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Phase IB/II Study of Nivolumab in Combination with Azacytidine in Patients with Relapsed or Refractory Acute Myeloid Leukemia
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Blocking PD-1/PD-L1 pathways enhances anti-leukemia responses by unleashing T-cells in murine models of AML (Zhang et al, Blood 2009). PD-1 positive CD8 T-cells are increased in bone marrow (BM) of pts with AML (Daver et al, AACR 2016). PD1 inhibition alone demonstrated limited activity in AML (Berger et al, Clin Cancer Res 2008). Rational combination strategies to enhance the anti-tumor and immunogenic effects of PD1 inhibitors in AML are needed. AZA up-regulates PD-1 and PD-L1 in AML and the up-regulation of these genes has been associated with emergence of resistance to AZA (Yang et al., Leukemia 2013). These could be blocked with the PD-1 inhibitor nivolumab.

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Hello, I am Dr. Naval Daver from MD Anderson Cancer Center in Houston, Department of Leukemia. Today I will be giving a brief overview of my study that will be presented tomorrow morning as an oral presentation at the American Society of Hematology Meeting at San Diego. So, this study was a combination of azacytidine and nivolumab in patients with a relapsed or refractory Acute Myeloid Leukemia (AML). The background of the study comes from a lot of research that we have been doing looking into the applicability of immune checkpoint based therapies in different leukemias, including AML, MDS, which is also called Myelodysplastic Syndrome, Myelofibrosis, NCLL, and we have a large program that started by looking at expression of different T-cell subsets immune checkpoints in patients with AML, MDS, and Myelofibrosis.

We're doing these studies in collaboration with the immunotherapy platform at MD Anderson, led by Dr. Jim Allison and Padmanee Sharma.  In one of the posters at this ASH, we actually have shown that in acute myeloid leukemia patients, there is an overexpression of PD1 on the total T-cell subsets as well as on the CD8+ and the CD4+ effector. What this basically indicates is that the patients with AML do have a high level of PD1 suppression of their TH1 T-cells, and we could manipulate this to improve their responses. Based on this, we began the study, and the study initially has started for the relapse refractory population, included all salvages. Patients would have standard inclusion criteria, so no major organ dysfunction, but other than that it was very similar to any other Phase-1b/2 relapse refractory AML population.

Overall, we had an initial dose escalation phase where we would evaluate for safety and we enrolled six patients in the dose escalation phase. The first six patients received azacytidine 75 per meter squared Day 1-7, which is a standard dose of azacytidine, along with the PD1 inhibitor nivolumab on Day 1 and 14. Also, the standard dose of three milligram per kilogram. The therapy was well tolerated without any major toxicities seen in the first six patients, and so this was determined to be the recommended Phase 2 dose. We have now expanded and we have a total of 47 additional patients at the recommended Phase 2 dose. So a total of the initial six plus the 47, 53 patients, and that is the data that we will be presenting.

What we are seeing at this time is that the overall response rate for these patients, the CR/CRi rate, is in the range of 20 to 22 percent, with an additional 13 to 15 percent having a PRHI, for a total response rate of 35 percent. And the 8-week mortality in this population, which is traditionally expected to be in the range of 12 to 18 percent, was actually lower at 8 percent. The response rates of 35 percent also compare favorably to a traditional response rate with azacytidine alone in a similar population at MD Anderson of about 15 to 18 percent.

We also looked at a number of toxicity parameters. We do see that these patients [inaudible 00:03:04] level of immune-mediated organ specific toxicity, we had only one patient with cytokine release syndrome out of the 53, but we did have about 25 to 30 percent patients who had either pneumonitis or nephritis or skin toxicities that all responded very rapidly to steroids, so improved awareness of these toxicities and rapid initiation of steroids was quite crucial and has made a difference in not letting them progress to major organ toxicities.

Towards the last part of the study, we have been working very closely with the immunotherapy platform and analyzing baseline bone marrow aspirates as well as peripheral blood, and then bone marrow aspirates every two months sequentially on patients, including responders and non-responders. What we saw is that patients who had a high CD3+ bone marrow infiltrate, and especially those who had a high CD8+ to Treg infiltrate in the bone marrow baseline had a much higher predisposition to response, indicating that patients who already had a favorable T-cell immune infiltrate could easily be manipulated to get a response, whereas those who had very few T-cells to begin with, getting a response with the azacytidine and nivolumab was much more difficult.

The other factor that we saw that was of interest is that the CTLA4+ levels were much higher at baseline in the non-responders, and actually continued to go up with treatment, whereas this was not seen in the responders, indicating that high CTLA4+ checkpoint may be a mechanism of primary resistance, as well as secondary resistance to PD1 inhibitors, something that has been shown repeatedly in multiple solid tumor trials, but also indicates that by using a dual checkpoint inhibition of PD1 CTLA4+, we may be able to enhance the responses.

So, in conclusion, we're seeing encouraging response rates better than what we have seen with azacytidine alone in a similar matched population. The responses are very durable, this was a very important point, all of the patients who have had CR have maintained it except for one relapse, so the median CR duration is now around 10 months, which is very encouraging in a salvage population. And it does seem there are particular bio markers, such as high CD3+, or a high CD8+ to Treg baseline ratio, that could be used to select the patients most likely to respond, and maybe a combination approach of a CTLA4+ plus a PD1 with azacytidine could enhance these responses further as has been seen in solid tumors.  With that I would like to stop and thank you very much.