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Topics in Pediatric Leukemia -- Myelodysplastic and Myeloproliferative Disorders of Childhood

Posted 3/14/2005
Joseph Lasky, MD; Kathleen M. Sakamoto, MD, PhD

Introduction
The myelodysplastic and myeloproliferative syndromes are rare in childhood, accounting for about 3% of childhood malignancies.[1] They consist of a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis; impaired maturation of hematopoietic cells; progressive cytopenias or erythro-, leuko-, or thrombocytosis; and an increased risk of developing acute myeloid leukemia (AML). Conceptually, it is helpful to consider these syndromes as part of a continuum with the (MDS) on one end and the myeloproliferative syndromes (MPS) on the other, with a group of "bridging" syndromes in between.[2]

The MPS disease most commonly seen in children is the adult form of chronic myelogenous leukemia (CML) (t[9:22] or BCR/ABL containing CML). This is the subject of a separate review and is not discussed here. Other MPS seen in adults with some frequency are exceedingly rare in children, such as polycythemia vera, essential thrombocythemia, and agnogenic myeloid metaplasia. The transient myeloproliferative disorder in children with Down syndrome is a unique entity recently linked to mutations of the GATA1 transcription factor.[3]

The MDS entities of childhood can be divided into de novo (primary) forms of MDS or secondary MDS. The secondary forms are either a result of exposure to chemotherapy or radiation, secondary to a congenital or constitutional disorder (eg, Down syndrome), or the result of associated bone marrow failure syndromes (eg, Fanconi anemia). These disorders are often considered "preleukemic" conditions, and differentiating some forms of MDS from de novo AML can be difficult. Indeed, the conversion rate for the MDS conditions approaches 40%.[1] However, multiple studies have suggested that AML developing after a period of myelodysplasia may be a distinct clinicopathological entity, often with a worse prognosis than true de novo AML.[4-6] Although there is a close link between these 2 diseases, this review focuses on MDS as a separate classifiable disease. Classification of primary MDS in childhood mirrors that of the adult classification.

Finally, there are the bridging disorders, such as juvenile myelomonocytic leukemia (JMML), which is the most common of these disorders, although accounting only for 2% of childhood hematologic malignancies.[7] Chronic myelomonocytic leukemia (CMML) is also included in this classification, but it is exceedingly rare in children. The adult form of CMML accounts for about 16% of adult cases of MDS.[8] The pediatric incidence has not been quantified. CMML was originally grouped together with JMML, but it has recently been defined as an entity similar to the adult form of CMML, and is reserved for cases secondary to previous chemotherapy.[7]

Predisposing Factors and Classification
A number of environmental/toxic exposures and genetic conditions have been found to predispose children to the development of MDS. Previous chemotherapy, especially alkylating agents (eg, cyclophosphamide), topoisomerase II inhibitors (eg, etoposide), and ionizing radiation, may increase the probability of MDS and AML. A number of congenital conditions are also associated with an increased risk for MDS, including Down syndrome, neurofibromatosis, Kostmann's syndrome, Diamond-Blackfan syndrome, thrombocytopenia with absent radii, Klinefelter's syndrome, Fanconi anemia, Noonan's syndrome, Schwachman's syndrome, and trisomy 8 mosaicism.[1,2,9]

Until recently, the childhood MDS syndromes were defined with adult criteria, such as those developed by the French-American-British (FAB) Cooperative Group in 1982.[10] This classification recognized 5 distinct forms of MDS: refractory anemia (RA), RA with ringed sideroblast (RARS), RA with excess blasts (RAEB), RA with excess blasts in transformation (RAEB-T), and CMML. A more recent classification has been proposed that addresses specific diagnostic problems and the rarity of specific disease entities (such as the adult MPS) in children.[7] This classification subdivides the MPS-MDS syndromes into 3 categories:

Myelodysplastic/myeloproliferative disease: JMML, CMML (secondary only), and BCR-ABL-negative CML;

Down syndrome disease: transient abnormal myelopoiesis (TAM) or transient myeloproliferative disorder (TMD) and myeloid leukemia of Down syndrome; and

MDS: refractory cytopenia (RC) (PB blasts < 2% and BM blasts < 5%), refractory anemia with excess blasts (RAEB) (PB blasts 2% to 19% or BM blasts 5% to 19%), and RAEB in transformation (RAEB-T) (PB or BM blasts 20% to 29%).

Another classification uses relevant medical history (category), cytology, and cytogenetics (the CCC system) in an attempt to classify these patients.[8]

Clinical Presentation and Diagnosis

Childhood MDS
Most children with MDS present with nonspecific symptoms as a result of pancytopenia, including pallor, fatigue, bruising, petechiae, and infections. Children with MDS characterized by monosomy 7 may also have chemotactic defects of their neutrophils leading to infectious complications. Hepatosplenomegaly is uncommon. There are dysplastic features of the peripheral blood and bone marrow in single or multiple of the granulocytic, megakaryocytic, monocytic, or erythrocytic lineages. These include nuclear abnormalities (hyposegmentation or multinucleated forms), megaloblastoid maturation, Pelger-Huet-type abnormalities, and hemophagocytosis. The peripheral blood may demonstrate an increased number of blasts from any of these lineages.

Cytogenetic studies of pediatric and adult de novo MDS cases have demonstrated clonal cytogenetic abnormalities in approximately 80% of patients.[11] As the disease progresses, an increasing number show cytogenetic abnormalities. The most common cytogenetic abnormalities in pediatric MDS are trisomy 8 and monosomy 7. Of note, the chromosomal abnormalities commonly found in adults, including -5, 5q-, and -Y are rarely present in pediatric MDS cases. In addition, if recurrent abnormalities typically associated with AML (eg, t[15:17], t[8:21], inv[16], t [9:11]) are found, a diagnosis of AML should be made and the patient treated accordingly even in the setting of less than 30% blasts.[4]

Childhood MPS
Childhood CMML and BCR-ABL-negative CML are rarely seen and are not discussed further. JMML commonly presents with marked hepatosplenomegaly, generalized lymphadenopathy, and skin changes, including dermal neurofibromas and café-au-lait spots (if associated with neurofibromatosis), or an eczematous rash. Laboratory tests may reveal moderate leukocytosis with monocytosis, anemia, thrombocytopenia, elevated fetal hemoglobin, and hypergammaglobulinemia. JMML is a clonal stem cell disorder. Cytogenetic features may include the presence of monosomy 7 (not necessarily required for diagnosis) or other clonal abnormalities.

Loss of heterozygosity at the NF1 locus and activating ras mutations have also been implicated in the pathogenesis of JMML.[12,13] Diagnosis requires the absence of bcr / abl rearrangement, a peripheral blood monocyte count > 1 x 109/L, and bone marrow blasts < 20%. Two additional criteria from the following are also required: hypersensitivity to granulocyte-monocyte colony-stimulating factor, increased fetal hemoglobin, myeloid precursors in the peripheral blood, white blood cell count > 10 x 109/L, or clonal abnormalities (eg, monosomy 7).

TMD in Children With Down Syndrome
TMD is typically present in the first few months after birth in children with Down syndrome. The incidence of severe TMD is thought to be as high as 10%, and subclinical cases may make the incidence even higher and contribute to a higher incidence.[14] Children may present as early as at birth with hydrops fetalis secondary to severe anemia or cardiac infiltration by myeloblasts.

Other features include hepatomegaly, pleural / pericardial / peritoneal effusions, disseminated intravascular coagulation, renal failure, and respiratory failure. The blood counts typically show elevated white blood cells with circulating myeloblasts. Recently, the development of TMD and subsequent AMKL (M7-AML) in these children has been associated with mutations in the GATA1 transcription factor, which is essential for normal maturation of megakaryocytes and the erythroid lineage.[3,14,15]

About 30% of children with TMD go on to develop M7-AML within 3 years of the initial TMD diagnosis, whereas about 70% resolve spontaneously. Initial treatment therefore consists of supportive therapy only, with blood-product support and/or leukapheresis as necessary. Those who develop AML are treated with standard AML therapy. Of interest, the Children's Cancer Group 2891 trial showed that standard timing with AML chemotherapy alone resulted in an 88%, 4-year disease-free survival for the Down syndrome patients, as compared with 42% in patients without Down syndrome.[16]

Treatment

MDS
Developing effective therapies for MDS has been made difficult by their relative infrequency and by the heterogeneity in the natural history of these diseases. The clinical course of childhood MDS is known to be quite variable. An approximate 40% conversion rate to AML is about the same as in the adult forms of MDS.[17] Although a number of supportive care measures, chemotherapy combinations, hormones, hematopoietic growth factors, differentiating agents, and immune modulators have been studied in the treatment of the various forms of MDS, cures are generally achieved only through the use of allogeneic hematopoietic stem cell transplantation (HSCT) following myeloablative chemotherapy and radiation.

Long-term survival has been seen in children with RC (or RA) with only supportive measures. In addition, spontaneous remissions have been observed in patients with MDS characterized by monosomy 7, although this is very rare.[18] However, therapy for MDS is similar to therapy for AML: high-dose intensive chemotherapy, with or without HSCT.[17, 19-26] The Children's Cancer Group 2891 study compared chemotherapy alone, autologous HSCT, and allogeneic HSCT for treatment of AML/MDS. The overall survival for these groups with regard to AML was 57%, 54%, and 70%, respectively.[25]

Specific results with regard to secondary MDS have not been reported, although a separate report on treatment-related MDS/AML found that the prognosis for these secondary conditions was much worse than the primary forms.[20] The Children's Cancer Group 2961 study, just recently completed, builds on these results and involves all patients with an allogeneic donor going on to HSCT and those without, proceeding to further chemotherapy with or without interleukin (IL)-2 immunomodulation. A recent retrospective study of 94 pediatric patients with MDS treated with allogeneic BMT revealed a 3-year disease-free survival of 74%, 68%, and 18% for patients with RA/RARS, RAEB, and RAEB-T, respectively.[26]

It has become apparent that interplay between the bone marrow stromal microenvironment and the MDS clone is necessary for clonal expansion and regulation of apoptosis of bone marrow progenitor cells.[27] This may include genetic abnormalities in the stroma, the formation of autocrine "loops" allowing for maintenance of a dysregulated microenvironment, in addition to an altered stroma cellular subpopulation composition (eg, osteoblast enrichment).[28] New agents attempting to target more specifically the molecular physiology of MDS are currently being studied.[27] These include:

Farnesyl transferase inhibitors that target the ras signaling pathway, a key regulator of cell proliferation[29,30];

Angiogenesis inhibitors, such as thalidomide, that inhibit both basic fibroblast growth factor and vascular endothelial growth factor (VEGF)-induced angiogenesis, thalidomide analogs, and specific VEGF receptor tyrosine kinase inhibitors[31-33];

Anti-tumor necrosis factor (TNF)-alpha therapies with monoclonal antibodies to TNF-alpha, such as infliximab[34];

Arsenic trioxide, which acts through multiple mechanisms, including induction of apoptosis and tumor cell differentiation and angiogenesis inhibition[35]; and

Antisense RNA against p53, proteosome inhibitors, and glutathione- S -transferase inhibitors are all in phase 1 trials in adult MDS.[27]

JMML
Consistently effective therapy for JMML has not been found. Only allogeneic HSCT has been shown to result in extended survival.[19,36] Unfortunately, the relapse rate even after HSCT is very high, with 5-year, disease-free survival rates of only 25% to 40%.[37] Given the pathogenesis of JMML with dysregulation of the ras pathway, mechanism-based targeted molecular therapy now seems feasible for JMML. A recent Children's Oncology Group phase 2 window/phase 3 trial for newly diagnosed JMML was activated in 2001, AAML0122.

The initial phase 2 window of the protocol involved 2 months of treatment with an farnesyl transferase inhibitors (R115777) to target the ras pathway. This was followed by 13-cis-retinoic acid as a prodifferentiation agent, combined with fludarabine and cytarabine for cytoreduction. Most patients then underwent splenectomy, which has been shown to improve survival after HSCT for JMML in some studies.[38] HSCT was then performed, followed by 1 year of cis-retinoic acid to prevent relapse. Efficacy results are not available at this time, and study progress to date consists only of the demonstrated tolerability of 300-mg/m2 dosing of R115777.

Additional phase 2 agents may be included in this protocol after the evaluation of R115777 is complete. These include a granulocyte-macrophage colony-stimulating factor (GM-CSF) antagonist, E21R, engineered through a single amino acid substitution in the GM-CSF molecule. In addition, a fusion product consisting of the GM-CSF molecule fused to diphtheria toxin has shown some in vitro toxicity to acute leukemia and JMML cell lines. Finally, other signaling inhibitors, such as those targeting gene expression of Raf 1 and the mitogen-activated protein kinase inhibitor PD184352, have shown activity in vitro.[37]

Conclusion
The myeloproliferative and myelodysplastic disorders of childhood comprise a rare but important subset of childhood malignancies that are still in need of successful treatment approaches. Several novel, prospective clinical trials are being undertaken by the Children's Oncology Group and the European Working Group of MDS in Childhood (EWOG-MDS), which may shed further light into the pathogenesis of these disorders and help to improve the long-term survival of afflicted children.

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