The last day of my treatment is Sept 16th, the treatment went without a hitch. After two weeks all my blood test were within the normal range. My question is, How long after the end of my O+V treatment should a uMRD test be given. My doctor told me that testing for uMRD was not standard but I am requesting the test regardless of past practices.
Good Luck Everyone
Hi Test_Tech
Ridgid/Structured HMO like organizations like the VA (Veterans Administration) will likely argue that the MRD results don't provide actionable information. No treatment decision can be made from the results.
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Some clinical trials are using MRD results for data tracking to show that MRD-U predicts a longer PFS (Progressive Free Survival). But that is data only useful to the scientists, not the individual patient or their medical team. It might be useful, in the future, to determine if rather than a fixed duration treatment it would be better to treat until the patient reaches MRD-U.
I believe those MRD tests are done immediately at the time treatment is stopped.
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Len
This month, the journal, Blood, included two articles on the topic of how uMRD may be used in the future, prompted by the five-year follow-up to the MURANO trial. One is titled "Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab" and the other "uMRD: “the” endpoint or “an” endpoint for CLL?"
In the second article, the authors, Adam S. Kittai and Jennifer A. Woyach write that the five-year follow-up to the MURANO trial and the frontline CLL14 trial have put some questions about the role of uMRD to rest for venetoclax/antibody combinations.
"In both trials, treatment with venetoclax/antibody induced high rates of uMRD, and uMRD predicted long-term PFS. These 5-year data continue to show that attaining uMRD leads to improved PFS, and, similar to CLL14,7 show a slower MRD growth pattern for patients treated with VenR vs chemoimmunotherapy, and critically, improved OS for patients who attain uMRD compared with those that do not."
"In the long-term follow-up of this group of patients, the investigators report the median time to conversion to MRD from uMRD was 19.4 months, and median time to progression of disease (PD) from MRD conversion was 25.2 months (see figure). Patients at the highest risk of converting to MRD, which are also the same patients who had worse overall PFS and OS, were those patients that had unmutated IGHV, del(17p), or genomic complexity. "
"Although it is reassuring that the time from MRD conversion to relapse is long, based on these data, the question can be raised of whether some patients would benefit from continuous venetoclax, as opposed to time-limited therapy. Although this approach should be studied for select patients, continuous venetoclax may lead to the development of resistance mutations,8 clonal hematopoiesis,9 and cumulative toxicity, all of which would be expected to be less common with time-limited approaches."
"These data confirm that uMRD is a viable surrogate endpoint for survival with venetoclax/antibody regimens. Two important questions remain: What is the ideal way to test for MRD, and what is the optimal cut-point for MRD assessment?"
The article concludes: "5-year follow-up of the MURANO trial continues to show deep and durable responses to VenR in patients with R/R CLL. It further cements the use of MRD testing as a surrogate for survival in patients with R/R disease treated with VenR. Therefore, we would assert that MRD is “the” endpoint for venetoclax/antibody treatment in CLL."
Adam S. Kittai, Jennifer A. Woyach; uMRD: “the” endpoint or “an” endpoint for CLL?. Blood 2022; 140 (8): 797–798. doi: doi.org/10.1182/blood.20220...
John F. Seymour, Thomas J. Kipps, Barbara F. Eichhorst, James D’Rozario, Carolyn J. Owen, Sarit Assouline, Nicole Lamanna, Tadeusz Robak, Javier de la Serna, Ulrich Jaeger, Guillaume Cartron, Marco Montillo, Clemens Mellink, Brenda Chyla, Anesh Panchal, Tong Lu, Jenny Q. Wu, Yanwen Jiang, Marcus Lefebure, Michelle Boyer, Arnon P. Kater; Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood 2022; 140 (8): 839–850. doi: doi.org/10.1182/blood.20210...
Question is rhis goid news - from what I read above -' the conversion was 25.2 months Patients at the highest risk of converting to MRD,... which are also the same patients who .... worse overall PFS and OS, were those patients that had unmutated IGHV, del(17p)... "
As you've noted, a group of patients had less durable responses (those with "unmutated IGHV, del(17p), or genomic complexity"). Figure 1 from the article (reproduced here) provides more detail about patient dispositions after attaining uMRD at end of therapy.
The article by Kittai & Woyach asks if some patients might benefit from longer treatment with venetoclax and explains that further research is needed to determine this.
The other question that remains unanswered for now is whether re-treating those whose disease progresses will bring about high responses.
The article by Seymour et al gives a hint, saying that "the investigators provided a glimpse into treatment after relapse, with reassuring data showing that re-treatment with a venetoclax-based regimen or a Bruton tyrosine kinase inhibitor (BTKi) led to high-response rates in patients treated with VenR"
The ReGenV trial, a phase 2 study of venetoclax plus obinutuzumab retreatment in patients with relapsed chronic lymphocytic leukemia (CLL), will provide further important insights.
clinicaltrials.gov/ct2/show...
So, while there is some disappointing news regarding the durability of response in some patients, there is also very encouraging news regarding ways to deal with that and very encouraging news for those patients who do not sit in a higher risk category.
In addition, so far as those patients who are TP53 mutated and/or have a 17p deletion are concerned, the preferred initial treatment still appears to be a BTK inhibitor although the recent use of ibrutinib plus venetoclax may provide a viable way forward for these patients, too.
Well, Medicare now pays for it, so it's definitely a "standard of care." It's "not standard" in the sense that the tests are fairly new and there aren't decades of use or detailed protocols behind them right now. Protocols are being developed, as others noted. My CLL specialist recommends verifying a patient is uMRD before stopping, not just blindly following whatever a protocol recommends. If it takes you 6 more months, or another year, to reach uMRD, the chances of a deeper remission increases. It's why the test was developed in the first place, docs needed a way to verify a patient truly was in a decent remission before stopping meds.
How is uMRD or MRD tested? Is it by flow cytometry?
There's several different tests. Blood or bone marrow may be used. I had a bone marrow biopsy after Campath SC treatment late 2012 and flow cytometry done that indicated no abnormal cells At.All. While there seems to be a close correlation between blood and bone marrow, I have bone pain which I am told is unusual so I didn't want a blood test. If I had a SLL presentation I personally would be asking for any large nodes remaining after treatment to be biopsied, looking for residual disease that may not show up in blood.
The most recent uMRD Jan 2022 used the NGS testing from Adaptive Technologies, which requires a baseline sample (pre treatment). I once again did bone marrow. I don't know it this place also does blood or if a baseline is needed for blood. It was 12 CLL cells in a million, which is technically uMRD. This was after a year of Venclexta. We are re-doing the test in December to see if I can take a drug holiday.
CLLSociety.org has a lot of information on uMRD, testing, where it may be used clinically, etc.
I just finished, I had my bone marrow biopsy which showed I was completely void of cancer cells on July 21. I kept taking V until August 2 when we did confirming CT scans and an MRI of my foot (which was special deal because i had a gout tofus that had to be surgically removed and was full of cancer cells at the time, to confirm it had not returned. So I officially stopped V on August 2nd, and that is the official time of my uMRD diagnosis result. I started the drugs on July 17, 2020.
KevinCLLITP, absolutely great news for you. It's also a wonderful hope for the rest of us that treatment does get good results. I'm so happy for you. Kevin, you previously posted you are having trouble recovering your "old self". Your moods and energy have been "off". Prayers are still rising to the heavens for a complete healing.🙂Sandra
Thank You Kevin
I hope you get the answer you're looking for.
In standardising terminology we have moved from Minimal Residual Disease (MRD) to Measurable Residual Disease (MRD), which makes sense as long as you qualify it with the measurement system you're using or can assume the threshold value is 10^-4 (this will change in time).
But where is the logic in retaining a pair of opposites, Undetectable Measurable, to describe Residual Disease? It's one adjective or the other. Both together is a dog's breakfast.
😊
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Silent hypoxia; measure your Oxygen 
