Optimizing Treatment in Myeloproliferative Neoplasms - Episode 6
Transcript:Daniel J. DeAngelo, MD, PhD: The majority of patients with chronic myelofibrosis will have one of three mutations. About 30% to 40% will have a JAK2 mutation; 5% to 10% will have a mutation in the thrombopoietin receptor known as MPL, or mipple; and then another 40% or so will have a mutation in the calreticulin, or CALR mutation. These are all part of the same pathway. JAK2 inhibition, therefore, works in any patient who has a mutation not only in JAK2, but in one of these other two areas or mutations because it’s all driven through the same pathway. There are those rare patients who are triple-negative. It’s so rare that it’s unclear how JAK inhibition helps them, but the vast majority of patients will have an effect, whether they have a JAK2 mutation or a mutation within these other genetic lesions.
Kim-Hien T. Dao, DO, PhD: In terms of the role of ruxolitinib in managing myelofibrosis patients, currently it’s FDA-approved in the United States to treat patients who are intermediate- or high-risk according to the IPSS or DIPSS systems. So, for me, when I evaluate a patient, I make the determination of the risk group. I look at their symptom burden and assess that very carefully. I also evaluate their spleen size. For some patients, it’s very clear when you talk to them and evaluate their symptom score that they are very symptomatic from their myelofibrosis and would benefit from ruxolitinib. This is also considered very carefully for some low-risk patients who might have increased symptom burden, but according to the DIPSS score, they do not have the intermediate- or high-risk category of warranting ruxolitinib. But, again, this is done case-by-case, and also we could consider using hydroxyurea to alleviate some of those symptoms as first-line.
Srdan Verstovsek, MD, PhD: Ruxolitinib has been approved for quite some time now in the United States and Europe as a therapy for myelofibrosis. In United States, the indication is for intermediate- and high-risk myelofibrosis patients. In Europe, in general, it’s for patients with symptomatic splenomegaly or general symptoms from the disease, which, in fact, describes the population of the patients that benefits the most from the therapy. Ruxolitinib does not really improve the blood cell count, and we don’t have evidence that it prevents progression to acute myeloid leukemia. However, from the COMFORT I study and COMFORT II study—these are two prospective long-term randomized studies that led to approval of ruxolitinib—we know that the patients live longer with good control of signs and symptoms with ruxolitinib.
And that is reflected now in final analysis of the COMFORT I study, for example, which was presented 2 months ago. Patients that were initially randomized to ruxolitinib were compared to patients that were randomized to placebo, and about 75% of these placebo-treated patients randomized to nothing, basically, were eventually given ruxolitinib. And median time to crossover from placebo to ruxolitinib was about 41 weeks. So, despite the crossover, though, for three-quarters of the patients to ruxolitinib, we see significant difference in the overall outcome of the patients, which is a prolongation of about 3 years, about 33% longer survival of the patients that were initially randomized to ruxolitinib. This confirms that with good control of the signs and symptoms, and not really elimination of the disease, we can make a huge difference.
Now, this has two connotations. One is that it appears quite obvious that we should not wait for patients to be so advanced to have less of a chance for a good response to therapy. We should be treating patients when they really do have symptomatic splenomegaly or systemic symptoms and not wait for them to be in a dying process. I think this is quite normal to accept, and we do this in normal, everyday practice. You’re not really postponing therapy if this is present. And the other question is whether the earlier introduction of the therapy in patients that are not symptomatic at all and do not have a big spleen would make a difference for the survival.
The presence of different mutations in therapy that are treated with ruxolitinib do not have real evidence to affect the outcome. The first question was whether the presence of a JAK2 mutation makes a difference, and it doesn’t. Patients who have a calreticulin mutation, an MPL mutation, who have no mutation at all or have never been tested for a mutation have the same outcome because it is not about ruxolitinib targeting any specific mutation. It targets the JAK/STAT pathway, and that is the underlying problem—hyperactivity of the JAK/STAT pathway in all the patients with myelofibrosis. So, one does not even need to test for any mutation that is just a part of the diagnostic process, but not a prerequisite for introduction of the ruxolitinib.
Now, we and others are looking at the reasons for some people doing better on the ruxolitinib than the others. There is some suggestion that the presence of perhaps a number of other additional mutations may affect the overall outcome of the patients. That is a preliminary result published only once in a limited number of patients so far. We are also interested why some patients lose the response. Is there a clonal evolution or acquisition of other mutations over time on therapy with ruxolitinib? This is all just a research question, nothing really to do in everyday practice or to monitor, for example, the number of the JAK2-mutated cells in blood and bone marrow as a test during the therapy with ruxolitinib. There is no need for that.
One practical point that I’d like to highlight is the clear correlation in all the studies so far with ruxolitinib between the degree of spleen reduction and the overall survival of the patients. So, my goal usually is not to be skimpy at the beginning with the dose of ruxolitinib. [My goal is] to follow the guidelines and use the maximum tolerated dose, and not to, for example, worry about the anemia. Anemia is not a contraindication for use of ruxolitinib, nor is anemia affecting the overall outcome of the patients if it’s therapy-related. I also try to shrink the spleen at the beginning as much as I can in a safe way. Everything happens in the beginning usually for patients to benefit from the therapy as long as possible, and that certainly, now we know, translates into longer survival.
Transcript Edited for Clarity