Just wondering……. I just completed two years of treatment in the V plus R arm of the LOXO trial in July 2024. Had a great response: MRD negative in blood and bone. This is my third line of treatment after FCR in 2012 followed by a trial of acala in 2017-22. The LOXO protocol provides that if I make two years without relapse, I can be retreated when necessary with the V. I know there is no research on it yet. But it occurs that since I am not being treated with V any further, when I do relapse, it will not be to the V itself. Am I incorrect in this? If I am correct, I am wondering whether I might be able to get retreatment with Veneto in repeated episodes until it is no longer effective. I know there are pirto, CAR-T, and degrader trials waiting in the wings. But just trying to buy more time until the next great leap forward in treatment arrives. Any thoughts among our august group?
Thanks,
Bud
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Agiledog
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You are I are in similar situations, and each time I try to engage Dr. Furman in a what's next discussion, he reminds me that everyone of the 5 times we had to make treatment decisions, the options available and overall landscape were new and changing quickly. So projecting more than a month ahead of the decision was a waste of time. So he tells me to wait until we get to the juncture and instead of plan A or B, we will likely have F & 32 to consider. LOL
You and I share the same CLL specialist, Richard Furman. I thought you lived in England. How did u link up with Dr. Furman and his faithful ‘sidekick’ Leslie Rudolph?
Of the 9 Admins & Moderators here, 6 are in the UK, 2 in Australia, and I'm the only one in the USA.
After being diagnosed in 2008, I had a bad experience with a local hematologist in Oakland CA, and found Dr. Furman on CLLSLL-Yahoogroups.
Since my wife is a Brooklyn girl, she believes that the only good doctors are in NYC. So we flew in to see him in 2010 and I joined his clinical trial in 2012 to avoid Chemotherapy.
Idealalisib worked for 30 months, ibrutinib for 9 months, venetoclax for 6 years, acalabrutinib for 1 year, and pirtobrutinib for 15 months so far.
That's VERY helpful to know you're the lone US connection.
Also, you've been dealing with this disease a lot longer than me. Even though I was pretty sure I had CLL back in 2016 (my sister has been navigating CLL since 2012), I wasn't officially diagnosed until Jan 2019.
After receiving subpar care locally, my sister - with the help of her husband and other medical professionals in our extended family - found Dr. Furman. She was accepted into his practice ~2015/2016. I simply tapped into her pre-existing relationship with him when my local family doctor confirmed my 'journey' had begun.
Not surprisingly, he was intrigued by our family's history with blood cancers. Three out of 4 siblings have either CLL or Waldenstrom's.
The GOOD NEWS: she is now in remission; I hope to be shortly.
I did First therapy IOV second OV third Venetoclax because it was mostly marrow involvement 90% when I was down to less than 5% in the bone marrow a Waldenström clone appeared and I was switched to Brukinsa The treatment went good. My former hemoglobin which was 5 is up to 10,8 and my bloodwork is almost normal now. However CLL and Waldenström are very aggressive clones in my case CLL Ki67 of 21 Waldenström Ki67 of 25 This is a cell dividing factor which I think is normally less than 10 in CLL.
We are also in similar situations. I am on Trial 20-044, achieved MRD -6 at 6 months, am now back on WW. My Dr. said if I remain WW for two years I can do O &V again. I asked is it two years from when I started medication or two years from when I stopped medication? He didn't answer, just said by the time you need medicine again there will be even more lines of treatment available. Still, I would like to do O and V again and save other lines for later.
Most of what I've read is that they don't see known drug resistance mutations in people treated for a year or less. Between a year and 2 years, it's possible.
Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax. Int J Mol Sci. 2023 Mar 18;24(6):5802. pmc.ncbi.nlm.nih.gov/articl...
"Screening for BCL2 G101V and D103Y mutations was performed on samples obtained from 67 R/R patients using locus-specific ddPCR assays designed and optimized for the sensitive (10−4) interrogation of these two mutational hotspots. BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with 4 patients carrying both alterations. The two variants were detected after a median of 15 months (range: 5–48 months) of venetoclax therapy with 90.9% (10/11) of the affected patients experiencing relapse or disease progression."
The 67 R/R were not a representative sample. Most had high risk markers like you:
"Del(17p) status analyzed by FISH and TP53 mutation positivity screened by targeted NGS were available in 94.0% (63/67) and 83.6% (56/67) of the cases, respectively. Patients harboring del(17p) and/or TP53 mutation(s) comprised 40.3% (27/67) of the patient population. Additional cytogenetic aberrations including del(11q), del(13q), and trisomy of chromosome 12 were identified in 22.4% (15/67), 22.4% (15/67), and 11.9% (8/67) of the cases, respectively. IGHV mutation status was assessed in 52 patients, with 82.7% (43/52) of them carrying unmutated IGHV (IGHV-U). Patients with high-risk genetic features associated with adverse prognosis including TP53 aberrations, and IGHV-U status represented 83.6% (56/67) of the study cohort, which together with the failure of prior therapy lines depicted an R/R patient population typically selected for venetoclax therapy."
But those 4 who had the resistance mutations are a tiny subset.
I think the 2 years without a relapse requirement is to try to separate aggressive relapse from less aggressive. i.e. if you relapse after 2 years, maybe the Ven didn't work well, and you should pick something else.
There's a ton of data on continuous venetoclax in relapsed/refractory CLL, but not as much on fixed duration. But I'm sure there is data from people who stopped continuous Ven due to adverse events. But whether you can find your demographic within such reports is not so hopeful, I think.
I'd say you have a lot of options. Ven plus Pirto is a possibility (I like combos for beating resistance mutations). Sonrotoclax might be ready by the time you are, so repeating Ven might be moot.
This is a timely article for me as I have been second guessing my decision to stop Ven at 17 instead of 24 months, although it has been 6 months since stopping.
It sounds like I could have been tested for Ven resistance before I stopped treatment. My oncologist had told me that the numbers were too low to test, but this article seems to say otherwise.
I had reached 4/10,000 MRD at 12 months on Ven and at 14 months started having a gut feeling that I was going to develop resistance if I completed the full 2 years. So I had a repeat BM Bx at 17 months and was at 8/10,000. Although it is within margin of error for comparison, it seemed to me that I was not getting any closer to MRD neg so I stopped.
I just need to find out where to go to have these resistance tests done????
Venetoclax resistance testing was not available commercially mm 2 years ago. Only a few research labs had the capability, I also asked this. My specialist is very very involved in research, and I was told "no". So unless your oncologist was part of the research group doing this study, there was no place to send a sample to get tested even if your lymph number was high enough.
The current US specialist consensus thinking is, if you go about 2 years in a "remission", repeat treatment *may* be considered. Of course, this would be more or less patient specific, docs may have good reasons to NOT want to prescribe a repeat course.
I never got zero CLL on Clonoseq when stopping venetoclax after 2 years. My number was 12, and I have 2 dominant clones. My NGS number was mmm 6400? the year after that, but my lymph numbers hadn't jumped appreciably at the appointment after that, which my specialist commented was unexpected. He had expected my variant to grow quickly. It took another year for my lymphs to hit "normal" and then the doubling time is back to approximately 4 months. He has said I can repeat ven if I wish. I had few side effects, just a single bout of neutropenia during induction that resolved within a week without fever. I have no other major comorbidities; anxiety, depression, and fibromyalgia aren't in the same category as diabetes, cardiovascular, respiratory, or other major organ system disease.
So you just have to wait, I guess. You had severe side effects, yes? Your doc may argue against a repeat based on that, and want to try something else to see if there would be fewer side effects. I too second-guessed my decision to stop at 2 years, before attaining zero on the Clonoseq. But 2 years of a drug holiday has been great. FWIW there is a new study coming out this spring sometime, comparing venetoclax and sorontoclax. If you suddenly relapse, perhaps this is something you could do.
Sounds reasonable to me. I was told if remission was 3 years or greater, I could do repeat of Venetoclax as I was able to withstand the one year of Venetoclax. Blessings.
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