I wanted to share an update as my “N of 1 trial” have so far been a success for me. I reached remission in a very unexpectedly and to me almost miraculous way when combining Ibrutinib + Idelalisib + Venetoclax. My disease have proven resistant to all these when they where used separately or in other combinations.
I have a new bone marrow aspiration this week that I hope will confirm this remission to still be in place, now after about 7 weeks.
The core of this story is that I started a combination of Idelalisib + Ibrutinib + Venetoclax, and this have cleared the diffuse B cells (Richter’s) in three weeks. There was also only about 6.5% CLL left in BM after these three weeks. I’m not sure if there was any activity in any lymphnodes when I started the triple combination, but PET shows there no activity in any nodes now. On the previous BM biopsy the pathologist could not say how much CLL was left due to the large amount of diffuse B cells in my bone marrow.
This development happened after I first developed RT on Ibrutinib, then after Allogenic HSCT and an early relapse I had progression on other combinations of these medications. First I had progression on Venetoclax + Ibrutinb and then progression on Venetoclax + Idelalisib +Obinutuzumab.
The dramatic nature of the situation escalated when transplant doctors in Norway decided against a new Transplant and I was only offered Palliative care. (My Haematologist was positive to another HSCT.) I was in good form and I started looking for options elsewhere in Europe, USA and China. In the end I sourced trials in US with the goal of remission and second allogenic HSCT as the best options for me.
I had in my (quite extensive) research read two articles pointing to a possible reactivation of efficacy of Ibrutinib when combined with Idelalisib. Information I found in two articles on with laboratory In-Vitro research of this combination, one article pointing to potential high synergy between Idelalisib and Ibrutinib, and the other with a very interesting quote "Moreover, in vitro inhibition of PI3K has been shown to reverse ibrutinib‐resistance and enhance anti‐lymphoma activity".
At the point we added Ibrutinib the BM was getting more and more suppressed by the disease. Neutrophils hit all-time low of 0.2 from the disease progression, and the main risks of trying to add Ibrutinib was now worth it. My haematologist, slightly reluctantly, accepted to again add a low dose of Ibrutinib (I had some left from earlier treatment), in hope to slow down the disease progression enough to allow me to travel to take part in LOXO 305, DTRM-555 and CAR T trials.
I had hope this would give some control of the spiralling disease, at least enough to help me to reach the relevant trials, I did not dream that this would lead to a remission. Now I have too little disease to take part in these trials..
The high efficacy this have had for me in just three weeks, would to me, indicate that this reversal is also valid in vivo. The synergy can be clearly seen from the toxicity.
I did two "tests" before committing to adding Ibrutinib. The first test I took one tablet, 140mg, for one day, in combination with Idelalisib and Venetoclax. Three days later I had a blood-test and this indicated a clear effect (neutrophils went up from 50 to 80 for the first time in over two months), only after trying one tablet for one day. I believe this indicates any efficacy was/is clear to see very quickly. The second test I added one tablet, 140mg, for two days. I did not have a blood-test after this second time, it was more to do a small trial for adverse side-effects. My doctor was later emphasising that my disease was not progressing as fast as they would have expected. I did these “tests” weeks before committing and it seems in my case to not have caused any “new” resistance. The disease was already technically resistant to Ibrutinib.
The triple combination have fairly high toxicity and have suppressed the normal function in the bone marrow as well as fought the disease. But with the very quick effect on the disease, this have for me so far worked out well. We have lowered the dosage of Ibrutinib and Venetoclax to try to help lower the toxicity. I started with 2x150mg Idelalisib + 280mg Ibrutinib + 200mg Venetoclax. This is now lowered to 2x150mg Idelalisib, 140mg Ibrutinib, 100mg Venteoclax pr day, the bone marrow is still suppressed on this combination and it would not be a good treatment long term. The first test I did would indicate that this combination with lower doses will still be highly effective. The toxicity for me have only been marked on the blood-tests, otherwise I am in good form.
I can add that toxicity is more manageable after about one week on the lower dose. All results are moving towards a more normal reading. Specifically platelets recovered to 129 from 59. Neutrophils is 0.6-0.8 from 0.2. HGB is back within normal at 12.9 from 10.5. WBC is 3.2, but have been at 3.1 since I added Ibrutinib.
So as long as this remission remains in effect and hopefully even have deepened I will go into another transplant shortly.
I'm not a doctor so I cant give anyone medical advice, but I really really hope this can be of help to someone else as well!!
PS.
My results over such a short time also makes me wonder if there is an avenue for thinking of utilising combinations of targeted therapies in a similar way to Chemo. Combining these medications have a very high synergistic effect, but if they can be used over shorter time periods this could be potentially be manageable. As soon as I lowered the dosage the BM started recovering. If I stop I am fairly confident it would bounce back very quickly. Not after 10 days of Neutropenia, like it did after the last round I had of R-EPOCH at 140%. It is clear to me that the general and long term side-effects are much lower than the extremely heavy course of chemo I took with R-EPOCH. The risk is resistance, but the curious event is that resistance (might) have been reversed in my case.
I also see there are trials coming up for combining BTK and PI3K inhibitors. If my experience is any reference this could be very promising!
These where the articles that inspired my "trial".
Reversing Ibrutinib resistance:
onlinelibrary.wiley.com/doi...
”Idelalisib, the first in the class of phosphatidylinositol 3‐kinase (PI3K) inhibitors, has never been tested in RS. However, ibrutinib resistance is mediated by a dynamic feedback between neoplastic cells and the tumour microenvironment leading to PI3K/AKT activation. Moreover, in vitro inhibition of PI3K has been shown to reverse ibrutinib‐resistance and enhance anti‐lymphoma activity (Zhao, et al 2017: see Appendix S1). These data might explain the activity of idelalisib in 2 (Patients 1, 5) of our ibrutinib‐resistant patients and support the investigation of PI3K inhibitors in this setting."
Synergy:
