Remission

[Vinweesel2023]

Does CLL ever go into total remission where a person no longer has to take Acalabrutinib or is it referred to as medical remission. My oncologist has told me that I will be on it for the rest of my life. She might reduce the dose to 1 x's per day.

[Yuck]

Hi!

After six successful years, you might stop for a long multi-year break until numbers eventually call for more treatment. Hope this comment helps and all continues well!

Good luck!

~ Yuck

[AussieNeil Administrator]

CLL is considered incurable. The only proven cures in a percentage of those treated, being provided by allogenic stem cell transplantation of someone else's immune system or FCR chemoimmunotherapy treatment. Stem cell transplants become increasingly risky with age and you can end up with unpleasant long term Graft vs Host disease symptoms. FCR only gave long remissions for mutated IGHV folk, with about 55% achieving extensive ones, with some managing 20+ years of living without needing to repeat treatment. Problem is, you ideally need to be under the age of 65 to tolerate treatment, plus there's an increased risk of developing Acute Myeloid Leukaemia or Myelodysplastic Syndrome.

In this new era of targeted therapies, we are still learning how long remissions can last between treatments when the amount of CLL remaining after treatment is very, very low (achievement of uMRD or undetectable or unmeasurable Minimal Residual Disease). The problem with BTKi treatments like acalabrutinib, ibrutinib, zanubrutinib etc, is that while they are very good at keeping CLL under control, they struggle to eliminate all the CLL. On an early ibrutinib clinical trial, only 10% of the trial patients managed to get to uMRD after 4 years of treatment. We are finding that some people can go off a BTKi treatment and have remissions of a year or more, but in some, the CLL can quickly come roaring back. It depends on the CLL prognostic markers as well as the depth of remission.

Adding other drugs in combination with a BTKi generally improves the likelihood of getting to uMRD and having a drug holiday, but again, how long that may last, depends on prognostic markers and how little CLL remains after treatment. Venetoclax works best in combination with a BTKi, but you need to be on venetoclax and the BTKi for a year or more to hope for a reasonable length drug holiday. We are still discovering how long these remissions can last after combined targeted therapy treatments, with research of them only going back a bit over 6 years, with the first 1 to 2 years being treatment time.

So currently, what your oncologist has advised you is pretty well correct - stay on acalabrutinib, perhaps on a reduced dose if your CLL can still be kept under control, for as long as it can do this before resistance develops. You might be able to add venetoclax or get to the point that there is so little CLL left, so that you can have a drug holiday. Watch for developments reported here and explore future options for possibly having a drug holiday with your oncologist when we know more about the possibility.

Neil

[roszika in reply to AussieNeil]

Aussie Neil- I have meant to ask you this for a long time- Are you yourself a doctor or qualified in some medical field because your knowledge is way more than most of us on this forum. I don't mean to get personal but I am impressed with your extensive knowledge and once again I would like to thank you for a post back in late 2018 where you spoke of a very good CLL specialist and I have been his patient since 2019 and I think he saved my life- Cheers.

[AussieNeil Administrator in reply to roszika]

Thanks, I'm glad I was able to help. I don't have any medical qualifications - I've just done a lot of self study for self preservation purposes and decided to share what I've learned

[Stacky66 in reply to AussieNeil]

Think you should become a Haematologist, seriously your knowledge is immense 👏🏻👏🏻👏🏻

[Aerobobcat in reply to AussieNeil]

Yes, I too have gained much from your knowledge and expertise.

Aerobobcat

[bennevisplace in reply to AussieNeil]

Thanks for those valuable insights Neil.

The ongoing IFCG phase 2 clinical trial is intriguing, in offering "low risk" CLL patients* durable remission (potential cure?), with a combination of chemotherapy and immunotherapy drugs: fludarabine, cyclophosphamide, ibrutinib and obinutuzumab. The two chemo drugs FC are given for 3 cycles, half that of the FCR treatment regime, in order to lessen the risk of treatment-induced cytopenias and MDS.

* IGHV mutated, no TP53 or 17p mutations

From the 6-year follow up report published last November:

41/45 pts completed 12 cycles of treatment (4 pts came off study prior to Cycle 12). All 41 pts achieved marrow U-MRD and per protocol, discontinued ibrutinib. After a median follow-up of 61 mos post-discontinuing ibrutinib, 8 pts had MRD recurrence (defined as 2 consecutive values of ≥0.01% in peripheral blood by flow cytometry) at a median of 32 mos (range, 20-67 mos) after stopping all therapy. Of the 8 pts with MRD recurrence, 2 pts had clinical relapse (described below); remaining 6 pts are being monitored with no clinical progression or active therapy.

The 6-year PFS and OS are 92.2% (95% CI= 77.7-97.4) and 97.7% (95% CI= 84.9-99.6), respectively

sciencedirect.com/science/a...

[Skyshark]

Complete Remission or Complete Remission with incomplete hematologic recovery (CR/CRi) rate gradually increases over time on Acalabrutinib.

nature.com/articles/s41375-...

In the acalabrutinib-containing arms, the CR/CRi rate increased from the primary analysis at 28.3 months (...; acalabrutinib: 7.8% [9]) to the current report at a follow-up of 4 years (... and 11.2%, respectively

People stop due to intolerance/AE at a faster rate.

Further increases have not been reported in 5 and 6 year reports. 20/179 that reached CR/CRi at 4-yr were tested for MRD. Just 2 out of the 20 were uMRD4, the rest had detectable disease. Stopping treatment with detectable disease is generally unwise (unless m-CLL?).

themedicalxchange.com/en/20...

Now at year 6.

ashpublications.org/blood/a...

And for completeness the 28.6 month report [ref 9 in quote above].

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

Short duration Venetoclax treatments have around 70% with uMRD4 and a drug free "holiday", CLL is expected to return, unfortunately quite quickly for those that fail to reach uMRD4. A few people in the US have tried to add Venetoclax to a BTKi in an effort to stop taking drugs (~2yr). This is dependent on them having a doctor that can make the insurance spring for the cost. In UHC the protocols are more rigidly defined and such additions are not usually possible (unless out of pocket?).

[bkoffman CLL CURE Hero]

The standard of care is to stay on acalabrutinib until disease progress or intolerance, but recent research suggests that dogma might be reassess as recent data showed that many patients with low disease burden on ibrutinib (similar BTKi to acacia) were able to stop it and not relapse. That however is not standard of care today.

[LeoPa]

There are clinical trials under way now which are trying to establish weather suspending BTK inhibitors periodically can be safely done. Right now they are for life or until they fail.

[SeymourB]

Vinweesel2023 -

There's no definition of "Total Remission" that I can find for CLL. I see the term used as being synonymous with Complete Remission, which is indeed defined.

Each type of cancer can have a different standard definitions of various degrees of remission.

For CLL, the standard is still the 2018 iwCLL Guidelines:

ashpublications.org/blood/a...

iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL

See Table 4, Response definition after treatment of CLL patients

Those guidelines were written at a time when cytotoxic chemotherapy was still the most common therapy, and continuous therapy BTKi's like ibrutinib and acalabrutinib had just been approved in various countries. Venetoclax was just beginning. So they didn't address continuing therapy, and MRD was only referenced in regard to clinical trials.

So it's possible to be in Complete Remission, and still continue BTKi therapy. There's no standardized, accepted criteria to stop the continuous therapy. Trials have experimented with limited duration BTKi, especially when given in combination with Venetoclax.

Undetectable MRD status looks like it may become one criterium for stopping continuous treatment, but there's no accepted timing of how often to check MRD for BTKi after end of treatment.

=seymour=