Myeloproliferative Neoplasms: Targeting CALR With Novel Therapy


Key opinion leaders on myeloproliferative neoplasms review the potential of CALR as a therapeutic target following data from the ASH 2022 Annual Meeting.


Naveen Pemmaraju, MD: Well, team, with our remaining time, let’s get into some of the exciting novel developments. We’ll call this section beyond JAK inhibitors, the new agents. We’ll start back with Ruben. Ruben, I was compelled by the novel discovery, it was presented in the ASH [American Society of Hematology annual meeting] plenary session of the mutation-specific CALR targeted agent, as a monoclonal antibody, marking the first time in our field. In general, Ruben, you’ve seen and been a part of so many developments, how excited are you about this seemingly novel development in our field?

Ruben Mesa, MD: It’s very exciting. It’s always with the caution, we don’t know the unintended consequences of using a monoclonal antibody against calreticulin, or toxicities, or if the agent that was presented is the right agent. Just a nonbiologist explanation of the rationale, the mutated CALR is on the cell surface, so you can target it, and the nonmutated is not on the cell surface, so there’s a difference. What we’ve always struggled with in cancer is specificity. There’s a bit of biologic specificity that is attractive, and people are looking at a range of ways. Earlier at EHA [the European Hematology Association meeting]this year, there was a vaccine study that was presented, and it was a big goose egg. No responses. Now, is it the right vaccine? Is it the right dose of the vaccine? Again, there’s a lot that is involved. But this plenary session, in preclinical models, a monoclonal antibody. Again, it’s highly suggestive it is both specific for the mutation, which is a plus, and then hopefully it would have a significant impact, potentially in MF [myelofibrosis] with CALR, potentially with ET [essential thrombocythemia] with CALR. A reminder for folks, [polycythemia vera] should not have calreticulin. So interesting in both, but again, we’ll have to look at the trials, I think there will there be great enthusiasm. We don’t know.

When you do this in the dynamics of the bone marrow and the individual, people have already said, “If a lot of the stem cells have CALR and you take them all out, are they going to be aplastic? Are they going to have severe cytopenias?” Hopefully not, but there is great interest. I think there has been great interest in seeing if there is something we can do to go for a deep remission-like therapy. People ask, “What is the unmet gap?” The unmet gap is that we do not have therapies that lead to remission, no evidence of disease. We’re making great increments, but we haven’t had a game changer. Stephen, as our panel MPN [myeloproliferative neoplasm] sage and biologist, what do you think? You hit CALR, what do you think is going to happen?

Stephen Oh, MD, PhD: Let’s see if I can earn those titles. There’s no doubt that this new antibody that appears to be selective for mutated CALR is extremely exciting, both in terms of the concept and the prospect of moving forward with early phase clinical trials. Lots of excitement for all of us. It remains to be seen what we’re going to be able to achieve. Some of it is the stuff that applies to any new therapy and development, as you outlined, in terms of is it the right antibody? How is it going to work in actual patients? The preclinical studies that were presented looked very encouraging, but there’s still quite a bit of a gap in terms of, is that going to be reflected in what we see in actual patients? I’m cautiously excited. There is a question as to, if you selectively target the mutated CALR, the preclinical studies look good in terms of selectivity and lack of detrimental effects otherwise, but in patients, when you target the mutated CALR, whether you’re disrupting function of CALR otherwise in a way that is not necessarily read out by the studies that were included in the presentation. So we need to see. Absolutely I’m very excited to move forward, but again, cautious enthusiasm.

Naveen Pemmaraju, MD: Great discussion. As you both mentioned, the scientific discovery is there, and they announced at the end of the plenary session that’s moving into phase 1 clinical trials in this coming year, so we’ll eagerly wait and see.

Transcript edited for clarity.

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