Erba Shares Treatment Considerations in 3 PV Case Scenarios


Harry P. Erba, MD, PhD, recently shared treatment considerations he would make when treating patients with polycythemia vera (PV) based on 3 case scenarios.

Harry P. Erba, MD, PhD

Harry P. Erba, MD, PhD

Harry P. Erba, MD, PhD, recently shared treatment considerations he would make when treating patients with polycythemia vera (PV) based on 3 case scenarios. Erba, professor of medicine, and director, Hematologic Malignancy Program, University of Alabama School of Medicine, discussed these cases during a live case-based peer perspectives dinner.

Case 1

February 2017

In the first case, a 58-year-old male presented with symptoms of frequent headache and dizziness. He was being treated for hypertension. A physical examination was unremarkable.

The patient’s hemoglobin level was 20.1 g/L, his hematocrit level was 60.3%, his mean corpuscular volume (MCV) was 81 fL, his leukocytes were 9.8 x 109L, and his platelets were 375 x 109L.

TARGETED ONCOLOGY:What are your initial impressions of this patient, and what further diagnostic evaluation would you do?


The discussion becomes one of how to evaluate a patient who has isolated polycythemia. When looking at this patient, we consider the differential diagnosis of polycythemia. Dehydration and volume depletion can cause a relative polycythemia. That would be pretty unusual in this man because his hemoglobin is so high and he has no symptoms of nausea, vomiting, and diarrhea, so volume depletion is unlikely.

Then the differential diagnosis becomes limited to 3 major categories. One is physiologically appropriate polycythemia, and that’s basically erythropoietin (EPO)-driven, so that is systemic hypoxia, which would include lung disease, cardiac disease, tobacco abuse, or sleep apnea. Basically, hypoxia leading to elevated erythropoietin levels and a secondary polycythemia.

The next major class would be pathologically-driven, but erythropoietin-dependent. Here, you’re talking about etho-doping—people who take erythropoietin shots, or tumors or other disorders where there is elevated erythropoietin secretion, such as renal and liver tumors.

Then you get to epo-independent autonomous bone marrow production, and that’s basically what PV is.

There are rare cases of autonomous production by the bone marrow because of mutations in the erythropoietin receptor or hypoxia sensors, but those are pretty rare.

For a patient like this, there’s no splenomegaly, there’s no thrombocytosis, and there’s no leukocytosis, so there’s nothing that is pointing to this patient having a myeloproliferative neoplasm.

The way we would evaluate a patient is by getting 2 major tests: erythropoietin level, which should be suppressed in PV, and aJAK2mutation analysis. The V617F mutation should be present, and if it is not, then an analysis for theJAK2exon 12 mutation should be done.

There are some difficulties with those tests. WithJAK2, you should get a quantitative test. In other words, you should know what the allele frequency is, because very low levels of theJAK2mutation can be seen in otherwise normal populations. Just a positive or negative result from your laboratory may be misleading. If it’s positive, it may be a false positive. Likewise, with erythropoietin, if the patient has already undergone phlebotomy, that can make the erythropoietin level go up. Another cause of a low erythropoietin level is rare mutations in the erythropoietin receptor making it sensitive to EPO. You have to understand the shortcomings of those tests.

We do not do red blood cell mass determination anymore, the test is not available. In the European LeukemiaNet guidelines, bone marrow biopsy is included when looking for panmyelosis, but most people don’t do a bone marrow biopsy and haven’t found it very helpful in cases that are more difficult to diagnose.

In terms of common things people think of for a man this age, it would be sleep apnea and the use of testosterone, which are both common causes of elevated hemoglobin without it being polycythemia.

His MCV is 8.1 fL, which is low/normal, suggesting the possibility of iron deficiency, which is not uncommon in patients with PV, and iron replacements should not be given to a patient like this until their disease is controlled with a cytoreductive therapy, if at all.

TARGETED ONCOLOGY:Can you discuss the heterogeneity of PV? What is the range in terms of patient presentation?


Like this patient, patients may present with isolated elevation of hematocrit or hemoglobin levels and no real symptoms. They may present with splenomegaly, they may present with constitutional symptoms, night sweats, fatigue, and sometimes bone pain. A very common symptom in PV is pruritus, and often it’s called aquagenic pruritus, which means after a warm shower or bath, people get very itchy. A third major way of presenting would be with an episode of thrombosis.

The major complications of the disease are thromboembolic events, which is the major cause of mortality in this disease. The major goal of therapy is to do things prevent thromboembolic disease. They may present with common things like myocardial infarction or strokes, or they may present with unusual complications of the disease, like Budd-Chiari syndrome. In series of patients who are diagnosed with Budd-Chiari syndrome, almost 50% of them were found to have theJAK2V617F mutation, suggesting that they had PV.

The last category would be symptoms of microvascular thrombosis, and that would be including things like erythromelalgia—which is red, painful skin, usually in the hands or feet—migraine headaches, and dizziness.

Case 2

August 2014

In the second case, a 62-year-old female was diagnosed withJAK2V617F-positive PV. She presented with symptoms of aquagenic pruritus, night sweats, and left upper quadrant fullness.

The patient’s past medical history included unstable angina treated with angioplasty and coronary artery stent 2 years ago. She was receiving ongoing treatment for type 2 diabetes. A physical exam was remarkable for palpable splenomegaly.

TARGETED ONCOLOGY:Can you describe your initial impressions of this patient, based on her presentation? How would you approach treatment?


This patient has a known diagnosed PV. The important thing about her is that she has constitutional symptoms of night sweats and pruritus. She has symptoms related to splenomegaly—upper quadrant fullness—so she has indications for therapy, based on constitutional symptoms and splenomegaly, and she also has 2 features that have been associated with high-risk PV: age over 60 and prior thrombotic events. She also has unstable angina. Additionally, she has risk factors for further thromboembolic events with diabetes. This is a patient that we believe should get therapy; in addition to phlebotomy and hydroxyurea, she should get cytoreductive therapy at presentation.

February 2016

For 1.5 years, the patient was maintained on treatment with aspirin and hydroxyurea at 500 mg per day. She required 4 phlebotomies in the last 6 months. She still has palpable splenomegaly. Hydroxyurea was increased from 500 mg to 1,000 mg daily.

August 2016

As of August 2016, the patient had no phlebotomies in the last 3 months. A physical exam showed no remarkable splenomegaly, but her spleen tip was now just at costal margin and non-tender. She had a 3.5 cm poorly healing leg ulcer for the last 2 months.

TARGETED ONCOLOGY:How would you alter management based on her current presentation?


The patient received cytoreductive therapy with hydroxyurea. There were 2 recent studies presented at the 2016 American Society of Hematology (ASH) Annual Meeting showing that the response rates were similar between patients with PV treated with hydroxyurea compared to pegylated interferon. There was more toxicity related to the pegylated interferon, however, long-term results in terms of potential survival benefit weren’t clear yet. Further follow-up of those studies is needed.

She was started on hydroxurea, but still had splenomegaly, and she was still getting phlebotomy, so the dose is increased. She seemed to respond, but she developed a leg ulcer, so she now has intolerance. In August 2016 she stopped getting phlebotomy and her blood counts were normal, her spleen was just barely palpable, but she showed a sign of intolerance.

TARGETED ONCOLOGY:What are the criteria for intolerance to hydroxyurea?


At the usual doses required, gastrointestinal intolerance (nausea, vomiting, diarrhea, and alopecia) is pretty unusual. Some of the more unusual complications that people should know about include leg ulcers, which do not heal if you keep them on hydroxyurea and will likely recur if you put them back on hydroxyurea, as it often needs an extended period of time to heal. Very rare complications include non-melanoma skin cancers, mostly squamous cell and basal cell cancers of the skin. That would be a reason to stop. Another very rare complication is alveolitis or pneumonitis—a pulmonary injury with fevers.

The development of cytopenias at the doses of hydroxyurea required to control the symptoms and signs of PV is another sign of intolerance. This patient had clear intolerance to hydroxyurea. We wouldn’t switch to interferon because of her age and the risk of side effects from it. This would be an indication for ruxolitinib (Jakafi).

TARGETED ONCOLOGY:When starting ruxolitinib, what dose adjustments may be needed?


The label dose of ruxolitinib for patients with PV whose disease is poorly controlled by or intolerant of hydroxyurea is 10 mg by mouth twice per day. That’s the starting dose.

For patients with renal insufficiency, hepatic insufficiency, and patients on CYP3A4 inhibitors, such as posaconazole (Noxafil), the dose should be reduced.

After starting the drug, if a patient does not achieve a response within 4 weeks, you can go up on the dose by 5 mg twice daily increments, for a maximum dose of 25 mg twice daily.

Those changes should not occur in the first 4 weeks and no sooner than every 2 weeks after that. In the clinical trial, about a third of patients required dose increases and about 10% or less of patients will require dose reduction.

Case 3

January 2015

In the third case, a 39-year-old male presented with headache and palpable splenomegaly 2 cm below the costal margin. He was a 1-pack-a-day smoker, but had no prior thromboembolic events. A polymerase chain reaction analysis was positive for theJAK2V617F mutation. The patient was started on phlebotomy as needed and a daily low dose aspirin.

January 2016

The patient had 3 phlebotomies in the last 3 months. He now complains of increasing dizziness, headaches, nausea, and abdominal fullness. His spleen length is 16 cm, and his spleen volume is 2847 cm3.

The patient’s hematocrit level was 48.5%, his white blood cell (WBC) count was 14.8 x 109/L, and his platelet count was 709 x 109L.

TARGETED ONCOLOGY:How would you manage this patient? What are the treatment options?


Phosphorus-32 is hardly ever used anymore and is reserved for very old patients with limited life expectancy. In Europe, pegylated interferon has been used more, but again, those 2 randomized studies I mentioned earlier showed no difference in response rate, including molecular response.

What people continue to debate is using hydroxyurea in a young person because there’s still a fear that it’s leukemogenic. Again, there’s no proof that it’s leukemogenic, but the problem is if you have a 40-year-old like this, who might have another 30 or 40 years of life, the studies that have been done looking at the risk of leukemia usually only look at 10 or 15 years of exposure and not 30 years of exposure. It makes people a little worried about using hydroxyurea in a younger patient using interferon.

The patient continued phlebotomy as needed, and also continued taking aspirin. He was started on hydroxyurea 500 mg daily.

July 2016

The patient came back 6 months later. His spleen was a little smaller and he had had a couple of phlebotomies.

TARGETED ONCOLOGY:What would you do at this point? Would you consider increasing the dose of hydroxyurea?


He was started on an arbitrary dose. Like with any drug we use in oncology, you push the dose to the maximally tolerated dose. Just because he got started on whatever he got started on, it doesn’t mean you can’t titrate up the dose if he’s still requiring phlebotomies and has splenomegaly. The patient’s dose was titrated up to 2000 mg over the next 3 months and he still had symptoms.

Hydroxyurea was increased to 2000 mg/day over the next 3 months.

January 2017

The patient returned 6 months later with some abdominal fullness, pruritus, and still required phlebotomy. He had restless legs and was complaining that his tongue was sore and that food tastes funny.

The patient’s hematocrit level was 45.5%, his WBC count was 11.6 x 109/L, and his platelet count was 689 x 109/L.

TARGETED ONCOLOGY:How would you treat this patient now?


At this higher dose of hydroxyurea, he’s still symptomatic. He still requires some phlebotomies and shows signs of iron deficiency, such as sore tongue, restless legs, loss of hair, brittle nails—those are some of the more common ones. Some people also include generalized fatigue and memory problems.

If we use the treatments that could better control his myeloproliferative disease, you might be able to give him back iron as well. I would use ruxolitinib again at the label dose. Once we had his disease controlled and he didn’t need phlebotomy anymore we would judiciously and cautiously add back iron, so maybe a multivitamin with iron and watching his counts, or 1 iron sulfate tablet per day. I would not advocate intravenous replacement of iron, that might be too risky. The cautious reinstitution of iron might help with some of his symptoms like restless leg, mouth sores, and change of taste.

TARGETED ONCOLOGY:What is the effect of reduction on risk of thrombosis?


The RESPONSE trial was not powered to look at differences in reduction of risk on thrombosis. It was a crossover design, so many patients after the primary endpoint of 32 weeks crossed over, so patients were on best available therapy for less than a year before many of them crossed over. Because of the trial design, it’s not possible to look at the reduction of risk on thrombosis, so that claim cannot be made based on this data with ruxolitinib. In the paper, there were numerically fewer thromboembolic events in patients taking ruxolitinib, but the numbers were very small and no firm conclusion could be made.

The benefit of ruxolitinib in this population has been shown to be resolution of phlebotomy requirement and reduction in spleen volume. We cannot make any claims about improvement in survival or decreased risk of thromboembolic events.

TARGETED ONCOLOGY:How has the approval of ruxolitinib changed the treatment paradigm?


In the RESPONSE trial, where patients had resistant or intolerant PV, if they got randomized to best available therapy, 60% of them went back on hydroxyurea, so there are very few options. Other options were immunomodulatory agents like lenalidomide and thalidomide, interferon, steroids, anagrelide. Ruxolitinib gives us an option for these patients.

In the follow-up of the RESPONSE trial, at 80 weeks, the majority of patients were remaining on the drug and the majority still had a hematologic response and all but 1 had control of the spleen volume.

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