Srdan Verstovsek, MD:There was a patient that I saw a week ago, about a 77-year-old gentleman, who has been living with polycythemia vera for about 7 years now. He has been treated properly with hydroxyurea because he is, by default, being older than 60, a gentleman with a high risk for thrombosis. And, hydroxyurea was very well tolerated. He had no problems with taking it for all these years, until recently. His blood cell count was controlled with no symptoms at all, but now he presented to me for a second opinion because over the last 6 months, he developed ulcers around the ankle on the right leg. Now, that was not recognized, unfortunately, over the last 6 months as one of the side effects of hydroxyurea. In fact, I asked him more questions and he also had the mouth ulcers for quite a long time before that. So, there was already what we call mucocutaneous toxicity of hydroxyurea present there. With the dose adjustments, this is unlikely to resolve. One really needs to stop hydroxyurea therapy when you have significant ulcers on the leg for this to go away.
And, that is the case that is clear-cut in a need of a different therapy than hydroxyurea. It is not wise to continue therapy in the face of toxicity. Replacing therapy in a patient who is experiencing toxicity like that or any other types of hydroxyurea-related toxicity like a low-grade fever, hair loss, diarrhea, low-grade fevers, those would be indications for a change of therapy related to toxicity. And, in this case, we actually did suggest a change to ruxolitinib. Starting dose, 10 mg twice a day, did very well. A lot of patients do feel well. Without any mouth ulcers anymore, his appetite actually increased. His fatigue that he also complained of improved. And over the next 4 months, I would expect that his leg ulcer would heal completely.
In clinical studies, so far, with ruxolitinib in polycythemia vera, we aim to control signs and symptoms of patients with polycythemia vera that are at high risk for thrombosis, previously on interferon or are resistant to hydroxyurea. We were assessing the benefit of that therapy in randomized prospective studies comparing ruxolitinib to best available therapy, whatever the patient’s doctor wanted to do, either continue hydroxyurea, switching to interferon, or using any other available active therapy. And the benefit of ruxolitinib was multi-leveled in controlling the red blood cell count, in controlling the spleen in one of the two studies where the patients with spleen were mandatedin the other study, it wasn’t mandated—controlling the symptoms in general from the itching to the low-grade fevers, night sweating, bone aches and pains, or fatigue, and allowing patients to fully recover to their pre-therapy activity levels and enjoy life fully. You would expect that in the majority of the patients in all these aspects, and we need to understand that we are treating a person, not just the red blood cell count.
HU intolerance is seen in about 10% to 12% of the patients. It is manifested most of the time by the ulcers on the leg or in the mouth. One cannot avoid stopping the therapy because for full healing of the leg ulcer in particular, one needs to stop this therapy to allow full healing, otherwise you have chronic ulcerations on the leg. And, it obviously predisposes patients to further complications, not just infectious complications, but sacral artery complications and decreases the ability to walk in many patients.
To discontinue hydroxyurea therapy, there must be a good reason, and it’s not only about inability to control the red blood cell count. In fact, one needs to understand that the control of the red blood cell count with hydroxyurea really means to control the hematocrit below 45% without the use of phlebotomy. The goal of cytoreductive therapy in general, once you start it, is to eliminate the need for phlebotomy and have hematocrit below 45% all the time. If that is not possible, then one should consider alternative therapy like ruxolitinib. Also, elevation in white blood cell count, particularly progressive leukocytosis or progressive increase in the platelets, as well as progressive loss of quality of life, or progressive splenomegaly, are additional four factors that would indicate a loss of control of the disease with hydroxyurea and require a change in therapy. And now we have ruxolitinib approved for that indication.
For polycythemia vera after hydroxyurea, ruxolitinib is indicated and the starting dose is 10 mg twice a day. Everybody starts at 10 mg twice a day. The first 3 months are the most important parts where the dose adjustments may be needed. And, we know from the two large prospective studies that about 70% of the patients may indeed need a different dose than 10 mg twice a day. About 60% of the patients will need more, meaning 15 mg twice a day, 20 mg twice a day, or even 25 mg twice a day, which is the maximum dose, or you may need to decrease. And, about 10 mg twice a day can be lowered to 5 mg twice a day in about 10% of the patients.
Long-term tolerability of ruxolitinib in polycythemia vera is very well documented. We have experience from the phase II study where patients have been on therapy for many years. There is hardly any patient that stopped the therapy because of loss of response. In fact, that is a very unusual event. And, now we have long-term results from the prospective randomized RESPONSE study, where patients were randomized between ruxolitinib and best available therapy and where ruxolitinib has markedly outperformed the best available therapy, that led to approval of ruxolitinib for polycythemia vera. And the long-term follow-up says clearly that if you have a good response, it’s going to last. Hardly anybody loses their response.
A Patient with Intolerance to Hydroxyurea