I'm about mid way through the O+V journey. I asked my hemo/oncologist about MRD testing when its over and he replied (as I've since ready many times) that MRD in itself is not an indication of my future or if/when I'll need to go back on an active treatment; they will rely primarily on my CBC and any symptoms that develop. He also said they don't/won't run the test and the reason so many people talk about it, is its done in clinical trials to help gather data.
I understand all of this, but it would still be a "nice to know" and a data point for future cytometry tests that will be run.
If I demand it and they reply inusrance won't cover it, any recommendations what to do next? Is it expensive? I know there are 3 options (cheapest, but least sensitive first): Blood draw, bone marrow biopsy and the NGS. I'd assume the blood draw should not be that expensive?
Or is there some medical reason that a doctor can justify having the test run and covered by insurance?
(reside in USA, with "obama-care" insurance)
I know this issue has been discussed before, but I cant find any posts about people that pushed to have it done when told no.
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You aren't seeing a true CLL Specialist, are you. They are aware of how & why MRD testing is used. I first had it done back in *2012* (flow cytometry on bone marrow) to verify if I was in a remission. My insurance paid. I do have a highly marrow invasive variant. But I am unaware of any billing codes accounting for variant differences, it's one of the problems I had with the various disability insurance folk.
The current thinking is that as a generality, the most effective treatments are time limited, with the treatment continuing until a patient is in uMRD of some sort for 6-12 months. So unless you are testing for uMRD, a simple CBC won't be able to tell. A few here have mentioned their original treatment went longer than anticipated; there's also a few who had shorter treatments. It was based on MRD testing, like my treatment was, and I am not currently in a trial. They didn't get extra medication just because the protocol said "give X for Y amount of time".
A number of trials out right now are trying to determine the best way to use MRD testing in the clinical setting. So saying that "MRD testing is only done is trials" is incorrect, and to me indicates someone who isn't really keeping up with the current CLL literature/recommendations.
Since Medicare pays for MRD testing, most US insurances likely will. Flow cytometry can be done on blood or marrow. Some are having lymph nodes biopsied, if they had extensive nodal disease. I think the "best" test is somewhat determined by how your CLL expressed. I was told several years ago that for an ideal NGS comparison they needed a bone marrow pretreatment baseline, but that may have changed. And if you happened to have a long W&W, with a slow growing variant, with FISH/flow/IGVH showing favorable markers, and slowly crept up to "time to treat", I can also see a case being made for MRD testing to be unnecessary.
MRD testing as a " relevant test parameter" in CLL:
So if you really want one, it seems reasonable to insist at the end of treatment, to verify the depth of remission, or if you should continue on venetoclax a bit longer if your tumor burden hasn't yet gotten to uMRD.
Having a MRD test won't change this unless there's a better response to a dMRD result than "Well that's bad luck, see you back sooner rather than later".
The story coming from CLL14 trial of V+O changed in June of this year (2023).
You need to be armed with slide 23 and 24 of this.
Slide 23 : "Depth of remission correlates with longterm PFS, indicating the prognostic value of the end-of-treatment MRD status."
Slide 24 : "Patients with MRD ≥10-4 after Ven-Obi have a shorter OS than patients with MRD <10-4, highlighting the need for dedicated MRD-guided approaches"
On 18 April 2023 they flagged an amber light but it's well buried in the text.
"In addition, dedicated randomized studies that explore the long-term benefit of MRD-guided treatment extension or intensification compared to continuous or fixed-duration regimens are warranted, since patients with detectable post-treatment MRD levels are at high risk of shorter survival" (my emphasis)
Two years ago everything was green to go, 17 June 2021.
"Fixed-duration Ven-Obi continues to be an effective treatment for all pts with CLL and coexisting conditions."
Other short/fixed duration trials show similar results.
V+I CAPTIVATE poster for ASCO 2023 (this month). Chart on second poster with supplement states.
"4-Year PFS Rates by MRD Status 3 Months After Stopping Treatment Were Significantly Higher Overall in Patients With Undetectable Versus Detectable MRD in PB"
The same will almost certainly apply to any other short/fixed duration therapies. As Ven + mAb and Ven + BTKi both show poor results for dMRD it's down to all other short/fixed duration drug trials to prove that they don't have the same issue. There are lots of questions : What drug to continue with? How long? Does reaching uMRD4 at 18/24 cycles remove the risk? Is there a genetic IgHV/TP53 combination or some prognostic that is more likely to fail to reach uMRD4? CAPTIVATE MRD trial, anyone that failed to reach uMRD4 continued with Ibrutinib with good results but it's continuous. More Qs: Better than if they had only taken Ibrutinib from the start? Was the 11.25 cycles of V a waste of money for these patients? MAJIC trial is MRD guided with stop points at 12 and 24 cycles but won't be giving any answers for about 4 or 5 years.
I think at the current level of knowledge, docs want their patients to be at least uMRD4 before stopping even a time limited treatment. Similar to how my venetoclax got extended another year. I was uMRD at 10-4 but not at 10-6. A second year didn't drop that 10-6 number, but I wanted a holiday after 5 odd years trying to get into a decent remission.
Now I am wondering if I should go back on, if my AIHA is due to the CLL. The rate of my red cell changes since stopping suspect drugs has made my specialist think the drug is responsible, but if I can't clear there has already been talk about "do I want to go back on venetoclax or try rituximab, or what" because I can "feel" the hemolytic process. I can tell "something" is going on & it's not super pleasant. If my ability to sleep normally doesn't come back (I wake up during the night with some sweats) I will likely try some kind of treatment. And I will repeat the NGS MRD test again, after a year is up. I plan on doing that test yearly moving forward, to monitor disease activity.
NGS testing is really expensive (its also the most sensitive to detect the lowest levels of MRD)... where do you live and how did you get insurance to cover it?
I am in the Rocky Mountains USA (noted in my profile) and my Humana Medicare Advantage plan paid for it. At the time of my original test, I think it was around $1800. IDK what it costs now.
In 2019 the test was Medicare approved for other cancers, CLL got covered early 2020. If you don't have a Medicare plan, it may not be covered, and most likely needs a Prior Authorization.
Cost effectiveness for MRD testing has been demonstrated in Multiple Myeloma, perhaps it can be used as a basis to argue for CLL use if the insurance denies.
NCCN Guidelines Version 3.2023, page CSLL-E 2 OF 2 (PDF page 30 in this version)
"RESPONSE DEFINITION AFTER TREATMENT FOR CLL/SLL
Minimal Residual Disease (MRD) Assessment:
• Evidence from clinical trials suggests that undetectable MRD in the peripheral blood after the end of treatment is an important predictor of treatment efficacy.
• Allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) and six-color flow cytometry (MRD flow) are the two validated methods used for the detection of MRD at the level of 10-4 to 10-5.
Next-generation DNA sequencing (NGS)-based assays have been shown to be more sensitive, thus allowing for the detection of MRD at the level of 10-6."
I’ll tell you about my experience with V + O and how MRD testing is playing into it. First, doctors don’t typically conduct this test unless it is done to determine a treatment decision or to gather information for a clinical trial. That being said, when I transferred my care to Dana Farber after my initial treatment (BR ) my doctor did check for MRD in my bone marrow. I believe it is standard procedure to conduct extensive testing upon beginning care at a teaching hospital.
When I started the V + O (second treatment) protocol in December 2022, I took part in a clinical trial which was for the accelerated ramp up of V. I stayed in the hospital for a week and ramped up the V on an accelerated basis. Essentially, I was in a clinical trial within the standard of care for V + O. As part of this mini clinical trial for accelerated V ramp up, I had a BMB done about two months in to check for MRD. I believe I had 8 CLL cells per 10,000 cells at this point. My doctor told me not worry about these MRD results as it was very early in my treatment and the test was being done for research purposes.
In September 2023, I had another visit with my doctor and I asked about MRD testing. He said he would test my blood in December2023 (after one year of taking V) for MRD. The reason being he wants to determine whether I should continue with V for a second year or stop the drug. I believe his thought is if the CLL is detectable in my blood he will have me continue the V for a second year without a BMB as if it is found in my blood it is in my marrow so no need to test in the marrow. However, if there isn’t CLL detectable in my blood we will have a decision to make which is should we do a BMB to see if CLL is present in my marrow? My sense is if there aren’t any CLL cells in the blood we will do a BMB to check the marrow and if I am uMRD there we will stop the V. If I have detectable CLL in the marrow we will continue the V for another 6-12 months. My case may be different from yours as I have SLL and my disease has historically been very active in my bone marrow. At the start of each treatment my bone marrow involvement has been over 90%. My situation illustrates how my doctor may potentially use MRD via a BMB to make a treatment decision (stop V or continue V for a second year).
I hope this information helps you understand the process a little better.
Very helpful! Thank you Mark (and the others who've chimed in). By the way... I'm very aware of that accelerated V rampup trial, as it was offered to me at D.F. as well, but I declined as I didnt want to be in a hospital for a week. I'm still not certain why that 5 day rampup is beneficial vs. the more conservative V rampup over 5 weeks, but I'm sure they have a good reason to run such a trial!
The accelerated ramp up is used for high risk patients (heavy disease burden) and for folks whose schedules don’t allow for a lot of back and forth trips to the hospital, I believe. I chose this method in the clinical trial setting because I wanted to get the process over with quickly and avoid constant blood sticks and back and forth appointments. I had a Picc line pit in which made the many blood tests easy. If I have to make the V ramp up decision again I think I’d do the hospital a second time. Although it’s like choosing CLL treatments in general in that there are often no clear “best” choices. Lots of trade offs between the two methods. I had never spent a night in a hospital before that stay and hopefully I won’t be back soon because six days is a long time.
As far as having the MRD test it may also depend on first line versus second line, CLL versus SLL, etc. I do think insurance coverage may play a part in the process, too. I’m not entirely sure.
I’ve asked about the more precise MRD testing (the initial MRD tests I’ve had at DF were based on 10,000 cell samples). I recall asking about the deeper more precise testing early on in my V + O journey and receiving a non committal answer. I hope to get the more precise MRD test via bone marrow if it comes to that. Interestingly, as I think about my situation I realize that I’m not sure whether my upcoming MRD blood testing is the more precise 1: 1,000,000 test or the less precise 1: 10,000. Hmmm. I’m taking it day by day. Unfortunately, I’ll have many more appointments in my future. I asked my doctor about how long V + O might hold my disease and he said it could be 2-5 years but it’s impossible to tell as anything can happen.
Good luck in your journey and it is a journey. I’ve just started my seventh year.
The original purpose of Rapid Dose Escalation (RDE) was to transition patients on to Venetoclax that had started to fail on BTKi. Coming off BTKi can cause a flare.
Why they let someone on treatment ever reach the point that they are "medium risk TLS" let alone become "high risk TLS", beats me.
I think there's concern about "treating too early" when the CLL isn't impacting other organs/health significantly. The treatments have side effects, including concerns about mutagenic side effects. With our CLL rarely being 100% eliminated, and multiple treatments possibly ending up with CLL resistant to one or more drugs, the idea wanting to "always treat early" isn't there. I am an advocate for "don't drag out time to treat if you're feeling awful or want to treat" but if one got the diagnosisthrough routine testing, and appears asymptomatic, why do it? What if that person ends up as one of the 1/3 who never needs treatment? One member here has written how they noticed a significant die off after like 7-8 years, without treatment. They've been lucky enough to not have significant marrow involvement (based on not being urged to start immediately due to neuts, RBc's, etc.). So some can get high levels of cells before marrow/nodes start affecting things, and the wait even if one reaches medium or high risk TLS can gain some of us at leastseveral more years. My neighbor with CLL went mmm 6-7 years after diagnosis before he *had* to do something, even though his hem-onc (not a CLL specialist) urged him to treat at diagnosis. So his lymphocyte number climbed all those years, but nothing affected his to "need to treat" for quite a while.
It's one thing if someone *wants* to treat early, or if one has markers that may mean more problems down the line that some researchers are talking about treating earlier than conventionally, but with the monitoring and drugs available now, TLS isn't likely unless one isn't following induction protocols. Plus, until/unless one gets a CT, one won't know about any large internal nodes, not everyone may get a CT. I looked like a medium risk until the CT showed a single large node. But my specialist wants to treat all his patients with enlarged spleens as "high risk", and get hospitalized, and I was fine with that.
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Developed AIHA while only slightly MRD positive 
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Unmutated CLL and MRD-
