Myeloproliferative Neoplasms - Episode 4
Rami Komrokji, MD: These are just some of the data with ruxolitinib from the COMFORT-II study. We know that there were 2 trials, the COMFORT-I and COMFORT-II, that looked at use of ruxolitinib in patients with intermediate- and high-risk myelofibrosis, and compared to Hydrea, our best available therapy. In reality, if you look at this, the majority of the patients will achieve a spleen response. Now, in the study, there was a requirement of 35% reduction by MRI [magnetic resonance imaging] volume of the spleen, which correlates typically to 50% between the spleen size, and that was achieved probably in half of the patients. But the majority of the patients will achieve some spleen reduction with ruxolitinib. There is no doubt that it’s a treatment that improves the functional status for the patients, their quality of life as well.
Now, what we’ve learned is that if patients have adverse mutations, that the response to ruxolitinib may not be as good. If you think of patients that have somatic mutations such as ASXL1, EZH2, or DNMT3A1, those patients did not do as well in terms of durability of response. That also matters by the number of mutations. However, if you look compared to Hydrea, the patients treated with ruxolitinib, even with high-risk mutations, tend to do better than those treated with Hydrea. However, it’s not as durable a response as obtained in those patients that don’t have those adverse somatic mutations.
When we think of the overall survival for patients on ruxolitinib, I think clearly those patients will drive survival benefit. This is pooled analysis from the COMFORT-I and COMFORT-II trials, showing the median overall survival around 5 years for patients treated with ruxolitinib versus 3.8 years for patients that were in the control arm, keeping in mind that there was a crossover in those studies. I always discuss with patients that the goal of therapy is not improving overall survival. There is no evidence that the ruxolitinib treatment will probably reverse the natural history of the disease. However, those patients’ symptoms improve, their spleen is reduced, their functional status is improved, their performances improve, and thus they drive survival advantage. So, if I have a patient who is intermediate or high risk, that is symptomatic with splenomegaly and constitutional symptoms, I do think that they derive survival advantage from the treatment.
When we look at the responses and the survival, correlating the spleen response with survival, we know that there is correlation between a spleen response and survival. When we look at the spleen response at 6 months and overall survival, there is correlation with that and correlation between those patients that have a stable response or an unstable response when compared to nonresponders. So, there is correlation between spleen volume reduction and overall survival for those patients.
One thing to keep in mind, it’s important to titrate the dose early for those patients. In many occasions, we shy away from using the appropriate doses of ruxolitinib. Sometimes, we are worried about the myelosuppression, and we start on a lower dose. In cases of borderline cytopenia, maybe that’s acceptable. However, I think the message is if the patients are tolerating the treatment, one should escalate quickly. You definitely do observe a dose-dependent spleen response. The higher the dose of the Jakafi, the higher the spleen reduction or the response. The symptom improvement typically starts at around the dose of 10 milligrams twice a day. What I do, if patients’ counts are appropriate, I start with the full dose. If the counts are borderline and I start them at the lower dose, within the first month or 2, based on their blood counts, I’ll try to escalate the dose to the maximum tolerated by the patient.
Now, obviously the major concern is the myelosuppression, where almost half of the patients will develop some anemia on treatment. Typically, the hemoglobin level will drop between 1 to 2 grams; around week 8 is where the nadir is. Thrombocytopenia can be observed as well, but less often, we will be dealing with neutropenia in those patients.
Now, there have been studies trying to look at patients with platelets between 50 to 100 x 109/L— the COMFORT-I and COMFORT-II study—platelets above 100 x 109/L. Subsequently, there were patients that had thrombocytopenia in the range of 50 to 100 x 109/L, that use of ruxolitinib was tested in those patients. It was determined that probably a 10-mg starting dose is safe in those patients, with the same expected thrombocytopenia and anemia that we observed in patients when their platelets were above 100 x 109/L. Sometimes, we would start at a 5-mg twice-daily dose in this group and escalate up to the 10-mg twice-daily dose, and if they are tolerating that, we could consider even further escalation in those patients.
When you look at the spleen response and the symptom improvement in those patients, the magnitude of benefit driven if one would go with this dose escalation policy is similar to what we expect or see in patients with platelets above 100 x 109/L.
Transcript edited for clarity.