Clinical Pearls of Myelofibrosis Management and the Importance of Multidisciplinary Collaboration

Kathryn E. Kennedy

Hi Sarah! Welcome back to our conversation about myelofibrosis. We've talked in detail about the APP's role and the pharmacist’s role in myelofibrosis. Let’s talk now about multidisciplinary collaboration and how that's been key for us in managing patients, as well as some clinical pearls in myelofibrosis management.

Sarah Profitt

Sounds good. One patient that comes to mind is our elderly patient with a history of atrial fibrillation, and now with a diagnosis of post–essential thrombocythemia (ET) myelofibrosis. I remember when this patient saw you in clinic, you noticed that she was on dofetilide and diltiazem for cardiac medications, and then we were planning to start pacritinib for the new diagnosis of MF. I remember our first step in this patient's management was discussing the drug-drug interaction between the diltiazem that she was already taking and pacritinib. Diltiazem is a moderate CYP3A4 inhibitor, so we worry about increased exposure to pacritinib, the CYP3A4 substrate in this case, potentially exposing the patient to a higher risk of adverse effects.

The first thing that we would do in this scenario is consult the prescribing information for pacritinib and see if there are any specific recommendations given by the manufacturer that we should be following. If there aren't specific recommendations available, then my approach is to make a patient-specific plan to ensure that we do things safely. In this situation we decided on an empiric dose reduction of pacritinib to start, which, luckily, we can do with the dosage forms that are available for pacritinib. We also discussed overlapping toxicities between the dofetilide and the pacritinib as well

Kathryn E. Kennedy

This was a tough one. The dofetilide and the pacritinib can both cause pretty significant increased QTc intervals. So early on we got our electrophysiology colleagues involved. We had initially tried momelotinib which would not have this specific overlapping toxicity of prolonged QTc intervals, but she unfortunately failed that. Her platelets and hemoglobin were too low for ruxolitinib, so we really didn't have another option for her. Pacritinib was this patient’s best option. Her AFib was very well controlled on dofetilide and she had failed multiple other interventions for that as well, so stopping dofetilide was not felt to be in her best interest.

When starting pacritinib, the provider should monitor the QTc interval. Frequency depends on the patient and situation. Ultimately, with the help of our electrophysiology colleagues, we preemptively dose reduced her dofetilide because of the overlapping risk and our shared concern for significant QTc prolongation. We were also a bit concerned that she might flip back into AFib as we were dose reducing the dofetilide. We opted to admit her for 72 hours for cardiac monitoring. The half-life of dofetilide is about 10 hours, so we were thinking about time to steady state, and 72 hours seemed like a reasonable timeframe to monitor and ensure that we weren't going to see recurrence of AFib. We also monitored QTc intervals with the medications, and then once she was discharged, we used serial EKGs to monitor the QTc intervals for 4 weeks. We involved a lot of people on that case.

Sarah Profitt

I remember that. Antiarrhythmics are a class of medication that we handle with great intentionality and care. So this is a really good example of how much we benefit from having a multidisciplinary approach to tough cases. We've relied on our colleagues in cardiology for several patient cases to help us manage those tough issues, and it’s really nice to have them within our system here at Vanderbilt.

Kathryn E. Kennedy

Yes, in fact, we had another patient who had severe aortic stenosis. She had post–polycythemia vera myelofibrosis and was also on pacritinib, related to her severe thrombocytopenia, since pacritinib has an FDA approval specifically for patients with platelet counts less than 50. She'd been recommended for a TAVR [transcatheter aortic valve replacement] procedure, and we were considering whether pacritinib should be held prior to this procedure. The attending physician and I came to you to talk through pros and cons of holding the JAK inhibitor therapy prior to the procedure.

Sarah Profitt

I remember this case also. Pacritinib does have a recommendation in the prescribing information to discontinue 7 days prior to any surgery or any invasive procedure due to the risk of bleeding. Grade 3 or higher bleeding events were reported in the clinical trial for pacritinib, PERSIST-2, at around 15%.^1,2 So, not insignificant. Those did include some post-procedural hemorrhages as well. PERSIST-2 was a study that preselected for a patient population with a high risk of bleeding, because they included patients with baseline platelet counts of less than 100 prior to even starting the pacritinib. But still, this is a recommendation that we take seriously about holding medications that could increase bleeding risk before a procedure. However, there are obviously disease-related concerns about holding a JAK inhibitor as well. We know that JAK inhibitor withdrawal syndrome was reported a long time ago, many years ago, with our oldest JAK inhibitor, ruxolitinib. When patients have to hold treatment or stop ruxolitinib abruptly, it could lead to this withdrawal syndrome that can include an acute rebound of symptoms, increased or accelerated splenomegaly, worsening counts, and sometimes even a shock-like picture where patients experience hemodynamic instability. So stopping JAK inhibitors in patients with myelofibrosis is something that we consider very carefully, and it's led to a general recommendation to taper off JAK inhibitors instead of abruptly discontinuing.

In this patient's case, being on pacritinib, we took a look first at the PERSIST trials, the incidence of bleeding, like I mentioned, as well as considerations for holding pacritinib. The authors actually did comment on withdrawal symptoms in the PERSIST publications.^1,2 Pacritinib has a particularly long elimination half-life, which may help with the gradual decrease in a patient's exposure to the drug if the treatment is being discontinued. But when the PERSIST trials went on a hold and patients had to stop pacritinib abruptly, they did observe this withdrawal syndrome, where patients experienced a rapid return of constitutional symptoms and an increase in spleen size. So even with these newer JAK inhibitors for treatment of myelofibrosis, stopping treatment unnecessarily is a really big concern.

There are some strategies to help prevent this withdrawal syndrome if treatment really does need to be held or discontinued. In this patient's case, having that severe thrombocytopenia that you mentioned and heading into a procedure, we did want to hold the pacritinib temporarily for the bleeding risk. So one strategy we used was bridging corticosteroids. There is some data for using steroids to mitigate the symptoms of withdrawal if patients have to come off treatment. We worked through some of those strategies for this patient. Anything else you remember about this case that we should discuss?

Kathryn E. Kennedy

Definitely. So we did all of those things, and despite our best efforts, her spleen still grew pretty quickly. She had severe splenomegaly to begin with, measuring around 22 cm from her left coastal margin, and it grew to 27 to 28 cm. Her hemoglobin, hematocrit, and platelets dropped precipitously, likely from sequestration, and they weren't robust to begin with. We wound up in a situation where we'd held a drug for a procedure, and now her platelets and her hemoglobin were not where the cardiology team needed them to be able to perform the procedure safely. My initial plan had been to transfuse the day before and get her up to where they wanted, because she'd been maintaining well enough hemoglobin and platelet levels on pacritinib. The TAVR was really important to her quality of life. It was really contributing to some of her symptoms like fatigue, shortness of breath, and headache. So ultimately we had to coordinate with the cardiology team, and we admitted her for transfusions and the perioperative time period.

The last case I think we should talk about today is our 72-year-old patient who had a previous medical history of chronic kidney disease with waxing and waning kidney function and also a new diagnosis of primary myelofibrosis. On presentation, he had notable thrombocytopenia with platelet counts running in the 40k range. We'd started him on pacritinib 200 mg BID when his creatinine clearance was waxing, was better, and then we saw him, and it had dipped below 30 mL/minute, and I came to you and said, “What do I do with this?”

Sarah Profitt

Absolutely. So making sure that patients are on the safest and most effective dose of a medication in the setting of organ impairment is something that I do frequently in clinic and that we work together on. This was one of those scenarios where our colleagues in the pharmaceutical industry really helped us with gathering important data for helping this patient. The company that makes pacritinib conducted a study of patients with myelofibrosis and renal impairment and compared the exposure of pacritinib, the pharmacokinetics (PK), to patients that didn't have renal impairment and found that the PK didn't appreciably differ in patients with or without renal dysfunction.³ So we were able to confidently prescribe the full dose of pacritinib for this patient, based on this study looking at patients specifically with renal impairment, and that it could be done safely with more frequent EKG monitoring and watching the patient closely. Data like this in special patient populations is not something we always have access to, so this study being performed by the pharmaceutical industry and the findings being accessible to us was really helpful. I know we reached out to our MSL [medical science liaison] colleagues to help get this information. Collaboration between patient care and industry is very important.

Kathryn E. Kennedy

This was one of our patients who comes to us about every 3 months but receives most of his care locally. So this is somebody that I had quite a bit of education with the outside oncology group. I sent him the poster presentation you mentioned that the MSL had sent us to explain our plan for this patient and the importance of EKG monitoring. And he actually did great with it.

Sarah Profitt

That's awesome. Education is a big role for us, not only for our patients, but also for other providers who may not see this disease as frequently. Thanks for sharing about that. This has been a great chat about multidisciplinary collaboration.