinking on sticking with treatment to get to uMRD-6?
My understanding is that it's worthwhile in most cases.
I have achieved uMRD-4 in both blood and bone marrow. However, multiple papers I've come across seem to indicate promise in the idea that achieving uMRD-6 will improve the odds of remission and/or the length of time before requiring further treatment.
My read is that I should continue treatment until reaching uMRD-6 if possible. On current progression/trend of ALC counts, that will likely happen in a few months. I've been in trial for two years already, and I'd rather finish it out. Does that make sense?
The odds in my head are: it's only 3 months additional treatment on drugs that have had tolerable side effects. I've seen some charts indicating the difference between u-MRD4 and u-MRD6 patients can be many more months or years.
I'm in early-stage clinical trial on fixed duration combination therapy, so I do have access to MRD-6 level testing, and cost is not a consideration.
A complicating factor: my CLL is a very fast-progressing case (doubling times <3 mo at treatment start, was in W&W only 18 months). My oncology team tells me that my doubling rate is likely to persist in future progression. As an aside, they're doing extensive genetic testing to identify any confounding factors.
I understand there's a chance I will plateau, and I don't intend to continue indefinite treatment to minimize CLL mutation risk. That was a motivator for me entering clinical trial in the first place. Just trying to figure out if doubling down on my initial treatment round makes sense.
To make sure it's an apples-to-apples discussion...
MRD = minimal residual disease, i.e. we can only find cancer cells below a certain count threshold.
MRD-4 = Standard flow cytometry can detect 1 cancer cell in 10000 / 1 in 10^4 / 0.01%
MRD-6 = More advanced/expensive testing can detect 1 cancer cell in 1000000 / 1 in 10^6 / 0.0001%
uMRD = undetectable MRD, i.e. couldn't find that one cell in 10000 / 1000000
Corrections welcome.
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scryer99
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scryer99, You ask a really good question and you have the right concerns. The question of continuing treatment for a deeper remission, but at what cost. I'm no expert , but I think the risk of selective pressure mutation goes up after 24 months. If you don't get a mutation then potentially you can retreat with the same regiment and have a similarly good response. If you press you may take retreat off the table.
My thought is the disease is not curable in most cases so it will come back. If you can treat it successfully in its current form why not accept that and stop. If you press to uMRD6 and buy an extra year or two of remission but it comes back much more aggressive with new resistance mutations have you traded a longer Progression Free Survival for a shorter Overall Survival?
There are a couple studies out looking to see if merely "reaching a level of uMRD" is sufficient for a decent remission, or if there is some "time after reaching uMRD" that gives an optimal remission.
My experience with varying uMRDs is this. One treatment was 16 weeks, I had a nice deep remission for mmm almost 5 years. There was "zero CLL" in a bone marrow biopsy but the technology available was only to the uMRD-4 level. It was a severely immune suppressing treatment, not as harsh as standard chemotherapy but not quite as targeted. It took out both B and T cells, and I had to have antibiotic, antifungal, and antiviral prophylaxis similar to standard chemotherapeutic regimens. I got my first case of shingles mmm 5?6? months after treatment stopped, even on an antiviral.
I attempted a repeat of this treatment some years later. Circumstances and my health were not the same, and I had an 8 week course of treatment. There was data indicating bone marrow was cleared out by week 8, again at the uMRD-4 level. This remission lasted a year. In retrospect, I wish I had pushed myself to suffer the side effects another 8 weeks. My first go-round was a different time of year, and other than a need for a blood transfusion from anemia, was pretty uneventful. This time it was winter, the travel/living situation/ everything, was different & difficult/stressful.
There's a person here on a trial, who has been taking venetoclax for mmm 5? years, and finally reached uMRD. I don't recall the level of it, but do recall them saying their doc was surprised, they weren't expecting to reach uMRD since they had been on it so long. It was still working, no resistance,
I had a uMRD-6 level of mmm 12? after one year of venetoclax monotherapy. It didn't really change after year 2, and I went off it. So 2 years of drug, no resistance. That number went up to 64 year 3. My doc thought my levels would start to skyrocket as usual, but it took another year for lymphs to rise into low normal, and my more-or-less "4 month lymphocyte doubling time" to start showing. Instead of another MRD test year 4, a flow cytometry was done. About a third of my "low normal level" lymphocytes were CLL ones.
Others here have had various drugs quit working in shorter timeframes. Some have also have 5+ year remissions on standard time limited treatments,
Since you're like me with a fairly aggressive variant, it may be worthwhile to try a few more months to tamp the thing down harder. Especially since severe side effects don't seem to be a problem. Single therapy is more likely to cause resistance than dual, and you are on dual correct? I've stopped one treatment that was "working beautifully" because of miserable side effects. If you aren't having those, why not? You'll gain some useful data about your variant, IMO. Maybe you'll be like me and not able to tamp it down to "zero at the 10-6 level", but maybe you will. You won't know unless you try.
Doubling every 90-100 days, means about a year's remission from each order of magnitude in uMRD. Order of magnitude is the index number of the uMRD, uMRD1, uMRD2, uMRD3, uMRD4, uMRD5, uMRD6. uMRD6 to uMRD4 should take about 2 years. CLL14 trial of Venetoclax+Obinutuzumab (V+O) after end of treatment shows 21 months difference in median PFS between uMRD6 and uMRD4.
GLOW trial of Venetoclax + Ibrutinib (V+I) has found that uMRD4 is not a prognostic of remission duration for mutated IgHV (m-CLL). As yet no one has looked for this in V+O trial data. This fortunate given the reduced number of m-CLL patients on 15 cycles V+I that reach uMRD4.
FLAIR trial of V+I for twice as long as time to reach uMRD4 has lower PFS at 4 years than short duration 15 cycles GLOW or CAPTIVATE FD for m-CLL. The median and mean time on treatment was 4 years for m-CLL (about 40% reach uMRD4 in a year). This is thought to be due to drug toxicity from extended time of treatment. Unmutated IgHV (u-CLL) had a median time on treatment of 2 years (about 55% reach uMRD4 in a year) and mean of 3 years. At 4 years the longest anyone with u-CLL has been off treatment is 2 years and the apparently good results reflect this short duration of drug free remission.
Overall 74% reach uMRD4 on V+O, there isn't any data for u-CLL and m-CLL.
The increase in percentage reaching uMRD4 on V+O compared to V+I is not reflected in PFS durations. They are quite closely comparable.
Chasing uMRD4 (or 6) is vital for u-CLL remission duration but for m-CLL maybe harmful (with cBTKi?).
uMRD is not a thing for continuous cBTKi.
(80% is where I place the divide between acceptable duration of remission and disappointing but obviously disappointing for all those that didn't reach uMRD4.)
The proportion of V+I treated and reportable patients that fail to reach uMRD4 (dMRD) is higher 57/159 (reportable 147) than for V+O 23/212 (reportable 192 ). But unlike CLL14 V+O the median PFS for V+I dMRD is higher. This is likely due to the dMRD having a higher proportion of m-CLL when on V+I.
For CLL14 V+O 15 out of 23 (65% = 35% PFS) dMRD had progressed at 36 months off treatment. For CAPTIVATE FD at 33 months off treatment 20 out of 57 (35% = 65% PFS) had progressed.
Skyshark's data is excellent as always and SofiaDeo makes great points. One thing I'll add is I was at Mayo Rochester yesterday for my cycle 1 follow-up of P+V MRD4 guided trial of between 15-27 months. I've responded really well to the 1st month of Pirto (all nodes are gone to clinical exam, bloods normal) and I was told 15 months is not hard and fast as the first end date, if my response continues to be good. There is a bit of a grey area where they can decide to stop treatment earlier. They added, "we don't want to over treat".
Clinical trial observation suggests that MRD status in leukemia is a strong predictor of relapse, however, a deep remission indicated by a higher uMRD does not necessarily mean that a longer remission will be reached.
The current role of MRD testing in leukemia is to help doctors assess treatment effectiveness, predict relapse risk, and monitor disease status to help guide treatment decisions intended to improve the patient outcome.
However, in my reading about this subject MRD testing in CLL had not yet been admitted as a standard of care in general practice, and in part because many medical centers do not yet have the sensitive testing equipment required for uMRD. A patient related consideration is that the expense is not yet covered by insurance. High sensitivity uMRD is still more of a tool in clinical trial research where it is a standard of measure.
Below is a link to one of the more simplified uMRD comparative publications from August 2022. The publication is only one of many hundreds of articles stating uMRD predictive probabilities.
If in fact uMRD testing is made available as an affordable choice, I for one would choose it as a peace of mind probability. Yet again, the tests speak to themselves and uMRD may not even be reached. For that matter, you may reach it at any time.
If your trial allows the choice, you are strong and healthy, you have a low side effect profile, and it is only three more months to scheduled drug discontinuation?
I just finished 2 year V&, unfortunately was only able to finish 3 cycles of Rituximab. My Clonoseq test in last July came back at 26. I was sure I would get to uMRD before the end of my treatment but Clonoseq in November came back at 109 while still at Venetoclax. I asked if it would make sense to continue Venetoclax a bit longer but he said that research showed that after 24 months most patients reach a plateau. In his view uMRD 6 is something to aim for and great for patients conscience, “all cancer is gone”, but not necessarily an indication that remission will be much shorter if not reached. I do wonder if I could have finished all cycles of Rituximab or obinutuzimab if I would have made uMRD 6 but it was not meant to be.
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