Case Studies in Myeloproliferative Neoplasms - Episode 11
Experts in MPN review data on predictors of response to ruxolitinib in high risk myelofibrosis.
Jamile M. Shammo, MD: Let’s move on to the NCCN [National Comprehensive Cancer Network] Guidelines for the treatment of high-risk myelofibrosis [MF]. Here, you’ll see that patients will be evaluated for their candidacy for stem cell transplantation. If they’re not stem cell transplant candidates, then you need to evaluate whether they have symptoms related to splenomegaly or whether they have anemia. The second point of evaluation is whether they have thrombocytopenia, because obviously the platelet count is below 50 per mm3. Perhaps a clinical trial has to be considered. Otherwise, you need to consider 1 of 2 available JAK inhibitors, although fedratinib is a category 2B. After which, you need to evaluate the patient’s response moving forward. If they are responding, then you continue treatment. If they have lost the response, then perhaps you can switch to fedratinib. If they’ve progressed to either advanced-stage MF or AML [acute myeloid leukemia], then you need to switch treatment altogether. This is obviously a very challenging patient population to treat.
We’ve all seen the clinical trial data with COMFORT-II, which randomized patients who have intermediate-2 to high-risk MF to ruxolitinib and compared them with best-available therapy. They were looking at 35% reduction in spleen volume at week 48. As you can see, the majority of those patients had some improvement in their spleen volume when they had received ruxolitinib vs about half the patients who had some improvement in the spleen, whereas 44% of patients who had best-available therapy had an increase in spleen volume vs a very small minority in people who received ruxolitinib.
Of course, there has been an update from Dr [Claire] Harrison and the 4.3-year follow-up has been published as well. What’s interesting is that spleen reduction with ruxolitinib had been independent of the type of driver mutation. A lot of times, physicians ask whether the patient is JAK2 negative and can use a JAK inhibitor. Spleen volume reduction is independent of a driver mutation, but what’s been shown in this interesting paper is that the number of mutations may correlate with the duration of response to ruxolitinib. In that particular analysis, when 95 patients had been enrolled on the phase 1 study at [The University of Texas] MD Anderson [Cancer Center], it was done in retrospect. There was some next-generation sequencing that was done on those patients who had been enrolled and received ruxolitinib. It was shown that there was some degree of correlation in their spleen volume reduction relative to the number of mutations. For some of those people, the higher the number of mutations, the shorter treatment response and the faster they worked to discontinue their treatment.
There had been a compilation of COMFORT-I and COMFORT-II data to show that there may be an impact on prolongation of overall survival. This was reported by Dr [Srdan] Verstovsek from MD Anderson. We can discuss the ramification of this particular analysis. Be that as it may, in this paper, it appears that the risk of death was reduced by about 30% in patients who were randomized to ruxolitinib compared with those who received best-available therapy—or placebo, as was the case in COMFORT-I.
What about spleen response and outcomes of patients who were treated with ruxolitinib? This was a complex analysis of European patients who were followed over time to see what happened to spleen volume as they received ruxolitinib, and whether that actually mattered in relation to their outcomes. It was shown in this particular analysis that if patients attained a spleen response at 6 months, their outcome is better than those who don’t. Furthermore, those who have durability of their spleen response also have better outcomes. What is interesting is that those who don’t do so well have a much higher disease rate, higher risk, spleens larger than 10 cm, higher white blood cell count, and lower doses of ruxolitinib at the time of therapy.
This is not a prospective trial. This is basically retrospective analysis of patients treated in a real-world setting. But it causes you to pause and think about dosing when it comes to patients who we are treating because these are data that are taken from the COMFORT trial, and here you see the responses relative to spleen volume and total symptom score when it comes to the doses. Here you can see the responses based on the doses: 10, 15, 20, and 25 mg. And the same relative to spleen volume. You see that the minute you go below 10 mg twice a day in both end points, the numbers become really small. This has been common knowledge, but we have to consider that 10 mg twice a day is the least effective dose. We need to be very cognizant of the doses recommended based on the guidelines. For example, for patients with platelet count between 100 and 200 per mm3, we need to begin 50 mg twice daily, assuming normal kidney and liver function tests. Above 200 per mm3 is 20 mg twice a day. If you happen to start low for your patients, then you need to consider dose escalation to a maximum safe dose.
This transcript has been edited for clarity.