Transcript
My name is Naval Daver. I'm an associate professor in the Department of Leukemia at the MD Anderson Cancer Center in Houston, Texas. My focus is clinical research in acute myeloid leukemia, including immunotherapies and novel targeted therapy combinations.
At this year's ASH 2019 meeting, I will be giving an oral presentation on a combination of hypomethylating agent azacytidine with immune checkpoint treatment of PD-1 inhibitor nivolumab. In some patients, we had a triple combination that I will also be giving updated results on of azacytidine with PD-1 inhibitor nivolumab and the CTLA-4 checkpoint inhibitor ipilimumab.
I would like to start by saying that in general there has been a tremendous progress in the understanding of the immune system in solid tumors, but also in the last 5 to 6 years in acute leukemia and MDS.
As compared to a few years ago when there was very limited data on immunotherapy, expression of different immune checkpoints, clinical activity, mechanism of resistance. We now have a number of presentations and posters on different immune therapy combinations.
Also, importantly, we’re finding novel immune pathways, such as TIM-3, CD47, others that may be very specific and more effective in the myeloid malignancies.
In this study that we did, this was one of the first immunotherapy clinical trials to start, a few years ago. A combination was evaluated with azacytidine and nivolumab in relapsed refractory AML. Historically, relapsed refractory AML patients have response rates of 15 to 20% to high dose chemotherapy or other epigenetic combinations, which has been what we have done for many years.
With this combination, we saw an encouraging response rate of about 33%. Really, what was more important was that there was a good subset of patients who had stable disease, 10 to 15%, in addition to those 30% response, so about 40 to 45% of patients had what we would consider clinical benefit in an older relapsed population.
Then, when we looked at the different clinical characteristics of these patients, we were able to find specific subsets that had significantly more benefit than others. One of these subsets were people who had first salvaged AML. These people had a median overall survival of 10.5 months, which is almost double of the 5 to 6 months we have historically seen with azacytidine alone in the first relapse population.
We tried to understand what was the difference and why these patients had a better response. What we found is that in the people who had first relapse as compared to those who had subsequent, second, third, fourth relapse. They had a more preserved T-cell infiltration.
Also, functionally, when we did single-cell cytokine analysis, we found that the function of those T-cells in the salvage 1 situation was much higher than in subsequent conditions where both numerically and functionally, the T-cells were shut down.
This was a good mechanistic rationale to explain why we were seeing this benefit. We also looked at multiple biomarkers, using both CyTOF as well as single-cell RNA sequencing that is ongoing, as well as single-cell cytokine secretion.
We found a number of different biomarkers that are predictive for response, but among them, the one that is probably the easiest to put into clinic as a biomarker for selection is bone marrow CD3 or bone marrow CD8 infiltration. We found a distinct difference in response rates in patients who had higher bone marrow CD3/CD8 infiltration. This was in our published manuscript last year on this study.
The way I think that this would develop in the future is if we identify patients who have more than 15%, that is the cutoff we identified by statistical logistic regression, more than 15% T-cells infiltrating the bone marrow, at baseline those will be the patients who have a good chance of responding to AZA/PD-1.
I think that would be the way to develop and eventually, potentially, try to get these drugs through registration.
We also saw that as one of the mechanisms of resistance on patients who either did not respond or had a response and then relapsed a few months later, there was significant upregulation of CTLA-4, another important coinhibitory pathway.
This has now led us to the triple combination of azacytidine with PD-1 with CTLA-4 to prevent emergence of resistance, as well as to improve response rates. We are now seeing response rates of about 45 to 50% when we consider CR, CRI, MLFS, which is better than the 30, 35% we saw with AZA/PD-1.
Important to note that these drugs do have unique immune mediated organ toxicities. These are usually specific to different organs. Skin, liver, gut, and lung are the common ones we have seen.
These can be severe if they are missed and not treated very quickly. With expertise among our group, I think we have gotten better at identifying and rapidly initiating steroids with or without antibiotics as the clinical presentation may be.
With that, we actually see early mortality rates of 5 to 8%, which in relapsed elderly AML is actually very good. I think that this field is moving. There are other oral presentations combining pembrolizumab with HMA by Dr. Goja from Hopkins, as well as high dose cytarabine with pembrolizumab by Dr. Ziegner, as well as a front-line study of AZPD-L1 presented by Dr.Zeidan in my same session.
I think we are seeing a lot of progress. Hopefully, in the next few years we will be able to get one of these strategies to approval.
Also, there's exciting data with another immune checkpoint that targets macrophages, not T-cells. This is a drug called azacytidine CD47, which is showing very, very high response rates in front line MDS/AML and has generated a lot of excitement for immunotherapy at this year's ASH for myeloid malignancies. Thank you.
