These results, from the CLL14 study (ClinicalTrials.gov Identifier: NCT02242942), were presented at the European Hematology Association (EHA) 2021 Virtual Congress.
Extended follow-up suggests that venetoclax plus obinutuzumab prolongs progression-free survival (PFS), but not overall survival (OS), when compared with chlorambucil plus obinutuzumab in patients with previously untreated CLL.
432 patients were randomly assigned at a 1:1 ratio to receive venetoclax plus obinutuzumab or chlorambucil plus obinutuzumab. In each arm, patients received 6 cycles of the assigned combination, followed by 6 cycles of either venetoclax or chlorambucil alone.
The median age was 72 years in the venetoclax arm and 71 years in the chlorambucil arm. Roughly 60% of patients had unmutated IGHV, and 12% had TP53 aberrations.
At a median follow-up of 52.4 months, the PFS was superior for venetoclax plus obinutuzumab (hazard ratio [HR], 0.33; 95% CI, 0.25-0.45; P <.0001). The median PFS was not reached in the venetoclax arm and was 36.4 months in the chlorambucil arm. The 4-year PFS rate was 74.0% and 35.4%, respectively. For patients with TP53 aberrations, the median PFS was 49.0 months in the venetoclax arm and 20.8 months in the chlorambucil arm. For patients with unmutated IGHV, the median PFS was 57.3 months and 26.9 months, respectively.
The median time to next treatment was not reached in either arm. The 4-year time-to-next-treatment rate was 81.1% in the venetoclax arm and 59.9% in the chlorambucil arm (HR, 0.46; 95% CI, 0.32-0.65; P <.0001).
An analysis of minimal residual disease (MRD) status showed a longer duration of MRD negativity in patients treated with venetoclax plus obinutuzumab. The median time to MRD conversion was 21 months in the venetoclax arm and 6 months in the chlorambucil arm.
There was no significant difference in OS between the treatment arms. The median OS was not reached in either arm. The 4-year OS rate was 85.3% in the venetoclax arm and 83.1% in the chlorambucil arm (HR, 0.85; 95% CI, 0.54-1.35; P =.49).
Second primary malignancies were seen in 40 patients in the venetoclax arm and 30 in the chlorambucil arm. There were no new safety signals identified with extended follow-up.
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Jm954
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Thanks for posting this Jackie. I could be way off in my interpretation of this data as I have no science background, but I would guess Abbvie was disappointed with this result.
Abbvie has the patent on venetoclax, maybe the most powerful Cll drug there is. We know already venetoclax rapidly kills Cll cells and gets rapid remisssions. What we don’t know is how durable these remissions will be.
I think for most of us with Cll, the end game is overall survival, not progression free survival. Give us the drugs that make us live the longest.
In this study venetoclax was pitted against chlorambucil, chlorambucil not being a drug I think people see as a Cll powerhouse. Chlorambucil is an older Cll drug and I think Abbvie and the rest of us figured venetoclax would blow chlorambucil out of the water in a head to head competition.
Could it be venetoclax is great at getting quick remissions which do not turn out to be durable? That is what this data seems to say to me, but I might misunderstand the study.
It’s particularly interesting to me because I am considering adding venetoclax to my acalabrutinib, a move that is not without risk. Acalabrutinib is working great for me now, why should I risk additional toxicity by adding venetoclax if it doesn’t improve my overall survival?
Of course this study did not look at venetoclax added to ibrutinib, two drugs that appear to have great synergy when added together.
Time will tell. I’ll probably still add venetoclax. But if I read this study right, venetoclax did not perform as hoped. I am sure they thought it would have a big survival advantage over chlorambucil.
This result is not what I expected either and is very disappointing but as the follow up continues we might see the curves separate and the V patients live longer. It seems the Obintuzumab is more important and doing more of the heavy lifting than we first thought.
We are in uncharted territory regarding long follow up with these targeted therapies and their combinations. However, as the new drugs are coming along so quickly and the follow up is limited so far I think our knowledge will always be behind the curve.
I don't think it's disappointing for a fixed duration (12mo) treatment. The PFS and TTNT are incredible. The lack of OS difference is likely because those who need retreatment are likely doing well on BTK inhibitors.
Toxicity aside, the synergy of a BTKi and a BCL2i is beguiling, no? I don't see why Acalabr should be any less of a partner than Ibr, and the 3-year outcomes - so far - with that combo are pretty darned good in a high-risk group (albeit a smaller one and slightly younger than in CLL14 study) jamanetwork.com/journals/ja...
I am wondering the same as cajunjeff. What matters to me is OS. The way this result reads is that V+O does not help to live longer, which is counterintuitive given all the excitement about the targeted therapy. It helps to live better.... but not longer...
"The median time to MRD conversion was 21 months in the venetoclax arm and 6 months in the chlorambucil arm." - what does this mean? They reached MRD faster on Ch+O?
I read it the other way round. Ch+O is almost as efficient as the V+O combination. Great news for those of us that have no easy access to the super expensive new drugs. 😊
OK, the overall survival is the same (high) for both group. BUT, the following sentence set off alarms for me: "Second primary malignancies were seen in 40 patients in the venetoclax arm and 30 in the chlorambucil arm." Thus, 70 of 432 patients "at a median follow-up of 52.4 months" had a diagnosis of secondary tumors!!! That is, 16% in less than 4.5 years. I remember CLLCanada (Chris) telling me about his secondary and tertiary tumors, not to mention our susceptibility to life threatening infections (e.g. COVID-19, Candida auris, Aspergillus, Mucormycosis aka "black fungus", etc) and of course the dreaded Richter's Transformation, which seems to occur at a rate of 1%/year for anyone with CLL.
And in spite of these numbers, I can't even get my doctors to authorize a skin cancer check-up? Perhaps the new blood test for 50 types of cancers will help get earlier diagnoses of 2° and 3° cancers in CLL patients. (theguardian.com/society/202...
Don't forget this was in 70 +years age group. Given that most people die either of cancer or heart disease it's not surprising to see cancer incidence rising with age.
That is a good point. So, the question of whether CLL patients as a whole, or perhaps just a subgroup (chemoimmunotherapy experienced, untreated watch & wait, taking small kinase inhibitors, p53 mutated, IGHV hypermutated, 13Q deletion, complex karyotype, etc., etc., etc) have a higher risk for secondary cancers than an age equivalent group without CLL? I think we can agree that the incidence of developing DLBCL is astronomically higher in CLL patients relative to any control. However, some have argued that the elevated incidence of skin, colon, liver, etc, solid tumors may be due to the fact CLL patients have more doctor appointments and are more alert to these changes? IMHO, I can't believe that our immunocompromised status, and all CLL patients are believed to have some degree of immunocompromised status, does not result in increased tumorigenesis. Just look at the huge increase in certain cancers in AIDS patients...
Thanks so much Jm954, this is very useful info. Seeing how many patients on Ibrutinib or Acalabrutinib have to move on to Venetoclax after years, this will go into my CLL file. It's good to be able to ask informed questions.
Thank you Jackie. My very first treatment was Chlorambucil and Obinutuzimab in 2019almost immediately after being diagnosed and not understanding a thing about CLL
Unfortunately, it worked only 40%. Maybe because my tumour burden was huge and some of my abdominal ones didn’t shrink much with the treatment. Few months later I had to be back in treatment with Acalabrutinib and after two episodes of atrial fibrillation and heart failure I am on Venetoclax/Rituximab now.
This study shook me a bit as I was so hoping this one will be the silver bullet. The good news is that it gives us longer PFS and hopefully better quality of life while in MRD than Chlorambucil.
As far as overall survival I think the time will show. There is so much research going now that, there might be a perfect combination to not only give us PFS, but longer OS for all of us 🙏🏻🤞🏻 I am hoping Venetoclax in combination with some other drug will get us there.
In my case, quality of my life over quantity is important.
It appears that the perspectus analyticus is for what an observer measures as important to ages 72 thru average life expectancy. Other than that, It appears that Venetoclax overwhelmingly outperforms chlorambucil in most every way. There is a lot between the lines here even the term "4 year OS rate".
In the U.S pre covid data suggests average life expectancy as 77 for male and 80 for female. Post covid current data suggests average life expectancy is 75 for male and 78 for female.
In my case quality of life defined by progression free survival is a measure that I consider well in contrast over living long enough to be capable of watching my skin fall off.
If data from other studies is taken into consideration, my take is that chlorambucil has a history of mild to moderate durability for those who cannot tolerate much else . As for Venetoclax, the jury is still out on durability, and it would be interesting to see comparative long term data comparing Venetoclax to all the chemo drugs for younger age groups E.g, 40 - 60 years old, fit vs unfit, comorbidities vs ...
The data that I am eager to see is still 5 to 10 years out. I am betting on venetoclax and the new comers. Until then, chlorambucil may be a better option than venetoclax for some patients 70 years and older with tolerability issues or other health challenges. The extra 4 years of OS regardless of what the drug of choice is still is near or at the norm for average life expectancy for those in the age group studied.
If we want to live forever, probably not going to do it well on any substance that injures healthy cells as well as bad ones.
I couldn't have put it better. Quality of life versus watching my skin fall off - beautiful. What we all want & can't get from these studies, is a very large sample, broken into age groups, fit versus unfit, comorbids etc. i.e where do I fit into this profile. I've often been accused of overthinking, but am happy to have had week2 of Obinut, with a wonderful affect on my WBC (220 down to 3.2). One day at time & deal with what is front of you has become my mantra & the doctors will hopefully take care of the rest. If I'm here in 20 years time, ainsi soit il, if not I can't do much about it.
Wishing everybody a good & relative pain free journey.
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Progression Free Survival
CLL SOCIETY'S ASH POSTER on our Free second opinion program plus two important papers from ASCO
AbbVie Pharm--positive phase 3 for CLL!
