Emerging Agents for Myelofibrosis - Episode 7

Long-Term Survival and Adverse Effects With Ruxolitinib

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Ruben Mesa, MD, FACP: We have long-term survival data for ruxolitinib that is favorable, from both studies. Both studies had a crossover design, which does limit the analysis as it relates to survival. However, utilizing different statistical techniques that account for the impact of crossover we clearly see in pooled analysis that there is a very significant improvement in survival.


I think clinicians see this in their practice. As an individual that cares for many patients with myelofibrosis, I have no question in my mind that the survival advantage is very real. Now there are patients that remain on the ruxolitinib even from the days of the early clinical trials in 2007 and 2008. These are individuals that when they enrolled in the study had expected survival of under 3 years. There is no question this drug prolonged survival.

The main adverse events associated with ruxolitinib are the potential for the development of cytopenia, anemia, and thrombocytopenia. These are typically managed by the modification of the dose. I find though that cytopenias are very frontloaded, and I will tend to start a patient on 10 mg twice a day if their counts are compromised. The important piece we’ve learned over time is that once a patient is on a stable dose, sometimes escalation of the dose is important to get the optimal response. I would say in 2018 one unmet need is adequate dosing of ruxolitinib. I do see many patients that are probably on suboptimal doses of ruxolitinib. It is okay to start a patient on 5 mg twice a day if they have marked thrombocytopenia. However, over time it is probably crucial for the efficacy of the drug to increase that dose further.


Moshe Talpaz, MD: There is no such thing as a perfect drug, and accordingly even ruxolitinib is not a perfect drug. It has adverse effects. And there are some adverse effects that were known from the onset, from very early development of the drug, from the phase I studies and some adverse effects that gained in significance after a much larger experience with many patients. Perhaps the most significant adverse effect of ruxolitinib is the development of anemia, and sometimes it's a trade-off. The patient feels much better, but the hemoglobin is getting worse. We noted that in several of the patients there is a dip in the hemoglobin, typically by 2 or 3 months of therapy and in some of them, it tends to recover a few months later. But it’s not a generalized rule. In some patients, the anemia can persist and be significant, and we have not developed effective means to reverse it. So it can affect, in a major way, the ability to treat the patients with an adequate dose of ruxolitinib.



Another important adverse effect of ruxolitinib that perhaps was not subject to that much attention early but appears to be a rather significant toxicity is that of immunosuppression and development of opportunistic viral, fungal, and bacterial infections. And for the doctor who uses ruxolitinib, he has to have awareness for the risk of development of those infections. And when these develop, it’s not necessarily a reason not to continue with ruxolitinib, but upon recovery from the infection, it may require dose reduction.



John Mascarenhas, MD: Ruxolitinib has been approved since 2011 and prior to that we were using it in clinical trials since 2007 in the COMFORT studies. It’s clearly proven itself to be effective in reducing spleen and symptoms. What it doesn’t probably do is have a significant anticlonal activity, meaning that the disease can still persist and progress, even on a JAK [Janus kinase] inhibitor like ruxolitinib. The median time to discontinuation of the drug is approximately 3 years So patients and physicians alike have to be aware of that and have to prepare for the possibility that at some point they may need to switch therapies, whether it’s an experimental therapy or be prepared to move on to stem cell transplantation.