Progression Free Survival

[EastBayDad]

Hi. Can someone explain Progression Free Survival (PFS)? Here is example. I am 54 years old. I start V + O. The average PFS for V + O is 72 months or 6 years. If I am average, my CLL will begin progressing again when I am 60. When would the average person have to start a new treatment again after their disease starts progressing again? The answer to this question is important to the Under 60 CLL group.

[Shepherd777]

Venetoclax has only been available for about 6 years, so the average PFS is lengthened with each day. My wife was placed on it about 6 years and two months ago and is still kicking. There are other meds that work as well as Venetoclax that will extend the CLL journey probably until my wife dies with CLL and not from it.

[EastBayDad in reply to Shepherd777]

What is average time between end of PFS and start of 2nd line treatment? That is my question.

[Shepherd777 in reply to EastBayDad]

My wife was on watch and worry 2017 and than went on Venetoclax for about all of 2018. She then was in clinical remission and took nothing for 3 years and 7 months. In 2022 she could have gone back on Venetoclax again and repeated the one year again as many do, but chose to go on Calquence for a change and for less adverse side effects. Those who stay on Venetoclax longer tend to have longer remissions (4 or 5 years so far) with out any Venetoclax or other meds. Starting a different line of treatment or Venetoclax all over again is so recent that there may not be a clear average answer at this time. Someone else on this site will have a better understanding of what you are looking for.

[SofiaDeo in reply to EastBayDad]

I am not sure there is yet a definitive answer for the targeted treatment regimens, they are so new. Remember everyone is different, and these are averages. My experience since early 2011 diagnosis has been:

1st treatment 1a trial drug, halted growth but didn't remiss, considered a failure.

2nd treatment MAB mmmm 4-6 months later, treatment lasted 4? months, remission about 5 years. This was a highly immune suppressing MAB withdrawn from the market.

3rd treatment BTK monotherapy was working , I voluntarily stopped before remission due to side effects after mmmm 8 months?

4th treatment attempt to repeat #2 for 2 months, remission lasted a year.

5th treatment 1a/b trial drug started working then stopped after a few months, off drugs mmm 2 months. FWIW I was in one of the lower dose cohorts, the study is ongoing, it may turn out to be efficacious at a higher dose. It's also being tested for AML & MDS. I think it ends late 2024.

6th treatment venetoclax monotherapy 2 years. Technically uMRD4 but not zero CLL. I wanted a drug holiday instead of driving it down deeper. Remission i.e. no growth lasted a year.

Trying to decide what to do next. FWIW there is discussion that if a patient gets a 2 year remission from any treatment, it can be considered to simply re-treat again. I had relatively few side effects, so not sure if going to repeat, or add another drug, or try another trial. My CLL is at a low enough level that if a trial drug fails, I have lots of time to start something else. I am considering one of the BTK degrader trials, my specialist is involved in at least one I think. I'll know more when I see him next week.

There are studies out trying to determine if depth of remission correlates to length of remission, and if short term time limited treatments work as well as longer ones. MRD is now being measuring to the 6 level (millions) and likely the literature will slowly reflect changes in definition of "deep remission" since the previous level that could be tested was to the 4 level (10,000).

So in conclusion, I am not sure there is any definitive "time" one waits at the end of a PFS time period until treating again. If you need treatment, you need treatment. If you are asymptomatic, and your CLL is growing slowly, what's the rush? The treatment guidelines don't change much just because you had one or more treatments.

[Deilginis in reply to Shepherd777]

Hi, is she on it as a continuing therapy or a fixed duration course of treatment?

[Shepherd777 in reply to Deilginis]

My wife has been on Calquence for over a year. Calquence appears to control her CLL very well, but our understanding is that it will not put her into remission, but presently has basically kept the CLL in an indolent stage with her WBC remaining in the 7000 tom 9000 territory.

[avzuclav]

Look for papers that mention TTNT (time to next treatment). For V+O, the CLL14 data from 2023 shows:

"The PFS and TTNT difference between the two arms was maintained across all risk groups, including patients with TP53 mutation/deletion (median PFS 51.9 vs 20.8 months; median TTNT 57.3 vs 29.0 months) and unmutated IGHV status (median PFS 64.8 vs 26.9 months; median TTNT 85.4 vs 40.6 months). Multivariate analysis identified TP53 deletion/mutation, unmutated IGHV and lymph node size ≥5 cm as independent negative prognostic factors for PFS in patients treated with Ven-Obi."

source:

VENETOCLAX-OBINUTUZUMAB FOR PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA: 6-YEAR RESULTS OF THE RANDOMIZED CLL14 STUDY

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

So for unmutated patients the median PFS was 64.8 months and median TTNT was 85.4 months so ~20 months of W&W?

[Skyshark in reply to avzuclav]

CLL14 was for older (median 71 years), sicker patients (CIRS > 6) and unsuitable for FCR/BR chemotherapy. This probably has more effect on overall survival than response to treatment. Overall results are of little use as IgHV and TP53 status have a major effect on duration of remission.

Another good source for the 6-year results are the slides here (slide 15 shown, the answer to the question is "yes you are!" check the box):

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

Lots of stuff in this are very uncommon in other trials reports: TTNT - time to next treatment and the unclaimed "landmark" slide 15 PFS by "real world" IgHV / TP53 status. PFS and OS by MRD status at 3 month follow-up from end of treatment (first reported in 2022 5-year results), since claimed as a "landmark" by CAPITVATE FD for V+I in 2023.

IgHV mutated = m-CLL, unmutated = u-CLL. Del(17p) or TP53 mutated = TP53 aberrations = TP53ab.

Overall median for CLL14 V+O is 76.2 months.

For u-CLL with TP53ab the median is 47 months (-29 months, 62% from overall results). The confidence index is poor due to small number n=16.

For m-CLL with TP53ab they appear to do just as well as m-CLL without . With n=5 the CI (PFS 15%-95% (eyeballedish) at 72 months) says this result is highly uncertain.

For u-CLL without TP53ab the median is about 66 months from start of treatment (-10 months, 87% of overall).

For m-CLL w/o TP53ab the median hasn't been reached and PFS is 74% at 72 months. For this group the trend would put the median in excess of ten years (+36 months?) or it could reach a "knee" this year and fall sharply.

There is also the question : At what point would you feel cheated or "short changed" by a lower than expected duration of remission from looking at medians? One in five? 80% PFS (my line in the sand) for u-CLL w/o TP53ab is 41 months and for m-CLL w/o TP53ab it's 53 months. There was little divergence up to 36 months but since then u-CLL w/o TP53ab has dropped sharply. Early results may not hold up very well. ELEVATE TN for Acala and Acala + Obin is just starting to show a statistically significant divergence between these treatments at 6 years but not for TP53ab.

All first line novel drug regimes BTKi / BTKi+MAb / BCL-2+MAb / BCL-2+BTKi show very similar trends of divergence for KM plots by IgHV/TP53ab status from the overall KM plot. I have yet to see a R/R trial that presents results by IgHV/TP53ab status. These have greater numbers of higher risk u-CLL, TP53ab, complex karyotype patients that with similar divergences will tend to skew the overall result downwards.

CLL14 PFS by IgHV and TP53/17p status.

[EastBayDad]

This is super helpful. Learning all of CLL lingo is tough. My question came after I read this interview. Jennifer Brown saying we need more treatments for young people like me is anxiety producing.

onclive.com/view/zanubrutin...

[Snakeoil in reply to EastBayDad]

Yes, lots to grasp. However, so many people have explained in replies to your posts that you will very likely have decades to learn it all 😊

Plus, you are seeing a CLL spesialist. Some of us do not have that luxury.

Relax. Forget about CLL until your next appointment.

[RosettaClapp]

It's important to all of us even us who have lived with CLL for decades! But as these treatments are relatively new there is scant widespread info on when a second treatment might be necessary..

[MisfitK]

You'll see a lot of advice on this board that for young CLL sufferers, the object of the game is "slow and extend." You want to slow down the disease and lengthen the time between treatments as much as possible, b/c there are about 10-15 years of great treatments currently around for CLL, (less if you're a 17p deletion) and then it's time for early stage clinical trials and other higher risk treatments.

That's why there so much more potential payoff to a 40 year old who gets their exercise, diet, sleep, and stress in order vs a 75 year old one. None of these things will cure your cancer, but they will put you in better shape for treatments and they may help slow down your cancer progression (and what do you have to lose, b/c as mentioned, right now, they only have 10-15 years of great treatments for you, but if you can extend a day/week/month/year, there might be many more).

seer.cancer.gov/statfacts/h... That said, if you're under 55 at diagnosis, you are in the distinct minority of CLL sufferers on this page - only 9.5% of new diagnoses of CLL are in that age range. If you're under 45, like I was at diagnosis, you're even rarer, with only 1.8% of new diagnoses in that age range. And if you're under 35, you're a unicorn, with only .2% of cases diagnosed in that age range.

So, being rare, you'll see less direct advice and life experience directed right to your circumstance. And less thought about "what if I run out." It just doesn't and really can't happen to 90%+ of the folks here.

It's like the "you won't die from this disease" - 1.5% of all CLL deaths happen in the under 55 age range (stats from 2016-2020, so with some of the new therapies, but still probably with effects from old ones). Since only 9.5% of all sufferers are diagnosed that young (Edit fixing Math) - if you take 18740 newly diagnosed * .095, you get 1780 diagnosed under 55. Then, you take the 4490 deaths last year * .015 (number of deaths in that young), you get 67 dead. Or about a 4% chance of dying in that group from CLL, even that young.

That's not to be a downer. It's just to say - what can't happen to 90% of the folks here can happen to us. But, we can help avoid that fate by getting ourselves healthy (and stress-free - that's so big), seeing a CLL specialist (or at least a hemo onc versed in the disease), and staying up on disease info by being here.

[EastBayDad in reply to MisfitK]

Thank you for the excellent and depressing analysis.

I learned something new about my CLL yesterday. I had perfect lymphocytes and WBC in early 2023. I had a bad case of COVID in August. Multiple lymph nodes developed above my collar bone and never went away. I went to my next annual last month. My WBC and lymphocytes were in the 70s. Doctor thinks COVID may have triggered my CLL.

[SofiaDeo in reply to EastBayDad]

I agree, I had a bout of apparent drug induced AIHA shortly to my remission, and I think it was an "activator" for my CLL again. That plus severe emotional stress made the quiescent cells awaken IMO.

[Skyshark]

I didn't answer the 64 million dollar question. My estimate, rule of thumb, for short duration Venetoclax therapies is detected progression to treatment is about a week for every months remission from end of treatment. You won't know until you get there.

BTKi monotherapies it's zero, they try to start the Ven based treatment while still on BTKi but showing progression.

[SofiaDeo in reply to Skyshark]

Yes, there's some data/thought that adding Ven as soon as the BTK shows signs of resistance works better than just switching to Ven. Not an actual study, more case reports/doctor discussion at conferences.

[avzuclav in reply to Skyshark]

Skyshark For fixed-duration (albeit six years) BTKi monotherapy, I wouldn't say it's zero. The FLAIR trial folks presented at iwCLL 2023 about this.

"In most CLL patients who have received six years of ibrutinib, the levels of residual disease decrease or remain stable for the subsequent 6-12 months after stopping ibrutinib. " as reported per bkoffman at cllsociety.org/2023/11/is-i...

[Skyshark in reply to avzuclav]

That's an impressive number that were stable for a year. There were a few that had further reductions in levels of detectable CLL cells after stopping treatment but they comment that the CLL cells may have taken up residence in lymph nodes or bone marrow.

By current clinical practice, progression (treatment failure) while taking BTKi will require an urgent immediate switch to Venetoclax. Because of this urgency there have been studies in "Rapid Dose Escalation" of Venetoclax.

ashpublications.org/bloodad...

On FLAIR the 112/172 that had stopped Ibrutinib by 6 years were those that hadn't progressed or suffered intolerance leading to stoppage. I've not found out how many of the 60/172 actually progressed while on Ibrutinib rather than stopped early for intolerance.

The early addition of Venetoclax to Ibrutinib is effective for those with detectable mutations that are known will lead to resistance and progression.

ash.confex.com/ash/2023/web...

Progression while on BTKi has quite an adverse effect on further treatments.

ash.confex.com/ash/2023/web...

[Big_Dee]

Hello EastBayDad

Not sure there is an answer. My CLL specialist told me I would have about 5 year on B+R if mutated or 3-3.5 years if unmutated. I am unmutated and had about 4 years. I am 3 months post V&O and expect 2-3 years remission on V&O, but unknown. Good thing is I may repeat either of my treatments. Blessings.

[rafew]

Unfortunately, there really is no definative answer. I relapsed after 9 months on V+R - but that was my 4th line of treatment and I have tended to relapse quicker than what was expected. Time to treatment just depends on how aggressive your CLL becomes and the symptoms it presents with. For me, the growth of abdominal lymph nodes exploded between the 6th and 9th month after treatment. But as i said, that was my 4th line of treatment. It sounds like V+O is your first treatment and unless you have higher risk markers, I would think you can expect good outcomes from your treatment. Best wishes.