For what it may be worth, thougbt some of you might like to see this:
"Lysosomes in chronic lymphocytic leukemia (CLL) cells have previously been identified as a promising target for therapeutic intervention in combination with targeted therapies. Recent studies have shown that antihistamines can induce lysosomal membrane permeabilization (LMP) in a variety of cell lines. Furthermore, our previous data indicates that lysosomotropic agents can cause synergistic cell death in vitro when combined with some tyrosine kinase inhibitors (TKI). In the current study, we have shown that three over-the-counter antihistamines, clemastine, desloratadine, and loratadine, preferentially induce cell death via LMP in CLL cells, as compared to normal lymphocytes. We treated primary CLL cells with antihistamines and found clemastine was the most effective at inducing LMP and cell death. More importantly, the antihistamines induced synergistic cytotoxicity when combined with the tyrosine kinase inhibitor, ibrutinib, but not with chemotherapy. Moreover, the synergy between clemastine and ibrutinib was associated with the induction of reactive oxygen species (ROS), loss of mitochondrial membrane potential and decreased Mcl-1 expression leading to apoptosis. This study proposes a potential novel treatment strategy for CLL, repurposing FDA-approved allergy medications in combination with the targeted therapy ibrutinib to enhance drug efficacy." — Antihistamines are synergistic with Bruton’s tyrosine kinase inhibiter ibrutinib mediated by lysosome disruption in chronic lymphocytic leukemia (CLL) cells, Leukemia Research, Volume 96, September 2020, 106423
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Pogee
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I have sent the email to Dr. Furman and asked if that might be useful for someone like me that gets a skin rash on Ibrutinib and is no longer U-MRD on Venetoclax.
I took an antihistamine for skin rash from Ibrutinib. The rash faded however I still have it. I stopped the antihistamine because my dentist said i was getting dry mouth.
The only thing I take at this time is ibrutinib. I'm simply researching a number of other potential options. AussieNeil, who has vastly more knowledge—and angelic patience with me!—advises against any of the things I've come across and suggested as possibilities. My advice, Sir: Listen to him!
Pogee, When I read your post (my) yesterday and checked the paper, I thought exactly as Len reported Dr Furman responded. As I've shared with you previously, CLL cells do very well establishing a supportive micro-environment in the nodes and bone marrow, which protects them from attempts to kill them with substances that trigger apoptosis when they are in vitro. See: healthunlocked.com/cllsuppo...
There are plenty of papers like those below, showing why this is a huge problem with extrapolating the results of in vitro research with CLL cells to effective treatments. Basically, you need to find some way to establish high enough blood serum levels to overcome the CLL cells' protective endeavours without causing severe side effects.
By the way, the Leukaemia Research editor, Dr Clive Zent, is a well respected CLL specialist and researcher, who moved to his current practice after many years with the Mayo Clinic. The Mayo Clinic has an excellent reputation as a CLL centre of excellence and does look at the use of natural substances, generally in conjunction with proven CLL drugs, hoping for synergistic effects - just as this article hints at.
By the way how are you going whittling down your list of possible papers on interest in your post? : healthunlocked.com/cllsuppo...
I'll give you a big tip that will help you knock out many of your papers. Any paper that just tests against the HL-60 tissue line you can quickly dismiss. This is from an acute myeloid stem cell, line, not the lymphoid line, so totally different signalling is involved.
Once again, many, many thanks for your comprehensive and scholarly comment. I haven't had time to read the links, but I'll be re-reading my initial links and comments with an eye toward eliminating references to the HL-60 cell line. Thank you so much for your invaluable advice!!!
Further to my earlier reply, gardening-girl responded thus about this study, in the CLL/SLL Groups.io community.
"A reminder in reference to the Leukemia article on antihistamines and ibrutinib. The article is a result of in vitro studies, meaning CLL cells in culture were studied. Do not attempt to self medicate with antihistamines! The article states that "One limitation is the relatively high concentration of antihistamines required to induce cytotoxicity to CLL cells." I could find no clinical trials set up to study the in vivo implications of this work." (My emphasis).
As I pointed out before, a major challenge with translating promising in vitro cancer research to useable in vivo results sufficient enough to encourage investment in a clinical trial, is achieving high enough serum concentrations in vivo without causing serious side effects. Due to the way CLL cells nurture a protective stromal cell environment, that's particularly challenging with CLL. CLL cells are ironically more fragile in the blood than healthy B-cells, so much so that they often don't survive processing for a blood test. Hence we commonly see the comment "Smudge cells present" on our lab reports. The smudge cells are CLL cells that have died due to their cell wall membrane failing. CLL cells are easily killed by lots of substances in vitro. In vivo is usually a very different outcome.
Agan, my thanks...with a question or several. *** Do you recommend, non-medically, of course, ANYTHING besides targeted therapy drugs, such as Imbruvica, Calquence, and/or Venetoclax? *** Does anything other than these types of drugs even appear promising to you? Inducers? Inhibitors? *** If targeted therapy drugs ultimately don't seem to be working, or the toxicity levels get too high to keep using, are there any other treatments, supplements, or other things you might recommend, non-medically, of course? *** Would your opinion change with an end-of-life scenario (which, fortunately, I'm not presently facing)? Thank you in advance for your anticipated timely reply.
Honestly, if all the targeted therapies you had access to stopped working or toxicity levels became to high, then your best option for CLL treatment would be a CAR-T or CAR-NK trial.
The best (by far) evidence for any supplement working was the pharmacy grade Polyphenon-E (EGCG) from Mitsui Norin, but that hasn't been available for about 10 years and treatments have come a long way in that time. Trying to get an adequate dose of EGCG by taking green tea supplements, comes with the risks associated with the lack of regulation of supplements.
Thank you for your honest reply. I'm not there, by any means, but if I do get to the point of seriously looking at supplements EGCG would be my preferred supplement, and I appreciate your thoughts on the matter. *** By the way, would EGCG likely have a synergistic effect with Imbruvica, thereby leading to the possibility that a lesser dose of Imbruvica might be indicated? If so, that would appear to be an optimal result, as it would lead to less toxicity and adverse side effects. Your thoughts here would be most desired!
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BTK inhibitors for the treatment of CLL - the current state of play of 'brutinibs'
