Starting tx early

[Koda1234]

Hi everyone! First post here...I was wondering what everyone’s thoughts are on treating a little earlier with few symptoms (fatigue, semi swollen lymphnodes, SLL presentation). I know that this is a new topic of research with the targeted novel therapies. My husband is young, 34 and fit, 11q- (Unmutated) and has been in ww since March 2019. We are seeing a cll expert at Dana farber and his disease looks stable overall but Im curious about early tx to avoid possible transformation or accumulation of additional deletions. Especially with the new trial combos getting patients to Mrd-. Just asking opinions/perspectives on this because it’s been on my mind !! Thanks everyone...this site has been extremely helpful, hopeful, and informative<3

[Smith123456]

I see a specialist at Dana Farber myself. I would go with what they say if he is stable. New drugs keep appearing. In a couple of years he might have even better options.

[Koda1234 in reply to Smith123456]

Who do you see?

[Smith123456 in reply to Koda1234]

Now Brown. I have also seen Davids.

[Koda1234 in reply to Smith123456]

Any reason for the switch? We currently see Brown but we’re thinking of switching to David’s lol

[cajunjeff]

Koda. you are asking a great question. I think it was clear in the days of chemo treatment that not only is there benefit to early treatment, but that early treatment might make matters worse by accelerating clonal evolution by "selecting" harder to treat cll clones.

My understanding is that they are now challenging the wait to treat paradigm due to the novel drugs, but that at this time the standard of care remains the same, delay treatment until the treatment criteria is met.

I do not know at this point if they know whether early treatment might avoid accumulation of additional deletions or if it could make it worse. Since drugs like ibrutinib are known to treat all kinds of cll, its reasonable to think it will not select for harder to treat cll like FCR can do.

My guess would be that at most cancer centers they will want to follow the current criteria for watch and wait. Its a good discussion to have with your doctor. Some doctors are understandably concerned about treating people outside of established criteria, even if their instincts tell them the criteria needs to change. If someone has a bad result from a treatment decision, a doctor is almost always better at having followed established procedures as opposed to taking a chance on a hunch.

I think it is a really good discussion to have with your doc and see what he/her thinks.

[Koda1234 in reply to cajunjeff]

Thank you for your comment, canjunjeff! I will definitely ask at the next appointment

[Smith123456 in reply to Koda1234]

Having seen both Davids and Brown i can say they are both equally tied in to all the latest protocols and trials. However you are far younger than me and have a longer journey ahead. If your numbers are stable-i would go with your specialist. I don;t think Davids will give you a different course than Brown.

Oh-and i forgot. There is a special protocol to actually change a doctor at DF. You will be challenged to say why.

[AdrianUK in reply to cajunjeff]

They will however select for cll clones that become resistant to them. So it all depends how long your CLL takes to randomly develop such a mutation (unless of course there is one there already was one there when you start at low levels)

[cajunjeff in reply to AdrianUK]

That assumes that resistance is inevitable with the new drugs, and that's not clear. The majority of people who started with ibrutinib as a first treatment have not shown resistance and we are 8 years out with that cohort.

FCR doesn't treat 17p cll well, so if one treats with FCR and has a small, undetectable 17p clone, FCR could allow that clone more room to grow.

The novel drugs treat all cll, 17p and 11q as well. So as I understand the original poster's question, is why wait for a subclone to take root, hit it earlier with drugs that keep it down.

Put another way, suppose two twins had identical cases of cll and both had 25% 11q cll and 2% 17p. One twin starts treatment immediately and one waits five years until he has 65% 11q cll and 25% 17p.

Ten or twenty years from now, which twin has the better outcome? I think they know the answer to that with chemo, its best we wait to treat. I think the jury is out with when to start with novel drugs. Did the twin who got on it early do better long term and have less damage to his immune system 10 to 20 years out? Its a good question. I have seen some cll doctors who say we might be treating earlier in the future.

I had a bout with AIHA before I treated, probably triggered by my untreated cll. Should I have started earlier and would that have spared me a bout with AIHA? I do not know, in retrospect I think probably so.

[AdrianUK in reply to cajunjeff]

I think you hit the nail on the head. We do not know how often mutations will come up that produce resistance. And we don’t know the best approach yet. Only time will tell. Ideally there should be a large randomised control trial between early treatment and late treatment.

I don’t even think we know for sure which is the best treatment approach to reach for first line either.

[avzuclav in reply to cajunjeff]

The German CLL study group is testing the hypothesis of early treatment with ibrutinib vs watch and wait in the CLL12 study. It's complicated.

ascopost.com/News/60167/

[cajunjeff in reply to avzuclav]

It is complicated and not very clear what they were trying to prove in the study. Of course people treated early with ibrutinib had better progression free survival than those not treated, Was that not a given going in?

I am no expert, but it seems to me to determine if early treatment was the better choice, these two groups have to be compared ten to twenty years out. I didn't read up on the study, maybe it is a much longer term study and these are just early results.

[VidaPlaya]

Hi, welcome, I'm new too with a (slightly less) young husband with CLL.

He was on W&W from 2013 until just two months ago. And sadly, he had fatigue for most of that time and swollen lymph nodes for last 4 years or so. While his markers at diagnosis weren't too alarming, it was the fatigue that eventually nearly disabled him.

In a way I wish he could have had treatment earlier, but then again we never felt comfortable enough with one until these new ones came out (he's on Calquence, starting course of Gazyva this week ).

I'm so glad you're with a specialist. Just continue to speak up and be an advocate. You know best how CLL has affected him.

[Koda1234 in reply to VidaPlaya]

Hoping that treatment will help with his fatigue !! That is a quite a long watch and wait, wow!!

[lankisterguy Volunteer]

Hi Koda,

Here is a link to one of our pinned posts that addresses your question in depth:

healthunlocked.com/cllsuppo...

Some of the replies add additional perspectives.

-

Len

[Koda1234]

Thank you everyone for the replies!!

[czbm]

There is an early treatment phase II trial that is open at Mayo Clinic.

[AdrianUK in reply to czbm]

Is it randomised? Do you have the link?

[czbm in reply to AdrianUK]

Acalabrutinib With or Without Obinutuzumab in Treating Participants With Early-Stage Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Here's the description. I don't know how to do a link. I'll try to figure that out.

[AdrianUK in reply to czbm]

I found The link by googling your title. You just have to copy and paste the link from the address bar. This is a randomised trial so should help Answer the early treatment question. Though of course we need a LONG time to really answer it.

clinicaltrials.gov/ct2/show...

[czbm in reply to AdrianUK]

Thanks Adrian!

[Koda1234 in reply to czbm]

Early treatment with a monotherapy doesn’t make much sense to me because it rarely gets patients to mrd -...which means the patient will be starting their “treatment clock” early as there is a likely chance of disease progression/relapse ( especially patients with higher risk CLL). Therefore in my mind early treatment wouldn’t be beneficial with this regimen. Maybe acala + O gets patients to the mrd- point .. not sure on that.

[bennevisplace]

This is unfamiliar territory to me, but I'll chip in with something I came across recently. Lab evidence that novel drug combinations, targeting PARP as well as BCR, might work better on 11q del CLL nature.com/articles/s41375-... and nature.com/articles/s41467-...

Yet to be trialled in the clinic but maybe worth mentioning to your specialist in the context of when (and with what) to start treatment?

[Smakwater]

Koda1234,

The curent IWCLL standard still uses Rai staging protocol. I believe that it is the consensus with most CLL specialists that W&W is still the best choice with indolent disease. There is not yet evidence that early treatment prevents clonal resistance, or that the presence of risk markers guarantee clonal activity.

The benefit that most of us are contemplating with early treatment is the rapid advancing progression that comes with high risk CLL, or rather the opposite of indolent disease in conjunction with co-morbid conditions. In a nut shell "to avoid early onset suffering".

Be assured that the presence of advancing symptoms, the increase in progression frequency, and the impact on a patient are allowable considerations for beginning treatment. He can be active in monitoring his lab reports and self advocating measures of how the disease impacts him as well.

There are now approved novel drugs that effectively treat most chronic leukemia's according to IWCLL standards, and there is a lot of advancement in research to be made available in the near future.

In my opinion If your husband is feeling well and his disease progression is trending slow, you would do well to continue to study treatment possibilities and live life as full as possible.

Even with the best treatments available, there are risks, side affects, and numerous other considerations that may or may not come to play.

Avzuclav hit the nail on the head with the response to this post, "it's complicated".

Hope that you get to the best resolve,

JM

[bkoffman CLL CURE Hero]

The answer until recently was clearly to wait, and that is still the standard of care, enforced by the fact that treatment keeps getting better, so waiting makes sense. There is new thinking that treating when the disease burden is lower might prevent aggressive mutations from arising, an unproven but logical hypothesis. That idea is pushing some to earlier intervention or at least design trials to answer those questions.

Brian Koffman CLLSociety.org

[larrymarion]

You and your husband are in great hands at DFCI. Drs. Brown and Davids are excellent and au courant on the research, including clinical trials testing the early intervention theories. Other comments from cajunjeff, lankisterguy, briankoffman, et.al. are important since they're experts, but let me add one other consideration--will your husband's insurance cover the enormous cost of novel agents like ibrutinib, etc.?

If your discussions with the Dana Farber team get to the point where treatment may make sense now, ask them to send a letter to your insurance company first, to get an idea about how it will react. Especially if his symptoms don't fit into the IWCLL standard of care.

[bennevisplace in reply to larrymarion]

Good point.

[JustAGuy]

I think it's too bad it's monotherapy with ibrutinib...

[Justasheet1 in reply to JustAGuy]

You’re spoiled. 5 years ago you would have given your left arm to get in this trial.

Jeff

[JustAGuy in reply to Justasheet1]

Perhaps, but now 5 years down the road, the combination therapies seem to be working better. Who knows if in 5 more years the thinking will be different still.

The idea of early treatment to reduce possible future complications is compelling, but there's still not enough evidence. It seems like it can only be determined by waiting many more years...