Ruben Mesa, MD, and Srdan Verstovsek, MD, PhD, define inadequate response to hydroxyurea for treatment of polycythemia vera and triggers to switch to second-line therapy, and discuss the data for ruxolitinib in this setting.
Ruben Mesa, MD: The patient who has failed hydroxyurea has many potential, different paths to get to that clinical determination. Indeed, an inadequate response to hydroxyurea is a clinical observation that can be on the basis of resistance, intolerance, or both. Resistance is really having an inadequate control of the disease at the dose the patient tolerates. Does inadequate control mean that the spleen is too large, they have too much in the way of symptoms, they’re having vascular events, or the counts aren’t controlled? Or are they intolerant where, at the dose that controls the counts, they have the development of either neutropenia or thrombocytopenia? Do they have gastrointestinal toxicities? Do they have cutaneous toxicities such as recurrent skin cancers, mucosal ulcers, or leg ulcers? So, it is really a balance. Some patients will have some components of both. They have both aspects of resistance or intolerance, and we need to factor in all of these considerations as we determine if they are really having a good response to hydroxyurea or do we need to consider a second-line therapy?
Srdan Verstovsek, MD, PhD: Polycythemia vera patients who are treated with hydroxyurea can benefit from that medication for a long period of time, but the medication needs to control not just the red blood cells, but also platelets, white cells, symptoms, and the spleen. This is what we would like to achieve in every patient—to look at the person, not just at the blood count. About 20% to 25% of patients on hydroxyurea do not do well. They do not achieve a control of the blood cell counts, symptoms, and spleen. In that case, we look for other options. Not too long ago, there was a significant development in polycythemia vera, with the approval of ruxolitinib, a JAK inhibitor, as a second-line therapy in patients who are intolerant, refractory, or progressing on hydroxyurea. And now, ruxolitinib is a full-fledged option, which can provide benefits, again, for these patients in controlling the red blood cells, white cells, platelets, spleen, and symptoms.
Ruben Mesa, MD: The approval of ruxolitinib in polycythemia vera has been very impactful. First, it’s actually the only approved therapy for polycythemia vera. Hydroxyurea, although used as a front-line cytoreductive therapy, is really used in a historical context. It’s not actually approved for that indication, but certainly is used as a historical drug in that setting. So, ruxolitinib was very impactful in terms of bringing a lot of consideration, science, and thoughtfulness in terms of how we are managing these patients.
Now, the availability of ruxolitinib for these patients has been very impactful. As we look at the phase III RESPONSE study that led to the approval of ruxolitinib, it helps to highlight the benefits of the therapy, specifically with control of counts—control of erythrocytosis, helping patients who had already failed hydroxyurea; helping to control the counts of patients no longer needing phlebotomy; helping to control leukocytosis; and helping to control thrombocytosis.
Next, it’s helpful in terms of controlling splenomegaly, if present. Third, it improves symptoms. Have they difficult symptoms? Particularly, in some symptoms that really respond to very little else in these patients—pruritus, night sweats, fatigue—it can make them respond well. And finally, a key goal is to decrease the risk of thrombosis or bleeding. Compared to the control arm, patients with ruxolitinib seem to have a very significant decrease in that risk of vascular events; that might be multifactorial. It might be an improvement in those counts, but it may also be regarding improvement in the inflammatory milieu that these patients face—that those inflammatory markers may be contributing to the risk of thrombosis.
Srdan Verstovsek, MD, PhD: While hydroxyurea is an established first-line therapy for patients with polycythemia vera who need cytoreductive therapy, not everybody benefits. So, in patients who are intolerant or resistant to hydroxyurea, we need new therapies. Ruxolitinib was recently approved based on the RESPONSE study. Patients who were previously taking Hydrea [hydroxyurea] and not doing well, not responding, or being intolerant to it—intolerance is sometimes seen as skin ulcers, mouth ulcers, low-grade fever, or hair loss—these are all possibilities that are not related to its effect on the bone marrow.
These types of patients were then randomized to receive a new medication at the time, ruxolitinib, which is now approved. So, ruxolitinib was one arm, and best available therapy was the other arm. Patients were monitored for improvements in their red blood cells and spleen, because patients in this study were mandated to have a big spleen. But also, as a second goal, there was a control of red blood cells, white cells, spleen, and symptoms. Altogether, 5 factors were monitored, so this is a complete hematological response including symptoms and the spleen. This was achieved, significantly, in a number of patients on ruxolitinib versus best available therapy, and this led to approval of ruxolitinib as a second-line choice.