The National Institutes of Health were founded by Congress in 1887 and charged with being the preeminent research center in the world.
The CLL Society is proud of our educational partnership with one of the institutes, the NHLBI (NATIONAL HEART, LUNG, AND BLOOD INSTITUTE) as it serves the CLL community under the leadership of Dr. Adrian Wiestner. We are very proud that Dr. Wiestner has agreed to join our medical advisory board.
The NIH does research that others don’t do, and they cover all the expenses related to their trials including help with the cost of travel.
I was excited to interview Dr. Adrian Wiestner by submitting a series of questions about a trial for high risk CLL. This is trial worth considering if you are at risk of developing resistance to ibrutinib and/or venetoclax.
Here is my Q & A with th Dr. Wiestner
What is high-risk CLL?
- Different tests are used to detect high-risk genetic changes.
- Deletion 17p by FISH
- Complex karyotype by metaphase cytogenetics
- TP53 mutation and NOTCH1 mutation by sequencing
How do high-risk CLL patients respond to ibrutinib?
- Much better than to chemotherapy
- However, lack of deep response à permanent continuation of therapy
- Transformation and drug resistance à Limited duration of response on ibrutinib monotherapy
Your study includes a checkpoint inhibitor. What is a checkpoint-inhibitor and why use it in CLL?
- PD-1 inhibitor – goal is releasing a break that is put on the immune system by the tumor cells
- Works well in some solid cancers – for example melanoma
- T-cell dysfunction and genetic complexity are well-described in CLL. CLL cells can be killed by immune cells: e.g. allogeneic bone marrow transplantation, CAR-T cells
- Here we hope to make it easier for the patients own T cells to attack CLL cells
You also use fludarabine. Why?
- Fludarabine is given for one cycle (as compared to 6 cycles when used in chemotherapy)
- The goal if you wish is to “reboot the immune system”. Fludarabine will lower T cell counts, provide space for normal T cells to grow back.
- Our FI study showed FI is well tolerated, achieved a much better complete response rate than we have seen with ibrutinib alone and it looks like there is a positive effect on the T cells.
What are the goals of your study?
- Goals: to improve quality of response, to eliminate the “bad actors”, meaning those CLL cells with mutations that lead to drug-resistant CLL
- The first measure will be the complete response rate after one year of treatment with pembro; long-term we hope to see that these responses are long-lasting.
Why this combo versus ibrutinib and venetoclax or obinutuzumab?
- Ibrutinib and venetoclax are working very well together and induce deep responses. However, very little is known how long these responses will last.
- The high-risk patients (as defined above) are more likely to develop resistance to ibrutinib and to venetoclax when used alone. Whether the combination can overcome this risk is not known.
- Recruiting an immune response against CLL is one approach, combining two effective drugs to kill (all the) cells is another
- The randomized trial comparing BR vs IR vs I suggested that the addition of rituximab to ibrutinib does not make responses better or longer lasting.
Who should participate on the IFP trial?
- This treatment, we hope, will serve those patients well who are at an increased risk of developing resistance to ibrutinib and/or venetoclax.
- Mostly patients with r/r CLL with del17p or TP53 mutation and treatment-naïve patients with del17p and additional risk factors such as advanced Rai stage or complex karyotype
Let me emphasize the single course of fludarabine is not to treat the CLL, but to reset the T cells. Prior studies suggest this is an effective strategy.
For high risk CLL, I recommend considering a clinical trial with a combination of complementary therapies. This trial should be on your list
For more info see here.