Considerations in Front-Line Therapy Selection

Lindsey Lyle

How do you typically approach a newly diagnosed patient and decide on which frontline therapy to start? And which blood counts do you think play the greatest role in this decision?

Lindsey Kalhagen

That's such a good question, and something we obviously think about every day when we're seeing patients and especially first meeting them. Risk assessment tools help guide us in deciding who warrants transplant up front versus a different type of therapy, especially in patients who are intermediate to high risk and who may not be transplant eligible. But ultimately, as far as deciding what to use first line, it really depends on the patient’s main clinical problem. If it's anemia, we should focus on the best therapy to help potentially improve their hemoglobin levels and lessen the need for blood transfusion. However, if the primary problem is splenomegaly, that may be more of a determining factor for which drug we think about for first-line therapy. For example, if a patient’s spleen is extending into the pelvis and across the midline and is now impacting daily life, then choosing a drug that is effective at shrinking the spleen would be very important.

Other symptoms, including fatigue, weight loss, drenching night sweats, and bone pain, factor into treatment decisions as well. We also want to consider their presenting labs. How high is their white count? What is the degree of anemia? And are they transfusion dependent? Platelet counts are also very important in considering treatment options and dosing and if we’re able to safely use a dose that will hopefully be effective in treating symptoms and blood counts.

Lindsey Lyle

Absolutely. In addition to these things, you and I would both agree that talking to patients about their goals is important too. In addition to treating these main clinical problems, what do they want out of therapy? What are their goals, and how do we try to get them there? We also want to reduce major complications from their disease and hopefully delay disease progression.

So, I've got a patient case to share with you. I'm wondering what you might do in this scenario. This is a 67-year-old gentleman with heart disease and a history of polycythemia vera that progressed to myelofibrosis. He was being followed pretty regularly for his PV, and then over time, his hemoglobin levels started to decline. He was not needing phlebotomies, and hydroxyurea was stopped to see if this would improve counts. With no change in his CBC, it became evident that his disease was progressing. Bone marrow biopsy confirmed this. So now his white blood cell count is 11,000. He doesn’t have any peripheral blasts. His hemoglobin is 8 g/dL. Platelets are 150,000, and his spleen is enlarged and causing some symptoms.

Lindsey Kalhagen

It seems that anemia and splenomegaly are the primary concerns at present for him. I would first make sure we're not missing anything else that may be contributing to the anemia. So I would check all of his vitamin levels, including an iron panel. For some post-PV myelofibrosis patients, if they've had extensive phlebotomy over the years, they may actually be iron deficient. This is counterintuitive for PV, but for myelofibrosis, we might need to replenish iron, which could help the baseline anemia somewhat.

The other important thing to consider for this patient is his underlying heart disease. He might be more symptomatic at a hemoglobin of 8 than someone of similar age or even older age who doesn't have underlying cardiovascular disease. Certainly transfusion could be considered, but we also need to be thoughtful about deciding who warrants blood transfusion based on symptoms and consider if a different therapy would be more ideal or effective long term. For someone like this, who has underlying cardiovascular disease and some degree of anemia with stable platelets and symptomatic splenomegaly, I would consider starting him on ruxolitinib at the recommended starting dose of 15 mg twice a day with close monitoring.

Lindsey Lyle

How frequently would you monitor him at the beginning after starting ruxolitinib?

Lindsey Kalhagen

Due to the potential for worsening cytopenias with initiation of ruxolitinib,¹ and knowing that although his platelets are robust, his hemoglobin is only 8 g/dL, we would probably monitor labs every 2 weeks up front until he's been on this dose for at least 2 months or so, in addition to monitoring for side effects. Then, depending on how he's responding and what his counts look like, we might think about lessening the frequency of his labs. But I would say on average, even for our patients who are stable on therapy, we probably still check labs every 4 to 6 weeks because we know that counts can change and that the disease can progress over time. Progression may not be evident from a symptom perspective initially, so sometimes labs are what show us that disease progression is happening. What is standard for your practice as far as monitoring goes?

Lindsey Lyle

I agree. I would monitor him every 2 weeks, at least for the first 2 months, just to be sure that we're not seeing any unwanted side effects, increased transfusion support, or any undesirable cytopenias.

Lindsey Kalhagen

I have another patient I'd also be curious to get your input on. She's a 70-year-old female, otherwise healthy. She saw her primary care practitioner after noticing increased bruising on her arms and was found to have thrombocytopenia on labs, along with leukocytosis and a mild anemia. She ended up getting a bone marrow biopsy and was diagnosed with primary myelofibrosis. She came in for evaluation and discussion, and at this point, she's someone I'd consider symptomatic. She's had 10 pounds of weight loss in the last 6 months. Her hemoglobin was 10.4, her white blood cell count was 16,000 with 1% blasts, but her platelets were 60,000. So from this perspective, with someone who's presenting with platelets below 100,000, I’m curious what you would consider for her first-line therapy.

Lindsey Lyle

Despite her age, I would look at this patient’s functional status and possibly think about transplant in her future, but regardless, she does need therapy from the perspective of this leukocytosis and anemia. Also, her thrombocytopenia puts her at a higher risk overall and makes her slightly more challenging to treat, as you noted. Patients with platelets less than 100,000 fall into a more unique population. So I would weigh the pros and cons of starting fedratinib with her. This has been studied in patients with lower counts and specifically platelets between 50 and 100.¹ And knowing that patients had similar responses in splenomegaly reduction and improvement in symptoms, regardless of platelet counts in the JAKARTA studies,² I think this would certainly be a viable option for this patient.

One thing I would talk to her about is the potential for GI toxicity and thiamine deficiency. This is an older woman who seems to be functionally younger than her actual age, but due to the weight loss and early satiety, she might be at risk for increased nutritional deficiencies if she developed diarrhea with fedratinib, which we know is a possible side effect.² But knowing that in patients with platelet counts between 50 and 100, we've got to start at a pretty low dose of ruxolitinib¹—which may not control her symptoms and her white blood cell count quite as well up front—fedratinib would be my choice.

Lindsey Kalhagen

Are there other side effects that you typically educate patients about and watch for with fedratinib?

Lindsey Lyle

Yes, along with monitoring closely for GI toxicity and checking thiamine levels prior to starting therapy and at certain time points, it is important to note that there is a black box warning for Wernicke's encephalopathy, thought to be secondary to thiamine deficiency.³ This concern was raised due to a few cases in the early trials of fedratinib. So we should certainly inform the patient and discuss mitigation strategies.

As with all of my patients on JAK inhibitors, I do make sure that they see a dermatologist on a fairly regular basis, due to the increased risk of nonmelanoma skin cancers, and I also discuss the potential for infectious complications.

Lindsey Kalhagen

Have you had any patients who’ve had GI toxicities with fedratinib, and how have you managed those patients?

Lindsey Lyle

I have. I would say that getting patients on a decent antidiarrheal regimen can really help control this. We do have patients in general on different therapies for blood cancers that can cause GI distress, and trying to stay on top of it by anticipating and being able to implement these preventative strategies is all really helpful.

The other thing is that the GI toxicity seems to lessen over time. So talking about this with the patient is really important, letting them know that they may see a little bit more symptoms up front, but potentially as time goes on, it may improve. We should also discuss with them whether or not they want to continue treatment if they do experience GI side effects. How do you have these conversations with your patients?

Lindsey Kalhagen

Part of our role as APs is educating our patients about potential side effects and black box warnings for treatments and having very up-front conversations about what to monitor for. It’s also important to ensure patients feel very comfortable and confident in their relationship with their provider, to be able to discuss any symptoms as soon as they begin happening. This will help the AP get a handle on how to manage the symptoms or decide if they warrant dose adjustment or a temporary interruption or potentially discontinuation if side effects are severe.

Lindsey Lyle

Absolutely. This is an ongoing conversation with our patients. From presentation all the way through various treatment stages, we’re continually assessing pros and cons of therapy, discussing this therapy versus that therapy, and other potential options down the road. It’s a really rewarding part of our job getting to know these patients and developing these relationships with them.