Raajit Rampal, MD, explains how he considers safety profiles when deciding on appropriate treatment for myelofibrosis and how he manages toxicities for patients.
John Mascarenhas, MD: We know that Raajit sticks to guidelines. He’s always very concerned about toxicity profiles. The next question is directed to Raajit. Understanding that these drugs can differ in their adverse effect [AE] profiles, can you give the audience a sense of how you package that up? Are there certain toxicities that you consider more significant that might direct your therapeutic decision-making? How do you manage the toxicities?
Raajit Rampal, MD, PhD: I’m nothing if not by the book. With any therapeutic decision-making, there’s always the risk-benefit ratio. But now have the luxury to look at the different toxicities of these drugs and include that in the discussion. So far, we’ve framed the discussion very much in terms of platelets and where we can use the drugs. That’s the principal way in which we make our therapeutic decisions. On the other hand, these drugs have slightly different toxicity profiles, but they do have similarities. The similarities have to do with hematologic adverse events.
Coming back to basic principles, these are all JAK/STAT inhibitors, and that pathway is fundamental to erythropoiesis and thrombopoiesis, so expected on-target adverse effects are anemia and thrombocytopenia. These are seen as AEs in all the studies we’re discussing today: the PERSIST, JAKARTA, and COMFORT studies. These toxicities are observed with all these drugs to various degrees. That’s where there’s subtlety, but these are expected adverse effects of all the drugs.
What about nonhematologic AEs? With some of the newer agents, with pacritinib and fedratinib, there are some very specific things that we have to be cautious of. With both pacritinib and fedratinib, gastrointestinal [GI] adverse effects have been well documented in the JAKARTA and PERSIST studies. In fedratinib more so, there was quite a number of grade 1 to 2 GI AEs, including nausea, vomiting, and diarrhea, that occurred in the majority of patients: close to about 60% of patients. The vast majority of those were grade 1 or 2, whereas grade 3 events were in maybe 5% of patients.
Let’s not trivialize grade 1 or 2 GI AEs. We’re still talking about something that can impact a patient’s ability to function, if we think about those definitions. That likely has to do with fedratinib’s FLT3 targeting. The same thing is true with pacritinib, which also has anti-FLT3 activity. GI AEs are certainly seen with pacritinib in a proportion of patients. We aren’t talking about a high proportion of grade 3 events. We’re talking about mostly grade 1 or 2 events. We have to keep those adverse effects in mind.
How do we manage those? The most important thing is to try to get ahead of the problem. The way we do that is by counseling patients on these expected adverse effects and encouraging prophylaxis with things like loperamide or, in some cases, Zofran as needed. You have to be a little careful about drug interactions, but it’s important that we counsel the patients and give them medications to prepare for expected gastrointestinal toxicity. These are manageable adverse effects, but one has to be cognizant of them prior to starting therapy, and one has to actively manage and not passively manage. In other words, don’t wait for a patient to start having lots of diarrhea on these drugs before you intervene. Intervene before you start the drugs or at the time that you start the drugs.
Beyond these adverse effects, the other thing to keep in mind with fedratinib is that there’s a black-box warning for Wernicke encephalopathy, which was initially seen in early studies with fedratinib and led to an FDA hold with the drug. In that particular case, it’s important to always check the thiamine levels prior to starting medication and to replete them before you start fedratinib. That’s the only other thing to carefully consider when using fedratinib.
You have to think about the patient when you’re picking the drug. In a patient who already has a large number of gastrointestinal comorbidities for whatever reason, you may want to think a little differently about which drug you pick. But in most cases, these are manageable adverse effects.
John Mascarenhas, MD: What about a line or 2 about concerns centered on thromboembolic events with JAK inhibitors in general?
Raajit Rampal, MD, PhD: There have been some concerns. With regard to pacritinib in particular, there was a concern—at least early on with the PERSIST data—that patients could experience cardiac events, but it’s important to point out that in subsequent studies and pooled data from subsequent studies, including PAC203, this wasn’t observed as an event that occurred at a rate higher than in the best available therapy arms. This was part of a concern that led to the drug development being halted for pacritinib, but subsequent studies and re-analyses haven’t indicated that it’s a particular concern.
Transcript edited for clarity.