Page 1246 - Hematology_ Basic Principles and Practice ( PDFDrive )

1092 Part VII Hematologic Malignancies

(2) teardrop RBC morphology; (3) extensive BM fibrosis; (4) a leu- patients treated with chlorambucil from years 2 to 7 after randomiza-
koerythroblastic blood picture, systemic symptoms including fatigue, tion; however, the risk for acute leukemia became alarmingly high
weight loss, night sweats, bone pain, and fevers; and (5) anemia and after 10 years of study, suggesting that the risk of acute leukemia
or thrombocytopenia. The patients may be entirely asymptomatic but increases with time even after the drug has been stopped. One half
often complain of fatigue, dizziness, weight loss, and anorexia. of the cases of acute leukemia in the chlorambucil arm occurred
Splenomegaly can lead to abdominal pain caused by repeated splenic during the first 5 years, with the remainder equally split between
infarcts and to early satiety caused by mechanical obstruction of the the second and third 5-year periods. In contrast, 60% of the cases
upper gastrointestinal tract. Patients with post-PV MF are virtually of acute leukemia in the group treated with radioactive phosphorus
all JAK2V617F positive and characteristically have high JAK2V617F occurred 6–10 years after randomization. Of particular concern is
allele burdens. the high incidence of leukemia recently reported in patients who
The anemia that characterizes post-PV MF is primarily a result of were initially treated with radioactive phosphorous or busulphan and
splenic pooling, ineffective erythropoiesis, hemolysis, and extramed- then switched to maintenance therapy with hydroxyurea, previously
ullary production of RBCs with a shortened RBC survival. Patients believed to be a nonleukemogenic agent. These findings suggest that
positive for JAK2V617F are less likely to require blood transfusions a combination of an alkylating agent, busulphan, piprobroman, or
but have a poorer survival. Occasionally, the anemia is exacerbated by melphalan, and another chemotherapeutic agent (hydroxyurea) may
folate or iron deficiency. Before assuming that a patient has entered particularly increase the risk of leukemia. Approximately 30–50%
post-PV MF, it is prudent to assess BM iron stores. Replacement of patients with PV who develop acute leukemia have previously
therapy with iron may lead to the resurgence of erythropoiesis and entered the post-PV MF phase. In contrast, approximately 50%
prevent the faulty categorization of disease progression. of patients progress directly from the erythrocytotic phase to acute
Bleeding abnormalities caused by thrombocytopenia or qualitative leukemia. The phenotype of the leukemia cells that characterize
platelet abnormalities are especially common during this phase of the leukemic phase is overwhelmingly myeloid, although rare cases
the disease. Frequent instances of epistaxis or ecchymoses occur, of lymphoblastic and biphenotypic leukemias have been reported.
and gastrointestinal hemorrhage caused by esophageal varices arising Patients with JAK2V617F-positive MPN are also at a higher risk
from portal hypertension is a recurrent problem. The majority of of developing both additional hematologic malignancies and solid
hemorrhagic events are minor in nature. Frequently, patients have tumors. The SNPs for TERT, which is a susceptibility factor for
generalized wasting characterized by progressive asthenia and weight familial and sporadic MPNS, have also been shown to be associated
loss. Severe hyperuricemia, leading to secondary gout or uric acid with a variety of solid tumors. The presence of this SNP predis-
nephropathy, may also complicate the clinical course. poses to the development of MPNS and the cooccurrence of solid
The median survival for patients with post-PV MF is 5.7 years. tumors, especially in patients receiving cytoreductive therapy. Some
Patients with post-PV MF are at a high risk for the development of investigators have suggested that prolonged cytoreductive therapy
acute leukemia. Of patients who develop post-PV MF, approximately be avoided in patients with the TERT polymorphism. In addition,
18% will undergo leukemic transformation after 3 years and likely a low-grade lymphoproliferative disorders such as chronic lymphocytic
greater number with longer follow-up. leukemia and MGUS have been shown to coexist in patients with a
The leukemic transformation of PV has been extensively described. variety of MPNs, including PV, and not to have an adverse effect on
The possibility, that a relationship exists between the therapeutic prognosis.
modality used during the erythrocytotic phase and the frequency of In some instances, a preleukemic phase characterized by refractory
development of acute leukemia, has been a point of heated discussion. anemia with excess blasts has been described. In fact, half of such cases
Some of the controversy surrounding this question was formerly of acute leukemia in one series were preceded by a myelodysplastic
caused by a lack of understanding of the basic origins of PV. Clinical disorder.
hematologists in the 1950s and 1960s frequently thought of PV
as a benign hematologic abnormality and believed that therapeutic
interventions either with alkylating agents or radiotherapy were solely LABORATORY MANIFESTATIONS
responsible for the development of acute leukemia. That concept
has proved erroneous, and PV, similar to the other MPNs, has been Laboratory evaluation of patients with erythrocytosis involves the
shown to be a clonal malignant hematologic disorder. The evolution careful use of a broad range of diagnostic studies. These studies
to acute leukemia can therefore be thought of as a natural conse- must be used in a rational manner or the evaluation can become
quence of this malignant disorder, which can be accentuated by the extremely costly. Because PV is a panmyelosis, the overwhelming
therapeutic interventions already discussed. In fact, 25% of patients number of patients has elevated hematocrits, WBC counts, and
who develop acute leukemia have never been exposed to any form platelet counts. The diagnosis of PV has been greatly simplified by
of cytotoxic therapy. the discovery of the JAK2V617F mutation, which is present in more
Further insight into the relationship between acute leukemia than 90% of PV patients. Hematocrit values greater than 49% in
and PV has been best provided by the results of the PV Study males and greater than 48% in females are abnormal and require
Group (PVSG), which described a randomized trial comparing the further evaluation. Documentation of the absolute increase in RBC
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use of phlebotomy, chlorambucil, and P for the treatment of this mass is rarely required and is a test that is available at smaller and
disorder. The incidence of acute leukemia was approximately 1.5% smaller numbers of institutions. A hematocrit value greater than 60%
in patients treated with phlebotomy alone, 17.5% in patients treated in men or greater than 55% in women is almost always associated
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with chlorambucil, and 10.9% in patients treated with P after with an absolute erythrocytosis. Occasionally, an elevated RBC mass
over 15 years of follow-up. The incidence of acute leukemia in the can actually be present in the face of a normal hematocrit value. In
patients treated with phlebotomy alone is therefore much higher cases of splenomegaly caused by portal hypertension, an expanded
than that expected in a normal age-matched control group, again plasma volume may mask an elevated RBC mass. In addition, iron
indicating that leukemia is a natural evolutionary event in the clinical deficiency can also lead to a normalization of the hematocrit in PV,
course of an individual with PV. The incidence of acute leukemia making the diagnosis difficult. PV is associated with a 20–30%
can be increased, however, by the institution of therapy with either frequency of peptic ulcers and gastritis, which can be associated
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alkylating agents or P. The time course for the development of with blood loss. In this situation, thrombocytosis may be exacer-
acute leukemia appears to be dependent on the treatment used to bated as a consequence of the iron deficiency. Iron supplementa-
control the polycythemia. The development of acute leukemia in tion is not necessary to make a diagnosis of an MPN because of
patients treated with phlebotomy in the PVSG trial was limited to the the availability of molecular diagnostic studies. Administration of
first 5 years of treatment, suggesting that the development of acute iron to such patients must be performed carefully to avoid a rapid
leukemia is not solely attributable to the prolongation of survival. increase in RBC mass, which can be associated with a high risk of
In contrast, analysis of the hazard function was virtually flat for thrombosis.