eMedicine Specialties > Hematology > Stem Cells and Disorders
Polycythemia Vera: Treatment & Medication
Updated: Jan 23, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
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Treatment
Medical Care
Phlebotomy or bloodletting has been the mainstay of therapy for the polycythemia vera (PV) disease process for a long time. The object is to remove excess cellular elements, mainly red blood cells, to improve the circulation of blood by lowering the blood viscosity.
Patients with hematocrit values of less than 70% may be bled twice a week to reduce the hematocrit to the range of less than 45%. Patients with severe plethora who have altered mentation or associated vascular compromise can be bled more vigorously, with daily removal of 500 mL of whole blood.
- Elderly patients with some cardiovascular compromise or cerebral vascular complications should have the volume replaced with saline solution after each procedure to avoid postural hypotension.
- Because phlebotomy is the most efficient method of lowering the hemoglobin and hematocrit levels to the reference range, all new patients are initially phlebotomized to decrease the risk of complications. The presence of elevated platelet counts that may be exacerbated by the phlebotomy is an indication to use myelosuppressive agents to avoid thrombotic or hemorrhagic complications.
- Once the patient's hemoglobin and hematocrit values are reduced to within the reference range (ie, <45%), implement a maintenance program either by inducing iron deficiency by continuous phlebotomies (frequency of the procedure depends on the rate of reaccumulation of the red blood cells) or using a myelosuppressive agent. The choice depends on the risks of secondary leukemias and the rate of thrombosis or bleeding. Patients must be cautioned to not take iron supplements.
- The risks for secondary leukemia depend on the type of therapy (eg, phlebotomy, radioactive phosphorus-32 [32 P], chlorambucil) or the type of myelosuppressive agents (eg, hydroxyurea [HU], anagrelide, interferon alfa) and duration of therapy.
- The PVSG demonstrated a decreased survival rate and increased mortality rate from acute leukemia in the first 5 years, and a total of 17% of patients had leukemia after 15 years with chlorambucil and with32 P.10 An increased incidence of thrombotic complications occurred in the phlebotomy arm. This indicates that phlebotomy is not ideal for patients with elevated platelet counts and previous thrombosis, as are observed in patients who are older. In this situation, using HU has decreased these complications.
- Hydroxyurea has been the mainstay therapy for polycythemia vera (PV) after the PVSG results indicated it is an effective agent for myelosuppression; however, concerns have been raised regarding long-term risks for leukemic transformation.11 In the PVSG trial, HU therapy reduced the risk of thrombosis compared with phlebotomy alone and should be the drug of choice for patients older than 40 years.12
- The role of HU in leukemic transformation is not clear, but several nonrandomized studies have supported or refuted a significant rise in leukemic conversion with the long-term use of HU in persons with ET (from 0% to 5.5%) and in persons with polycythemia vera (PV) (from 2.1% to 10%).
- The PVSG closed the chlorambucil arm because of increased rates of acute leukemia after 7 years. However, in the 15-year follow-up of the HU arm compared with the phlebotomy-alone arm, the trend for leukemic transformation was greater in the HU arm but the differences did not meet statistical significance. PVSG data after a follow-up examination of a median of 8.6 years and a maximum of 795 weeks showed that 5.4% of patients developed leukemia in the HU arm compared with 1.5% of patients treated with phlebotomy alone.
- Other case series have reported secondary leukemia in 3-4% of patients, which is relatively low compared with the benefits of preventing thrombotic complications.
- Anagrelide (Agrylin) is a cyclic adenosine monophosphate phosphodiesterase inhibitor that prevents platelet aggregation and inhibits megakaryocyte maturation, thereby decreasing platelet counts. The total response rate for controlling platelet counts with anagrelide is greater than 70% in patients with MPDs (ie, PV, ET). Acute side effects include headaches, palpitations, and fluid retention.
- The most frequent adverse effect was headache (44%), followed by palpitation (26%) and diarrhea (26%) due to lactose deficiency and intolerance.13 Approximately 17% of patients withdrew from therapy because of intolerance or adverse effects.13
- Long-term treatment with anagrelide in 3660 patients with polycythemia vera (PV) or ET, with a maximum follow-up of 7 years, was efficacious and safe with respect to leukemic transformation.14,15 To date, this agent does not appear to increase the risk of acute leukemia in patients with PV and ET over time.
- Interferon alfa has been demonstrated in small anecdotal studies to possibly be useful in patients who have relapsed or progressed into AMM or large hepatosplenomegaly. However, only low doses are tolerated and significant adverse effects from long-term use may limit its usefulness.16
- Do not administer alkylating agents to younger patients (<40 y) who need long-term treatment. Alternative nonleukemogenic agents are needed for these patients.
- Although HU has been considered safe for long-term maintenance, a study assessed the use of low doses of aspirin (40 mg/d). Therapy with low-dose aspirin in patients with thrombocytosis suppresses thromboxane biosynthesis by platelets, which is increased in polycythemia vera (PV) and ET.
- The Italian study, European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP), found aspirin efficacious for preventing thrombosis and controlling microvascular painful symptoms (erythromelalgia), which result from spontaneous platelet aggregation, in patients with polycythemia vera (PV) and ET without a bleeding diathesis.17
Surgical Care
Consider splenectomy in patients with painful splenomegaly or repeated episodes of thrombosis causing splenic infarction.
- Budd-Chiari syndrome occurs in patients with MPD and most frequently in young women. Surgical approaches to the management of Budd-Chiari syndrome are, therefore, relevant to patients with MPD.18
- Budd-Chiari syndrome is a liver-related condition associated with large vessel thromboses and outflow obstruction with inferior vena cava or portal vein thrombosis. This is associated with the development of ascites, hepatosplenomegaly, abdominal pain, and GI bleeding, but 20% of patients are asymptomatic.
- The diagnosis is made by using ultrasonography to identify portal vein patency. In addition to the standard CT scan and MRI, patients with Budd-Chiari syndrome may need invasive angiographic imaging to determine the hemodynamics of the liver and the intrahepatic and vena caval gradients to determine the best surgical procedure. The histology of the liver helps determine the acuteness of the problem, the presence of chronic changes, and the degree of cirrhosis. This determines if a patient requires a shunt or a liver transplant.
- The following procedures have been used in patients with Budd-Chiari syndrome:
- Transjugular intrahepatic portosystemic shunt (TIPS)
- Side-to-side portocaval shunt or mesocaval shunt, portocaval/cavoatrial shunt, or mesoatrial shunt.
- These procedures have been reported to be successful in 38-100% of patients, with follow-up ranging from 9-98 months.
Consultations
A consultation with a hematologist is recommended in cases of polycythemia vera (PV) because experience in long-term follow-up care of these patients and managing complications of the disease and their treatment can be difficult.
Medication
Another objective of therapy is to control the myeloproliferative activity of PV. Evidence of an increase in white blood cells and/or platelets and organomegaly indicate uncontrolled myeloproliferative activity that requires a myelosuppressive agent. Studies by the PVSG have led to the abandonment of long-term therapy with32 P and most alkylating agents (eg, busulfan, chlorambucil), and the use HU instead. However, long-term data seem to indicate a possible slight late increase in cases of acute leukemia in patients with PV who are treated with HU for more than 15 years.
Antimetabolites
HU is a nonalkylating agent that inhibits DNA synthesis and cell replication by blocking the enzyme ribonucleoside diphosphate reductase.
Hydroxyurea (Droxia, Hydrea)
Inhibitor of deoxynucleotide synthesis and DOC for inducing hematologic remission in CML. Less leukemogenic than alkylating agents such as busulfan, melphalan, or chlorambucil. Myelosuppressive effects last a few days to a week and are easier to control than those of alkylating agents; busulfan has prolonged marrow suppression and can cause pulmonary fibrosis. Can be administered at higher doses in patients with extremely high WBC counts (>300,000/µL) and adjusted accordingly as counts fall and platelet counts drop. Dose can be administered as a single daily dose or divided into 2-3 doses at higher dose ranges. Droxia, available in smaller tabs of 200, 300, and 400 mg, is for patients with sickle cell disease.
Adult
Initial: 1-2 g/d (500-mg tab), CBC count q2wk, adjust accordingly to maintain at normal
Maintenance: 20-30 mg/kg PO qd (usual total maintenance dose in adults is 500-1000 mg/d)
Pediatric
Not established
Coadministration with fluorouracil can increase neurotoxicity.
Documented hypersensitivity; severe anemia or bone marrow suppression
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Continuous surveillance is necessary in long-term management; experienced hematologists should monitor patients on maintenance therapy, because fine dose adjustments are often necessary; after maintenance dose is determined, decrease follow-up care to q2-3mo, depending on efficacy of control; late dose adjustments are often necessary as the disease changes into spent phase; most common adverse reaction is myelosuppression (dose related); effects last approximately 1-2 wk; unusual reactions include febrile reaction; long-term effects include nail color changes and skin ulcers
Imidazole Quinazolines
Imidazole quinazolines have been demonstrated to have powerful anti-aggregating effects on platelets and to cause thrombocytopenia.
Anagrelide hydrochloride (Agrylin)
Primary activity is to lower platelet levels but shows slight decrease in mean hemoglobin and hematocrit while WBC counts maintained. Effective in polycythemia vera with elevated platelet counts. Adjust dosage to lowest effective dose to reduce and maintain platelet counts, WBC count, and hemoglobin levels within reference range.
Adult
0.5 mg PO qid or 1 mg PO bid for 7 d
Pediatric
Not established
Sucralfate may decrease absorption
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in patients with possible heart disease, reduced renal function, or hepatic dysfunction; thrombocytopenia appears to be main dose-limiting adverse effect; adverse effects include headaches (27%), fluid retention (20%), diarrhea (lactose intolerance) (20%), nausea (19%), cardiac arrhythmias (generally atrial) (approximately 15-20%), abdominal pain (18%), and dizziness (11%); rare life-threatening adverse effects are CHF and pulmonary effusion
Interferons
Recombinant interferon alfa is a biologic response modifier with myelosuppressive activity.
Recombinant alfa-2a (Roferon) or alfa-2b (Intron) interferon
Protein product manufactured by recombinant DNA technology. Can lower counts and shrink enlarged spleens.
Adult
1.5-3 million U SC 3 times/wk
Pediatric
Not established
Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Documented hypersensitivity; low platelet and WBC counts
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in patients with brain metastases, severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, or compromised CNS; adverse effects include acute phase with flulike symptoms; long-term effects include chronic fatigue, liver function abnormalities, and occasional neurologic or psychotic reactions
More on Polycythemia Vera |
| Overview: Polycythemia Vera |
| Differential Diagnoses & Workup: Polycythemia Vera |
 Treatment & Medication: Polycythemia Vera |
| Follow-up: Polycythemia Vera |
| Multimedia: Polycythemia Vera |
| References |
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References
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Further Reading
Keywords
polycythemia vera, PV, myeloproliferative disorder, myeloproliferative disease, MPD, erythremia, plethora vera, primary polycythemia, stem cell disorders, bone marrow disorder, red cell hyperproliferation, increased red blood cells, blood hyperviscosity, impaired microcirculation, leukemia, red blood cell hyperproliferation, bone marrow cancer, bone marrow neoplasm, marrow neoplasm, bone marrow malignancy,
neoplastic marrow disorder, panhyperplastic marrow disorder, pan-hyperplastic marrow disorder, malignant marrow disorder, unregulated neoplastic proliferation, Budd-Chiari syndrome, hepatic portal vein thrombosis, mesenteric vein thrombosis, uncontrolled red blood cell production, panmyelosis, hyperhomocystinemia, acquired von Willebrand syndrome, von Willebrand factor,
headache, dizziness, vertigo, tinnitus, angina pectoris, intermittent claudications, epistaxis, gum bleeding, ecchymoses, GI bleeding, venous thrombosis, thromboembolism, stroke, arterial thromboses, splenomegaly
splenic infarction, hepatomegaly, plethora, ruddy complexion, hypertension, deletion of 20q, deletion of 13q, trisomy 8 , trisomy 9, trisomy of 1q, deletion of 5q, monosomy 5, deletion of 7q, monosomy 7, Janus kinase-2,
