Assessing Treatment Response in Myelofibrosis


Dr Raajit Rampal provides a brief overview of the criteria used to define response to myelofibrosis treatment.

Case: A 67-Year-Old Man With Myelofibrosis

Initial presentation

RF is a 67 y/o man who visits his primary care physician for his yearly checkup. He reports having fatigue and bone pain for the last few months. More recently, he’s been complaining of abdominal discomfort which he thinks is probably related to the big Thanksgiving dinner party, he and his wife hosted.

He enjoys spending time working on antique cars in his garage, but his wife says he becomes tired after just an hour.

RF has not noticed any changes in his eating habits, but his wife mentions he doesn’t eat as much as he used too. Upon examination, RF has lost close to 13 lbs. since this last yearly exam.


Primary myelofibrosis diagnosed about 1 year ago

Diabetes (controlled with diet and exercise)


SMH: Smoked 3 packs/day but quit 5 years ago; he drinks occasionally

PE: abdominal exam reveals spleen palpable 5cm below left coastal margin, visible bruising

Initial Labs/Workup:

Platelet count: 184 x 109/L

Hgb: 10g/dL

WBC: 34 x 109/L

Bone Marrow Biopsy

Shows an increase in megakaryocytes

Bone Marrow Fibrosis

Megakaryocyte Atypia

Molecular testing

JAK-V617F mutation: positive

Initial treatment:

Patient was started on ruxolitinib 10mg BID when initially diagnosed

Current Presentation/Labs:

One year later, RF reports increasing fatigue and abdominal pain

Current Labs:

Platelet count: 57 x 109/L

Hgb: 8g/dL

WBC count: 29 x 109/L

Raajit Rampal, MD, PhD: How do we know if our switch of therapies is working? What do we look at? Do we look at the spleen, the symptoms, and the blood counts? I think the answer to that question is, all of the above. Our patient is fundamentally telling us that they are having more symptoms, such as worsening abdominal pain presumably from their spleen enlargement. If those things improve either by measure of the total symptom score or radiologically or just by the patient self-reporting, those are all things that tell us we are moving in the right direction. Those are things that are telling us that our treatment has been successful. Could switching to a JAK [Janus Kinase] inhibitor incur further cytopenia? The answer is always possibly yes. That has been observed with fedratinib and pacritinib as well. Although it seems to be less so with pacritinib whereby stabilization of counts has been observed particularly for the platelet count. Worsening of blood counts in the short term is not necessarily an indication of treatment failure. I think stabilization is certainly a welcomed finding. Improvement in any of these, which can and has been observed, is absolutely an indication that I think our treatment is having the right effect or the wanted effect.

Let's talk a little bit more about the mechanism of action. As I mentioned a moment ago, there are a number of JAK inhibitors that are currently available for treatment, 3 of them are FDA approved; ruxolitinib, pacritinib, and fedratinib. They all differ to some degree. Ruxolitinib targets both JAK1 and JAK2, whereas fedratinib and pacritinib are JAK2 selective inhibitors. Pacritinib in particular has some other targets that it can hit such as IRAK1 for which there is ongoing work to evaluate whether or not this may be a pathway that has a pathogenic role in myelofibrosis. The expected side effects of the drugs also differ to some degree. All of these drugs by virtue of being JAK inhibitors do have anemia and thrombocytopenia as potential side effects of their utilization. Other side effects have been observed. Fedratinib has been associated with Wernicke's encephalopathy in rare cases. In clinical trials, gastrointestinal effects are seen in fedratinib as well as with pacritinib. As well as other side effects with pacritinib such as dizziness and peripheral swelling. These are things to be cognizant about when switching therapy. It's important to realize that when we think about this array of JAK inhibitors, there are to some degree niches for these drugs. With pacritinib, we've talked about cytopenic myelofibrosis. The FDA [US Food and Drug Administration] label indication for pacritinib allows the drug to be used in patients with under 50,000 platelets. Prior to the approval of pacritinib, we did not have a JAK inhibitor that was authorized for use in this patient population with a particularly poor outcome. We do now have this agent, which allows us to treat patients with a platelet count of 50,000 and below and does not require dose attenuation. That's an important thing to think about. Again, in the landscape of patients with cytopenic MF [myelofibrosis], pacritinib has an indication but a specific indication in patients with a platelet count of less than 50,000. However, it's important to realize that there is gray area here when we think about a patient per the guidelines. If we divide patients who have say less than 50,000 platelet count or greater than 50,000 to 100,000, these patients are not a homogenous group. For example, a patient with 95,000 platelets as well as a patient with 55,000 platelets fit in this group of 50,000 to 100,000. But it's very hard to argue that those 2 patients are phenotypically the same, or that perhaps they should be treated the same. One could make an argument certainly that dose-reduced ruxolitinib could be used in a patient with either of these platelet counts. Then the dose-escalated over time to try to achieve optimal dosing of ruxolitinib. As we talked about, the dosing of ruxolitinib makes a difference in terms of its expected efficacy. This has been studied. It's important to realize that dose escalation has been performed in patients with a platelet count of 50,000 or 100,000 with ruxolitinib. But in the studies that have been performed, only about 56% or so patients can undergo that escalation without incurring further cytopenia. It is reasonable not to think about 50,000 as sort of a line in the sand if you will. But rather a sort of barrier that one can think about either way. Whereas platelet counts that may be hovering around 50,000 or closer to 60,000, those patients might be thought about more like patients who have less than a 50,000 platelet count. That needs to be taken into account particularly as we discussed a moment ago. We know that introducing a JAK inhibitor will in all likelihood cause some degree of anemia and thrombocytopenia. Starting a patient with 55,000 platelets, it is not an unreasonable expectation that that patient's platelet counts are going to decline once treatment has started. Again, I'm not sure that the platelet count should necessarily be a line in the sand but you need to think carefully about that particular clinical scenario that the patient is in. Speaking specifically about pacritinib, we've talked about using it in this specific scenario for less than 50,000 platelets. But, as we discussed a moment ago, using it in the second line after exposure to a prior JAK inhibitor is certainly something that is supported in the NCCN guidelines. And [it] can be thought about for a patient with less than 50,000 platelets as well as a patient with more than 50,000 platelets. Our case here is really a case in point. Our patient RF, a year after starting ruxolitinib has a platelet count of 57,000. Switching to a drug like pacritinib could make a lot of sense for this patient in this particular scenario but you can use it either in the upfront or after, prior exposure to ruxolitinib. In thinking about the use of pacritinib in the first line or in patients with prior exposure to JAK inhibitors, certainly, I have used the drug in clinical trials as well now that it’s commercially available and in the setting of either being treatment naïve or having prior exposure to JAK inhibitors. Certainly, I have not experienced or observed any differences in side effects in patients. Even in hematologic side effects, they seem to be roughly the same. Certainly, we have absolutely seen patients have an improvement in symptoms as well as spleen size in both of these settings.

Transcript edited for clarity.

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