Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease

[Jm954]

From the New England Journal of Medicine 10th December 2023

"The CLL treatment landscape has been transformed by targeted drugs. Continuous BTK inhibitor therapy has improved outcomes in patients with CLL. Fixed-duration venetoclax in combination with obinutuzumab or ibrutinib has also been shown to improve patient outcomes.

However, only trends toward improvement in overall survival have been seen as compared with chlorambucil and obinutuzumab. These approaches are based on the principle that “one size fits all,” and therapy is not individualized on the basis of response. Using MRD to define the duration of ibrutinib–venetoclax treatment, as in the FLAIR trial, may result in improved outcomes, allowing the individualization of therapy based on response in real time.

In this UK FLAIR trial, MRD-guided ibrutinib–venetoclax, including individualized treatment duration beyond undetectable MRD, resulted in significant improvement in progression-free survival and an apparent benefit with respect to overall survival among patients with previously untreated CLL.

The positive outcome of the FLAIR trial appeared most marked in patients with IGHV-unmutated CLL, with substantial improvements in progression-free and overall survival. However, a benefit was not observed in patients with IGHV-mutated CLL. MRD-defined ibrutinib–venetoclax resulted in better outcomes than FCR in all conventional cytogenetic subgroups, with particularly marked improvement in patients with ATM-deleted CLL.

In this cohort of the FLAIR trial in which patients with previously untreated CLL were randomly assigned to receive ibrutinib–venetoclax, ibrutinib monotherapy, or FCR, we found that MRD-guided ibrutinib–venetoclax was superior to FCR with respect to progression-free survival (97.2% vs. 76.8% at 3 years); results for overall survival also favored ibrutinib–venetoclax over FCR (98.0% vs. 93.0% at 3 years). The results appear better than those in previous studies of ibrutinib monotherapy or venetoclax, as monotherapy or in combination with anti-CD20."

More detail here: nejm.org/doi/full/10.1056/N...

Jackie

[Newdawn Administrator]

Excellent info…thanks Jackie.

Newdawn

[mrsjsmith]

Agreed Newdawn and thank you for all your hard work Jackie. Sitting having IVIG so something to read to relieve the boredom.

Colette

[annmcgowan]

Thank you Jackie.

Ann

[hope-73]

That’s very interesting, thanks. Unfortunately, at the moment I believe it is the one size fits all approach being followed but hopefully these results will change things

[Jm954 Administrator in reply to hope-73]

Not necessarily so in the UK and I hope these results will encourage more MRD testing.

I had Venetoclax treatment outside a trial and my treatment length and decision to move to allo SCT was driven by my MRD results. However, my consultant was one of the authors of this paper so I know I am lucky.

[LeoPa]

"After 5 years of ibrutinib–venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. " - Oh my, this beast is hard to scrub out.

Now could they test taking this combo for 3 months and then stop, wait and see how long before progression? Then take it again. That would be a more tolerable regimen if it worked.

How are you doing Jackie? How were your last 3 months?

[Jm954 Administrator in reply to LeoPa]

I'm doing well thank you, just my continuing anaemia that is challenging

[LeoPa in reply to Jm954]

Thanks, may it improve soon!

[SofiaDeo in reply to LeoPa]

This sounds like a good way to select for resistence! The idea behind MRD guided treatment is to "tamp it down to below X before pausing, as opposed to fontinuing for extended times once X is reached"" not "do short term treatment whether or not X is reached". And X has yet to be determined precisely, although my understanding is that initial studies are looking at uMRD 10-4 as a starting point.

[LeoPa in reply to SofiaDeo]

How does it select for resistance? And how do we know that resistance would develop faster than during the standard treatment? What if it did not? I assume resistance sooner or later develops in most cases. Probably younger and fitter patients would benefit from pushing till MRD, while older and frailer patients with shorter life expectancy due to other health issues, from a gentler approach.

[johnliston]

Jackie , what are the currently available front line treatments in the UK?

john

[Jm954 Administrator in reply to johnliston]

nice.org.uk/guidance/TA931/...

nice.org.uk/guidance/TA891/...

nice.org.uk/guidance/TA689/...

nice.org.uk/guidance/TA663/...

plus FCR or bendamustine or chlorambucil are still available

[Snakeoil in reply to Jm954]

From this paper it seems like FCR is not going away quite yet:

The positive outcome of the FLAIR trial appeared most marked in patients with IGHV-unmutated CLL, with substantial improvements in progression-free and overall survival. However, a benefit was not observed in patients with IGHV-mutated CLL.

[Jm954 Administrator in reply to Snakeoil]

Maybe not but FCR has other disadvantages which are unpredictable for any individual. They include a 10% likelihood of myelodysplasia, acute myeloid leukaemia, delayed or incomplete recovery of blood counts and more chance of neutropenic sepsis during treatment.

Unmutated CLL patients will almost certainly do well whatever treatment they have and this study only said that there was no benefit observed during the short follow up period of this trial. Longer observation may see the curves widen in favour of the non chemo treatments.

[Snakeoil in reply to Jm954]

I suspect you meant to say:

Mutated CLL patients will almost certainly do well whatever treatment…

There is hope that, for Overall Survival, VI will beat FCR for young IGHV mutated patients but the evidence will take years to collect.

For unmutated IGHV, my reading is that VI wins.

[Skyshark in reply to Snakeoil]

UK NICE doesn't seem to be able to react to developments that indicate FCR is just as unsuitable for u-CLL as it is for TP53 aberrations. I believe that NHS doctors do not routinely offer FCR since the availability of V+O in 2020 and Acalabrutinib in 2021. Both of these regimes are available for all. V+O requires CDF funding for patients that don't have TP53 aberrations but application for this is viewed as a formality. V+I has been added this year without restrictions but FLAIR indicates 15 cycles is not enough and one size doesn't fit all. Zanubrutinib was added last month with same restrictions as Ibrutinib.

royalsurrey.nhs.uk/download...

[Skyshark in reply to Snakeoil]

FLAIR PFS u-CLL 95%, m-CLL 89%. More u-CLL patients reached uMRD4 and reached uMRD4 sooner. But no one had less than 2 years V+I and they stay on V+I for twice as long as it takes to reach uMRD4.

It's odd as all other trials KM plots I've seen (SEQUOIA, ELEVATE TN, CAPTIVATE FD (see chart), CLL14) show m-CLL without TP53 aberrations doing better than u-CLL. FLAIR initially excluded those with TP53 abnormalities and over 75 years old. It was then expanded to include an Ibrutinib only arm and TP53 aberrations but those are reported separately. All patients on FLAIR are "fit" for FCR.

CAPTIVATE FD V+I

[Snakeoil in reply to Skyshark]

Sounds too good to be true for u-CLL.

[Poodle2]

I never quit understand the terms "progression free survival" and "overall survival" - what exactly do they mean? I think I have an idea but it always confuses me. Hope you are well Jackie. Have a peaceful Christmas break. Petra ❤️

[HopeME in reply to Poodle2]

Progression Free Survival is the time between treatments essentially and Overall Survival is how long a patient lives after he/she was diagnosed. I believe that is correct anyway.

[Poodle2 in reply to HopeME]

Ok, thanks Mark, that was my thinking, thanks for clarification. How about median PFS? What does that mean?

[HopeME in reply to Poodle2]

That is the point at which 50% of the patients have progressed or died. Just like any median calculation. 😀. I hope you are doing well.

Thanks,

Mark

[Poodle2 in reply to HopeME]

Gosh, sounds so morbid. Thanks Mark...I'm doing great, thank you. Have been surprisingly quite healthy, much better than last year at this time...so I'm just waiting for the storm🙂hope you are good yourself!❤️

[HopeME in reply to Poodle2]

Let’s hope your storm stays out at sea indefinitely!

[Skyshark in reply to HopeME]

Progression free survival is not time to next treatment. On short duration therapies V+O and V+I it's the time from start of treatment to detectable progression by blood test, just like an initial diagnosis. That will be some time after someone that is uMRD4 has converted to become dMRD4. Once progression is detected (blue line) there is a further time during which it progresses to treatable (grey line).

Link below to CLL14 trial V+O.

Slide 14 shows overall median is 76.6 months. (Blue line on plot)

Slide 17 shows time to next treatment (TTNT), median TTNT has not been reached, it's still around 60%. Median TTNT will be over 100 months - about 2 years longer than time to progression. For the first 3 years of CLL14 trial it was about the same, patients that were found to be progressing needed treatment. After 3 years there is a widening gap between progression and TTNT. This time will be longer for slower mCLL than faster uCLL. (Grey line on plot)

Slide 19 shows Overall survival, this is 78% at 6 years, CLL14 patients had a median age of 72 and were frail or in poor health with a high CIRS score >6, (slide 4). They were not suitable for FCR or BR.

Slide 22 shows conversion from uMRD4 to low dMRD4, to high dMRD and to Progressive Disease. Very few are remaining with uMRD4, it's only a matter of time until they are detected as progressing (I don't think this is a "cure"). Time between conversion from uMRD4 to dMRD4 and progression is difficult to determine, at 18 months about 50% were uMRD4, it could be years or a year.

Slides 23 and 24 show that those that failed to reach uMRD4 have poor outcomes. Unlike other KM plots these 2 are time from end of treatment.

medically.gene.com/global/e...

For continuous BTKi therapy there is usually little time between detectable progression and next treatment. It can be a rush, which has led to trials of "rapid dose escalation" for getting up to full dose on Venetoclax in TEN days instead of 5 weeks, obviously starting with a low but increasing B-cell burden.

MRD - Measurable/(Minimal) residual disease.

MRD4 - MRD tested at 10,000 cells (10^4)

uMRD4 - undetectable MRD4, no CLL cells detected in 10,000

dMRD4 - CLL detected in 10,000 cells.

CLL14 PFS and TTNT quick and dirty overlay