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Verstovsek Clarifies Risk Stratification and Management in Patients With Polycythemia Vera

Shannon Connelly
Published Online:4:46 PM, Tue October 10, 2017

Srdan Verstovsek, MD, PhD
Srdan Verstovsek, MD, PhD, recently discussed treatment considerations and decisions in the cases of 2 patients with myeloproliferative neoplasms. Verstovsek, professor of medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discussed the case scenarios during a Targeted Oncology live case-based peer perspectives dinner.

Case 1

February 2017

A 58-year-old man presented with symptoms of frequent headache and dizziness. He was being treated for hypertension. A physical examination was unremarkable.  Laboratory findings showed hemoglobin was 20.1 g/L, hematocrit was 60.3%, mean corpuscular volume (MCV) was 81 fL, leukocytes were 9.8 x 109/L, and platelets were 375 X 109/L.

Targeted Oncology: What are your initial impressions of this patient?

Verstovsek: He has elevated red blood cell count, as well as headaches and dizziness, which possibly may be related to too many red blood cells going around his blood. On his laboratory findings, he has very low MCV, which is red blood cell volume, which is typical in patients with polycythemia vera [PV] because they present with iron deficiency, which is subsequent to uncontrolled red blood cell growth. This is one of the signs of PV. 

When should PV be suspected?

Based on these 2 factors of high red blood cell count and low MCV, I would suspect PV. I would then order tests for JAK2 mutations. A JAK2 V617F mutation is present in 95% of the patients. If that is negative, then I would add JAK2 exon 12 mutation, which is present in about 3% of the patients. I would also test erythropoietin levels, due to uncontrolled growth of red blood cells. Erythropoietin is a growth hormone for red blood cells. In PV patients, it would be low. It's not necessary, so the body shuts down its production. Combined findings of very high red blood cell count, very low erythropoietin level, and JAK2 mutation would be enough to say this patient has PV. A protein test would measure iron, which would explain low MCV. If they are low, it's further support for PV.

The erythropoietin doesn't necessarily need to be low. For example, if MCV is low because iron deficiency is there due to gastrointestinal bleeding. We don't have any evidence of that, but you need to exclude other possibilities. The gold standard for evidence of PV would be bone marrow biopsy. 

How do you evaluate prognostic risk?

Prognostic risk is based on 2 factors: age over 60 and history of thrombosis. If either factor is present, or both, these patients are at a higher risk for blood clotting and would be treated differently than patients who do not have either of the 2 factors. You have low-risk patients with PV and you have high-risk patients with PV for thrombosis. The primary goal is to assess the thrombotic risk. If the patient has low-risk disease, then we do phlebotomy to decrease the hematocrit—one of the parameters for measuring red blood cells—to below 45%, and maybe aspirin to make blood flow easier to decrease the stickiness between the cells.

If the patient has high-risk disease, we start the phlebotomy, but we also start with medications to decrease the red blood cell count and make it lower all the time to eliminate the phlebotomy need. The standard frontline cytoreductive therapy is hydroxyurea. The highest-risk patient would require phlebotomy and hydroxyurea, and baby aspirin. Hydroxyurea would be adjusted to eliminate the need for phlebotomy to make the hematocrit below 45% all the time. An alternative medication to hydroxyurea is interferon, which is usually reserved for younger patients, or females who would like to have babies, because it's a biological adjuvant, and hydroxyurea is a chemotherapy. 

For low-risk patients, if the patient also has elevated white cell platelets, as is typically seen in patients with PV, we do not treat that patient for elevation of white blood cell platelets, because the therapy is only based on normalization or control of hematocrit for red blood cell count with phlebotomy. Phlebotomy does not do anything for white blood cell platelets. Therefore, there are situations where one does need to intervene with cytoreductive therapy, even in low-risk patients. This is progressive leukocytosis, so the white blood cell count keeps going up and up. Particularly when they go above a million to a million and a half, at that point patients are at risk of bleeding and we would like to lower those platelets with cytoreductive therapy. 

Other unusual situations for introduction of cytroreductive therapy in otherwise low-risk patients is if the phlebotomies are too frequent and the patient doesn't want them anymore, but despite the phlebotomies, the patient has too many symptoms from the disease itself. Sometimes the cytoreductive therapy can help with the symptoms as well. In the patient who is on cytoreductive therapy, you will look at the benefit of the therapy by first controlling the hematocrit below 45% without the use of phlebotomy, and then number 2 would be normalization of the white cells to ensure the normalization of the platelets and symptoms, and lastly, the normalization of the spleen size if it is enlarged.


Case 2

A 62-year-old woman is diagnosed with JAK2 V617F-positive PV. She presented with symptoms of aquagenic pruritus, night sweats, and left upper quadrant fullness. Her past medical history included unstable angina treated with angioplasty and coronary artery stent 2 years ago. She is receiving ongoing treatment for type 2 diabetes. A physical examination was remarkable for palpable splenomegaly.

February 2017

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

August 2016

The patient had no phlebotomies in the last 3 months. A physical examination was still remarkable for splenomegaly, but spleen tip was now just at coastal margin and non-tender. She had a 3.5 cm, poorly healing distal leg ulcer for the last 2 months.

How would you alter management based on her current presentation?

This patient has PV by diagnosis. She is already 60, so she's at a high risk for thrombosis. She also has multiple symptoms, which are apparently related to PV, such as aquagenic pruritus and night sweats. She also has left upper quadrant abdominal fullness, which is related to an enlarged spleen. That is a possibility in some patients with PV. She has other cardiovascular risk factors that are not good to have when you have PV because they increase the risk for thrombotic events, which is part of her past medical history. She is in need of an intervention, as a high-risk PV patient. She needs to be treated with phlebotomy to decrease the hematocrit below 45% and immediately start with cytoreductive therapy to normalize the hematocrit below 45%. If she has elevated blood cells and elevated platelets, all these symptoms, it could possibly be controlled with cytoreductive therapy. She also needs to be on baby aspirin as a standard practice to decrease the stickiness of the cells. 

This patient requires intervention for multiple reasons. Age on its own is a risk factor for thrombosis, but she also has splenomegaly that is symptomatic, and general systemic symptoms from the disease. You can try hydroxyurea as a first choice. You can also try interferon. These days we also try peginterferon alfa-2a [Pegasys], which has better tolerance and is injectable once a week, rather than 3 or 5 times a week. Hydroxyurea is usually the first choice. You usually start 1 pill per day at 500 mg standard dose, then you titrate up and down with a goal to normalize the blood cell count and eliminate the need for phlebotomy and eliminate the symptoms in the spleen.

If you follow this case, she was given aspirin and hydroxyurea. She still requires some phlebotomy in February 2016. She still has some spleen splenomegaly, but her dose was increased properly to eliminate the need for phlebotomy. In 2016, no phlebotomies needed anymore. The spleen is normal, highly palpable, but now she has a poorly healing leg ulcer, which is a typical side effect of hydoxyurea.

Hydroxyurea is very well tolerated in many patients, but about 10% to 15% of the patients have side effects, and among them, the most common is skin ulcers, usually around the ankles. The other possibility is ulcers in the mouth, preventing people from eating properly. Other side effects are very rare, including low-grade fevers, diarrhea, hair loss, or skin rash. In this case, the patient has skin ulcers, so one needs to stop therapy because this is not going to go away. In terms of the counts, we see on the next slide that his counts in 2016 were well controlled with a high dose of hydroxyurea. But she had a side effect that is not acceptable so she needed to stop therapy.

How would you alter management based on her current presentation?

Intolerance is easy to understand. Something that compromises the patient's quality of life, like skin ulcers. The resistance on the other hand is inability to control the blood cell count, spleen, or symptoms with the maximum tolerated dose, so basically no satisfactory response that would be resistance. So now you have to do something different. Once you stop hydroxyurea, she still is at high-risk for thrombosis. You can replace hydroxyurea with ruxolitinib [Jakafi]. Ruxolitinib is a JAK inhibitor approved for this indication in the United States and Europe where patients are intolerant or resistant or not responding very well to hydroxyurea. Ruxolitinib has the potential to allow healing of the ulcers. It doesn't have anything to do with the skin, but it has a lot to do with bone marrow production of the cells and symptoms. The likelihood is that blood cell count will continue to be controlled and symptoms in the spleen are present on ruxolitinib. 

When starting ruxolitinib, what dose adjustments might be needed?

When starting ruxolitinib, the starting dose for every patient is 10 mg twice per day. About 60% of the patients will need more. The dose goes up by 5 mg for each dose. From 10 mg twice per day to 15 mg twice per day, then to 20 mg twice per day to 25 mg twice per day, if necessary. This is usually done in monthly increments. When you find a dose that is the best for the patients to control all those factors, the durability long-term is excellent. About 10% of patients experience suppression of the blood cell count too much, and then you decrease the dose from 10 mg twice per day to 5 mg twice per day. Hardly anybody has any other known hematological toxicity and they usually do not require dose adjustments. There are patients that require perhaps different doses. Those are doses effected by the kidney failure or liver failure. And there are special guidance on how to adjust the dose.

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