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Mesa Discusses the Management of Patients With Polycythemia Vera in 2 Case Studies

Samantha Hitchcock
Published Online:1:56 PM, Tue April 17, 2018

Ruben A. Mesa, MD
Ruben A. Mesa, MD, recently discussed the treatment considerations and decisions he makes when treating patients with polycythemia vera. Mesa, director of the Mays Cancer Center, the newly named center home of UT Health San Antonio MD Anderson Cancer Center, explained his treatment decisions based on 2 case scenarios during a Targeted Oncology live case-based peer perspectives presentation.

Case 1

February 2017

A 58-year-old male presented with symptoms of frequent headache and dizziness and he is undergoing treatment for hypertension. His physical examination was unremarkable. Laboratory findings showed hemoglobin levels at 20.1 g/L, hematocrit levels at 60.3%, mean corpuscular volume at 81 fL, white blood cell count at 9.8 x 109/L, and platelet count at 375 x 109/L.

TARGETED ONCOLOGY: What are your impressions of this patient?

Mesa: This patient is clearly an individual who has factors that are a concern for me regarding polycythemia vera (PV). First of all, although he is not 60 years of age, he is clearly older and age is a major factor in the risk for PV in terms of thrombosis, bleeding, and other factors. I always use the risk factor as a continuum. Things that make me more concerned are when a patient has additional cardiovascular risk factors, [such as his] hypertension. He also presents with a very high hematocrit; that again gives me concern about a more active phenotype at presentation and a greater risk of thrombosis. I think he likely has PV and it is likely high-risk PV.

TARGETED ONCOLOGY: What is the diagnostic workup of this patient?

Mesa: This individual with significant erythrocytosis would have an assessment of a JAK2 mutation, particularly an unexplained erythrocytosis. As well as look for common secondary causes of erythrocytosis, such as sleep apnea, abnormal hemoglobin, and things of that nature. We can also look at the serum erythropoietin level to see whether there is any suppression with erythropoietin, which would lean more toward a PV, or whether it’s markedly increased, which would be associated with a secondary [condition].

Given the height of the hemoglobin at presentation, in terms of efficiency, I would start with a JAK2 mutation. If it is positive, it would make a lot of that other workup, other than the erythropoietin, somewhat irrelevant. If he does end up being positive for JAK2, by the 2016 World Health Organization criteria, we would also take a bone marrow aspiration and biopsy as a baseline to confirm the features of PV, as well as to be sure that there are no karyotypic abnormalities or increase in fibrosis.

TARGETED ONCOLOGY: How would you evaluate prognostic risk?

Mesa: Prognostic risk in PV includes many factors, which are readily available clinically. It includes age or prior thrombotic events. Age over 60 is associated with a higher risk and that is a continuous variable, so at age 58, in the case of this patient, you are almost there. It does not seem that the patient has had a prior vascular event, but I would take a detailed history to be sure that is not the case; [I’d also be sure] there has not been any occult pulmonary embolism or deep vein thrombosis that was not diagnosed. Next, I assess cardiovascular risk factors. If those are present, that might increase my concern regarding the patient’s risk, and those include hypertension, hyperlipidemia, mild diabetes, and others. Family risk of premature coronary artery disease would be another factor. I would also look at the white blood count and the platelet count; significant leukocytosis or significant thrombocytosis can both add risk, in particular in individuals with significant leukocytosis levels over 11. This individual does not fall into that category, but [the measurement] is on the generous side. Finally, I assess his symptom burden. If he is having a lot of difficult symptoms associated with his PV, that is not technically a risk in terms of thrombosis, but certainly it is an assessment in terms of the disease burden.

TARGETED ONCOLOGY: What is the treatment approach for a patient with newly diagnosed PV?

Mesa: With newly diagnosed patients with PV, universally we would use a control of the hematocrit through at least phlebotomy to [get to a] hematocrit of under 45%. That has been shown to be helpful in randomized clinical trials. Next, barring an aspirin allergy, we would use a baby aspirin of 81 mg daily in all individuals in whom there was not a contraindication. 

For individuals who have higher-risk disease, prior thrombotic events, higher white count, difficult symptoms, or age over 60, we would consider cytoreductive therapy with either hydroxyurea (Hydrea) or an interferon. This individual would fall under the category of intermediate risk, and there would be a discussion with the patient to decide whether we start that at this point or hold off in case there are any changes.

TARGETED ONCOLOGY: What are the complications associated with PV and how should they be managed?

Mesa: Patients with PV can have a variety of difficulties in terms of disease burden. From the complications, technically as secondary events, I would say that they can include the risk of thrombosis, either in large or small vessels. These have been found to be both arterial, such as heart attack or stroke, or venous, ranging from in the skull to the liver, legs, and other parts of the body. There can also be risk of bleeding, either from portal hypertension or just direct coagulopathy. There can also be development of splenomegaly, with associated symptoms or impacts of the spleen. There can also be the complication of progression to either myelofibrosis or acute leukemia. Finally, patients can also have a range of complications, such as symptoms from high counts, symptoms from pruritus, and others.

Case 2

August 2014

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

TARGETED ONCOLOGY: What are your initial impressions of this patient based on her presentation?

Mesa: Case 2 is a higher-risk case. She is older, so she is over the threshold mentioned previously. She also has splenomegaly, which is a sign of a more problematic PV and a difficult burden. She also has significant symptoms, including aquagenic pruritus, and night sweats. Finally, she has coronary disease, which we know from her stent, and this again becomes clear that she is higher risk. The PV may have contributed to those coronary events.

TARGETED ONCOLOGY: How would you approach the treatment for this patient?

Mesa: This individual is both high risk and highly symptomatic. We would institute a program of phlebotomy to keep the hematocrit strictly under 45%. Given that she is a female, we may even consider a stricter cut—a hematocrit of 42%. Next, we would administer aspirin. She is already on aspirin for coronary disease and she might also be on an antiplatelet therapy. She would also require cytoreductive therapy on multiple levels including the spleen, the symptoms, and the risk. As standard, we would have begun therapy with hydroxyurea over the caveat that we will be monitoring closely to see whether she has an adequate response.

February 2016

For 1.5 years, the patient was maintained on treatment with aspirin and hydroxyurea 500 mg daily. She required 4 phlebotomies in the last 6 months and still had palpable splenomegaly. Her hydroxyurea dosage was increased from 500 mg to 1000 mg daily. Laboratory values showed hematocrit levels at 47.5%, white blood count at 10.2 x 109/L, and platelet count at 299 x 109/L.

August 2016

She did not have any phlebotomies in the last 3 months. Her physical exam was still remarkable for splenomegaly, but spleen tip was now just at costal margin and was non-tender. She also had a 3.5-cm poorly healing distal leg ulcer for the last 2 months. Laboratory values showed hematocrit levels at 46.4%, white blood cell count at 11.8 x 109/L, and platelet count at 238 x 109/L.

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

Mesa: At this point, she was high risk and treated with hydroxyurea. The dose was raised because of an inadequate response; residual splenomegaly continued the need for phlebotomies. Now, the patient has had a bit better response, although she still had some splenomegaly. So, she has not achieved the goal European Leukemia Network response that we seek. But, in addition, she had signs of hydroxyurea intolerance on the basis of the leg ulcer that she had developed.

On that basis, we would consider her to have failed hydroxyurea because of the combination of both inadequate response and intolerance because of the leg ulcers. When leg ulcers occur, the only way to have those heal is for the individual to discontinue the use of hydroxyurea all together. This individual would fit exactly for a switch to ruxolitinib (Jakafi) as second-line therapy. This is consistent with the label for ruxolitinib for those who have been resistant to or intolerant of hydroxyurea, and [consistent with] the National Comprehensive Cancer Network (NCCN) guidelines.

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

Mesa: Intolerance can be a range of different things as defined by the European Leukemia Network. This can include the development of complications such as mouth or leg ulcers, recurrent skin cancers, fever, cytopenia, neutropenia (among the most common), others. Any of those, or more than 1 of those, are contributors in terms of considering an individual to be intolerant to hydroxyurea.

The greatest unmet need I see is typically a delayed recognition of when a patient has become resistant to or intolerant of hydroxyurea. The purpose of our NCCN guidelines included 2 parts: not delaying the initiation of cytoreductive therapy when helpful, and when [intolerance or resistance] does occur, not hanging on to hydroxyurea for longer than it is likely to be helpful.

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

Mesa: With PV, barring her having significant cytopenia at the initiation, which would be unexpected, we typically start individuals on 10 mg twice a day. I will typically leave them at that dose, and increase after at least 12 to 18 weeks, and we [will also leave them at that dose] if there is residual splenomegaly, the blood counts are higher than our goal range, or if we have symptoms that are a bit more refractory. There are times, if individuals have very high counts or if they have a very significant degree of leukocytosis, where there would be a benefit in increasing the dose further.

Clearly, we would decrease the dose if the individual is having difficult problems with cytopenia. In the setting of PV, that has been quite rare. Usually it is associated with individuals with myelofibrosis who need a dose decrease, as opposed to those with PV.

TARGETED ONCOLOGY: What is the long-term tolerability with ruxolitinib?

Mesa: The long-term tolerability with ruxolitinib in PV has been shown to be very good. We recently published, at the American Society of Hematology meeting, data with more than 4 years of follow-up. It showed that the majority of the patients are remaining on the therapy and tolerating it well.

TARGETED ONCOLOGY: How do you manage toxicities associated with ruxolitinib?

Mesa: The management depends on the toxicity. I think around cytopenia, we would adjust the dose. Nonhematologic toxicities tend to be fairly uncommon. Ones that have occurred are the development of shingles and topical infections. But those tend to be relatively uncommon. Again, they are likely not things that are going to influence a need for a change in therapy.

TARGETED ONCOLOGY: Are there caveats for certain types of patients or those with certain comorbidities?

Mesa: I would say that there are no specific comorbidities that I have found to be overly limiting in terms of the use of ruxolitinib. It is not that big a driver in the direction of PV.

Kiladjian JJ, Verstovsek S, Griesshammer M, et al. Results from the 208-week (4-year) follow-up of RESPONSE trial, a phase 3 study comparing ruxolitinib (rux) with best available therapy (BAT) for the treatment of polycythemia vera (PV). Presented at: 59th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 322.

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