Robyn Scherber, MD: That’s a great question because I haven’t seen any good studies saying whether or not you do. I would out of due diligence, but the reality is we just don’t have the data.

Harry Erba, MD, PhD: My understanding is it’s the symptoms that get worse, and maybe that’s symptom control because the JAK1. It doesn’t make sense that fedratinib would necessarily protect you from those symptoms.

Moshe Talpaz, MD: Harry, you’re bringing up regretfully a very important point and I’ll say why it’s regretful. It pertains to clinical studies, which all require a washout period, and we ran into some disasters. Even if we taper off gradually, the minute there are 2 weeks between studies, we ran into serious problems with a splenic rupture in the case because the spleen was growing in an uncontrolled fashion off drugs. At this point, I have to recommend not to have a period of no treatment but to transition from 1 drug to the other. Or you can lower the dose and move from 1 drug to the other and not interrupt for a long period. I would also recommend the clinical studies have to modify their design to, say, a few days off, but absolutely not 2 weeks or longer. It creates a problem.

Harry Erba, MD, PhD: Well, that’s an important observation because it was true, the COMFORT-I study had to be off anything they were on. If you look at the placebo or best-available therapy arm, there was a lot of progression of symptoms and splenomegaly very early on.

Moshe Talpaz, MD: Absolutely, and we have to be very aware of it, especially in patients who start with a highly proliferative disease, and we can identify them, the high white blood cell count, big spleens, and so forth. Now, we shouldn’t allow very long periods of treatment interruptions, because even resistance to ruxolitinib does not mean total resistance. It means there is still some benefit, and you stop it and you will see it.

Harry Erba, MD, PhD: Before we get to some of the new things, let me bring up something that I think is incredibly cool in the pathogenesis of myelofibrosis, and that is in the patients with CALR deletion mutations, the frameshift mutations and how that actually contributes to pathogenesis of the disease. It’s my understanding that CALR, which is a chaperones protein endoplasmic reticulum to take them to the cell’s surface, but it stays in the cell unless there’s a mutation. The mutation leads to a loss of that retention signal, and this truncated CALR is then excreted into the extracellular space and combined to MPN. Actually, this is something that signals through MPL. I got it right. I’m not a scientist.

Moshe Talpaz, MD: You got it right.

Harry Erba, MD, PhD: I got it right. Here’s the question for my investigators here. Is anyone looking at small-molecule inhibitors that block that interaction for monoclonal antibodies against CALR?

Moshe Talpaz, MD: Some people are even trying to develop immunotherapy, a vaccine based on that. I hope we are not going to see a CAR T [chimeric antigen receptor T-cell therapy] based on that.

Robyn Scherber, MD: I know Hans Hasselbalch has already dosed a few patients with a CALR-related vaccine. I will see how effective that is. I think more than ever, if we do go with that approach, there might need to be approaches that actually augment the immune response from what I’ve talked to him about.

John Mascarenhas, MD: Just to add to that, the fact that the mutant protein is expressed on the cell surface obviously provides for a novel neoantigen that can be picked up by the immune system. We know there’s a lot of immune dysregulation in patients with myelofibrosis, so the concept of checkpoint blockade in those patients in particular that calreticulin [CALR] mutated may have rationale because those patients, if you release that T-cell repression, may actually be able to form an immune response against those cells.

Harry Erba, MD, PhD: Before we get to some of the new drugs I want to discuss, I want to ask Robyn about her experience in combining ruxolitinib, and maybe fedratinib as well. But we’ll say ruxolitinib with HMAs [hypomethylating agents] or other drugs to try to improve responses or gain responses.

Robyn Scherber, MD: That’s definitely something I see a lot in terms of referrals in patients who maybe are suboptimally dosed with ruxolitinib. I haven’t had the chance to see someone who is suboptimally dosed yet with fedratinib, but I’m sure that could happen. There are a few different approaches that have been looked at in phase II studies. Some of my go-tos are that we know that it’s safe and effective for patients with erythropoietin [EPO] level less than 500 mU/mL to consider the addition of erythropoietin with ruxolitinib. Some patients you can actually get a pretty robust anemia response, and that allows you to potentially go up with ruxolitinib dosing.

The other thing is Danazol. Although danocrine is less robust, we certainly can see a minority of patients respond, and it’s a safe and potentially effective combination. The other things we have recent data on that look pretty promising, we have data this ASH [American Society of Hematology] Annual Meeting & Exposition on the addition of pomalidomide, a dose of anywhere from 0.5 mg/day up to 2 mg/day in combination with a stable dose of ruxolitinib, having some anemia response.

We don’t have many good options in terms of thrombocytopenia. Some people have combined ruxolitinib with hypomethylating agents. I haven’t personally. Although I’ve done that strategy, it seems most effective in patients that are having some sort of signs of disease transformation with the increasing blast count. There have been some patients who’ve responded in terms of platelet counts. The addition of ruxolitinib plus thalidomide at just a stable dose of 50 mg a day after around 3 months of stable ruxolitinib therapy has been tried in a trial. They saw a 75% improvement in platelet counts. I think that more than ever, we have a couple of commercially available options that might actually help optimize our ruxolitinib dosing.

Transcript Edited for Clarity