Patients with Intolerance to Hydroxyurea

Harry Erba, MD, PhD:There are a number of scenarios where patients may be intolerant to hydroxyurea and benefit from ruxolitinib. GI toxicity and leg ulcerations are pretty uncommon, but I would say are the low-hanging fruit. If a patient is clearly having leg ulcers, I think stopping hydroxyurea, treating the leg ulcer, and switching to ruxolitinib really makes a lot of sense. In terms of other toxicities, it’s the hematologic toxicity that can sometimes be blurred with resistance to hydroxyurea, but hematologic toxicity of hydroxyurea can be a reason for using ruxolitinib. In that scenario, you cannot give enough hydroxyurea to accomplish your therapeutic goal, whether it be shrinking the spleen so it’s not symptomatic or maintaining the hematocrit less than 45% without phlebotomy, without that dose of hydroxyurea also causing leucopenia or thrombocytopenia.

Now, some clinicians would say, if their hematocrit is poorly controlled with the hydroxyurea, I’ll give them just enough hydroxyurea to keep their white count and platelet count in a safe range, and they may need periodic phlebotomy. The downside of that approach is the inconvenience of the phlebotomy, and the symptoms associated with the phlebotomy itself, and the iron deficiency that goes along with it. So, I do think that that would be a reason for considering ruxolitinib.

We know that patients who have intolerance to hydroxyurea, due to hematologic toxicity, are patients defined in a couple of studies as having a worse prognosis. We don’t know that switching to ruxolitinib changes that prognosis, but it gives you an opportunity to maintain the disease and treat their symptoms without requiring phlebotomy as well.

If a patient is intolerant to hydroxyurea and we switch to ruxolitinib, then many of the toxicities that I’ve seen with hydroxyurea will get better. The leg ulcerations and the GI toxicity either don’t happen or are very uncommon with ruxolitinib. So, there’s no cross-intolerance there. In terms of the hematologic toxicity, in the RESPONSE Trial, there’s actually very little neutropenia, thrombocytopenia, or anemia even with ruxolitinib. It’s very different than the COMFORT-1 Study. In the COMFORT-1 Study, patients who received ruxolitinib, 45% of them had a hemoglobin under 8, grade 3 toxicity, and 20% had platelet counts under 50,000, grade 3 toxicity. Less than 5% had neutropenia, so it is less common there. But, remember, in the COMFORT-1 Study, higher doses of ruxolitinib were used, 15 mg or 20 mg twice daily, and myelofibrosis is more of a bone marrow failure state. In polycythemia vera, using the labeled dose of 10 mg twice daily, those cytopenias are much less common.

There have been a number of retrospective analyses done either by investigators or a sponsored study looking at case charts, and hydroxyurea intolerance has been noted in about half. In about 25% of patients there is either intolerance or resistance, and about half of those cases are intolerant. So somewhere between 10% and 15% have nonhematologic intolerance. If you add hematologic intolerance, it’s closer to 20%.

Hydroxyurea, in my opinion, should be discontinued for the major, although rare, toxicities such as alveolitis and leg ulcerations. Hydroxyurea should be discontinued when you switch to ruxolitinib. There’s no reason to overlap them at all, and you may get combined myelosuppression. So, I would advise stopping hydroxyurea when switching to ruxolitinib. As I mentioned, I’ve had one patient with intractable and progressive multiple skin cancers. I would stop hydroxyurea definitely in that situation.

In patients with polycythemia vera who typically are being treated because of persistent leukocytosis, or thrombocytosis, or splenomegaly, I would use the standard labeled dose of 10 mg twice daily. The important caveats there are patients with renal hepatic impairment. The dose should be adjusted and decreased. Patients on CYP3A4 inhibitors, including moderately potent inhibitors such as fluconazole, should also have a dose reduction in that situation.

Once patients are started on ruxolitinib, whether for polycythemia vera or for myelofibrosis, after initial adjustment of the dose, long-term tolerability has been excellent. And, in fact, many patients in the RESPONSE Trial and in the myelofibrosis studies, COMFORT-1 and COMFORT-2 remain on long-term therapy with ruxolitinib.

There are a number of toxicities related to ruxolitinib that are peculiar to it. One of them that has been seen in the COMFORT Studies, and also in the RESPONSE Trial, is a higher incidence of Herpes Zoster, occurring in about 6% of patients in the RESPONSE Trial. Many of my colleagues and [myself] have not yet gotten to a point where we have given prophylactic antivirals. The incidence doesn’t seem that high. However, if a patient has a unilateral painful rash, definitely consider early intervention with an antiviral. The other thing that could be considered is vaccination against Varicella, but keep in mind that ruxolitinib actually is a potent immune suppressant by blocking the JAK1 pathway. And so, it’s not clear that vaccination would actually help. Many of my colleagues have recognized this toxicity, and I agree with this. We warn our patients about it. So, that’s one toxicity to keep in mind.

In the RESPONSE Trial, numerically there were slightly more patients with nonmelanomatous skin cancers during a very short period of time. It was not statistically significant, but was numerically a few more than in the best available therapy. So, periodic skin examinations should be done, but those should probably be done for all of us regardless of whether we’re on ruxolitinib or not.

Case 2: Patients with Intolerance to Hydroxyurea