MRD doubling time

[johnliston]

Has anyone seen data or have a feel for what is cosidered slow vrs fast time for MRD to double after fixed duration therapies?

john

[SofiaDeo]

At higher lymphocyte numbers, mine seems to have stayed approximately the same (4 months).

Remember we do get eventual die off, so there are bound to be periods where the lymphocyte numbers don't change as expected.

[johnliston in reply to SofiaDeo]

Right now mine's about 4 months also, I wondered how that compared to others.

[SofiaDeo in reply to johnliston]

Your recent Rituxan treatment may help tamp down lymphocytes, in addition to helping your platelets. Not sure if or how the oral steroids may affect rituximab effect on CLL.

[SeymourB]

Johnliston -

The CLL14 trial saw MRD doubling less than 3 months in both arms in the first 52 months:

ascopubs.org/doi/10.1200/JC...

Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study

Journal of Clinical Oncology, Volume 39, Number 36

[SofiaDeo in reply to SeymourB]

This is true, but the numbers of patients in each arm was what, fewer than 150? And MRD "doubling" was still low enough that these patients were still uMRD 4. Disease behavior at very low levels has not been broadly characterized to my knowledge.

The median time in the V&O arm until they technically became out of uMRD4 was 21 months. So this "3 months doubling time" didn't stay the same rate across the time of the study. And this study conclusions were more about how depth of remission at the end of treatment correlating with continued CLL growth, how those who reached uMRD faster took longer to come out of it, and postulated treatments could be modified to consider *not stopping* until a deep uMRD was attained.

MRD doubling time was not discussed in the conclusions, so we can't pull those data points that were reported and make a conclusion from them. We can say this occurred in these 300 patients, but I wouldn't want anyone to try to think this definitely applies to them. Or that a measurement taken early in to a remission will stay steady-state going forward.

For example, my history shortly after diagnosis, and outside of remission, has overall seen my "lymphocyte doubling time" as calculated from a CBC to be 4 months. The NGS number of CLL cells reported when I stopped venetoclax was 12 per million. A year later it was in the 6400's. Much more than "90 days". And yet the CBC taken 3 months after that 6400 reading, had my lymphocyte count lower than the previous. My specialist commented he was surprised, he thought it would be higher. So the data points in that study are information, but no one did any kind of math to be able to extrapolate it out.

I believe this is why docs don't get much concerned until lymphs go above 30,000. At low levels, who knows what is going on. Levels obviously bounce up & down. Once the tumor burden gets large enough, then they start monitoring it to see if & how it's affecting other systems. And apparently, once the tumor burden gets large enough, the doubling time becomes more of an indicator of how aggressive it is.

I am really glad you referenced this study, it's fascinating how the researchers are trying to help determine *how deep* of a remission, and for *how long*, will correlate with remission length, as well as disease progression. Talk about being able to customize treatment for each patient! Very exciting IMO.

[SeymourB in reply to SofiaDeo]

SofiaDeo -

Great observations!

I'll be digesting these papers in light of your comments for days, because I'm in the same boat, having been on a Fixed Duration therapy and getting repeated MRD testing, quarterly for the next 2 years at least.

[SeymourB]

Johnliston -

VenR mean doubling time:

ncbi.nlm.nih.gov/pmc/articl...

Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab

Blood. . 2022 Aug 25; 140(8): 839–850.

"Median MRD doubling time post-VenR EOT was 93 days, with 19 months from uMRD to MRD conversion and another 25 months from conversion to PD."

So, unless I'm misunderstanding the definition of MRD Doubling Time, I think you're doing great.

I'm still looking at papers and taking notes. I thought I had seen a graph in a webinar that some people see a rise in MRD numbers and then a plateau, while most saw a steady rise, and others a more dramatic rise.

=seymour=