Page 1136 - Hematology_ Basic Principles and Practice ( PDFDrive )

1002 Part VII Hematologic Malignancies

Clinical Manifestations efficacy of very low doses of cytosine arabinoside is being tested in
prospective clinical trials. Several additional questions related to the
Patients with Down syndrome typically present with TAM within 3 treatment of infants with TAM are also the subject of ongoing clinical
months after birth, although TAM can be manifest at birth. Some of trials. Among these is the identification of high-, intermediate-, and
these children present with hydrops fetalis secondary to anemia and low-risk populations, with treatment stratified on the basis of risk
cardiac dysfunction. Although some patients may be asymptomatic, group and a determination of whether treatment with very low-dose
others can have myeloblast infiltration of the heart, liver, and spleen cytosine arabinoside will prevent progression of TAM to ML-DS and
that can result in hepatosplenomegaly; hepatic fibrosis; pleural, hepatic fibrosis.
pericardial, and peritoneal effusions; and disseminated intravascular
coagulopathy. In some cases, organ dysfunction can be severe, with
failure of the liver, heart, kidneys, and lungs. In the COG’s recently Prognosis
published prospective study, death occurred in 21% of patients,
although only 10% died as a result of TAM-associated problems. 207 Recent data from the COG reporting the results of the POG-9481
prospective clinical trial offer insights into the natural history of TAM
229
and the identification of prognostic factors. This study followed 48
Laboratory Manifestations children with TAM. Eighty-nine percent of infants achieved a spon-
taneous remission, 74% had a normalization of peripheral blood
The complete blood count in infants with TAM typically demon- counts, and 64% maintained a clinical remission. Seventeen percent
strates an elevated white blood cell count with myeloblasts present of infants had an early death. Factors associated with early death
(see Fig. 63.6). The percentage of circulating myeloblasts exceeds the included a high white blood cell count (p < .001), increased bilirubin
percentage of BM myeloblasts. Rarely, a neonate without stigmata of and liver function test values (p < .005), and a failure to normalize
Down syndrome will present with similar features—in these cases, blood counts (p < .001). Nineteen percent of patients had a progres-
workup for either trisomy 21 mosaicism or a PTPN11 mutation sion to ML-DS at a median of 20 months. The greatest risk factor
should be pursued. Flow cytometric analysis of the myeloblasts from for progression to leukemia was the presence of karyotypic abnor-
TAM patients and ML-DS associated with Down syndrome show malities in addition to trisomy 21 in blasts cells.
many similarities between these disorders as well as patterns of cell The COG’s more recent A2971 study identified three groups of
surface antigen expression that is distinct from other types of AML children with different outcomes based on the presence or absence
226
207
in children. Specifically, all TAM and ML-DS blasts express CD45, of hepatomegaly and life-threatening symptoms. Children with
CD38, and CD33, but the majority of cases express CD36 and neither hepatomegaly nor life-threatening symptoms were at low risk
CD34. CD41 and CD61 also are expressed, consistent with mega- of death (overall survival [OS], 92%); children with hepatomegaly
karyocyte differentiation. CD14 and CD64 are usually negative. alone had an intermediate risk of death (OS, 77%), and children with
Most cases have aberrant expression of CD7, a T-lineage antigen. both hepatomegaly and life-threatening symptoms were at high risk
of death (OS, 51%).
Therapy
OTHER MYELOPROLIFERATIVE NEOPLASMS
The treatment of infants with TAM is generally supportive. Patients
without significant organ dysfunction can be followed closely without Essential Thrombocythemia
medical intervention. In the COG’s prospective study, peripheral
blood blasts and TAM-associated symptoms resolved in 36 and 49 ET has an estimated incidence of 1–1.25 cases per million in adults
207
days, respectively, for observation patients. In infants with signifi- but is even rarer in children, with an estimated incidence of 0.09
cant organ impairment, a number of therapeutic approaches aimed cases per million. 230–234 ET is a genetically heterogeneous disease.
at reducing the burden of myeloblasts are routinely used, including Mutations in JAK2 have been reported in adults with BCR-ABL–nega-
exchange transfusion, leukophoresis, and chemotherapy. According tive MPNs, including ET, PV, and idiopathic myelofibrosis (IM). It
to reports using cytosine arabinoside in children with Down syn- has been proposed that ET consists of several subtypes, with some
drome and ML-DS, 227,228 cytosine arabinoside is the chemotherapeu- children and adults having monoclonal disease but others having
tic agent now most commonly used in infants with TAM. The polyclonal disease. Further investigation into the mutational status of
JAK2 V617F also demonstrates mutation-positive (roughly 55%) and
mutation-negative patients. 231,235 Another cause of ET was recently
236
demonstrated to be mutations in CALR (calreticulin). Studies
suggest that a similar proportion of children and adults with somatic
ET display polycythemia rubra vera-1 (PRV-1) RNA overexpression,
237
JAK2 V617F mutations, and monoclonal disease. Rare cases of
familial ET have been shown to be caused by dominant activating
237
mutations in both c-MPL and in JAK2. 238
Patients with ET have thrombocythemia with an increased
number of megakaryocytes in the BM. Platelet clumps on peripheral
blood smears are common. Some patients have a concomitant increase
in the number of peripheral blood granulocytes. The differential
diagnosis includes familial ET, other forms of MPS, and increased
platelets as a reactive process.
A B C Although the clinical course can be uncomplicated, patients can
develop thromboembolic complications, including deep venous
Fig. 63.6 TRANSIENT ABNORMAL MYELOPOIESIS AND TRAN- thrombosis, and arterial thrombosis such as transient cerebral ische-
SIENT LEUKEMIA OF DOWN SYNDROME. The patient was a prema- mia and peripheral vascular ischemia. The clinical course for children
ture newborn girl with trisomy 21 and a white blood cell count of 195,000/µL is typically less aggressive than in adults, with fewer thrombotic
+
+
+
with 67% blasts (A). The blasts were CD34 , CD33 , and CD117 , and a episodes. 237,239 Adult patients have a median survival of at least 10
portion exhibited CD41, a megakaryocyte marker. Morphologically, some of years, with most deaths caused by thrombosis. 240,241 Progression to
the blasts appeared to be megakaryoblasts (B), sometimes with slight differ- AML has been reported in adult patients, usually those with a prior
entiation toward megakaryocytes (C). exposure to chemotherapy agents.