COMFORT Data and Ruxolitinib in Myelofibrosis

Ruben A. Mesa, MD: Ruxolitinib is the frontline medical option for patients with myelofibrosis [MF] in 2021, and that continues to be based on the subsequent real-world validation of the benefit of that therapy, which was demonstrated in the 2 COMFORT studies. I was involved with leading the COMFORT-I study—with my colleague Srdan Verstovsek and others—of ruxolitinib vs placebo inJAK inhibitor–naïve patients with myelofibrosis. The COMFORT-II study was ruxolitinib vs best-alternative therapy. These studies help demonstrate the significant improvement in MF-related symptoms and clear improvement in splenomegaly in a rapid fashion.

Over time we have seen strong evidence that ruxolitinib improves survival for patients with myelofibrosis, both from long-term analysis of the individual data from these 2 studies as well as pooled data, particularly when accounting for crossover. We do not see that there is a plateau. So these therapies are not a cure, but individuals are living longer. Even the delay in individuals who initially were randomized to a control arm and then crossed over to ruxolitinib, showing inferiority of survival compared with those who had been on ruxolitinib the entire time.

At last year’s ASH [American Society of Hematology Annual Meeting], the [University of Texas] MD Anderson [Cancer Center] group presented data looking at survival from 2010 to present vs prior for patients with myelofibrosis. They showed real-world evidence improvement in survival over both historical controls pre-2010 and that exposure to ruxolitinib was likely a driver of that.

How does one achieve survival advantage? Over time we’ve learned that the dose matters. The product label dosage is 15 mg or 20 mg twice a day based on the starting platelet count. For individuals with moderate thrombocytopenia, such as 50 to 100 per mm3, we start at a lower doe, like 5 mg twice a day, and potentially increase it over time. What we have seen is that response matters for correlating with improvements in survival, achieving splenic response, keeping dose intensity, and using a sufficient amount of a dose. In individuals with significant anemia, I may start at a lower dose, but increasing that over time is critical to achieve optimal response. The depth of response probably is important for achieving that survival benefit that we see.

My personal experience prescribing commercial ruxolitinib very much matches its performance in the clinical trials that I had experienced. It’s a good drug. It genuinely has been beneficial for patients. It’s the frontline therapy in all the treatment guidelines—and appropriately so. It makes an impact on splenomegaly and symptoms, but I genuinely believe that the benefit extends beyond that. The survival data are real. Although the trials were not designed with that as the end point, actual real-world experience managing hundreds of myelofibrosis patients over time, have shown me—without question—that these patients are living longer.

Why do they live longer? They’re less debilitated with fewer complications. The rate of progression is clearly slower. Patients still can transform to acute leukemia, but that occurs at a lower rate and probably at a slower rate.

I’ve also learned many aspects of managing ruxolitinib. It’s not a therapy patients feel well with if you stop it abruptly. I don’t stop it unless there’s a good reason. If patients are having routine surgical procedure, I have them take it like they would other important medications and have them remain on the medication. If they do need to come off it for some specific reason, particularly if they are on higher doses of the medicine, it’s helpful to taper the medicine. If they’re on 15 or 20 mg twice a day, trying to get them down to a lower dose is key.

In the real world, people are on a range of different things. I’ve seen individuals again who have needed solid organ transplantation. Let’s say individuals undergo a liver transplant. After acquiring a liver transplant because they have portal vein thrombosis, they’re on ruxolitinib as second line for P [polycythemia] vera. Trying to keep that going through that process can sometimes be beneficial. We’ve learned about ruxolitinib and stem cell transplantation that using it beforehand can be beneficial, keeping it going until the time conditioning begins, sometimes tapering down to a little lower dose. There are ongoing studies about keeping it going during transplant to decrease risk of graft-vs-host disease at more modest doses.

Many things are evolving. We’ve learned that dose matters. We know to be mindful of not being arbitrary in terms of discontinuing the medicine. Indeed, during the time of COVID-19, [Coronavirus disease 2019] it has been found that abruptly stopping ruxolitinib in the face of COVID-19–related pneumonia is probably a bad idea. One might imagine that if you allow inflammatory cytokines and other things are increased because of COVID-19–related pneumonia, the outcomes are likely worse. Continuing patients on ruxolitinib during the time of COVID-19 likely has been beneficial, and keeping it on as a concurrent med if they are recovering from COVID-19 also being helpful.

Again, many things are evolving, but it has been a very effective medicine for patients with myelofibrosis. We have other JAK inhibitors in development that will undoubtedly play important roles. Fedratinib is approved and is a consideration, particularly in second line, but has also a frontline indication. Then we have momelotinib and pacritinib in advanced phase 3 testing for certain segments of the myelofibrosis population.

Transcript edited for clarity.