Page 1137 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 63 Myelodysplastic Syndromes and Myeloproliferative Neoplasms in Children 1003

Asymptomatic children do not require treatment. There is no V617F mutations and endogenous erythroid colony growth, 237,278
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clear association with platelet count and thrombotic events. As such that the proposed revision to WHO’s diagnostic criteria, may
such, there is not a clear role for treatment with aspirin, which can be less helpful in the diagnosis of PV in children, although other
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increase the risk of paradoxical bleeding episodes. Risk factors reports suggest that the proposed WHO criteria are equally applicable
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for thrombosis include leukocytosis and presence of a JAK2 V617F to children. The proposed criteria include: (1) a hemoglobin
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mutation. A number of treatment approaches aimed at control- >16.5 g/dL in men or >16.0 g/dL in women; (2) a BM biopsy
ling thrombocytosis have been attempted for symptomatic patients, showing trilineage myeloproliferation and pleomorphic megakaryo-
including hydroxyurea, IFN-α, and anagrelide. 244–246 The JAK inhibi- cytes; and (3) either a JAK2 mutation or a serum erythropoietin level
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tor ruxolitinib may benefit some patients with ET, especially those below the normal reference range. Although the pathogenesis is
with JAK2 V617F mutations, although pediatric-specific data with currently unclear, patients also have abnormalities in tissue factor,
this agent are lacking. The successful use of allogeneic HCT has endogenous anticoagulants mechanisms, hyperhomocysteinemia,
been reported for a number of adult patients with ET, especially after and acquired von Willebrand syndrome.
transformation to myelofibrosis or AML. 247–249 Younger patients, and Children with PV may present with signs and symptoms associ-
those with matched related donors, did especially well, suggesting ated with an increased red blood cell mass such as headache, dizziness,
that allogeneic transplant should be considered in pediatric patients fatigue, pruritus, night sweats, and a ruddy complexion. Mild sple-
with ET. nomegaly may be present, but massive hepatosplenomegaly is rare.
As a result of hyperviscosity of the blood, elevated platelet counts,
and coagulation abnormalities, patients can develop thromboses and
Idiopathic Myelofibrosis CNS ischemia, although the incidence of thrombotic events may be
lower than that reported in adults. 237,278
250
IM is very rarely diagnosed in children and should be differentiated Many different agents have been used to treat patients with PV,
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from acute megakaryocytic leukemia; metastatic neoplasms; and including chlorambucil, melphalan, 6-thioguanine, uracil
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connective tissue, metabolic, and bone diseases. It is characterized by mustard, busulfan, carboquone, anagrelide, imatinib,
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BM fibrosis, megakaryocytes with bizarre morphology, splenomegaly, hydroxyurea, radioactive phosphorous, and IFN. Despite
anemia, and extramedullary hematopoiesis. IM is a clonal disorder, these efforts, the best approach to patients with PV remains unclear.
with approximately half of adult patients having mutations in JAK2 Therefore the British Committee for Standards in Haematology
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V617F. Recent studies have suggested that angiogenic cytokines formulated recommendations for the initial management of PV.
produced by megakaryocytes and monocytes and their receptors Recommendations include phlebotomy to maintain a hematocrit
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(platelet-derived growth factor receptors, vascular endothelial growth level less than 45%; low-dose aspirin unless contraindicated; and
factor receptor-2, and fibroblast growth factor receptor) may be cytoreduction if there is poor tolerance to phlebotomy, symptomatic
involved in the pathogenesis of the myelofibrosis. 252 or progressive splenomegaly, evidence of disease progression, or
Numerous treatment approaches have been attempted with vari- thrombocytosis. For patients younger than 40 years of age, pegylated
able degrees of success. These include splenectomy, splenic radiation, IFN was the recommendation for first-line cytoreduction, with
transfusions, androgens, corticosteroids, hydroxyurea, and IFN- hydroxyurea as second line. However, the JAK inhibitor ruxolitinib
α. 253–255 More recently, based on preliminary studies about the was recently found to have excellent results in controlling the hema-
potential role of angiogenic cytokines and their receptors, newer tocrit and splenomegaly with minimal side-effects in an open-label
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approaches have been tested, including the tyrosine kinase inhibitor phase III trial. This may eventually supplant IFN and hydroxyurea
imatinib 256,257 and the antiangiogenic agent thalidomide. 258,259 Selec- as front-line therapy once pediatric-specific dosing is available.
tive JAK inhibitors have been successfully used in patients with IM Finally, allogeneic transplantation has been successfully used to treat
with a dramatic improvement in the quality of life but without some adult patients, 247–249 especially those with progression to myelo-
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generalized reduction of the JAK2 V617F burden allele. In 2011, fibrosis or AML. Younger patients, and those with matched related
the United States Food and Drug Administration granted approval donors, did especially well, suggesting that allogeneic transplant
to the first of these agents, ruxolitinib, for adults with IM. However, should be considered in pediatric patients with PV.
the safety and efficacy of ruxolitinib in children is still unknown.
Further trials are investigating the combination of JAK inhibition in
combination with other therapeutic modalities, such as PI3K inhibi- FUTURE DIRECTIONS
tion, mammalian target of rapamycin inhibition, histone deacetylase
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inhibition, and antifibrotic agents. Finally, allogeneic transplanta- Although a clearer understanding of the biologic mechanisms under-
tion is the only potentially curative option for IM, with resolution lying MDS in children is slow in coming, dramatic progress has been
of BM fibrosis in donor-engrafted patients but high rates of transplant- made in our understanding of the genetic and biologic mechanisms
related complications. 248,262–265 The survival in children is unknown, contributing to TMD, JMML, PV, ET, and IM. There exists a
with a median survival in adults of 4 years. potential for targeted therapeutics for many of these disorders, with
the first targeted agents now receiving approval for use in adults.
However, the use of these approved agents in children remains
Polycythemia Vera investigational.
Progress for both MDS and MPN in children will require inter-
PV has an incidence of three cases per 100,000 in adults but is very national cooperation. The rarity of these disorders and limitations in
rarely seen in children, with fewer than 0.1% of PV patients diag- resources for pediatric cooperative cancer groups make clinical trials
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nosed before 20 years of age. PV in children is far more often the within each individual cooperative group increasingly difficult.
result of congenital or acquired causes of an increased red blood cell
mass. These include primary familial polycythemia (characterized by
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specific mutations in the erythropoietic receptor gene) and second- SUGGESTED READINGS
ary polycythemias caused by abnormal hemoglobins, cardiac and
pulmonary disease, excessive erythropoietin, and a relative polycythe- Arber DA, Orazi A, Hasserjian R: The 2016 revision to the World Health
mia that is the result of decreased plasma volume. Organization classification of myeloid neoplasms and acute leukemia.
PV in children and adults is associated with clonal hematopoie- Blood 127:2391, 2016.
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sis, JAK2 V617F mutations (in 95% of patients; with mutations Bhatia S, Krailo MD, Chen Z, et al: Therapy-related myelodysplasia and
in JAK2 exon 12 representing 2%–4%), 237,268–273 overexpression of acute myeloid leukemia after Ewing sarcoma and primitive neuroecto-
PVR-1 RNA, 274,275 and endogenous erythroid colony growth. 276,277 In dermal tumor of bone: a report from the Children’s Oncology Group.
contrast to adults, children with PV may be less likely to have JAK2 Blood 109:46, 2007.