Page 1252 - Hematology_ Basic Principles and Practice ( PDFDrive )

1098 Part VII Hematologic Malignancies

TABLE Risk Stratification in Polycythemia Vera Based on alkylating agents is associated with an established risk for leukemic
68.4 Thrombotic Risk transformation or evolution to MDS. Clearly, this risk is also associ-
ated with increased duration of the disease. The effect of hydroxyurea
Age >60 Years or Cardiovascular on leukemic transformation rates is limited, if any. In addition, the
Risk Category History of Thrombosis Risk Factors a influence of long-term IFN therapy on disease outcomes is not at
Low No No present clearly defined.
Intermediate No Yes
High Yes THERAPY
a Hypertension, hypercholesterolemia, diabetes, and smoking (see text). Extreme
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thrombocytosis (platelet count >1500 × 10 L ) is a risk factor for bleeding. Its The cumulative duration of survival for PV patients treated with
−1
role as a risk factor for thrombosis is uncertain. An increasing leukocyte count modern strategies is between 15 and 17 years. Despite the implemen-
has been identified as a novel risk factor for thrombosis, but confirmation is
required. tation of standard therapeutic strategies, the mortality rate of PV
Data from Finazzi G, Barbui T: How I treat patients with polycythemia vera. patients is increased by 1.84 compared with age- and sex-matched
Blood 109:5104, 2007. populations. The primary goals of treatment are to reduce the risk
for thrombosis, ameliorate the PV symptom burden, and prevent
evolution to MF and/or AML. Unfortunately, current therapies are
meaningful results can be generated determining their ability to not effective for this latter purpose, and controlling blood counts may
improve upon overall survival. have less of an effect than anticipated. The European Leukemia Net
Increasing age and history of vascular events have consistently (ELN) expert panel defined a complete response as a hematocrit less
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proven to be independent predictors of developing additional throm- than 45% without phlebotomy, platelet count less than 400 × 10 /L,
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boses in patients with PV. In the ECLAP trial, the incidence of car- leukocyte count less than 10 × 10 /L, normal spleen size, and no
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diovascular complications was higher in patients older than 69 years disease-related symptoms. However, in a study of 261 patients with
of age, patients with a history of thrombosis, and patients with WBC PV who were given hydroxyurea (HU) and followed up for a median
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counts higher than 15,000 × 10 L . Conventional cardiovascular of 4.4 years, no association was observed between achieving an ELN
risk factors, including hypertension, hyperlipidemia, diabetes, and or a hematocrit response and better survival or fewer vascular com-
smoking, are assumed to be associated with the same relative risk of plications. No particular platelet or leukocyte count could be shown
developing thrombosis in PV patients as that observed in the general to be protective against thrombosis. The ELN response criteria were
population. Although practicing hematologists are frequently con- updated in 2013, but they have not been validated to predict survival
cerned about elevated platelet counts in PV patients, several reports or progression to MF or AML. Therapy is also stratified based on the
have failed to show any association between platelet count and presumed risk of an individual patient to develop additional throm-
thrombotic events, suggesting that therapies in PV targeting reduc- botic episodes, with low-risk patients being treated with phlebotomy
tion of platelet numbers are ill conceived. therapy alone plus a therapy directed toward paralysis of platelet
These data have led to stratification of therapy in patients with function and high-risk patients receiving not only phlebotomy plus
PV based on clearly identifiable risk factors (Table 68.4) of develop- antiplatelet therapy but also some form of myelosuppressive therapy
ing additional thrombotic events. The development of acute leukemia (hydroxyurea, IFN, busulfan, melphalan, ruxolitinib). At present, the
was a relatively rare event in PV, occurring in 22 out of 1638 patients therapeutic goals are to reduce the risk of thrombosis by normalizing
in the ECLAP observational study after a median of 8.4 years from the hematocrit levels to 45% (some experts advocate reducing the
the time of diagnosis. Older age as well as treatment with alkylating hematocrit to 42% in females) based on a randomized prospective
agents was associated with a four- to eightfold increased risk of study that demonstrated a decreased risk of cardiovascular morbidity
developing AML or MDS compared with patients treated with and mortality with a goal hematocrit of less than 45% compared to
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phlebotomy alone, hydroxyurea, or IFN. The effect of JAK2V617F 45–50%. Previous studies have indicated a lack of a relationship
allele frequency on the prognosis of PV patients has been examined. between thrombocytosis at diagnosis or during the period of follow-
More than 95% of patients with PV are JAK2V617F positive, and up with thrombotic complications. Whether therapy should be
their mutational load can be determined by allele-specific PCR. directed at normalization of platelets remains uncertain at present
Approximately 30% of PV patients have a high JAK2V617F burden and should not be pursued unless within the context of a clinical trial.
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(>50%), and the remainder have a lower burden (<50%), with the Extreme thrombocytosis (>1 × 10 /L), if associated with spontaneous
small numbers being WT. Some investigators, but not all, have hemorrhage, is an indication for normalization of platelet numbers.
reported that high burdens of JAK2V617F in PV patients are associ- Phlebotomy therapy alone is the standard of care for low-risk PV
ated with larger splenic volumes, more frequent aquagenic pruritus, patients (see box on General Principles of Therapy).
a higher incidence of thrombotic events, and a higher rate of evolu- A series of studies, although completed more than 30 years ago,
tion into MF and acute leukemia. by the Polycythemia Vera Study Group answered several very impor-
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High leukocyte counts (>15,000 × 10 /L) at the time of diagnosis tant questions regarding the efficacy and associated complications of
have been identified as another independent predictor of developing particular therapeutic modalities. These investigations have aided in
a major thrombosis in PV patients. In addition, others have suggested the identification of optimal therapy for individual patients, which
that this parameter is predictive of evolution to MF and AML and must be selected on the basis of age and comorbid disease status to
an overall inferior survival time. minimize treatment-related complications.
In a study of more than 1500 patients with PV, risk factors for The first PVSG randomized trial (01 trial) evaluated three treat-
survival included advanced age, leukocytosis, venous thrombosis, and ment strategies: (1) phlebotomy alone to maintain the hematocrit
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2
abnormal karyotype. Median survival was 23 years in the absence of level at less than 45%; (2) intravenous P at 2.3 mCi/m repeated
advanced age and leukocytosis, and 9 years with the presence of both every 12 weeks, if needed (maximum, 5 mCi per dose) supplemented
of these risk factors. In another study of 327 patients with PV from by phlebotomy to maintain the hematocrit level at less than 45%;
France and Sweden, multivariable analysis identified age >70 years, and (3) myelosuppression with chlorambucil 10 mg/day orally for 6
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leukocyte count >13 × 10 /L, and thrombosis at diagnosis as risk weeks and then daily on alternate months with necessary dose reduc-
factors for survival. Patients with two or more of these risk factors tions and supplemental phlebotomy. More than 400 patients were
had a 10-year relative survival of 26%, as opposed to patients with randomly assigned to this protocol. The median survival duration
zero or one risk factors, who had a 10-year survival of 84% and 59%, from entry into the study until death was 9.1 years for patients treated
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respectively. with chlorambucil, 10.9 years for those treated with P, and 12.6
The choice of therapeutic agents used to treat the erythrocytotic years for the phlebotomy group. Long-term survival was inferior for
phase of disease clearly influences patient outcomes. The use of patients treated with chlorambucil compared with those treated with