Daniel DeAngelo, MD, PhD:In the COMFORT-1 and COMFORT-2 trials, which randomized patients to ruxolitinib versus either placebo for COMFORT-1 or best available therapy for COMFORT-2, patients required higher-risk diseaseintermediate 2 or higher, or patients with symptomatic splenomegaly—as eligibility criteria to enter on either of these studies. And what was discovered was that treatment with ruxolitinib improved responses in terms of shrinking the spleen and patients having improvement in constitutional symptoms.
What was surprising is that both COMFORT-1 and COMFORT-2 showed that patients who started ruxolitinib had a survival advantage against those patients who randomized to placebo in COMFORT-1 or best available therapy in COMFORT-2. This raises an issue. Not only are you trying to ameliorate symptoms in patients who have symptomatic splenomegaly or constitutional symptoms but also, for patients with higher-risk diseasebased on a DIPSS score of intermediate 2 or higher—you may actually be improving survival.
This case represents a young patient with primary myelofibrosis. The average patient age is in the 70s. So, many patients are older. This is a young patient, and that’s why the role of stem cell transplantation must be considered. But we don’t have long-term, good observational studies for patients with low-risk or asymptomatic intermediate-1 disease to determine how many of these patients will eventually, and over what period of time, require therapy. It is important to follow those patients with low-risk or intermediate-1 disease, who are also asymptomatic, carefully. This is a chronic disease. This is a progressive disorder, and most patients, throughout their lifetimewhether it be 5 years or 10 years—will develop progression of their symptoms and/or disease, requiring intervention.
It is important, however, to acknowledge that patients who are symptomatic at presentation or those patients with higher-risk diseasedefined by a DIPSS score of intermediate 2 or higher—really need an intervention at this point. Because, given the data from COMFORT-1 and COMFORT-2 with improvement in survival, it’s hard to not want to treat those kinds of patients, which will improve their overall outcome.
Splenomegaly is a hallmark of patients with chronic primary myelofibrosis or secondary myelofibrosis, those patients who have transformed from an underlying disorder, such as polycythemia vera or essential thrombocytopenia. The presence of splenomegaly is part of the diagnostic criteria for myelofibrosis. Patients with progressive splenomegaly often will develop symptoms of splenomegaly, and this can lead to the presence of early satiety and weight loss. In those patients, who are symptomatic from their splenic enlargement, it’s important to initiate therapy regardless of what their DIPSS score is.
Age is a criteria for all of the prognostic scores. The original IWG by Cervantes, as well as the DIPSS by Passamonti, both incorporated age. You have to remember, age is a linear variable. Patients get older. And this is a disease of older folks, typically in their late 60s or early 70s. It’s clear that age impacts overall survival. Age by itself, however, doesn’t necessitate initiation of therapy. It’s in concurrence with symptoms as well as risk score, which includes disease criteria such as the karyotype, other mutations, and the peripheral blood smear. In this particular case, in spite of the patient having a young age, there are enough criteria with her symptoms, as well as her anemia, to warrant therapy because of her higher IWG or DIPSS score.
Transcript edited for clarity.
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