Which of the newer non-kemo drugs have the least compromising effect on our immune system. I searched through the pinned post on how our immune system works suggested by AussieNeil which is very interesting. Can I make the assumption that all of the CLL drug therapies suppress our B cells, or do some have less affect on our immune system than others. Is there a difference between mono and combination therapies affect on our immune systems?
Thanks
Everett
Hi Test_Tech / Everett,-
I am not medically trained but I would guess that a CLL expert like Dr. Furman might say that our immune system is made up of multiple different systems and the portions easiest to measure are to count Neutrophils and B-Lyphocytes. Measuring whether T-cells are exhausted or whether humoral response is decreased is much more challenging.
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We know that immuno therapy (Rituxan or Gazyva) decreases all B-cells, both the cancerous CLL cells and the few remaining healthy B-cells, for long periods up to 6 months. Those drugs also can reduce Neutrophils for some but not all CLL patients, but usually for a shorter time.
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Venetoclax is known to depress Neutrophils in some CLL patients but not all patients.
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Ibrutinib is thought to help exhausted T-cells recover some function, but can also depress Neuts and eventually over several years it will reduce the cancerous CLL B-cells.
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In my own case the only drugs that depressed my Neutrophils was Idelalisib / Zydelig combined with Rituximab / Rituxan. I had no Neutropenia while on Rituxan alone, Ibrutinib alone or Venetoclax mono. I have been in nearly continuous treatment since 2012, and have had nearly no infections, colds, or bacterial problems, but I do have a refractory viral infection called HHV-6a- Roseola, that does not respond to any treatment.
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Len
How have your immunoglobulins sone over the years Len?
Here are the only tests results I have seen. You can see that my IgG has always been in normal range and my IgM and IgA is well below the normal limit.
So complicated. Any idea why your igG jumped so much in November of 2016? I can’t imagine you were having IvG with no infections and stable igG. Thank you for sharing.
No idea, I started Venetoclax in June 2016, that was the only "event" that year.
No events? November 8th, DT becomes POTUS - can't imagine why that would stimulate IGs.
Wow, thank you Len
An excellent question. I wish I had a good answer.
Everyone is different, and to what extent any drug will affect the immune system, let alone other organs & systems, is highly individual. The information out there speaks to trends and study results, but since cancer drugs are approved after relatively small studies compared to other agents, it isn't until decades, and thousands of patients' experiences, can we state generalities with a great deal of confidence. Your personal medical history and life circumstances will determine which agent could be the best for any treatment you may need. And remember, many never need treatment.
Hi Everett,
Further to Len's and SofiaDeo's replies:-
1) All currently approved CLL treatments deplete our healthy B-cells as well as our CLL cells, as the drugs aren't able to differentiate between them. That said, CLL cells do over-express some targets, so are likely to be more impacted. With CLL being so heterogeneous, the degree of over-expression varies, plus sub-clones with less expression can become dominant through natural selection. Anti-CD20 monoclonal antibodies are a good example of this, with CD20 expression usually dim, but not always and subsequent treatments can become less effective.
2) It's difficult to make definitive statements on which treatments are the least compromising, because of the heterogeneous nature of CLL in how it impacts immunity and how the drugs do likewise. CLL suppresses the immune system in many ways; reduced white blood cell production from infiltrated bone marrow, driving T cells to exhaustion and reversing the normal CD4:CD8 T cell ratio (like HIV in this regard), suppressing plasma cell production resulting in falling antibody counts (panhypogammaglobulinemia) and cytokine and chemokine signalling that confuses the immune system. Some treatments also hit T cells (e.g. FCR, ventoclax), but conversely, inhibiting and reducing the CLL burden lifts the immune system suppression. BTK inhibitors vary in their off target effects, so ibrutinib at least in some patients improves T cell function (studies vary in their findings - did I mention how heterogeneous CLL is?). Ibrutinib was also found to significantly improve IgA counts in some patients, but only minimally impacted IgG. IgA is found in our mucous membranes and has a very important role in the protection our respiratory and digestive systems, bladder and vagina.
3) The primary differences in the impact of mono vs combination treatments as I see it are that combination treatments quickly overcome the inhibitory effects of CLL, but you might see more of an infection risk because one or more drugs may have a cumulative impact on neutrophil production or T cells, for example. When you stop treatment, the immune system gradually recovers, depending on the recovery of the bone marrow, reappearance of hopefully healthy B cells and thus antibodies. That might take a few months with the inhibitor drugs and up to a year or so with the anti-CD20 monoclonal antibodies (obinutuzumab, rituximab, ofatumumab), as they continue circulating after the last infusion, as hopefully there are no B-cells left expressing CD20 to mop them up. Monotherapies are continually suppressing the immune system, but do lift the CLL immune system suppression.
CLL specialists are becoming increasingly confident that CLL can be cured in at least those of us with favourable markers (and what's considered favourable is increasing with the newer drug developments). We know from long term studies that the 55% of those treated with FCR who are IGHV mutated (about half of CLL diagnoses) who achieve a 7 year long remission, haven't seen their CLL return after 15 plus years. Clinical trials of combination treatments with targeted therapies only started about 3 years ago and specialists hope to see long remissions in far more patients, primarily because the median age of first treatment is about 75 and there isn't the age restriction with the newer treatments. (FCR is not recommended for those over 65). In conclusion CLL research specialists consider the restoration of our immune system after curing our CLL the last remaining challenge.
Neil
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