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Patient Scenario 2: JAK2 Inhibitors in Myelofibrosis
Author(s):
After reviewing the second patient scenario of myelofibrosis, experts from the John Theurer Cancer Center discuss the use of JAK inhibitors, specifically ruxolitinib, to manage patients in the frontline setting.
Transcript:
Geeny Lee, PharmD: Well, thank you for that robust discussion on that case. And now we’ll move on to our second case. So, I’ll present this one. We have patient SM, who is a 68-year-old woman who visits her primary care physician with symptoms of mild fatigue, moderate night sweats, and abdominal pain and fullness lasting about 4 months. It looks like she also reported increased bruising and weight loss. Since her last examination about a year ago, the patient has lost close to 11 pounds, and she has not been on any type of diet. Her past medical history is notable for controlled hypertension, glaucoma, and asthma that is also controlled with inhalers. Her social history, she’s a nonsmoker and drinks socially, and she has no family history of cancer and does have [a] son and grandkids who live nearby. Upon physical exam, her abdominal exam reveals spleen palpable 8 cm below left costal margin and has visible bruising. And moving on to labs, of note, she did have normal labs at last exam, which was about 1 year ago. But now she has platelets that are at 44,000, hemoglobin of 8, and white blood cell of 27,000. And bone barrow biopsy shows megakaryocyte proliferation and molecular testing shows that she is positive for JAK2 V617F mutation but is negative for CALR. And she is started on treatment with ruxolitinib. So, Dr McCloskey, can you start us off by discussing some data that support the use of different agents that may be considered in this scenario?
James K. McCloskey II, MD: Sure. I think that this patient currently is rather thrombocytopenic and cytopenic. So they have rather advanced disease based on their CBC [complete blood count], I think it’s likely, though, earlier in her history of her disease that we’ve seen her earlier that that may not have been the case. And I think that to start with…ruxolitinib, the drug that came to market first, I think that this still remains an incredibly important drug in this space. It’s probably what most people are going to start on first because most people are not going to be like SM that comes to us with these profound cytopenias when we’re seeing her initially, but rather that they’re going to have intact accounts. And so, ruxolitinib was initially approved based on the COMFORT-I and II trials, COMFORT-I [NCT00952289] being a [phase 3] randomized, double-blind, placebo-controlled study. So, the control arm there was placebo, [the phase 3] COMFORT-II [NCT00934544] was best available therapy, and in that case, 47% of the patients were on hydroxyurea. Some of the patients were on steroids, [and] some patients on interferons. But I think, again, [there were] not a lot of patients getting truly disease-modifying therapy, if we think of interferon [as] that, it was a handful of patients, but not much otherwise. So, what we saw in those studies, we did see improvement in spleen volume reduction; 41% in COMFORT-I compared to 0.7% in the placebo arm; in COMFORT-II, 28% compared to 0%. We saw also significant total symptoms score reduction. And as we follow those patients out over time, we saw an improvement in overall survival.
Again, this has been really tricky to dissect, [as] both studies allowed for crossover, and the data definitely get muddied a bit. But if we look at overall survival, at 5 years is 51% in COMFORT-I for ruxolitinib-treated patients compared [with] 40% in placebo-treated patients. COMFORT-II [overall survival] at 5 years [is] 56% in ruxolitinib-treated patients compared [with] 44% in patients treated with best available therapy. And so, I think again, in these studies we want to highlight that the average ruxolitinib dosing was 15 mg BID [twice a day] or more. And so, I think that we’ve mentioned spleen volume multiple times here, but I’d want to highlight for the audience really that we care about spleen volume reduction, because every study we do shows that by reducing spleen volume, we improve survival. That’s really why we care about it. It would be better to have other surrogate end points, obviously, but I think that spleen volume reduction is important to us because not only does it help the patient feel better, but if we can improve the spleen volume, we help those patients live longer. So that’s why [these] data [are] important.
There [are] other important data that came after this as well with ruxolitinib. I’d point out that pool data, looking at COMFORT-I and II, showed that early intervention with ruxolitinib seemed to improve survival. So if we looked at patients who were treated within 12 months of diagnosis compared [with those treated] later than 12 months of diagnosis, additionally they had a 2 times higher likelihood of having spleen volume reduction. They also had improved survival, 63% versus 57%, at 5 years. And obviously [these are] not perfect data. [They’re]…pool data. [They’re] post hoc data, and it has its limitations, but at the same time, I think it…fits. And I think that as I see patients often in a second opinion or even a third or fourth opinion, sometimes I see a person, they’re doing pretty well, and their spleen is enlarged. And I’ll say to the patient and their referring physician, “Hey, we should start you on ruxolitinib because your spleen is enlarged.” And sometimes even the referring physician has said back to me that, “Well, yes, their spleen is enlarged, but they can still eat.” And that may be true today, but I think that that may not be true 2 years from now and we’d like to be ahead of it. We’d like to get on top of it earlier. Likewise, I think that what we need to reestablish now is for those patients who are not responding to ruxolitinib any longer, maybe they’re not responding as we’d hoped, what are our other options? Now that we have all these other drugs we talked about, what are the options for those patients? Because we should consider switching to offer that patient spleen volume control.
And then lastly, with ruxolitinib, I would just comment on the [phase 3] JUMP trial [NCT01493414], which was the expanded-access trial looking at patients with intermediate-1 risk disease where again, we saw significant spleen volume control in patients with lower-risk disease. Then were treated in COMFORT, where that was intermediate-2 and higher. And I think that commenting…again on that idea that ruxolitinib is a great drug, it’s going to work for many of our patients, but may not work for them forever. We’ve talked about momelotinib and pacritinib, which…are addressing and been studied primarily in more cytopenic patients. There’s also fedratinib, which is not a commonly utilized JAK inhibitor in myelofibrosis. And part of that is because I think that in many cases, if we’re going to use it successfully, it likely needs to be employed earlier. I tend to use it primarily in patients who are more proliferative that requires us, again, to establish when ruxolitinib is not working for us. And I think that’s a hard thing to decide, especially in patients who are maybe having still intact myelopoiesis. But that’s really why you have to monitor patient spleen sizes, and if I have a proliferative patient, that’s a patient [to whom] we will often offer fedratinib.
And so that was approved based on a couple trials: JAKARTA-1 [phase 3; NCT01437787], which was a double-blind, placebo-controlled study with intermediate-2 and high-risk patients, where we did see spleen volume reduction by 35% or more in 40% of patients compared to 1% patients on placebo. Later we saw in JAKARTA-2 [phase 2; NCT01523171], where we were looking at ruxolitinib previously treated patients. When we look at that, the median exposure to ruxolitinib previously was about 10 months. So honestly, these are…higher-risk patients. They’re patients who were not responding early on in treatment. They weren’t patients who…lost response later. But we did see that of those patients, previously treated ruxolitinib, they had a 31% reduction in spleen volume by 35% or more. So it is a good option, I think, for those proliferative patients. One of the reasons, too, why…I think there’s a lot of concern around it is [that] it does carry a box warning for encephalopathy. And I think even for us, we don’t use the drug every day at Hackensack [University Medical Center], even, but it’s always a concern from patients. I think to reassure you, there were relatively limited cases of encephalopathy, and it is completely avoidable. It is a thiamine-related phenomenon. Thiamine deficiencies can occur in these patients because they could be very nutritionally deprived with their splenic enlargement. But it shouldn’t deter you; as long as you check at the beginning and you monitor serially, this is usually a drug that you can use effectively in patients.
Transcript is AI-generated and edited for clarity and readability.
