Sequencing and Managing Combination Therapy in Myeloproliferative Neoplasms


Following their overview on novel treatment modalities in myeloproliferative neoplasms, expert panelists consider how best to sequence and manage novel therapies in practice.


Naveen Pemmaraju, MD:Dr Palmer, bringing it back to the clinic, there are many more options that are already available, so many that we hope are coming, and there’s no great answer to this, but we must start talking and thinking about it. How does one sequence these? What do you picture it in the clinic? Let’s maybe focus on the non-transplant eligible, you can also discuss that as well. What do you think with all this?

Jeanne M. Palmer, MD: A lot of this is going to come down to side effect profile. When you take a drug like navitoclax, which results in significant thrombocytopenia, that’s not a drug you’re going to want to use for thrombocytopenic patients. Another thing will be cost, which is always going to be important. How do we use these? Do we use these upfront? Do we wait until they have certain evidence that they aren’t responding as well as they should have? I don’t know what the right answer is going to be there. I think it’s going to be a big challenge. On one hand, you want to try to give as much therapy as you can upfront and potentially make the biggest difference you can, but on the other hand, is that going to be needed at that time frame? Is this something that we’ll be doing, and are we even using it right? Should we be using it in a different way where we potentially don’t do dose interruptions for different counts going down? There’s still a lot that we need to learn about. Number 1, using these drugs, number 2, selecting them, and then we haven’t even gotten to the point of saying, “OK, let’s say that they are put on a BET [bromodomain and extraterminal] inhibitor and they progress through that.” Will navitoclax work at that point? Or will one of these other a PI3 [phosphoinositide 3] kinase inhibitors work at that point? How do you choose that? I think what this actually boils down to is that we need to have a better biological understanding of myelofibrosis and fully understand the wide heterogeneity of the disorder, so that we can potentially identify markers that would say this is the person who should respond better to X drug and this is a person who should respond to Y drug, but it’s going to take a while to get that.

Naveen Pemmaraju, MD:Your comments resonate with me because as excited as I am about the combination therapy, Dr Palmer reminds us of 2 important things. One, as you said, new combinations usually mean new toxicities. The case of navitoclax, which I’m part of, on paper, you may have a decrease in platelets thrombocytopenia, but so far, they’ve not seen any major bleeding or hemorrhages, but yet that thrombocytopenia still needs to result in dose modification, interruption. How does that happen on a clinical trial to commercial setting? This is something new in our field. The number 2 that you brought up is novel combinations, and we are still thinking about how to sequence the 3 or 4 JAK [Janus kinase] inhibitors that we have, but you brought up something very important, which is sequencing the novel agents or even novel combinations as John and I are trying to look at, which is combined BCL XL [B-cell lymphoma-extra large] inhibition and BET inhibition. John, what are some of the new toxicity side effects that you think the field should be looking out for? And how do we start to think about mitigating them in the clinic in the standard of care setting?

John Mascarenhas, MD:In terms of side effects?

Naveen Pemmaraju, MD:Exactly.

John Mascarenhas, MD:Whenever you embark on novel combinations, at least initially, you probably don’t know what the side effects are going to be, so that’s part of it. That’s why they typically start as early phase trials, because one needs to be vigilant for a whole array of side effects that could be immune-based side effects, or cytopenias from myelosuppression, GI [gastrointestinal] side effects or things you’re not even thinking about, like Wernicke’s encephalopathy. We have yet to see the obvious consideration and concern. Whenever we do a novel combination are we going to exacerbate the mild depression, which we typically see with each agent? Overcoming that is the first obstacle, which requires understanding the mechanism, perhaps understanding how best to deliver the 2 drugs to compensate for that, or avoid that redundant toxicity. With most of the combination therapies we’re seeing, it’s some of the most frequent treatment emergent adverse events, or cytopenias and myelosuppression, which is fine, if the doublet provides us with double the benefit. The appetite for toxicity is in direct relationship to what additional benefit we are getting from these combination therapies. It’s probably not simply enough to say, we’ll get some additional spleen benefits from additional symptom benefit. There must be something that’s worth the potential for toxicity that financial toxicity of 2 agents. There’s a lot of considerations when considering toxicity and benefit, and if they weigh out at the end of the day.

Transcript edited for clarity.

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