Page 1272 - Hematology_ Basic Principles and Practice ( PDFDrive )

1118 Part VII Hematologic Malignancies

identified based on retrospective analyses of registries of ET patients of the increased platelet numbers to the normal range with use of a
that have largely not been created using modern molecular and variety of agents, including hydroxyurea, anagrelide, or IFN-α.
histopathologic diagnostic tools. Using such patient-stratification According to some authors, such patients should avoid exposure to
strategies, patients have been placed into high-, intermediate-, or aspirin even if they have hemorrhagic complications and thrombotic
low-risk groups based on their predicted risk of developing an addi- episodes simultaneously.
tional life-threatening thrombotic event. This strategy is uniformly Another situation that requires treatment is discomfort caused by
implemented throughout Europe and North America. The benefit erythromelalgia or progression of erythromelalgia to frank gangrene.
of this strategy is based on a single clinical trial that indicated that Such patients respond within days to low-dose aspirin therapy or
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the reduction of platelet numbers to less than 600 × 10 /L with platelet-reduction therapy.
hydroxyurea therapy was associated with a reduction of developing During the 1980s and 1990s, hydroxyurea became the drug of
additional thrombotic events compared with a control group (see Fig. choice for the treatment of ET. The impetus for this practice was
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69.2). This study involved a total of 114 patients, and the median based on the knowledge that agents such as P and alkylating agents
follow-up period was only 27 months. Greater degrees of platelet such as melphalan and busulfan were leukemogenic. The popularity
suppression have not been shown to be associated with further reduc- of the ribonucleoside reductase inhibitor, hydroxyurea, for the man-
tion in the possibility of developing a thrombotic episode, which in agement of ET was due to the belief in the early 1970s that it was
hydroxyurea-treated high-risk patients has been reported to be 1.66% nonleukemogenic. Hydroxyurea can be administered at a dose of
patients per year. Although the implementation of such a strategy is 15 mg/kg initially, with adjustment of the dose to maintain a platelet
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widely accepted, it is important to be aware that this approach is not count (at the least) below 600 × 10 /L without inducing significant
based on robust data that one associates with modern-day evidence- neutropenia. After the agent is started, frequent monitoring of blood
based medicine. In fact, in several studies, an elevated leukocyte count counts is mandatory to avoid the development of neutropenia until
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of above 11 × 10 /L has been more closely associated with the risk the maintenance dose is determined. The use of this drug in a high-
of developing additional thromboses than the degree of elevation of risk group of patients with reduction of platelet numbers to less than
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the platelet count. These conflicting reports in the literature among 600 × 10 /L has resulted in reduction of thrombotic events compared
experts in this field make it increasingly more difficult to be dogmatic with a control population. The reduction of platelet numbers to this
about who to treat with platelet-lowering agents and what the target level did not entirely eliminate the occurrence of additional throm-
platelet count should be. The risk stratification of patients should botic episodes.
not be ignored, and patients with a life-threatening thrombosis or Hydroxyurea use is associated with some toxicity, including dose-
disabling symptoms because of microcirculatory problems should related neutropenia, fever, nausea, stomatitis, hair loss, nail discolor-
receive drugs that lower the platelet count. If a patient of any age ation, and lower extremity and oral ulcerations, as well as increased
has excessive thrombocytosis and a thrombotic or hemorrhagic event, risk of developing squamous cell carcinoma of the skin. Many of these
that patient must be treated. However, for asymptomatic ET patients problems resolve with withdrawal of the drug or dose reduction, but
in so-called high-risk categories, the decision to embark upon a strategy leg ulcers can be persistent, sometimes requiring skin grafting. These
including platelet-lowering agents is in reality a murky one that is ulcers typically heal within 1–9 months of cessation of therapy. Such
more based on personal treatment decisions rather than volumes leg ulcers have been reported to occur in 9% of patients treated with
of data. hydroxyurea and are an indication for immediate discontinuation of
The treatment of asymptomatic low-risk patients with ET is therapy and elimination of any rechallenge with the drug. Hydroxy-
controversial and remains largely problematic, yet greater insight into urea is also not universally successful in controlling the thrombocy-
the management of such patients has recently been gained. Manage- tosis; resistance to hydroxyurea has been reported in 11–17% of cases.
ment of ET patients with life-threatening hemorrhagic or thrombotic The criteria for defining resistance or intolerance to hydroxyurea have
episodes is more straightforward. Life-threatening thrombotic events been established by an International Working Group. They include
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require platelet pheresis in combination with the institution of a platelet count greater than 600 × 10 /L after 3 months of at least
myelosuppressive therapy. In this situation, immediate physical 2 g/day of hydroxyurea (2.5 g/day in patients with a body weight
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removal of large numbers of platelets is preferred because chemo- >80 kg); platelet count greater than 400 × 10 /L and WBC less
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therapeutic agents generally require 18–20 days before platelet counts than 2500/mm or hemoglobin less than 10 g/dL at any dose of
can be reduced to normal levels. It is recommended to reduce the hydroxyurea; presence of leg ulcers or other unacceptable mucocuta-
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platelet count to 500,000/mm by each platelet pheresis and sug- neous manifestations at any dose of hydroxyurea; and hydroxyurea-
gested that achievement of such a goal requires the passage of two related fever. In such situations, hydroxyurea can be substituted for
blood volumes over a 3–4-hour period. (or combined with) other platelet-lowering agents. These criteria for
Such a therapeutic approach has been used to treat acutely ill hydroxyurea resistance are imperfect because they do not include the
patients with problems such as cerebrovascular accidents, myocardial development of a thrombotic event while on therapy, which is the
infarction, transient ischemic attacks, or life-threatening gastro- central goal of therapy. Whether such patients who develop a new
intestinal hemorrhage. Long-term platelet pheresis is an ineffective thrombosis would benefit from use of another therapeutic agent has
means of controlling thrombocytosis, presumably because of the not been explored.
rapid rate of production of platelets. Therefore, most clinicians begin The risk of evolving to acute leukemia is extremely low in
by administering a chemotherapeutic agent that has a rapid onset of untreated ET patients. More recent prospective studies both in ET
action, such as hydroxyurea at doses of 2–4 g/day, simultaneously and PV have confirmed that hydroxyurea therapy is associated with
with the institution of platelet pheresis. The dose of hydroxyurea a low incidence of leukemic transformation when used alone (<5%)
requires close monitoring with appropriate reduction of dose to avoid and with long-term follow-up (≤14 years). However, the leukemic
excessive myelosuppression. risk increased significantly when the drug is used before or after
In patients found to have ET and who are clearly symptomatic treatment with alkylating agents, particularly busulfan. One can
and fall into the high-risk group, little controversy exists as to the conclude from these studies that hydroxyurea therapy alone is less
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need for lowering platelet numbers. The large number of thrombotic leukemogenic than alkylating agents or P alone, but a small increased
complications that occur in patients with ET who smoke points to risk for the development of leukemia secondary to its use cannot be
the urgent need for smoking cessation. Most investigators try to completely excluded. Of concern is the observation that a high
normalize the platelet count or reach a platelet count at which the proportion of AML and MDS occurring in ET patients treated with
symptoms of the high-risk patient resolve. Although major bleeding hydroxyurea alone have morphologic, cytogenetic, and molecular
episodes requiring hospitalizations are rare, patients with extreme characteristics of the 17p deletion syndrome. These patients are
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thrombocytosis (>1500 × 10 /L), acquired von Willebrand syndrome, reported to have a typical form of dysgranulopoiesis characterized by
and history of hemorrhagic episode are clearly at risk for developing hypolobulated polymorphonuclear leukocytes with small vacuoles in
additional bleeding complications. These patients require reduction neutrophils and p53 mutations.