Measurable residual disease (MRD) refers to the presence of disease at low levels not detected by conventional pathologic analysis. The association of MRD status as a surrogate end point of clinical outcome in chronic lymphocytic leukemia (CLL) has not been established in the era of targeted agents. Assessing the association of MRD with progression-free survival (PFS) may improve its role as a surrogate marker and allow its use to accelerate drug development.
Results: A total of 11 prospective clinical trials (9 randomized and 2 nonrandomized) including 2765 patients were analyzed. Achieving undetectable MRD (uMRD) at 0.01% was associated with an HR of 0.28 (95% CI, 0.20-0.39; P < .001) for PFS. Median PFS was not reached in both groups (uMRD vs MRD), but the estimated 24-month PFS was better in the uMRD group (91.9% [95% CI, 88.8%-95.2%] vs 75.3% [95% CI, 64.7%-87.6%]; P < .001). The association of uMRD with PFS was observed in subgroup analyses in the first-line treatment setting (HR, 0.24; 95% CI, 0.18-0.33), relapsed or refractory disease setting (HR, 0.34; 95% CI, 0.16-0.71), and trials using time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40).
Conclusions and relevance: The findings of this systematic review and meta-analysis suggest that assessing MRD status as an end point in clinical trials and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.
The results from this meta-analysis of nearly 3,000 patients treated for their CLL with targeted therapies, are covered in this Healio News item;
Measurable residual disease status predicts PFS for patients with chronic lymphocytic leukemia
Rios-Olais and colleagues used data from prospective trials that evaluated targeted agents or obinutuzumab (Gazyva, Genentech)-based treatment to evaluate the association between MRD and PFS for patients with CLL.
Key takeaways:
- Patients who achieved undetectable measurable residual disease (uMRD) had a 72% reduced risk for disease progression or death.
- The findings suggest MRD can be a surrogate endpoint for PFS in clinical trials.
As a result of this meta-analysis, expect more treatment protocols that extend treatment time or add additional targeted therapies or incorporate a combination of these, to increase the percentage of patients achieving uMRD and hence longer drug holidays. Longer remissions should also extend life expectancy, as there will be less risk of running out of treatment options.
Neil
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Ab….so…lutely grateful for this post, Neil, having just finished 3rd line(FCR, acala, and 2 years V+R in BRUIN trial) with marrow and blood uMRD NEG. Hope and grace abound for all in the shining light of this meta-analysis. Thanks for bird-dogging all this for us.
Thanks Neil , more great info .thanks for the nice photo . it brings back a lot of wonderful memories for me having grown up on an island and sailed to tahiti with my wife and children .. blessing , james
Hoping to be in the exception. I have never reached uMRD. My guess is the percentage of us with 17p deletions is less. I'm counting on AI to accelerate drug discovery!
Primarily, as the article states - "assessing MRD status as and end point measure in clinical and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.", and "The findings suggest MRD can be a surrogate endpoint for PFS in clinical trials."
Probable patient benefit - " Patients who achieved undetectable measurable residual disease (uMRD) had a 72% reduced risk for disease progression or death.;", and "longer drug holidays. Longer remissions should also extend life expectancy".
Neil, I have been told that it is impossible to get to uMRD if you are just on Acalabrutinib. I wonder what your thinking is. I'd do anything to get to uMRD and have a drug holiday. Been on Acalabrutinib for 4 years next month. I'm beginning to get joint issues now.
Kate, It is not impossible, just considerably less likely than with combination treatments, particularly those incorporating venetoclax. I don't know the specific percentage for acalabrutinib, but about 10% of those on long term follow-up from an early ibrutinib clinical trial achieved uMRD after four years of monotherapy treatment.
That's given me just a little bit of hope, thank you. However no chance of finding out as I'm not on a trial. Hospital not keen to reduce Acalabrutinib dosage as they consider me to be extremely well controlled. I'll keep talking to them I think.
I don't think that any particular level of MRD is a necessary requirement to take a drug holiday from BTKi monotherapy. Stable disease over a long period, plus a second reason to stop and observe, such as a surgery, might be enough for some doctors to try to stay off and monitor. Discuss it with your doctor.
MRD driven care is a paradigm for fixed duration therapy, though it may become a criterium in itself for stopping or restarting therapy. We need studies of BTKi monotherapy drug holidays, if anyone knows of any.
Hi Neil. Thanks so much for this post. Very interesting! Do you know how they defined MRD? I am on Majic and achieved MRD 10-5 but not to 6 as they want to see , and so I am on the doublet of A and V for another year. Just curious what your thoughts are .. would I be considered MRD for the purposes of this article ? Thanks again for all you do !
This paper uses uMRD4 or under 1 CLL cell in 10,000 white blood cells or 0.01%. "Achieving undetectable MRD (uMRD) at 0.01%" You achieved 10 times better at less than 1 CLL cell in 100,000 white blood cells or uMRD5. I achieved uMRD4 in my AVO clinical trial treatment in 2020 and I'm still in remission.
Neil - my hubby has the same protocal - he's been taking A&V for 2 years now - can you share how long you took A&V? Thank you- I'm hoping my hubby will too get int o URMD
On the AVO or AV protocols used in the ACE CL-311 trial I was on, acalabrutinib was given for 14x4 week cycles. The venetoclax ramp up began after 2 cycles of acalabrutinib for a total of 12 cycles. My arm with obinutuzumab started the 9 infusions of obinutuzumab in cycle 2. I achieved a complete response with incomplete recovery of my platelets 5 months after starting the trial. (CRi).
Thanks for the update Neil. It's very timely. I will be switching therapies next week after being on Venetoclax monotherapy for exactly 2 years.
Though I didn't achieve uMRD status, I came very close - 0.025%. Dr. Furman has decided to put me on Zanubrutinib monotherapy. His goal and mine: to keep the cancer tamped-down for as long as possible while moving towards uMRD. Not sure if I'll get there with BTKi therapy but one can only hope and dream.
A Smiley Face with two hands up showing a V for VICTORY!
Thank you for the posting the article. Very encouraging. Promising. Treatments/treatment protocols are getting better and better. The future is bright!!!!!
I'm not sure how MRD was defined in the UK when I had chemo in 2012, but was told I'd reached it - I think it may have been less than 1/10,000... in any case, I'm still in remission and have more or less assumed that I'm 'cured' to all intents and purposes. Time will tell.
We should add that MRD4 - 0.01% or 1 CLL cell in 10K WBCs - is an arbitrary level that simply makes comparison of studies easier and was inexpensive enough. There's nothing inherently good about that level. People who are stable at a higher level (>1 in 10K) will still have a long PFS and TTNT. So our goal should still be stability, and not simply uMRD. MRD simply allows comparison of studies and indication of earlier progression than currently standard lymphocyte counts.
Also, as noted in previous posts, PFS and TTNT are not necessarily the same, either, because of definitions. One can progress but not have symptomatic disease for awhile. MRD changes the perspective on progression, because it doesn't simply look at lymphocyte counts.
The question of when to re-treat based on MRD level is still being debated. Some doctors favor treating before the currently standard signs of symptomatic disease on the theoretical rationale that multiple fixed duration treatments could give longer PFS and prevent some accumulated clonal mutations.
Having been through an MRD driven treatment myself, I wonder how much longer a remission I might have if I had continued longer. I'm sure there's a diminishing gains sort of math, and it will be years before we see any sort of calibrated comparison trial to dial into specific numbers of months. The number of months of treatment in trials are arbitrary and confusing. So we see 12 months/13 cycles vs 15 cycles, 18 cycles, or 24 months in first-line treatment, each with varying lengths of extended treatment if detectable MRD.
Current trials use tougher MRD standars, especially uMRD5, while reporting on uMRD6 as well. So we will see a comparison of longer treatment to achieve uMRD5 produce a longer remission than older, shorter trials that shoot for only uMRD4.
Finally, the biggest caution about MRD testing is that it cannot see into lymph nodes and spleen at all. People with greatly enlarged nodes and spleen may suffer faster relapse, despite achieving uMRD.
It excluded CLL14 because they didn't find uMRD4 data. CLL14 published uMRD4 results in April 2023 (page 5 below). Obviously this was too late to update the presentation for the above presentation.
CLL14 Ven-Obi 76% reached uMRD4 at the 3 month follow up. If this trial's uMRD4 results had been used as trials end point everyone should be having Ven-Obi. Disappointingly PFS is not commensurate with this uMRD4 result.
There are trials of I+V that have shown PFS depends on both treatment and genetic mutations and not uMRD4 for some genomic profiles.
GLOW trial of I+V for subjects without TP53 aberrations, reports that MRD is not a prognostic of PFS for IgHV mutated (m-CLL) but is for IgHV unmutated (u-CLL). 40% m-CLL v 60% u-CLL attained uMRD4. 4-year m-CLL PFS 90%, u-CLL PFS 64%. Quite contrary to the findings of the original post's report. The GLOW trial had 32 m-CLL and 67 u-CLL, when combined the u-CLL swamped the signal from the m-CLL but the forest plot in the ASH presentation linked above for this trial crosses the unity line.
FCR showed that CLL can't be painted with a broad one size fits all brush. Too many n=1 unicorns.
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