Factors Identified for Risk of Second Cancer in CLL Following BTK Inhibition

[AussieNeil]

There was hope that non-chemo CLL treatments would avoid the increased risk of subsequent secondary cancers, with concern about Myelodysplasia Syndromes and Acute Lymphocytic Leukaemia (MDS and ALL) of particular concern with FCR, due to possible DNA damage to bone marrow stem cells. It was thought that the lack of DNA damage with Ibrutinib and Acalabrutinib would prevent this risk. Unfortunately, it may be that all CLL treatments carry with them an inherent higher risk of secondary cancers, due to the impact treatments have on our immune system vigilance against secondary cancers. Note that these findings are correlations and more studies are needed, but if you needed an incentive to quit smoking, perhaps this report will help.

"David Bond, MD, assistant professor at the Ohio State University, discusses 2 key findings from a recent study investigating the risk of developing a second cancer in patients with chronic lymphocytic leukemia (CLL) treated with a BTK inhibitor. The study analyzed 691 patients with CLL who were treated with either acalabrutinib (Calquence) or ibrutinib (Imbruvica) and developed a second primary malignancy. The rate of developing a second primary neoplasia in patients with CLL treated with this class of agents was 7.6% at 3 years.

:

Bond says patients with prior tobacco exposure are known to have an increased risk of cancer development, particularly in lung cancer and bladder cancer. These results validate the importance of counseling patients with CLL on treatment with BTK inhibitors regarding tobacco.

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a low CD8 count at baseline was associated with an increased risk of developing a second cancer. These data are the first to demonstrate this in CLL to date, but points to the close correlation between immune function and the risk of developing a second cancer, says Bond."

targetedonc.com/videos/fact...

CD8 cells are cytotoxic T-cells and it is well recognised that CLL can affect the number of CD8 cells and the CD4:CD8 ratio, per this 2010 paper: ncbi.nlm.nih.gov/pubmed/208... Higher CD8 count was associated with significantly higher median time of survival of patients (149.33 vs. 82.06 months).

Neil

This is an unlocked post

[Sushibruno]

Is this only for people that have smoked or everyone is at risk taking these inhibitors?

[AussieNeil Partner Administrator in reply to Sushibruno]

In the video, Dr Bond says tobacco exposure is one of the strong predictive factors. Given he talks about two factors, I would take it that those without tobacco exposure, but low CD8 counts are independently at risk. Having both risk factors would be the least desirable situation, but thankfully we can at least control tobacco exposure.

It's a pity that the study isn't referenced.

Neil

[Sushibruno in reply to AussieNeil]

Thank you Neil

[AussieNeil Partner Administrator in reply to Sushibruno]

I have received a copy of the paper. Of the 691 patients tracked in the study, median prior lines of treatment (tx) was 2 (20% tx-naïve, 66% with prior chemo-immunotherapy), and 56% were never smokers. Median age was 64.

13% died from a secondary cancer and there was a 2.9 fold increased risk of cancers in smokers.

Here are the relevant abbreviations:

SPN Second Primary Neoplasia (i.e. a second cancer)

BTKI BTK inhibitor, i.e. Ibrutinib or Acalabrutinib

CIR Cumulative incr

NMSC Non Melanoma Skin Cancer

Conclusions: The inc of SPN in pts treated with BTKi for CLL is increased relative to the general population. With a 5 y CIR of NMSC and SPN of 23% and 12%, these data support consideration of intensive cancer screening for CLL pts receiving BTKi.

[Sushibruno in reply to AussieNeil]

I'm sorry if I'm being ignorant but I'm really afraid to take any of these medications it fixes one thing and damages the other. And i know that's the chance we take with any medication.

[AussieNeil Partner Administrator in reply to Sushibruno]

Given you already have CLL, the question comes down to whether or not you are better off having treatment when the time comes and facing the increased risk of developing a secondary cancer or succumbing to the CLL. If you refuse treatment for your CLL, the outcome is sadly known. From these studies, having treatment increases the risk of having a secondary cancer but it might be a change in risk from 1 in 3,000 to 1 in 1,000 say. Meanwhile, you can ALSO reduce your risk of developing a secondary cancer by the likes of quitting smoking, avoiding unsafe sun exposure, achieving a healthy weight, exercising, avoiding specific foods and alcohol consumption and so on. Remember, we can modify our risk of developing about 40% of cancers by lifestyle changes: cancer.org/latest-news/more...

Neil

[Sushibruno in reply to AussieNeil]

Thank you Neil and i hope i didn't offend anyone. I'm feeling very anxious right now and am seeing a therapist for it tomorrow. I just really haven't accepted that i have this i need help.

[SethB34 in reply to Sushibruno]

I know exactly how you feel. With CLL, I’ve found it difficult to know where to turn. And it’s messed with my mind as well. Just know you are not alone.

[Sushibruno in reply to SethB34]

Thank you SethB34

[6468 in reply to Sushibruno]

It is certainly hard to wrap your head around CLL and the treatment.Everything with this can be so variable. Definitely helps to be in touch with others on the same path. I thank all on the site for contributing.Good luck to you and may you find the inner strength to help you confront this disease.

[Sushibruno in reply to 6468]

Thank you

[patagozon in reply to AussieNeil]

Are there any similar predictive factors for secondary cancers and chemo treatments?

[AussieNeil Partner Administrator in reply to patagozon]

This 2010 article by Chaya Venkat comes to mind:

updates.clltopics.net/2204-...

[PaulaS Volunteer]

Great photo, Neil.

[HopeME]

I wonder how much impact an occasional Cuban cigar does? I guess I need to eliminate them, too. First my scotch now my cigars😫. This disease really sucks.

[MelioraDay]

Venetoclax may have better outcomes in terms of second cancers than BTK inhibitors. I am taking Venetoclax front line monotherapy and my T-cells have more than quadrupled during treatment, normal B-cells have doubled (both now normal), and immunoglobulins are trending upwards in the normal range. ANC is 3-4. There are other very targeted therapies in the pipeline, like cirmtuzumab, so perhaps we can see better outcomes in the future. However i think smoking will always be a negative factor no matter what treatment you receive.

[AussieNeil Partner Administrator in reply to MelioraDay]

I agree 100%. What sense does it make to willingly expose your mouth and respiratory system to known carcinogens, along with direct access into your blood stream - particularly when your ability to eliminate incipient cancers is compromised? Unfortunately tobacco is legally available and nicotine is extremely addictive.

[Tommays56]

I am at a crossroads with possible treatment starting because of fatigue

If I don’t have treatment I can continue my life in a very limited fashion that puts me at risk for multiple physical and mental things due to a lack of activity

No matter how careful I am with diet and things within my control going from a 60 year old who could hike 50 hilly trail miles in 12 hours

To a 63 year old who struggles to cover 2.5 on flat ground and then does a few more things until lunch and needs to lay on the bed for a few hours to recover will just continue to have a significant negative impact on my health

Having already done a trial of Jakafi for fatigue which I had to stop-but I got a few few months of relieve from the fatigue which allowed me to work back up to a 40 mile week and enjoy my life again

I am scared about the risks of treatment but just can’t see not taking the risk after getting a taste of health again

[virdieblue in reply to Tommays56]

It's a choice between a partial life and a full life. Long partial? shorter full? A choice we all face.

Virginia

[AussieNeil Partner Administrator in reply to virdieblue]

For many of us, I suspect a fuller, more meaningful life as we learn who and what are really important in our lives.

[Big_Dee]

Hi AussieNeil

Great research article. I of course was concerned about being treated with B+R due to reports of increased risk of secondary cancers with FCR treatment. It has been reported that people in USA have 1 in 3 chance of having some type of cancer in their live time, therefore it is common issue no matter what you do. It is nice to know that research is looking at predicting predisposition to secondary cancers.

[Fulart]

Looks like I might be the first one to respond about having CLL, lung AND bladder cancer, BR treatment, and having smoked. I’d had a benign SPN in my left lung, but it got very angry quickly after the first line BR treatment for CLL in 2014. By Feb 2015, my left lung was removed due to Stage 2 Lung Cancer. By 2018, I was dx’d with Stage 3 Bladder Cancer. I opted for bladder saving chemo radiation treatment, finishing just over a year ago.

So far I’ve held off repeat performances of bladder and lung cancers. But it’s a scary life to live right now. Of interest, I quit smoking Feb 8, 1988. It took awhile for cancer to hit, but when it did, it hit with a vengeance. Quitting smoking was the hardest thing I’ve done. I used a therapist after I quit because I knew my tendency to go back to smoking. I encourage anyone who’ll listen, please stop now.

[Chemtrails-USA in reply to Fulart]

I quit Feb 12, 1988. Recently snagged an emphysema dx! Also got a 2nd cancer, but who’s counting? 🙃

Hang in there, Fulart! 💪🏼

- Bobby

[bhayes84]

Neil,

It doesn’t sound like there was a control group of patients not taking a BTK inhibitor. Do you happen to know the general risk to all CLL patients of developing a secondary cancer? My understanding is that just by having CLL we are at a greater risk.

[AussieNeil Partner Administrator in reply to bhayes84]

I've seen a range of papers reporting higher secondary cancer risks, with the relative risk by cancer type varying by studied cohort. That indeed makes it difficult to determine the cause - as does the fact that the patients studied had an average of two prior treatments. Skin cancers are typically reported at the highest increased risk.

[AussieNeil Partner Administrator in reply to bhayes84]

Seems SEER data was used as appropriate control: Standard inc ratio (SIR) with 95% confidence intervals (CI) were calculated using expected inc rates from the Surveillance, Epidemiology, and End Results Program, assuming a Poisson distribution for the observed inc. Cumulative inc (CIR) of SPN (excluding RT and NMSC) was calculated from BTKi start date to the diagnosis of SPN; death was a competing risk and pts without event were censored at last follow-up (f/u). SPN was correlated with bl data using the Fine-Gray model.

[bhayes84 in reply to AussieNeil]

Thanks Neil.

Then, because there was a control group they compared to, we probably have to take this study more seriously. Particularly given the study was 3 years whereas most of us will be on it for a lifetime.

I found this study on secondary cancers in Denmark looking at 12k patients from 1943-2003 and found 1105 incidences of cancer --> 10%, but that was over a much longer period.

ncbi.nlm.nih.gov/pubmed/173...

[leopardo]

Right on. I have been on Ibrutinib ( BTK inhibitor ) for 4 years with care from Sunnybrook Hospital in Toronto. Diagnosed with CLL in 2002. I am 76 years old. Ibrutinib has managed my CLL very well, although there has always some level of fatigue. As of four months ago, I was diagnosed with an additional Hodgkin's Lymphoma, stage 3. Currently in ABVD chemo with the Bleomycin (sp.?) now taken-out of the cocktail as it is very hard on the lungs. In fact, I am now successfully working to get rid of some pneumonia. Pet scan now says Lymphoma now disappearing. Bravo! I am assuming as I think you have suggested that this is now becoming not unique.

Leopardo, Georgetown, Ontario