Updates in the Management of Myeloproliferative Neoplasms - Episode 16
Harry P. Erba, MD, PhD: Let’s move on now. I want to discuss the clinical trial data that has led to first the approval of ruxolitinib: the COMFORT-1 and COMFORT-II trials. On our panel is Srdan, who has clearly played a major role among other faculty members here in the development of ruxolitinib for myelofibrosis. Srdan, tell us about the data.
Srdan Verstovsek, MD, PhD: The studies that we are talking about were done a long time ago. These are the COMFORT-1 and COMFORT-II studies that led to ruxolitinib approval.
As time goes on, we learn a lot about the overall outcome of patients, and that has led us to not only realize that the drug is very good for control of the large spleen, symptomatic splenomegaly, and for improving the quality of life, but also to be able to extend life of the patients by virtue of changing the metabolism in the body: the albumin goes up, cholesterol goes up, performance status goes up, the ability to walk improves, and improvement in the kidney function has been reported last year.
Organ function and metabolism improves, and you control the disease signs and symptoms, which translates into prolongation of life for a few years. It’s also recognized by regulatory bodies, and it’s on the label for its use, but that’s not the reason to use it, right? The reason to use it is to intervene for immediate benefit: controlling the signs and symptoms, and with that, hope that life will be prolonged.
It’s evident in other studies that came along later, for example the JUMP study that was published recently in a final form, suggesting that early intervention matters and that we should not wait for the patients to be in a dying mode with high risk, a very big spleen, bad blood cell counts, and bad quality of life.
Early intervention is leading us to be able to provide optimal dosing, meaning the highest dose in a safe way, which will then decrease the spleen the most because it seems that the decrease of the ultimate size of the spleen that you can achieve on therapy dictates the durability of the benefit, and in many studies, it has been associated with life extension.
We learned that earlier intervention gives you the opportunity to provide a better dose; you have less myelosuppression, which is a toxicity related to the ruxolitinib in particular, and that will translate in the overall outcome that is beneficial, so the patient is not only feeling well but also living longer. This is where the major issue is: How do you initiate? You should follow the guidelines on how to initiate best in those cases regarding when to initiate: earlier on, don’t wait for patients to be advanced.
You then optimize the dose to get the maximum safe dose in the early few months to get that response to the maximum. That is the tricky part because anemia happens in about 50% of the patients. Patients may already be anemic; by early intervention, perhaps you have less of a problem with that.
Many worry about providing a high dose, and as you know, last year, there was a very interesting report with the European Hematology Association of a study suggesting that you should start with a lower dose of ruxolitinib, 10 mg twice a day, and then increase. Every month, you would go from 10 mg twice a day, to 15 mg, to 20 mg, to 25 mg. In that way, you avoid unnecessary myelosuppression, yet you can optimize the dose to the maximum safe dose. The results were similar to results reported in COMFORT-1 and COMFORT-II trials 10 years ago.
If there is a point to learn from most recent data—which is not published in papers; it was the poster last year—it is that we learn as we go. We can get to the same benefits on the spleen symptoms and life prolongation by alternative dosing regimens. Go from low to high, but don’t stay low. Go from low to high in a few months.
Harry P. Erba, MD, PhD: That’s an important point. Without that data that you just mentioned from Europe, for years I’ve been starting at a lower dose and increasing, and quite frankly, it’s to enhance patient compliance. If you scare them away with complications in the first month, it might be hard to keep them on it. There might be some market data to suggest that many patients got 1 month and then didn’t get any more therapy.
Starting at a lower dose makes sense from a patient compliance standpoint, and they often feel better right away, even at the lower dose. The point you make is critical, both in PV and in MF, but this drug is not 1 dose fits all. You need to optimize the dose to maximize benefit. Thank you for that.
The other thing that’s interesting about the data is this: We’ve all seen that the survival curves from COMFORT-1 and COMFORT-II are superimposable early on and cross over, suggesting that the benefit in long-term outcome may be in controlling symptoms sooner rather than later. Those patients in the COMFORT-1 study, as I remember as 1 of the many investigators, were sick patients; they didn’t have anything else. They had big spleens and constitutional symptoms.
Srdan Verstovsek, MD, PhD: You’ll remember that 66%, two-thirds, of the patients in these studies were high-risk, and one-third were intermediate-2. There are more modern studies, even from analysis of general practice in Europe, that suggests that early intervention makes it easier for us to manage the patients, and the survival benefit is also enhanced because you can maintain patients much longer on the therapy.
It’s all a circle that we are trying to put together; the data that would help us achieve most of the benefit for our patients: early intervention, better dose and spleen as the target, in addition to quality of life. That is the way we are learning over the last 10 years about how to optimally use JAK inhibitors in the community settings.
Harry P. Erba, MD, PhD: Correct me if I’m wrong, but I don’t know of any data with ruxolitinib, fedratinib, or interferon that says intervention with those agents decreases the risk of leukemic transformation. If that’s the case, it suggests that it’s symptom control, improvement in quality of life, nutritional status, muscle mass, and all those things that may be most important with the treatment.
Srdan Verstovsek, MD, PhD: You’re absolutely correct. There is no evidence for improvement in the risk of a transformation for progression to acute myeloid leukemia, which is an important point, not only to emphasize the benefit but also to say the disease is still there, and it can transform. Early intervention with a transplant, as we talked about transplant quite a bit, is encouraged.
I encourage my patients, even though they may have excellent response to ruxolitinib, to look at transplant as an option and potentially do the transplant if they have a donor when they feel the best. There is now evidence that it means that there’s possibly a better outcome with the transplant itself. As Ruben described, these 2 issues—the medical management and the transplant—go hand in hand. There is no comparison between the 2; they should be combined.
Transcript Edited for Clarity