COVID-19 among fit patients with CLL treated with venetoclax-based combinations

[avzuclav]

New report from Europe published in Nature.

"Between March and April 2020 seven patients within the GAIA/CLL13 trial developed COVID-19, one in the CIT arm and six patients in the experimental treatment arms (Table 1). The baseline characteristics show a median age of 61 years (range 52–78) and in accordance with the inclusion criteria of the study only few comorbidities and no TP53 aberrations were documented. All but one patient had completed study treatment at the time point of COVID-19 diagnosis with a median time after end of treatment of 22 (range 1–30) months. All seven patients were tested positive for SARSCoV-2 by PCR collected from nasopharyngeal swabs. While one patient was isolated in home quarantine, six of seven patients (85.7%) had to be hospitalized and two (28.6%) required treatment on an intensive care unit (ICU), only one patient required invasive mechanical ventilation (Table 1). Two patients died as a result of their SARS-CoV-2 infection, one 58-year-old patient (patient 4) after a prolonged treatment with mechanical ventilation (52 days) on an ICU and a 78-year-old patient (patient 7) who decided against ICU treatment and was treated with best supportive care."

"To our knowledge, we here report the first analysis of COVID-19 in CLL patients receiving venetoclax-based combinations and CIT as first-line treatment within a large randomized controlled trial. This analysis suggests an increased rate of COVID-19 as well as an increased hospitalization rate in fit patients with CLL. Despite their various CLL-associated immune defects, the majority of patients recovered from COVID-19. As this is an ongoing clinical trial, a benefit-risk assessment is continuously performed by an independent data and safety monitoring board (DSMB). At this time the DSMB had no objection against continuation of the trial or subjects to continue treatment as allocated."

nature.com/articles/s41375-...

[PlanetaryKim]

Is this study saying venetoclax predisposes us to developing a worse more serious case of Covid than would happen if we had not had venetoclax? Yikes! Sounds like the opposite of the ibrutinib/Btk patients who get Covid and are somewhat protected from excess cytokine release causing the pneumonia thing. Or am I reading it wrong?

[Newdawn Administrator in reply to PlanetaryKim]

No I don’t think it is concluding a worse response Kim. It won’t let me copy the relevant section but despite the high level of hospitalisation, the comparison between those on V and those on BTK inhibitors doesn’t indicate higher mortality. In fact the previous research on the untreated suggests a higher mortality rate.

That’s my understanding of it and it’s important to see the high overall ‘survival’ rate in this study. Phew!

Newdawn

[PlanetaryKim in reply to Newdawn]

Not increased mortality perhaps, but increased everything else for the Venetoclax-treated patients: "To our knowledge, we here report the first analysis of COVID-19 in CLL patients receiving venetoclax-based combinations and CIT as first-line treatment within a large randomized controlled trial. This analysis suggests an increased rate of COVID-19 as well as an increased hospitalization rate in fit patients with CLL."

[Newdawn Administrator in reply to PlanetaryKim]

Oh yes, undoubtedly the immunosuppressive nature of CLL impacts response to Covid. I suppose I’ve always got my mind on survival but severity is a major issue. ‘More serious case’ to me screams non survival! 😱

However, the small study conducted on the untreated group did demonstrate a more unfavourable outcome. It was however a small cohort and hardly representative.

Dr. Koffman did say on here a week or so ago that work was ongoing looking at the immune modulating impact of Ibrutinib to impact more positively on Covid outcomes. The jury is still out it seems.

Newdawn

[cajunjeff in reply to PlanetaryKim]

True, but the study acknowledges that the high hospitalization rate might also be a function of them being in a trial and the doctors wanting to monitor them more closely.

I think to draw ultimate conclusions on how venetoclax or Ibrutinib therapy increases or decreases our chances with covid, we would need to see data involving hundreds, if not thousands, of patients.

That said, I have seen enough of these articles on how Cll folks do with covid to reach the conclusion I have long suspected. If someone with Cll gets covid, they will probably survive. But our risk is significantly higher than a comparable person without Cll.

By way of example, a healthy 65 yr old man without Cll probably has a less than 5% chance of dying from covid. The same man with Cll could have 3 to 5 times that mortality risk.

I assume if I get covid my mortality risk could be as much as 25%, way more risk than I want to take. I certainly don’t reach that conclusion because of the mortality rate in this study, it’s way too small a sample size. But I have seen larger studies that show we have a higher risk.

None of this is rocket science. Cll is a disease of the immune system. The question is really never whether an infection poses greater risk to us. The answer to that question is almost always yes. The real question is how much more risk. Cll is such a heterogeneous disease that impacts us so differently, quantifying risk for us as a group is almost impossible.

I think those of us with low immunoglobulin counts who are prone to infections are more at risk and those of us with normal counts who are not fighting frequent infections have less risk.

I personally think anyone with any stage Cll should assume they are vulnerable, particularly older folks.

[AdrianUK in reply to PlanetaryKim]

This idea that Ibrutinib makes things better in COVID19 is JUST an idea there is NO eidence to prove that, and I wouldn't bet my life on it. The problem with all these very small case series is that they are just that very short case series. The best data we have for blood cancers is discussed in this post of mine. We would be wise to work on the assumption that we are at higher risk of severe complications of COVID19 no matter what stage of treatment we are at. In the latest clinical data to be released people with blood cancers were twice as likely to have severe illness with COVID19 than people with any other cancer. (see thelancet.com/cms/10.1016/S... ) My article largely based on some large UK studies healthunlocked.com/cllsuppo...

[cajunjeff in reply to AdrianUK]

There is evidence ibrutinb and other btk inhibitors can help with covid and a very clear reason that it may help. Cytokine storms caused by over reactive immune systems are what puts most covid patients on ventilators. Ibrutinib is proven to lower the risk of cytokine storms and used for that reason to help those taking CarT therapy.

There is pre-clinical evidence in mice this might work and a small group of covid patients who appeared to be helped with ibrutinib. That evidence has led to clinical trials which are ongoing.

I don’t think anyone on here is operating under the assumption that if they are on ibrutinib they can go to a covid party. I agree everyone with Cll should consider themselves vulnerable. But I look for whatever good news I can get and I think the existing evidence on ibrutinib is what has led to the promising ongoing clinical trials.

Here is an article that discusses the evidence they have relied on to start clinical trials:

forbes.com/sites/nathanvard...

[mrsjsmith in reply to cajunjeff]

Jeff,

As someone who is on Ibrutinib I will clutch at any straws thrown my way ! So thank you, and keep them coming.

Colette 🙂

[AdrianUK in reply to mrsjsmith]

Lower lymphocyte counts more than double the rate of acute respiratory distress syndrome according to this systematic review. This night well be related to not being able to produce sufficient antibodies Early in the disease though the reason is not proven. (NB the odds ratio is calculated for higher lymphocytes so to get one for lower I simply did 1/0.37) cebm.net/covid-19/are-there...

[AdrianUK in reply to cajunjeff]

IF ibrutinib works in COVID-19 and it very well might not it will probably be like steroids. The largest clinical Trial in the world for COVID-19 took place in the Uk and clearly showed that if you already need oxygen or a ventilator dexamethasone saves lives. It’s the only drug with actual clinical trial Evidence that it saves lives for COVID-19. But it doesn’t work if given earlier on. A dampened down immune system will only make things worse at the early stages of infection. And there are other ways to get very sick with this disease. The disease itself attacks the lungs and we need some immune response to take place there just not too much. If we have little or no immune response to the virus it could overwhelm our bodies defences.

Sorry for sounding like a killjoy but some people are walking around with false hope about this disease when the reality is catching this disease when you have a blood cancer of any type or at any stage is rather like playing Russian roulette when we do not know exactly how many bullets are in the gun. For sure you can even say that the majority of us will be probably be fine and will survive but that doesn’t mean it’s a game any of us should want to play.

I think it’s best to think of our immune systems as dysregulated. This idea that we can’t generate a citokine storm on ibrutinib(or some people say even off) Seems highly likely to be entirely false to me. The mechanism of sepsis is not so dissimilar and we are well known to actually be at higher risk of that. With us our immune system can be sluggish early in an infection showing limited fever or other inflammatory response but we can suddenly switch into over Reaction mode later in the same sickness. I know. It happened to me in the pneumonia that led to my CLL being identified. Nobody realised just how sick I was early on because my immune system was so lazy till one day it suddenly went into over drive and I nearnly died. And sorry but I will not be convinced that ibrutinib will save lives of people with COVID-19 till the results of the trial are in and even if it does work in people with normal immune systems that does not mean it would prevent severe illness in those of us taking it who then catch COVID-19.

This whole idea that is floating around (not the study I mean but the idea idea cll patients might be somehow protected) seems to havd come from just four cases of COVID-19 in CLLers who happened to be on ibrutinib who happened to do well. Some people with CLL will have relatively mild illness with COVID-19 that much is true. But we are at much higher risk of severe illness and i will underline that on any thread that raises the idea we might be just fine. It has to be said and it has to be said often. We have to take extreme measures to avoid catching this thing.

[cajunjeff in reply to AdrianUK]

I consider covid a serious risk for those of us with Cll and don’t consider you a killjoy for pointing that out.

My post was more directed to your declaration that there is no evidence ibrutinib may help treat covid. There is considerable evidence it might help and that evidence has led pharma companies to invest serious money in trials.

And it’s not some throwing darts a board theory. Cytokine storms are known to be dangerous to covid patients. Ibrutinib is known to suppress cytokine storms.

I agree with your observation that ibrutinib may help in the same way steroids do, they both fight inflammation. But it might be Ibrutinib does it better, hence the trials.

[AdrianUK in reply to cajunjeff]

I understand that there is some limited pre clinical data. But I honestly think that it’s a stretch to say that there is yet good evidence that this drug will work. That’s why it’s being studied. And the idea that if it is given to those with relatively normal immune systems that are over reacting to covid it will also work in people who havd cll and are taking it in the early stages of an infection that’s yet another leap. To me preclinical ideas are not real evidence yet. That’s why for example many responsible people are cautious about what it means to havd antibodies in your blood to

COVID-19 even tho animal data (and many other diseases) strongly suggests that gives you immunity.

I havd seen too many promising drug candidates that we thought has great potential to work based on preclinical and even sometimes clinical trials fail to work in the big randomised controlled trials they are needed to prove things work. So far only ONE drug has good clinical evidence for its ability to save lives in COVID-19 and that’s dexamethasone. Everything else is either purely pre Clin, or based on a handful of cases where people got better (could be coincidence) or open label trials with no randomisation the UK study is huge and has already read out on two of the drugs it was looking at. Proper clinica Research is what we need. When I’m taking about real evidence that’s what I’m talking about.

[cajunjeff in reply to AdrianUK]

So there is evidence ibrutinib can be a treatment for covid, right? It’s evidently not enough evidence to convince you, but enough evidence to convince the expert doctors at Pharma companies to invest thousands, perhaps millions, of dollars in clinical trials.

Once again, I was just responding to your declaration there is NO evidence ibrutinib can treat covid. There is enough evidence to warrant a clinical trial. And it’s already proven that ibrutinib can reduce the risk of inflammatory reactions.

[CLLerinOz Administrator in reply to cajunjeff]

There are currently 2,427 clinical trials for Covid-19 listed on the clinicaltrials.gov website. They range from inhaling nitrous oxide to the impact of Coronavirus on Egyptian veterinary students. I could only see two listed for Ibrutinib and two for Acalabrutinib, only one of which is for a cohort higher than 100.

The CLL Society website has two pages about the potential role for medications like Ibrutinib and Acalabrutinib in the treatment of Covid-19, including some information about trials using them for Covid-19 patients.

There is this page from April 2020:

cllsociety.org/2020/04/ibru... and

this one from June 2020:

cllsociety.org/2020/06/inhi...

[cajunjeff in reply to CLLerinOz]

I don’t get your point. You think a clinical trial for people inhaling nitrous oxide is comparable to a trial with btk inhibitors that are known to suppress cytokine storms? Are you suggesting the btk inhibitor covid trials are not evidence based?

[CLLerinOz Administrator in reply to cajunjeff]

Not at all. My point was that there are so many different things being trialled, amongst them Bruton Tyrone Kinase inhibitors like Ibrutinib. The CLL Society information is very encouraging.

[newyork8 in reply to AdrianUK]

Good debate. bottom line for me: we are at much higher risk, vaccines may not work for us so we need effective treatments. However, a ray of positive news re those on Ibutinib is welcome. Stay away from people ...4 meters ideal...and prevention is key. I'm also taking quercetin in combo with vitamin C...some good "evidence" it may help.

[PlanetaryKim]

It says, in the report: "To our knowledge, we here report the first analysis of COVID-19 in CLL patients receiving venetoclax-based combinations and CIT as first-line treatment within a large randomized controlled trial. This analysis suggests an increased rate of COVID-19 as well as an increased hospitalization rate in fit patients with CLL."

[WDSmith]

Fascinating report and discussion. And yeah... basically keeping the husband home, though he hasn't started the Venetoclax portion of his trial yet.(Ultra V - Cycle 4, mid Sept start).

The part that intrigued me was that that about 'fit' patients on V doing poorer (in an admittedly super small sample).. what do we think they mean by 'fit'. (Sorry, haven't read the article yet, only what is excerpted here.) Fit as in - a generally ok patient CLL wise OR Fit as in - one who is actually physically fit. In general my husband has long (and annoying - ha!) history of being very physically fit, which we have to date thought of as an advantage.

[Newdawn Administrator in reply to WDSmith]

Looking at the profile of the patients, they’ve scored them in terms of co-morbidities such as diabetes, hypertension, asthma, cardiac disease, obesity etc. Interestingly the two deaths were in the second youngest and oldest in the study, male and female, both IGHV mutated, not with the worst genetic profiles and both with no co-morbidities which would presumably explain the description of ‘fit’ patient.

There seem to be many more variables at play in terms of how we individually cope with Covid than we’d expect.

Newdawn

[WDSmith in reply to Newdawn]

Yes... so many variables! Thanks for the clarification. Wish we could pool data like this from all over... you know, with the snap of a finger.