DR STEENSMA: Ruxolitinib improves the spleen size in many patients. It improves the constitutional symptoms, but it does not do much for the malignant clone. There are some patients in whom we see a reduction in JAK2-variant allele frequency, but not a lot. And so there are a couple of different approaches that are being taken to try to improve that.

One is to use interferon instead. And we saw 2 important trials presented at the meeting with forms of alpha interferon, comparing them with, actually, hydroxyurea rather than ruxolitinib. The second approach that’s being taken is to combine ruxolitinib with other agents like azacitidine, like hedgehog inhibitors. There are a couple of other classes of drugs that are being tried, histone deacetylase inhibitors, for example, to try to reduce the clonal burden and slow disease progression. And this was a trial of that combination.

So they enrolled 41 patients. And objective responses were noted in 69% of patients. And it was a mix. There were some patients that had ruxolitinib-type responses, where the spleen got better or their symptoms improved. But there were a few patients who had a reduction in immature cells or in fibrosis. And JAK2-mutant allele burden in 15 patients that were tested, 87% of them had a reduction in mutant allele burden. And that’s more likely to be an effect of the azacitidine than of the ruxolitinib.

Now, what that is going to correlate to long term, will it extend survival? Will it delay leukemia progression? We don’t know. But at the moment, it does appear that this combination can be effective not only at the usual ruxolitinib-type things, but also at reducing the size of the malignant clone.

DR LOVE: It was so exciting when the COMFORT trials came out, ruxolitinib. We started to hear about it and the incredible clinical stories that we heard. I don't know from a macro point of view outside here, it kind of seems like — considering that was such a revolutionary change, I don't know. It doesn’t seem like that much has happened since then.

DR STEENSMA: One of the things that’s been hard is to come up with other JAK2 inhibitors. There have been several that have died on the vine, so to speak, fedratinib, after its pivotal study, met its endpoint. We thought it was going to be FDA approved. There were cases of Wernicke encephalopathy. So that was the end of fedratinib, at least for the moment.

Pacritinib was moving forward, and then in the PERSIST-1 trial there were an excess of deaths that needed to be adjudicated. And that has actually finally gone through the process. January 2017, FDA lifted the clinical hold on pacritinib.

Momelotinib, another JAK2 inhibitor, didn’t meet its endpoint in the pivotal study. And so there have been some other JAK2 inhibitors. But, for the moment at least, ruxolitinib is still the king of the hill. And there are many patients who benefit from ruxolitinib. It just doesn’t clearly extend survival.

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