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".
”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."
Thanks for sharing your very good news. I can't think of a better reason for not being accepted onto clinical trials, than having "too little disease to take part"!
There's lots being done looking for combination synergies to try and achieve uMR in shorter periods. The early combination trials typically went for 2+ years, but are now down to 14 x 4 week cycles, or just over a year. That's still a lot longer than the 6 month course of the older chemoimmunotherapy combination treatments like BR and FCR.
Further to your comments about shorter period combined treatments, adding Rituximab to Ibrutinib gives a faster remission, but no real difference in Progression Free Survival: pubmed.ncbi.nlm.nih.gov/305... Time will tell whether we will see a different outcome with Ibrutinib or one of the many other BTK inhibitors in combination with Obinutuzumab or Ofatumumab and/or the BCL-2 and/or the PI3-K inhibitors and so on, We are at least now in a very enviable position of being able to try in combination so many different versions of drugs that target B-cells in different ways.
Yes, when the doctor called to let me know I did not qualify I first thought it was because my Neutrophils where too low..
The great surprise to me was the "reactivation" of Ibrutinib after the illness had progressed with it in two different settings previously. It took a week for me to process that this could actually be the result after combining it with Idelalisib and Venetoclax.
Thank you for so much information. I couldn’t grasp some of it at this reading, but am looking forward to understanding more as I continue gathering info. Sandra 👍
UniversallyPersonal, what an inspirational story! Thank you for walking us through your decision making. What a great example of the power of knowledge, combined with advocating for yourself in the presence of a cooperative, if reluctant, haematologist. You've set a great example for all of us.
I am completely in awe of your self advocacy and determination whilst you must have been feeling pretty unwell with Richter's . To be able to research, assimilate and process all this information and then engage with doctors is inspiring when palliative care was the only thing being offered.
This level of knowledge and an understanding of the interplay between all the factors doesn't come overnight and you're the perfect example of how informed patients get better care. If just one person reads this and decides to improve their knowledge of CLL, Richter's and treatments then I will be happy.
My only word of caution would be that a tendency to transform to Richter's is clearly in your CLL and unless it is completely eradicated this could happen yet again. My game plan might be to harvest T cells whilst you'r on Ibruitnib and save them for CAR-T or look for CAR-NK possibilities as a back up.
Good luck with the next transplant and life going forward.
Yes the goal of the transplant would be to cure, I have confidence the new team will do a better job. Assuming I will be ready to do a new transplant with a new unrelated donor, they will have to potentially harvest any T cells after the transplant.My haematologist was open for conversations which was important, and I was lucky enough to have these medications at hand after using them previously.
I am a doctor (Medical) with CLL... Found your account fascinating, Richter's has haunted CLL'ers for years.. Myself included. I recently met a survivor who was so well and full of Vim and Vigour as to make me feel 170!
A update on my very surprising results when combining Ibrutinib + Idelalisib + Venetoclax.
Initial Post with more detail:
healthunlocked.com/cllsuppo....
I just had a second Bone Marrow biopsy after about 8 weeks on this "triple combo" after the surprisingly positive result of the first BM we lowered the doses to 140mg Ibrutinib + 2x150mg Idelalisib + 100mg Venetoclax / day to mitigate toxicity. The result remains and now there is 0.27% CLL in the BM biopsy, still no trace of Richter's.
In the complete report from the initial BM biopsy/aspiration I have two results. One is labeled as "Peripheral blood" with 6.5% and the other is labelled BM biopsy with 0.34%. They did not mention any test of Pheripheral blood at this point so it might be mislabeled. I hope to have this clarified on next appointment. Around the same time as this first BM (3 weeks after starting triple combo) I had a separate flow cytometry from pheiripheral blood that shows 0% CLL.
So it was either 6.5% or 0.34% CLL with no trace of RT in BM after the first three weeks. The important factor for me is that the effect is remaining at a lower dose, as the normal bone marrow function was very suppressed at the original dose. BM Function is still suppressed with current dosage, but seems to still slooowly be improving. Will have a PET next week to confirm there is no new activity in Lymph Nodes.
I have had a few different opinions from doctors on what is the best direction going forward.
1. Straight for a new Bone Marrow Transplant.
2. Try DLI if there is no sign of GvHD (I have a slight rash on the arm). If DLI is not applicable or giving response go for second transplant.
3. Try to consolidate current response with DLI, then move to second transplant, seemingly also if disease responds to DLI.
DLI consists of infusing T Cells from the donor for the first transplant, doctors are checking if he is available / willing to donate. There seems to not be much data for efficacy of DLI with CLL/RT. To me it seems natural to try to utilise the first transplant to its full potential before moving to a new bone marrow transplant. Less invasive treatment would be nice, but a potential cure is far more important.
When realising that the "triple therapy" actually had worked, but caused the immune system to struggle, we lowered the dosage. It allowed the immune system to recover somewhat, but unfortunately this have also allowed the CLL/RT to come back. One spot in the Bone Marrow lit up on the latest PET scan. They did a biopsy from this specific spot as the BM biopsy in the lower back was still looking good with very little CLL.
Previously I have often asked doctors if bone marrow involvement is the same everywhere and they said that they assumed so, based on the CLL/RT coming from lymph nodes and spreads to BM. It seems to me that the new PET technology is allowing very good information also from the BM and they don't have to guess or assume. I'm pleased they found this development early, without the advancement (and the decision to seek out experts), we would not know about this development and just assume that it was fine everywhere based on the BM biopsy taken from the normal spot on the lower back.
I will be starting on a trial shortly. I'm very pleased that I can join this trial as the "tripple therapy" have been very toxic and difficult to balance with the synergistic effects. Just having Indian food (Korma with Turmeric) tipped the scale with too high toxicity.
It is probably not very good to stay on these three together for too long. With all the side-effects I see some people have from just use of one of these drugs I am surprised that I could stay on them combined for these four months at all.
I also enter this trial in a very different situation than when I first arrived to join it in December. Now having some CLL/RT in parts of BM, instead of having more than 90% RT in the BM everywhere.
Joining a controlled trial should also allow the immune system to normalise and give the BM specialist time to prepare for next treatment. My "N of 1" trial also indicates that with Richters it is important to act quickly and consolidate as soon as possible when there is control of the disease.
It would be interesting to know if the surprising efficacy I had of combining the three drugs after previously progressing on them individually was due to reactivation of Ibrutinib after a period with Idelalisib, or overall toxicity, possibly combined with reactivation of Ibrutinib. I am also curious if I went back to the dose I started on would that again work, or if Ibrutinib was taken away for a period, could Idelalisib alone (or with Venetoclax) again reactivate it.
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