Page 1253 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 68 The Polycythemias 1099

erythropoiesis. Although iron deficiency can be associated with a
General Principles of Therapy
number of clinical signs and symptoms, including glossitis, dysphagia,
1. The etiology of erythrocytosis must be correctly categorized cheilosis, koilonychia, fatigue, global weakness, cognitive deficits,
to be certain the patient has polycythemia vera (PV). This will neuromuscular disturbances, and pica syndrome, these rarely prompt
32
avoid inappropriate exposure of patients with nonmalignant treatment discontinuation. In contrast, the use of P led to a lower
disorders to the adverse effects of myelosuppresive agents. rate of thrombosis during the first 5 years, but the incidences of
To this end, a major contribution is played by incorporating leukemias, lymphomas, and nonhematologic malignancies increased
molecular marker testing (JAK2V617F and exon 12 JAK2 during the next 5 years to nearly 10%. After a 15-year period of
mutational determinations) in the diagnostic workup, and in this observation, the incidences of leukemia and lymphoma in the chlor-
way, early phases of PV can be recognized as well. In individuals ambucil group had risen to 17%. A statistically significant increase
with erythrocytosis without a JAK2 mutation, search for causes in skin and gastrointestinal cancers occurred in the P- and chloram-
32
of secondary causes of erythrocytocytosis as well as inherited
disorders that lead to erythrocytosis, which includes mutations in bucil-treated cohorts compared with the group treated with phle-
EPOR,VHL, PHD2, HIF-1 and HIF-2. botomy alone (see box on Algorithm for Management of Patients
2. Therapy should be individualized. With Polycythemia Vera). Based on these studies, therapy with
32
3. Initially, the hematocrit should be reduced to 45% as soon as chlorambucil and P are no longer recommended.
possible. The speed of phlebotomy will depend on patients’ Impetus for the use of nonchemotherapeutic agents for the treat-
general medical conditions (250–500 mL every other day). ment of PV was provided by an extensive natural history study of
Elderly patients with compromised cardiovascular or pulmonary 1213 patients reported by the Gruppo Italiano Studio Policitemia.
systems should be more carefully phlebotomized (twice a week), They showed that the age- and gender-standardized mortality rate of
or smaller volumes of blood should be removed. patients with PV was 1.7-times greater than the mortality rate of
4. Hematocrit levels should be maintained at 45%.
5. The use of chemotherapeutic agents should be avoided in control participants in the general Italian population. In addition,
32
low-risk PV patients, and treatment with hydroxyurea or interferon four times as many patients who had previously received P, alkylat-
(IFN) or ruxolitinib should be reserved for high-risk patients. Be ing agents, or hydroxyurea died of cancer compared with patients
on the lookout for toxicities from each of these agents. treated with phlebotomy alone. When this group combined the total
6. Hyperuricemia is treated with allopurinol (100–300 mg/day). number of deaths and the number of nonfatal myocardial infarctions
7. Pruritus may be improved with PV-directed therapy and strokes, they found an unsatisfactory risk-to-benefit profile in
(phlebotomyhydroxyurea or IFN). Empiric therapy with patients treated with chemotherapeutic agents and suggested that
antihistamines can be useful in selected patients. Selective antithrombotic strategies, such as low-dose aspirin, be carefully evalu-
serotonin uptake inhibitors (paroxetine 20 mg/day or fluoxetine ated for use in the care of patients with PV.
10 mg/day) or phototherapy can also be of use. Dramatic relief,
however, can be achieved in almost all cases with the institution PV platelets are known to have a generalized abnormality of
of ruxolitinib. Due to cost, ruxolitinib therapy should be reserved arachidonate metabolism that is characterized by enhanced synthesis
for individuals with pruritis not relieved by less costly strategies. of thromboxane A 2 , which likely reflects stimuli to platelet activation.
8. Elective surgery or dental procedures should be delayed The exact mechanism responsible for enhanced platelet synthesis of
until hematocrit levels have been normalized for more than 2 thromboxane A 2 in PV remains unknown and requires further
months. Aspirin should be withdrawn at least 1 week before investigation. A low-dose aspirin regimen (50 mg/day for 7–14 days)
surgery. If emergency surgery is contemplated, phlebotomy and has been shown to suppress more than 80% of the excretion of the
cytapheresis should be pursued. metabolites of thromboxane A 2 . A pilot study was performed in
9. Women and men who are contemplating having children should which the toxicity of low-dose aspirin therapy in PV patients was
be treated by phlebotomy plus low-dose aspirin therapy (81 mg/
day) or with IFN-α to avoid teratogenic effects of chemotherapy. evaluated. A very low-dose aspirin regimen (40 mg/day) was chosen
Such avoidance will also prevent deleterious effects on fertility. to prevent thrombosis yet minimize the risk of bleeding. After
During pregnancy, therapy is frequently not necessary; if it is, follow-up of the low-dose aspirin treatment group and control group,
phlebotomy plus low-dose aspirin should be exclusively used. If low-dose therapy was shown not to be associated with an increased
phlebotomy control is inadequate, treatment with IFN-α should incidence of bleeding complications. Aspirin therapy was well toler-
be pursued. ated and was associated with complete inhibition of platelet cyclo-
oxygenase activity. A large, randomized, placebo-controlled clinical
trial testing the risk-to-benefit ratio of low-dose aspirin therapy in
preventing thrombotic episodes in PV has been completed. Treat-
32 P or phlebotomy. An early finding was the appearance during the ment with low-dose aspirin (100 mg/day) compared with placebo
first 5 years of a significant excess of deaths from acute leukemia in reduced the risk of the combined end points of nonfatal myocardial
the chlorambucil arm, which reached 17% after 15 years of follow- infarction, nonfatal stroke, pulmonary embolism, major venous
up. As a result, the chlorambucil arm was discontinued, and patients thrombosis, or death from cardiovascular courses. Overall mortality
were assigned randomly to one of the other two arms. Even though and cardiovascular mortality, however, was not reduced significantly
32
no statistical difference in overall survival between P and phlebotomy by aspirin therapy. Importantly, the incidence of major bleeding
alone was apparent through the first 10 years, the morbidity and episodes was not significantly increased in the aspirin group. It is
mortality associated with each type of therapy were attributable to important to emphasize that patients require aggressive phlebotomy
distinctly different causes. Thrombosis as a cause of death was much therapy to the appropriate target hematocrit levels as well as the
more frequent in the phlebotomy-only group during the first 5–7 appropriate use of myelosuppressive agents as primary therapy, with
years of follow-up. Analyses of factors associated with thrombosis the addition of aspirin serving as an adjunct to this strategy. The
revealed that the performance of phlebotomy, the rate of phlebotomy, conclusions of this study have been questioned by several investiga-
advancing age, and history of previous thrombosis were statistically tors. In addition, a retrospective analysis performed by independent
significant factors predictive of this outcome. Historical studies have investigators of the 630 patients treated by the ECLAP group has
raised concerns about therapy with phlebotomy alone. The need for concluded that low-dose aspirin therapy in PV patients was associated
more than four therapeutic phlebotomies a year in the phlebotomy- with a statistically nonsignificant reduction in the risk of fatal throm-
26
alone arm was associated with an increased thrombotic risk. This led botic episodes without an increased risk of bleeding. This meta-
to the belief that frequent phlebotomy requirements were detrimental analysis is surely not a ringing endorsement of the widespread use of
and necessitated cytoreductive therapy. However, overall survival and aspirin therapy, which is a strategy that has been indiscriminately used
risk of evolution to MF and AML were lower in the phlebotomy worldwide to treat such patients. Because it is unlikely that the value
alone arm. Certain concerns about phlebotomy may be unfounded. of aspirin therapy will be examined in a properly powered random-
Iron deficiency is a consequence of repeated therapeutic phlebotomy; ized trial, it is suggested that since aspirin therapy is a relatively
but in fact, it should be viewed as a therapeutic goal to further limit innocuous therapy it should be used in high-risk patients judiciously.