Pediatric Myelofibrosis 

Bone marrow fibrosis, known as myelofibrosis, is an uncommon condition in pediatric patients. Fewer than 100 cases have been described in the medical literature. Most cases arise secondary to other disease processes.^[1] For example, myelofibrosis is frequently associated with malignancy (eg, acute megakaryoblastic leukemia [AMKL]). (See Clinical and Workup.)

Myelofibrosis may be observed prior to a clear diagnosis of acute leukemia,^[2] at the time of diagnosis of leukemia,^[3] or as a late event in patients previously treated for leukemia. Numerous nonmalignant diseases have also been reported in association with myelofibrosis. (See Treatment.)

Cases of primary or idiopathic myelofibrosis (IMF) are also described.^{[4, 5, 6]} These are chronic myeloproliferative disorders, which occasionally are familial. Among adults, 2 broad classes of primary myelofibrosis are recognized.^[7]Agnogenic myeloid metaplasia with myelofibrosis (AMMM) is an indolent myeloproliferative syndrome characterized by clonal hematopoiesis, splenomegaly, and an erythroblastic peripheral blood smear see the image below). (See Etiology.)

Median age at diagnosis is about 60 years, and median life expectancy from onset of symptoms is 10 years. In contrast, acute myelofibrosis in adulthood is a rapidly fatal disorder in which splenomegaly is not usually observed; bone marrow examination typically reveals numerous bizarre megakaryocytes and blasts. (See Epidemiology and Workup.)

Occasional pediatric cases of myelofibrosis, especially in older adolescents, are indistinguishable from AMMM. So-called acute myelofibrosis of childhood (C-AMF), in contrast, combines features of the 2 adult myelofibrosis syndromes.^[8] C-AMF is usually a fulminant disease (survival < 1 y), but most patients do exhibit splenomegaly, as well as erythroblastosis. Notably, this condition overlaps with AMKL in terms of clinical findings and population at risk (ie, younger children with Down syndrome).^{[9, 10]} In fact, many investigators now consider C-AMF to be a variant (potential precursor) of AMKL. The prognosis of childhood myelofibrosis varies depending on the clinical context in which it occurs. (See Clinical and Workup.)

Complications

Patients with myelofibrosis but no initial evidence of myelodysplasia or leukemia may ultimately develop either of these conditions. Patients can be expected to develop complications secondary to decreased blood counts (eg, anemia, hemorrhage due to thrombocytopenia, opportunistic infections due to leukopenia). Splenomegaly may lead to hypersplenism, thereby worsening pancytopenia. A single case report detailed subcutaneous lymphoma arising in a child with IMF. (See Prognosis.)^[11]

Patient education

Early onset myelofibrosis is occasionally inherited in a recessive pattern. Counsel parents about the possibility of a second affected child.

The hallmark of myelofibrosis is increased reticulin staining. However, increased reticulin can also be seen in patients with acute leukemias, especially M7 acute myeloid leukemia (AML). In one report, the extent of myelofibrosis at diagnosis was shown to have prognostic significance in childhood acute lymphoblastic leukemia (ALL).^[12]

The fibrous network observed in myelofibrosis is collagenous and contains fibronectin; the reticulin (silver or Gomori) stain reacts with a protein that is intimately associated with type III collagen and is generally considered to be a form of procollagen. Fibrosis of the bone marrow presumably reflects overgrowth of the normal marrow matrix.^[13] As previously noted, this can be observed in association with many diseases.

Matrix homeostasis results from a balance between the deposition of the matrix and its removal. The former is regulated by various growth factors, most notably platelet-derived growth factor (PDGF), whereas the latter presumably reflects the activity of collagenase-expressing monocytes, macrophages, and granulocytes. Thus, the diseases associated with myelofibrosis can be classified according to whether the basic defect is matrix overproduction, underresorption, or both. The last of these is typified by vitamin D deficiency, because 1,25(OH)₂ D₃, the active metabolite of vitamin D₃, inhibits the proliferation of megakaryocytes and also encourages monocyte/macrophage differentiation.^{[14, 15]}

In cases of acute myelofibrosis of childhood (C-AMF), myelofibrosis may be secondary to the release of granules by abnormal megakaryocytes. In addition to PDGF, these granules contain transforming growth factor b (TGF-b) and epidermal growth factor, both of which can stimulate proliferation of fibroblasts. TGF-b synthesis appears to be regulated by nuclear factor kappaB (NF-kB). Interestingly, the overexpression of an immunophilin, FK506 binding protein 51, has been observed in myelofibrosis megakaryocytes, and this protein appears, in turn, to activate NF-kB.^[16]

Some investigators believe that the abnormal fibrotic marrow stroma directly enhances the circulation and dissemination of hematopoietic precursors by an unknown mechanism.^[17] This leads to extramedullary hematopoiesis in the liver, spleen, lymph nodes, or (occasionally) kidneys, causing myeloid metaplasia in these organs, which then become enlarged. On occasion, hypersplenism may also contribute to cytopenias.

Among adults with idiopathic myelofibrosis (IMF), conventional cytogenetic analysis of the marrow reveals an abnormal clone in approximately one third of patients. Using a comparative genomic hybridization technique, Al-Assar et al studied IMF marrow specimens and found chromosomal imbalances in 21 of 25 cases.^[18] Gains of 9p, 13q, 2q, 3p, and 12q were among the most commonly seen abnormalities. Isolated del(20q) or del(13q) appears to confer a better prognosis. All other abnormalities confer an independent adverse effect on survival and are also associated with higher JAK2V617F mutational frequency.^[19]

The gain-of-function V617F mutation in the JAK2 gene (on chromosome 9p) is seen in many adult patients with IMF. Its presence correlates with a shift from thrombopoiesis toward increased erythropoiesis and may also predict progression to massive splenomegaly and leukemic transformation.^{[20, 21]}

Causes

Classification of myelofibrosis in children includes the following: primary (idiopathic) C-AMF, secondary (malignant) C-AMF, and secondary (nonmalignant) C-AMF.

Causes of secondary (malignant) C-AMF include:

• AML
• Acute erythroblastic (M6) leukemia^[22]
• Acute megakaryoblastic (M7) leukemia (AMKL)
• ALL^[23]
• Chronic myelogenous leukemia
• Non-Hodgkin lymphoma
• Essential thrombocythemia^[24]
• Hodgkin disease (reported cases in adults only)

Causes of secondary (nonmalignant) C-AMF include:

• Langerhans cell histiocytosis
• Hemophagocytic lymphohistiocytosis^[25]
• Sickle cell disease (a single case report)^[26]
• Fanconi anemia
• Vitamin D deficiency
• Infectious causes - Tuberculosis^[27] , visceral leishmaniasis^[28] , histoplasmosis (reported cases in adults only)
• Renal osteodystrophy
• Systemic lupus erythematosus^[29]
• Juvenile rheumatoid arthritis
• Gray platelet syndrome
• Osteopetrosis
• Hyperparathyroidism
• Hypoparathyroidism (reported cases in adults only)
• Pernicious anemia (reported cases in adults only)
• Gaucher disease (reported cases in adults only)
• Exposure to radiation, thorium dioxide, benzene (reported cases in adults only)

Occurrence in the United States

Fewer than 100 cases of pediatric myelofibrosis have been reported worldwide. This is likely an underrepresentation, because cases associated with AML (the most common association) are not generally reportable. Of the roughly 500 new cases of pediatric acute nonlymphoid leukemia (ANLL) in the United States annually, approximately 5% are megakaryoblastic (M7 subtype, AMKL). If as few as 20% of these patients have a significant degree of myelofibrosis, this yields roughly 5 new cases per year. Other cases of myelofibrosis (ie, not associated with AMKL) likely total only a handful per year, as well.

International occurrence

Cases of pediatric myelofibrosis have been described in association with tuberculosis (in Pakistan) and visceral leishmaniasis (in Sudan). Thus, myelofibrosis is presumably more common in areas of endemicity for these diseases. Epidemiologic data are not available.

Autosomal recessive familial myelofibrosis appears to be more common among children from Saudi Arabia.^{[30, 31, 32]}

Sex- and age-related demographics

In published cases of pediatric myelofibrosis, females outnumber males by a ratio of approximately 2:1.

Approximately half of published cases of pediatric myelofibrosis occurred in children younger than 3 years. These younger patients are more likely to have Down syndrome, rickets, or a familial (possibly autosomal recessive) form of myelofibrosis. Among older patients, ANLL, systemic lupus erythematosus, and tuberculosis are the most common associations.

The prognosis depends on the underlying cause of myelofibrosis. With appropriate treatment for rickets, tuberculosis, systemic lupus erythematosus, and other conditions, the myelofibrosis may completely resolve.

Idiopathic acute myelofibrosis of childhood (C-AMF) is a fulminant disease. Without effective therapy, life expectancy is typically less than 1 year. Potentially effective and/or curative treatments include chemotherapy and allogeneic bone marrow transplantation (BMT). Treatment with high-dose corticosteroids or interferon alfa may result in a temporary amelioration of the disease. Occasionally, pediatric patients have a more indolent course that is comparable to agnogenic myeloid metaplasia with myelofibrosis (AMMM) in adults. With supportive care alone, they may survive for many years.

A retrospective analysis of 203 adult patients with myelofibrosis suggested, in contrast to earlier reports, that myelofibrosis has little adverse effect on engraftment following allogeneic hematopoietic cell transplant.^[33]

In adult patients with myelofibrosis, several alternative prognostic scoring systems (PSSs) are available.^{[34, 35]} Neither the patient's symptoms nor the percentage of circulating blasts is taken into account in the Mayo Clinic PSS (in contrast to other PSSs). A retrospective review of 334 patients with myelofibrosis showed the Mayo Clinic PSS to be more effective than other PSSs in terms of (1) identifying long-lived patients and (2) delineating an intermediate-risk disease category.^[35] The Mayo PSS assigns a score of 1-4 by allotting 1 point for each of the following:

• Hemoglobin level more than 10 gm/dL
• White blood cell (WBC) count less than 4 or more than 30 X 10⁹/L
• Platelet count less than 100 X 10⁹/L
• Absolute monocyte count at or above 1 X 10⁹/L

Morbidity and mortality

Myelofibrosis causes, or accompanies conditions that cause, disruption of hematopoiesis. Patients may experience anemia, neutropenia, and/or thrombocytopenia. Patients may also experience pain secondary to hepatosplenomegaly. Neutropenia may lead to opportunistic infections, such as bacterial sepsis, oral thrush, or systemic fungal infections. Thrombocytopenia may lead to hemorrhage.

The prognosis for individual patients with myelofibrosis depends on the underlying disease process and its potential for treatment. Most cases of C-AMF have eventually ended in death; the course is usually fulminant.