Cancer Conference Update: A Multimedia Review of Key Presentations from the 2016 American Society of Hematology Annual MeetingAbstract 763: Rationale for and results of a Phase Ib/II study of azacitidine and nivolumab for relapsed AML
4:28 minutes.
TRANSCRIPTION:
DR LOVE: So let’s move on now and talk about, of course, the topic everybody wants to talk about nowadays, checkpoint inhibitors. DR STEENSMA: Yes. DR LOVE: And you guys are there, too. And I see there’s a paper here combining it with azacitidine in AML. DR STEENSMA: Right. DR LOVE: Can you talk about that? DR STEENSMA: I will. And I’ll first talk about what is some of the rationale and then what is some of the challenges with using checkpoint inhibitors in myeloid disorders. So the rationale, especially for combining it with an agent like azacitidine or decitabine, is that these agents change gene expression. They may change expression of antigens on the surface of the cells. And if then, with an immune checkpoint inhibitor you could trigger a T-cell response against those new antigens, that could be quite a potent approach that could lead to deep and durable remissions. One of the things, though, that we’ve been disappointed by thus far in myeloid disorders is lack of response as single agents to these drugs. You can give these drugs in metastatic lung cancer or melanoma as single agents and see robust responses. We don’t see that in myeloid neoplasms. Guillermo Garcia-Manero presented a study of nivolumab and ipilimumab alone and in combination in high-risk MDS and didn’t see any responses to the monotherapy. However, it’s possible that by adding these agents to either hypomethylating agents or chemotherapy that we might see a synergistic effect. And so this was a 50-patient study from MD Anderson in which they used nivolumab in addition to a hypomethylating agent in patients with AML. And they saw a response rate that I would say was consistent with what you would expect with azacitidine alone. So they had a complete response rate and a CRI rate of 21% and a hematologic improvement rate of about 6%. And so I think there weren’t a lot of additional adverse events. There wasn’t a lot of additional toxicity. But I think we really need randomized trials to know, is there a contribution in terms of response or survival to adding these checkpoint inhibitors? DR LOVE: What’s the rationale, theoretically, for, I guess, a synergy between a hypomethylating agent and checkpoint inhibitor? DR STEENSMA: Yes. So mostly it’s based on a way that hypomethylating agents change antigen expression. For instance, if you use a hypomethylating agent after transplant, some of the antigen expression changes that occur favor a graft-versus-leukemia effect and may reduce, actually, the graft-versus-host problem. And so we know that these agents, because of the way that they alter gene expression by changing methylation, that they can lead to expression of new antigens. There’s some data that that may lead to an immune response. There’s upregulation, for instance, of interferon pathway genes, which gets at the old debate about how exactly do these drugs work in MDS or AML as single agents? Azacitidine — is it a cytotoxic? Is it like cytarabine? Is it truly working by hypomethylation? Nobody’s been able to clearly show that in patients. Or is there a third method of response, which has triggered an endogenous immune response? And if it’s the third, then adding nivolumab, adding ipilimumab, adding pembrolizumab or one of the checkpoint inhibitors would be quite attractive. The one setting where checkpoint inhibitors have shown utility in myeloid disorders is in patients post-transplant who relapse outside of the bone marrow. So let’s say that we have somebody that relapses in the skin or in the lung. And they don’t have bone marrow disease, but they do have disease in these immune sanctuary sites. Those are patients that often do respond to ipilimumab. |