Human carcinogens to treat CLL?

Human carcinogens to treat CLL?

Someone asked me about this recently...

Funny ...I never thought of chlorambucil and cyclophosplomide as human carcinogens, but they are.... I always viewed then as doing good, which they do....

ntp.niehs.nih.gov/ntp/roc/t...

ntp.niehs.nih.gov/ntp/roc/t...

Even Fludarabine...has carcinogenic potential....

medsafe.govt.nz/profs/datas...

What is a carcinogen... en.wikipedia.org/wiki/Carci...

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  • Hi Dick, it is a curious dilemma, and why treating physicians could be considered artists when weighing up the balance. I can offer a few musings.

    Dr Sharman has written several informative overviews recently, they discuss more of the topic and help answer some of the questions about watch and wait and how treatment may impact on clonal evolution.

    Watch and wait: cll-nhl.com/2013/04/watch-a...

    Clonal Evolution in CLL: cll-nhl.com/2012/08/clonal-...

    Clonal evolution part 2: cll-nhl.com/2012/10/clonal-...

    Avoiding chemotherapy: cll-nhl.com/2012/09/cll-tre...

    In avoiding chemotherapy he mentioned :

    “Modern day chemo-immunotherapy regimens (FCR, FR, BR, R-CVP, R-CHOP) are what we call “geno-toxic.” The best example I can think that illustrates this is a study that came out of theHuman Cancer Genome Project looking at brain tumors: ncbi.nlm.nih.gov/pubmed/187... . In this project, they took samples of patients brain tumors and carefully examined the DNA in just about every technical way they could. In a few cases, they had samples from patients both before and after a treatment called temodar (similar to the “C” in FCR/R-CVP/R-CHOP or the “B” in BR). What they found was unsettling to me. After treatment, tumors contained more than 5x the number of mutations than were present before therapy started.”

    However I am confused because I attended the UK CLL Forum where several CLL genomic studies were presented by leading UK clinical researchers which identified the different number and type of clones in sequenced samples before and after treatment. The number of clone types following treatment appeared to be reduced although there were a few new ones created. The debate in the forum was an age old argument were these new mutations as a result of treatment or natural history? ( as a novice I think this is what they were talking about :-) }

    This did aid another argument; that treatment did upset the homeostasis between different clone types by selecting for harder to treat more aggressive clones, following removal of competition with “dumb” clones as Dr Sharmon also mentions. Do we know yet what the long term effect novel non chemo targeted therapies may have on clonal evolution or their carcinogenic effect on other cells lines??

    It would appear there are several theories. That may add up to a combination of reasons why we can’t treat our disease too soon? That may have less to do with the toxicity of the treatment but it’s effect on the clonal balance , future testing capability as well as improved treatments may overcome some of this. For the moment I remember my own consultant explaining we can’t treat yet because we don’t want to wake a sleeping tiger.

    Dr Sharman does point out that there are consequences for waiting too long.

  • Speaking of sleeping tigers....what happens to transformations? Will the small molecules effect this positively or negatively in CLL?

    All we know at the moment is that ibrutinib doesn't work on Richter's or GBC type diffuse large B cell lymphomas, based on a small study.

    Excluding Richter's patients from major Phase III trials, like ibrutinib, bendamustine and rituxan may prove to be very short sighted in the future, because of the lack of data.

    Only time will provide these answers...

  • Some other recent posts concerning clonal evolution and how it is influenced by treatment

    cllsupport.healthunlocked.c...

    cllsupport.healthunlocked.c...

  • This is very interesting and quite worrying. The idea that we take these poisons with such potentially dreadful side effects to treat an already compromised immune system seems illogical. Of course at the moment there's no alternative but roll on the new non chemo drugs I say. I think we might look back in the future to this era of chemo treatment as we now look back on blood letting in the nineteenth century.

    One thing that's always worried me about when I had a six month course of FC chemo was what happens to all that toxic residue that goes down into the drainage system? It says in the article that 40-60% of the given dose of Fludarabine goes out with renal excretion through the urine. With 1 in 3 people in the UK experiencing some sort of cancer, that seems like an awful lot of toxicity going into the water system, maybe it should be isolated in some way and treated separately?

  • Chemo has had long last effects on me (painful feet, comprised immune system and a general slowing down) but at the moment its the only option. I welcome the new drugs and hope that I am one of the lucky ones who get to take them.

  • I wonder about the standard doses of Fludarabine and Cyclophosphamide based on height and weight of the patient. Would it not be better to start with lower doses and then build up as necessary to prevent overkill damage considering the compounds are classed as carcinogenic..

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