Treatment of Primary Myelofibrosis

Daniel J. DeAngelo, MD, PhD

Daniel J. DeAngelo, MD, PhD, describes the new guidelines by the National Comprehensive Cancer Network for myelofibrosis, which provide guidance for therapeutic decision making based on risk status and patient age. He also covers the use of JAK2-targeted therapy for patients with symptomatic disease.
Daniel J. DeAngelo, MD, PhD: Primary myelofibrosis is a rare disease, and, at least in the community, it doesn’t represent a high percentage of patients. It’s nice to have guidelines from an expert panel to really help provide some clarity about whom to treat and with what therapy. The NCCN guidelines are new and are very well done. A lot of the guidelines tend to be more like recipes for therapy, but the NCCN guidelines in myeloproliferative neoplasia really took an objective pattern of trying to stratify patients based on their variety of risk calculations. Then, they tried to, in an organized way, give treatment options based on those patients with lower-risk disease and/or higher-risk disease with different algorithms along the way for patients who do not fare as well.

Within the NCCN guidelines, you see within the intermediate-1 classification that only those patients who were symptomatic should be treated. Other patients should be watched very closely. But, patients with higher-risk disease—intermediate 2 or high risk—should really be thought of as needing some form of therapy. It’s important—again, I cannot emphasize this enough—that younger patients who are appropriate candidates for stem cell transplant should be referred to a transplant consultant, and that will get that patient into an academic center. Most patients, unfortunately, are too old or too ill for transplant, and those patients can be treated in the community with appropriate therapy. All of these decision algorithms are really outlined very nicely in the NCCN guidelines.

Primary myelofibrosis is a disease that is JAK-mediated. JAK2 mutations, however, are seen in roughly 40% of patients. So, what about the other 60%? Well, they affect the JAK pathway by having mutations either at the receptor through the MPL, which is the thrombopoietin receptor, or through modifications in the endoplasmic reticulum through the calreticulin mutation. So, you have 3 different mutations, but they all affect the JAK2/STAT pathway, therefore allowing ruxolitinib, a JAK1/JAK2 inhibitor, to be effective. It’s the rare patients who are triple negative, who may or may not be appropriately treated with ruxolitinib.

The vast majority will have a mutation along the JAK/STAT pathway, and ruxolitinib is an appropriate therapy for this. The COMFORT-1 trial randomized patients between ruxolitinib and placebo. The COMFORT-2 trial randomized patients between ruxolitinib and best available therapy. Both included patients who were JAK mutation–positive, as well as JAK mutation–negative, and the responses were equivalent between the 2 groups, supporting the fact that even patients who do not have a JAK mutation can have benefit from ruxolitinib.

What ruxolitinib did, in both the COMFORT-1 and COMFORT-2 trials, was improve the size of the spleen; that is, it reduced significant splenomegaly, as measured by physical exam and MRI. And most importantly—at least I think it’s most importantly—patients on both COMFORT-1 and COMFORT-2 felt better. This was objectively annotated by having patients fill out a total treatment score. You can calculate what their symptoms were, and then follow them over time. Both studies showed that there was a significant improvement in the ruxolitinib-randomized patients in COMFORT-1 and COMFORT-2 who were having symptomatic myelofibrosis. Ruxolitinib should be initiated in patients with symptomatic splenomegaly, regardless of their DIPSS score, or for patients who have an intermediate-2 or higher DIPSS score. This is outlined nicely in the new NCCN guidelines, but these patients were included in both the COMFORT-1 and COMFORT-2 studies.

Determining the dose of ruxolitinib is important. Initially, patients had to have a platelet count of greater than 100,000. Then, the dose of ruxolitinib was dependent upon what their baseline platelet count was, and there were dose-reduction guidelines should the platelet count fall. This has been changed over the course of time as more studies have included patients with thrombocytopenia. So now, the use of ruxolitinib can be started in patients with as low a platelet count as 50,000.

What I usually do is follow the guidelines. I initiate ruxolitinib depending on the platelet count at baseline, and if the patient is tolerating it, I will consider up-titrating the dose of ruxolitinib in order to maximize the response. Again, the responses that I am trying to look for are reduction in the size of the spleen and improvement in symptoms—not just in what the patient is verbalizing but also improvement in the objective symptom score that can be determined at baseline through a simple questionnaire, and then followed longitudinally.

One of the problems for patients with chronic myelofibrosis is anemia. It’s actually part of the diagnostic criteria. Patients should all be anemic, and most of them are. A larger percentage of them, not just being anemic, will also require red blood cell transfusion, and this is a problem. So, as patients require more and more red blood cell transfusions, and if their erythropoietin level is low, I will augment or initiate an erythropoietin-stimulating agent to try to help with that. It has a modicum of benefit, but it’s something that can be easily used. Of course, you need to make sure that their iron stores are replete. This is something that needs to be checked periodically to ensure that patients haven’t had gastrointestinal blood loss or other issues prior to your visit that may have caused iron deficiency. Assuming a patient is iron replete, their erythropoietin level is less than 500, and their hemoglobin is less than 10, I will often initiate an erythropoietin-stimulating agent.

It should be noted that one of the principal side effects, at least over the first 2 to 3 months of initiating ruxolitinib, is a fall in the hemoglobin. You can make patients who were not red blood cell transfusion–dependent become red blood cell transfusion–dependent. This does not mean the disease is progressing. This does not mean that ruxolitinib is not effective. This is an on-target side effect of ruxolitinib. All erythropoiesis works through a JAK/STAT pathway. So, it is not uncommon that initiating a JAK inhibitor is going to cause anemia. What you need to do is counsel the patient to understand that this is expected and that, hopefully, over the course of the next 3 to 4 months, it will become less and less prevalent. And as you see, there is a sudden drop in the hemoglobin over the first 12 weeks that becomes less dramatic with continued therapy.

Thrombocytopenia is another problem that many patients with chronic myelofibrosis will present with. There are dosing guidelines for the initiation of ruxolitinib based on the baseline platelet count. But, if the platelet count falls—and it can with initiation of ruxolitinib—sometimes you’re going to need to reduce the dose and/or hold the dose to allow the platelets to recover. In patients with primary myelofibrosis, one of the principal issues is splenic enlargement. One of the treatment goals of ruxolitinib is to reduce the size of the spleen, but there are those patients in which ruxolitinib doesn’t work—or it works, but then the patient loses a response. Unfortunately, there are no FDA-approved treatments or medical therapies for patients who develop disease progression. These are the patients whom I tend to try to put on clinical trials, either by adding another agent to the ruxolitinib or switching to a different JAK inhibitor. And there are many that are in clinical trials as we speak.

For patients who have truly refractory disease, who are young enough, healthy enough, and without any significant comorbidities, I will consider splenectomy in those rare patients. To be honest, I rarely initiate splenectomy. In the last year, I can think of 2 cases where I sent a patient to surgery. But, you have to have a really dedicated surgeon who is talented in terms of removing these patients’ spleens, as patients with symptomatic splenomegaly who are refractory to JAK inhibitors typically have complications of their splenectomy that can be as high as 30%. So, you need to have a talented surgeon. It’s a rare time that you need to consider splenectomy, but it’s something that should always be at the back of your mind. More important is the role of stem cell transplantation, which is reserved for younger or healthier patients. And again, this is another thing that needs to be considered for patients who develop progressive disease or for any patient with high-risk myelofibrosis based on their DIPSS score.

There are several unmet needs in the treatment paradigm for patients with primary and secondary myelofibrosis. This includes those patients who present with severe thrombocytopenia. One of the problems with JAK inhibitors in general is that they can suppress the platelet count. So, that becomes an issue. What happens to patients who progress on standard therapy? That becomes an issue. These are clearly 2 unmet needs. The strategies are currently to add to ruxolitinib. Ruxolitinib has a relatively high bar. It’s hard to beat a drug that works. But, there are other JAK inhibitors that are being developed for patients who have ruxolitinib failure or were intolerant of ruxolitinib. These studies are ongoing, and there are combination strategies to add therapies to ruxolitinib.

In addition, we need more supportive care approaches. There are other agents that are being developed for patients with severe anemia to try to improve the anemia that’s seen with the disease, as well as with the therapy—ruxolitinib causes reduction in hemoglobin, and many patients will develop transfusion dependence.
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