Harry Erba, MD, PhD: Let’s move on to real-world management of myelofibrosis if you don’t mind. Moshe, why don’t you walk us through the results of the COMFORT-I and COMFORT-II studies, which led to the approval of ruxolitinib?

Moshe Talpaz, MD: Ruxolitinib was approved primarily based on its effect on symptom control and effect on spleen. It was not approved on the basis of survival impact, but it’s interesting to bring up that point. It clearly was superior to best-available treatment as far as symptom control in multiple ways. I don’t recall exactly the figure, but it was 50%-plus of the patients who had 50% improvement. Then there is a substantial improvement of splenomegaly that was measured by MRI [magnetic resonance imaging] and as far as change in spleen volume. A 35% reduction in spleen volume was considered significant, and it was seen in about 40% of the patients.

It turned out to be a significant number. The reason it’s a significant number is the degree of the splenic response, to a large extent, dictated by the duration of the response. It seemed that they are very tightly linked. About half the patients with splenic response greater than 35% by a volume of 50% by physical examination maintained their remission for 5 years plus, whereas the others, some of them have very fleeting responses that were not durable.

It clearly had a nice reproducible effect on symptom control and spleen response, which links nicely to symptom control as well because of the splenic symptom. This was confirmed in 2 studies, COMFORT-I and COMFORT-II. COMFORT-I, and I think subsequently also COMFORT-II, showed some survival advantage even though it allowed crossover.

The interesting point about survival advantage is that it happened early. When you look of the split of the 2 curves, it wasn’t late, it was early, which would suggest that high-risk patients were the ones who benefited from it early. We have a 5-year update, and the difference is maintained. As far as the low-risk patient, to what extent they have benefit really was not addressed. That’s a question that has to be addressed. We don’t have a definitive answer on the advantage of ruxolitinib as far as long-term survival advantage. I don’t think this was addressed as a specific question of the study, so we don’t have definitive answers.

John Mascarenhas, MD: There have been a number of analyses to try to fish out the potential for survival benefit with ruxolitinib in myelofibrosis, and they’ve done pooled analyses. They’ve used very fancy statistical tools, like the rank-preserving functional test to sort of map out what the control arm would look like if they had stayed on a therapy. I think the bottom line is there’s probably a benefit of JAK inhibition, mainly ruxolitinib in the COMFORT studies, that affords a survival benefit as it relates to improvement in symptomatology, reversal of cachexia, and improvement in performance status which underlies probably improvement in anyone’s survival.

I don’t really think it’s underlined by anticlonal activity or remissions, so that was really important. I think the concept that a CR [complete response] is going to make the patient live longer with ruxolitinib is not really what’s at play here. The reality is, if you really look at it for what it’s worth, probably what the COMFORT studies tell us is that the earlier you start ruxolitinib, the better the benefit you have. That’s probably the difference in survival. It’s starting ruxolitinib earlier in the course rather than waiting. There are very few malignancies for which you wait until someone gets really sick to start the therapy. I think it’s more a function of timing.

Harry Erba, MD, PhD: That’s why I want to come back to Robyn on this question about survival. Because as Moshe pointed out, the split in the curves occurred early, but they occurred around the median time of the crossover of most of the patients from the placebo or best-available therapy to ruxolitinib. It does suggest what John is saying, that earlier intervention may be important. Is that because we’re controlling, improving cachexia, fatigue, immune function? What do you think?

Robyn Scherber, MD: I agree entirely. I think that is exactly what we’re seeing. When we really look at the effects of ruxolitinib, I think from a mechanistic perspective, what we’re seeing is because of the proinflammatory mediated signaling. And then a lot of that inflammation being what mediates bone marrow fibrosis, so especially things like TGF beta. If you’re starting to see those cytokine levels go down, you might be able to slow potentially some of the disease fibrosis.

Along with the improvement in symptoms, I think you’re seeing a lot of improvement in terms of functional status, in terms of quality of life, and I really think that’s key to why ruxolitinib does have that survival advantage. What we’re not seeing is that it does, in any significant way, deter potentially disease progression, transformation. Especially from a symptomatology perspective, I do like to start ruxolitinib earlier rather than later, especially if I see a symptomatic patient. I do think we still have ways to go in terms of therapies.

Harry Erba, MD, PhD: Yeah, I think that’s an important point, because if you take that conclusion to its logical extreme, then even in patients with low-risk disease, you might say maybe you heed to start it. I really think the mechanism by which we’re seeing the benefit is by controlling that inflammatory milieu, which will translate into known symptoms at the time.

Transcript Edited for Clarity