DR STEENSMA: So this was an MD Anderson study. And they were looking at patients with higher-risk MDS for whom hypomethylating agents had failed. And that’s a very high-risk group. We know from several studies that their median survival is less than 6 months. So it’s a group for which there is no established therapy. There’s no FDA-approved therapy. There’s nothing we know that can prolong life in that setting. So it’s a huge unmet need. It’s one of the 2 biggest unmet needs in MDS, the other being lower-risk patients for whom EPO or lenalidomide fail.

So what the MD Anderson group did was design a study in which patients could get either nivolumab or ipilimumab or both. And they had different cohorts for each of these. And they continued the azacitidine — or I should say they added back the azacitidine in some patients who weren’t responding. And they found that the overall response rate to nivo alone was zero. But when you added back the azacitidine, it was 69%. Six out of 11 patients had a response, including two CRs. The response rate to the ipilimumab-alone arm was 22%. And there were too few patients who got the aza added back in that arm to say much.

They saw a few of the types of immune adverse events that have been noted in solid tumors. So there was a couple of cases of thyroiditis. And there was a case of colitis. And there was a case of adrenal insufficiency. And these are not things that we normally see with hypomethylating agents. So they were clearly related to the checkpoint inhibitors.

So their conclusion was that hypomethylating agent plus nivolumab was a reasonable thing to study in patients either for whom aza had failed or previously untreated patients. And so we definitely need more data here, but at least there are some responders to this combination.

DR LOVE: When you kind of look at this from a macro point of view, what’s your level of excitement?

DR STEENSMA: My level of excitement is modest. I’m more encouraged by the use of things like venetoclax plus a hypomethylating agent or vadastuximab, or a targeted agent plus a hypomethylating agent. I think it is going to be an uphill battle to replicate the type of success that’s been seen in the melanoma and lung cancer world with these agents.

The 1 caveat, though, is that we know from melanoma that patients don’t have to have a complete response to have improved survival. And we’re nowhere near being able to have any hint that that’s the case in myeloid disorders. But just because the overall response rate and the CR rate aren’t stellar doesn’t mean that we should abandon this approach. I think we still need to do the randomized trials and see: Does adding these agents to a hypomethylating agent improve survival?

DR LOVE: And of course this comes up all the time. And you kind of wonder whether there might be some other parameter that you could look at other than response, particularly the issue of, let’s say, progression-free survival for more than… whether it’s 18 months or 3 years, some time period that you just normally would not see.

DR STEENSMA: Yes. One way of doing that would be to follow a point mutation or a group of point mutations that are present in the MDS cells. One of the great things about doing molecular testing in MDS is that you can do it from blood even if there’s no blasts. Most of the cells circulating in MDS are part of the clone. So you could potentially serially monitor patients who are getting, say, a hypomethylating agent and note whether there’s any sort of clonal response or not. And that might give you an early indication of whether the patient seems to be likely to respond.

And so we saw a study at the ASH annual meeting by a group in Canada and in Taiwan. And they did exactly that. They treated patients with azacitidine, and they followed the mutation burden during treatment. And they found that there was a correlation between clinical response and reduction of mutation burden. And so I think 1 of the things that we then have to take a step back and ask is, is this really useful yet, clinically? Because there were some patients who did respond or had hematologic improvement, at least, who didn’t have a reduction in mutation burden.

So we’re not necessarily going to stop therapy in patients whose mutation burden isn’t changing. So what, then, does this really add clinically? And I would say right now it’s an interesting research tool, but it’s not something we’re doing in practice even though we have easy access to a molecular panel. I’m not checking after cycle 2 or cycle 4 and saying, “Hey, did that ASXL1 mutation go away,” because it isn’t that helpful at this point.

Up-front management of newly diagnosed multiple myeloma (MM)

Management of relapsed/refractory MM

Smoldering myeloma and primary amyloidosis

Non-Hodgkin lymphomas

Hodgkin lymphoma

Chronic lymphocytic leukemia

Acute myeloid leukemia (AML)

Myelodysplastic syndromes (MDS)

Myelofibrosis