eMedicine Specialties > Pediatrics: General Medicine > Hematology

Myelofibrosis

J Martin Johnston, MD, Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Pediatric Hematology/Oncology, Backus Children's Hospital; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital

Updated: Oct 2, 2009

Introduction

Background

Myelofibrosis (MF), bone marrow fibrosis, is an uncommon condition in children. 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]). 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 Causes).

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 (as defined below).

Photomicrograph of a peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows findings of leukoerythroblastosis, giant platelets, and few teardrop cells.

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 both 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

Pathophysiology

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 a recent report, the extent of myelofibrosis at diagnosis was shown to have prognostic significance in childhood acute lymphoblastic leukemia (ALL).¹¹

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.¹² As previously noted, this can be observed in association with many diseases (see Causes).

Matrix homeostasis results from a balance between its deposition 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.^13,14

In cases of C-AMF, myelofibrosis may be secondary to the release of a granules by abnormal megakaryocytes (see Histologic Findings). 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.¹⁵

Some investigators believe that the abnormal fibrotic marrow stroma directly enhances the circulation and dissemination of hematopoietic precursors by an unknown mechanism.¹⁶ 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 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.¹⁷ 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.¹⁸

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.^19,20

Frequency

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

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. Epidemiological data are not available.

Autosomal recessive familial myelofibrosis appears to be more common among children from Saudi Arabia.^21,22,23

Mortality/Morbidity

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.

Race

As noted above, an autosomal recessive form of myelofibrosis appears to be more common among children from Saudi Arabia.²¹

Sex

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

Age

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.

Clinical

History

Patients with myelofibrosis (MF) typically present with a fairly insidious onset of pallor and fatigue, with or without fever (about one third of cases), bruising, bone pain, or left upper quadrant abdominal pain.

• Down syndrome, systemic lupus erythematosus, or histiocytosis may have been previously diagnosed.
• Rarely, myelofibrosis may appear long after successful treatment for acute leukemia.
• A history of radiation exposure may be noted.
• Look for a history of similar illness in siblings, especially if onset is in infancy. Parental consanguinity may suggest an autosomal recessive form of the disease.
• Patients may have been exposed to tuberculosis.

Physical

• Physical findings reflect the blood counts.
  • Pallor (anemia)
  • Bruising or bleeding (thrombocytopenia)
  • Oral thrush (neutropenia)
  • Splenomegaly (frequent) or hepatomegaly or lymphadenopathy (less common)
• Stigmata of Down syndrome may be present.
• Multiple hemangiomas have been described in one affected pair of siblings with idiopathic myelofibrosis (IMF).

Causes

• Primary (idiopathic) acute myelofibrosis of childhood (C-AMF)
• Secondary (malignant) C-AMF
  • Acute myeloid leukemia (AML)
  • Acute erythroblastic (M6) leukemia²⁴
  • Acute megakaryoblastic (M7) leukemia (AMKL)
  • Acute lymphoblastic leukemia (ALL)²⁵
  • Chronic myelogenous leukemia
  • Non-Hodgkin lymphoma
  • Essential thrombocythemia²⁶
  • Hodgkin disease (reported cases in adults only)
• Secondary (nonmalignant) C-AMF
  • Langerhans cell histiocytosis
  • Hemophagocytic lymphohistiocytosis²⁷
  • Sickle cell disease (a single case report)²⁸
  • Fanconi anemia
  • Vitamin D deficiency
  • Infectious causes - Tuberculosis²⁹ , visceral leishmaniasis³⁰ , histoplasmosis (reported cases in adults only)
  • Renal osteodystrophy
  • Systemic lupus erythematosus³¹
  • 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)

Differential Diagnoses

Other Problems to Be Considered

Osteopetrosis
Gray platelet syndrome

Workup

Laboratory Studies

• CBC count: Expected findings include anemia or thrombocytopenia or both, with or without leukocytosis (with left shift). The peripheral blood smear may have an erythroblastic appearance (nucleated RBCs, teardrops, fragments, accompanied by immature myeloid cells). Platelets may be large, misshapen, or both. In rare cases, the platelet count may actually be elevated.³²
• Parathyroid hormone: Hyperparathyroidism (primary or secondary to vitamin D deficiency) has been described. Among adult patients with myelofibrosis (MF), hypoparathyroidism is sometimes observed.
• Antinuclear antibodies (ANA): Myelofibrosis occasionally complicates systemic lupus erythematosus.
• Neutrophil alkaline phosphatase (LAP) score: A low level suggests chronic myeloid leukemia; a high level suggests chronic inflammation, as might be expected with systemic lupus erythematosus.
• BUN/creatinine test: This is performed to rule out renal dysfunction, which suggests renal osteodystrophy as an underlying diagnosis.
• Coombs (direct antiglobulin) test, antineutrophil antibodies: Myelofibrosis has been observed in association with autoimmune hematologic phenomena.

Imaging Studies

• Abdominal ultrasonography or CT scanning often reveals hepatosplenomegaly, with or without adenopathy. Nephromegaly has also been described (secondary to myeloid metaplasia).^33,34
• MRI scanning, if performed because of particular symptoms (eg, headache), often shows diagnostic changes in marrow signal.

Other Tests

• Purified protein derivative (PPD): Myelofibrosis has been described as a complication of tuberculosis.

Procedures

• Bone marrow aspirate and biopsy
  • The aspirate is frequently hypocellular or shows insufficient cellularity ("dry"). An increased number of megakaryocytes that may be morphologically abnormal supports a diagnosis of primary myelofibrosis. Increased blasts are often observed, but the presence of more than 25% blasts is, by definition, more consistent with acute myelofibrosis.
  • Send the bone marrow aspirate for cytogenetic analysis. In addition to their prognostic value, cytogenetic studies in myelofibrosis ensure diagnostic exclusion of other myeloid neoplasms that are sometimes associated with bone marrow fibrosis (eg, BCR-ABL1 positive).¹⁸
  • Abnormalities may support a diagnosis of myelodysplasia (eg, monosomy 7) or acute megakaryoblastic leukemia (AMKL) (eg, t[1;21][p13;q13]).
  • The biopsy demonstrates increased silver (reticulin) staining.

Histologic Findings

• Marrow biopsies typically exhibit marked fibrosis with pockets of cellularity that have fibroblasts and atypical megakaryoblasts. Less commonly, hyperplasia with predominance of megakaryocytic and erythroid precursors is observed, with only a slight increase in reticulin staining. The latter pattern is more typical of (adult) agnogenic myeloid metaplasia with myelofibrosis and may be observed in an older pediatric patient.

Treatment

Medical Care

As noted, the workup of children with myelofibrosis (MF) frequently leads to a diagnosis of acute nonlymphoblastic (specifically, megakaryoblastic) leukemia or, less commonly, myelodysplastic syndrome. The treatment of these patients is not discussed here.

The identification of another treatable underlying diagnosis (eg, rickets, tuberculosis) should prompt treatment of that disorder.

Treatment should be directed at the underlying process when childhood myelofibrosis is identified. Other therapeutic options include transfusion support, corticosteroids, intravenous (IV) immunoglobulin, alfa interferon, vitamin D, conventional antileukemic chemotherapy (eg, hydroxyurea), and allogeneic bone marrow transplantation (BMT). In addition, splenectomy may be palliative in selected patients. 

Treatment with imatinib mesylate (Gleevec) is occasionally effective. Patients who do respond to imatinib sometimes exhibit increased platelet or WBC counts, which, in turn, require treatment with hydroxyurea or interferon.

Other promising new agents in adult myelofibrosis include thalidomide (alone or in combination with prednisone), lenalidomide, and decitabine.³⁵

• Vitamin D: Myelofibrosis is observed in some patients with severe vitamin D deficiency. In addition, cases of myelofibrosis associated with essential thrombocythemia or myelomonocytic leukemia, as well as acute (idiopathic) myelofibrosis, have responded to vitamin D administration.^36,37
• Corticosteroids: Corticosteroids have been used to treat many cases of pediatric myelofibrosis, with occasional apparent successes.³⁸ However, one concern is that the literature does not always allow for a clear distinction between primary and secondary cases of myelofibrosis. Patients with systemic lupus erythematosus or even acute nonlymphoid leukemia (ANLL) might show a response to steroid therapy, although this would be only a temporary effect with the latter diagnosis.³¹ In particular, treatment with high-dose methylprednisolone has been touted as an effective therapy; however, this recommendation is based on a published series of only 5 older pediatric patients (aged 9-14 y), at least one of whom had a positive purified protein derivative (PPD) finding and was also treated with isoniazid.³⁹
• Thalidomide: For palliation of anemia and thrombocytopenia in adult patients with agnogenic myeloid metaplasia with myelofibrosis (AMMM), the combination of prednisone and thalidomide appears to be reasonably effective.⁴⁰ Among 36 patients with symptomatic AMMM who enrolled in either a trial of single-agent thalidomide (n = 15) or a trial of low-dose thalidomide (50 mg/d) combined with prednisone (n = 21), 20 (56%) showed some improvement.⁴¹ Responses included improvements in anemia (15 of 36 [42%]), thrombocytopenia (10 of 13 [77%]) and splenomegaly (5 of 30 [17%]). The combination of low-dose thalidomide and prednisone was better tolerated and more efficacious than thalidomide alone. After a median follow-up of 25 months, 10 of 36 patients (28%) showed a persistent response, including 8 patients whose protocol treatment had been discontinued for a median of 21 months.
• Lenalidomide: Another inhibitor of angiogenesis, this agent has also shown efficacy in adults with myelofibrosis or AMMM.⁴² Protocol treatment consisted of oral lenalidomide 10 mg daily for 3-24 months, depending on response. Among 68 patients, overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed "impressive" in 8 patients. Additional observed effects included resolution of leukoerythroblastosis (4 patients), a decrease in medullary fibrosis and angiogenesis (2 patients), and del(5)(q13q33) cytogenetic remission accompanied by a reduction in JAK2(V617F) mutation burden (1 patient). A follow-up report suggests that responses are more likely in patients exhibiting del(5q).⁴³
• Intravenous (IV) immunoglobulin: An 8-month-old girl with myelofibrosis and dysgranulopoiesis responded to IV immunoglobulin (added to previous corticosteroid therapy).⁴⁴ Her disease was unusual and was characterized by a positive Coombs test result and antineutrophil antibodies, suggesting an autoimmune etiology.
• Alfa interferon: Alfa interferon has been used to treat at least 2 adults with acute MF and one 14-year-old boy with indolent myelofibrosis. The adolescent patient showed resolution of fibrosis and restoration of blood counts after 6 months of therapy with alfa interferon 3 million IU, 3 times a week.⁴⁵ He continued to do well for at least 2 years on a maintenance dose of 2 million IU twice a week. Two adult males (aged 63 and 71 y) with acute myelofibrosis (and excess blasts) were treated with subcutaneous interferon alfa-2a at doses of 1-6 million IU daily. Both showed resolution of fibrosis. The first patient was maintained on interferon for 12 weeks, but his disease progressed shortly after it was discontinued. After 4 weeks of interferon, the second patient stayed in an unmaintained remission for 4 months before dysplastic hematopoiesis recurred.
• Chemotherapy: Conventional chemotherapy, as would otherwise be used to treat acute myeloid/megakaryocytic leukemia, has been used to treat patients with acute myelofibrosis of childhood (C-AMF), under the assumption that C-AMF is a preleukemic condition. The details of such therapy are beyond the scope of this article and are discussed in Acute Myelocytic Leukemia. Decitabine, an S-phase specific inhibitor of DNA methyltransferase, has shown promise in adult patients with myelofibrosis.⁴⁶ Pediatric dosing for this drug has not been established, and no literature regarding its use in children with myelofibrosis has been published.
• BMT: Similarly, allogeneic BMT has been used successfully to treat patients with MF.⁴⁷ Thirteen adult patients with myelofibrosis (8 primary and 5 associated with either polycythemia vera or essential thrombocytosis) received allogeneic BMTs at the Fred Hutchinson Cancer Research Center.⁴⁸ Preparative regimens and donors varied. Four patients died of transplant-related complications. Nine patients are apparent long-term survivors, 2 of whom experienced a relapse and are in a chronic myeloproliferative state. Published experience from Sweden and Germany demonstrates that reduced-intensity preparative regimens are often effective for treating myelofibrosis and clearly have less treatment-related mortality than do myeloablative regimens.^49,50 In a recent report, 2 children with infantile myelofibrosis were successfully treated with unrelated hematopoietic stem cell transplantation.⁵¹
• Imatinib: In one published report, 11 adult patients with idiopathic myelofibrosis (IMF) or postpolycythemic myelofibrosis (PPMF) were treated with imatinib at a dose of 400 mg/d.⁵² Nine patients were in an advanced disease phase. At the time of publication, the patients had been followed for a median of 2 months. A beneficial effect of imatinib was documented in 3 patients. Leukocytosis and thrombocytosis were seen in most patients with myelofibrosis during treatment with imatinib. Other reports have been less encouraging.⁵³ Combination therapy with hydroxyurea or interferon seems safe and well tolerated and is followed by a decrease in disease activity.

Surgical Care

• Some adult patients with AMMM are candidates for splenectomy, but patient selection for this procedure is controversial.⁵⁴ Transfusion-dependent anemia, portal hypertension, and/or symptoms of hypercatabolism are potential indications for splenectomy, but the surgery-related mortality rate may be as high as 9%.⁵⁵ Similar statistics are not available for pediatric patients.
• In adults with symptomatic splenomegaly, irradiation of the spleen is sometimes performed as an alternative to splenectomy.
• Placement of a central venous access device may facilitate care in patients requiring complex therapies or frequent transfusions.

Medication

Treat any underlying disease (eg, rickets) as indicated for the specific disease. The medications listed here have shown some benefit in patients with idiopathic myelofibrosis (IMF).

Antirachitics

Myelofibrosis has been described in patients with severe vitamin D deficiency. In addition, some (adult) patients with myelofibrosis associated with essential thrombocythemia or myelomonocytic leukemia, as well as acute (idiopathic) myelofibrosis, have responded to vitamin D administration. A direct inhibitory effect on platelets has been proposed. However, other studies have not confirmed such a response in patients with idiopathic myelofibrosis (IMF).

Calcitriol (Rocaltrol)

Calcitriol (ie, 1,25-dihydroxyvitamin D) is the primary active metabolite of vitamin D3. It increases calcium levels by promoting absorption of calcium in the intestines and retention in the kidneys. Doses for MF are 5- to 10-fold higher than the physiologic dose.

Dosing

Adult

2.5 mcg/d PO

Pediatric

0.1 mcg/kg/d PO

Interactions

Cholestyramine and colestipol decrease absorption of calcitriol; magnesium-containing antacids and thiazide diuretics can increase calcitriol effects

Contraindications

Documented hypersensitivity; hypercalcemia; malabsorption syndrome

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Adequate response to calcitriol depends on adequate dietary calcium intake; maintain adequate fluid intake

Corticosteroids

These agents have both immunosuppressive and cytotoxic effects. The mechanism of cytotoxicity is unknown (but apparently mediated through glucocorticoid receptors).

Prednisone (Deltasone, Orasone)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocyte and antibody production. Efficacy in some cases of MF may reflect an underlying autoimmune defect and/or suppression of a proliferating clone.

Dosing

Adult

5-60 mg/d PO qd or divided bid/qid

Pediatric

2 mg/kg/d PO

Interactions

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI bleeding or ulceration

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Methylprednisolone (Solu-Medrol, Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Support for this higher dose therapy in the literature is limited.

Dosing

Adult

Pediatric

30 mg/kg PO/IV every am for 3 d, then 20 mg/kg PO/IV every am for 4 d, then 10 mg/kg PO/IV every am for 7 d, then 5 mg/kg PO/IV every am for 7 d, then 1 mg/kg every am maintenance until blood counts are adequate, then gradually wean as tolerated

Interactions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Immunomodulators

Proposed mechanisms of action are suppression of autoimmunity, enhanced immunoregulation of an abnormal clone, or both.

Interferon alfa-2a (Roferon-A)

Protein product manufactured by recombinant DNA technology. Acts by modulation of host immune response. This treatment has shown long-term efficacy in one adolescent patient with an indolent form of MF (essentially identical to adult AMMM). Transient responses have been observed in at least 2 adults with acute MF.

Dosing

Adult

1-6 million U/d SC

Pediatric

2-3 million U SC 2-3 times/wk

Interactions

Theophylline, zidovudine, or vinblastine may increase toxicity; cimetidine may increase antitumor effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Flulike symptoms are common (fatigue, myalgias and/or arthralgia, chills); headache, depression, occasional dizziness, nausea and/or vomiting, diarrhea, local reactions, partial alopecia, and rare hyperglycemia

Immune globulin intravenous (Gamimune, Gammagard)

Response to IVIG was reported in one case of pediatric MF, which was associated with autoimmune phenomena.

Dosing

Adult

Pediatric

0.5-1 g/kg IV infused over 2-4 h; 2-3 infusions may be administered over consecutive days; repeat treatments q1-3wk

Interactions

Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)

Contraindications

Documented hypersensitivity; IgA deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check serum IgA before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes mellitus, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Thalidomide (Thalomid)

Immunomodulatory agent that may suppress excessive production of tumor necrosis factor-alpha (ie, TNF-α) and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration. Because of concerns regarding teratogenicity, thalidomide can be prescribed only by physicians and dispensed only by pharmacists who are registered with the System for Thalomid Education and Prescribing Safety (STEPS) program. Patients must participate in ongoing surveys to receive therapy, and only a 28-d supply can be prescribed at a time.
Used to improve anemia and decrease blood/platelet transfusions associated with myelofibrosis.

Dosing

Adult

200 mg/d PO, then titrate dose to target dose of 800 mg/d PO
In combination with prednisone, doses of 50 mg/d PO have been used

Pediatric

Not established

Interactions

May increase sedation of alcohol, barbiturates, chlorpromazine, and reserpine

Contraindications

Documented hypersensitivity; sexually active males not using latex condom (risk to fetus from semen of patients taking thalidomide unknown), women of childbearing potential not using 2 forms of contraception

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Perform pregnancy test within 24-h period prior to initiating therapy (weekly during the first month, followed by monthly tests in women with regular menstrual cycles or q2wk with irregular menstrual cycles); bradycardia may occur; use protective measures (eg, sunscreens, protective clothing) against exposure to sunlight or UV light (eg, tanning beds); prescribing physician must register with the STEPS program established by manufacturer

Lenalidomide (Revlimid)

Indicated for transfusion-dependent MDS subtype of deletion 5q cytogenetic abnormality. Structurally similar to thalidomide. Elicits immunomodulatory and antiangiogenic properties. Inhibits proinflammatory cytokine secretion and increases anti-inflammatory cytokines from peripheral blood mononuclear cells.

Dosing

Adult

10 mg PO qd initially; dose adjustment required if renal impairment, thrombocytopenia, or neutropenia occurs

Pediatric

<18 years: Not established
>18 years: Administer as in adults

Interactions

Data limited; none reported

Contraindications

Documented hypersensitivity; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Available only through RevAssist, a risk management plan to prevent fetal exposure; only pharmacists and prescribers registered with the program may prescribe and dispense (program requires mandatory pregnancy testing and limits prescription to 1-mo supply via mail); male patients, including those with vasectomy, must use latex condom during sexual contact with female of childbearing potential; women must not become pregnant 4 wk before starting lenalidomide and 4 wk after discontinuing lenalidomide; may cause anemia, DVT, pulmonary embolism, thrombocytopenia, neutropenia, diarrhea, pruritus, rash, and fatigue; renal excretion substantial, caution in elderly patients or those with renal impairment (may need to decrease dose); not break, chew, or open cap

Decitabine (Dacogen)

Hypomethylating agent believed to exert antineoplastic effects by incorporating into DNA and inhibiting methyltransferase, resulting in hypomethylation. Hypomethylation in neoplastic cells may restore normal function to genes critical for cellular control of differentiation and proliferation. Indicated for treatment of myelodysplastic syndromes (MDSs), including previously treated and untreated, de novo, and secondary MDSs of all French-American-British (FAB) subtypes (ie, refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia) and International Prognostic Scoring System (IPSS) groups intermediate-1 risk, intermediate-2 risk, and high risk.

Dosing

Adult

15 mg/m² IV q8h for 3 d; infuse over 3 h; repeat q6wk for at least 4 cycles and as long as continued benefit observed

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Common adverse effects include neutropenia (90%), thrombocytopenia (89%), anemia (82%), pyrexia (53%), fatigue (48%), nausea (42%), cough (40%), petechiae (39%), constipation (35%), and diarrhea (34%); males must avoid fathering children while receiving decitabine and for 2 mo following discontinuation; decrease or delay dose if hematologic recovery requires >6 wk

Follow-up

Further Outpatient Care

• Supportive care of myelofibrosis (MF) with transfusions (RBC, platelets) is crucial to short-term management. Blood products should be leukodepleted (to decrease the likelihood of human leukocyte antigen [HLA] sensitization) and, ideally, cytomegalovirus (CMV) negative.
• Prophylaxis against opportunistic infections (eg, fluconazole) may be indicated for some patients with neutropenia.
• The Mayo Clinic recently described a patient-reported outcomes (PRO) instrument designed specifically to assess quality of life in (adult) patients with myelofibrosis.⁵⁶

Complications

• Patients with myelofibrosis but no initial evidence of myelodysplasia or leukemia may ultimately develop either of these conditions.
• As previously noted, 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 idiopathic myelofibrosis (IMF).⁵⁷

Prognosis

• 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.
• A retrospective analysis of 203 adult patients with myelofibrosis suggests, in contrast to earlier reports, that myelofibrosis has little adverse effect on engraftment following allogeneic hematopoietic cell transplant.⁵⁸
• In adult patients with myelofibrosis, several alternative prognostic scoring systems (PSSs) are available.^59,60 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.⁶⁰ 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
  • WBC count less than 4 or more than 30 X 10⁹/L
  • Platelet count less than 100 X 10⁹/L
  • Absolute monocyte count equal to or more than 1 X 10⁹/L
• Idiopathic acute myelofibrosis of childhood (C-AMF) is a fulminant disease. Without effective therapy, life expectancy is typically less than one 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 (see Medication). 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.

Miscellaneous

Medicolegal Pitfalls

• Splenectomy: Some adult patients with agnogenic myeloid metaplasia with myelofibrosis (AMMM) are candidates for splenectomy, but the surgery-related mortality rate may be as high as 9%. Outcome statistics of splenectomy are not available for pediatric patients. Splenomegaly alone is not an indication for splenectomy.
• Genetic counseling: Early-onset myelofibrosis (MF) is occasionally inherited in a recessive pattern. Counsel parents about the possibility of a second affected child.
• Occult or mosaic trisomy 21: Down syndrome is a risk factor for myelofibrosis. Consider chromosomal analysis in any child with onset before age 2 years.

Multimedia

Media file 1: Photomicrograph of a peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows findings of leukoerythroblastosis, giant platelets, and few teardrop cells.

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Keywords

myelofibrosis, MF, bone marrow fibrosis, myelosclerosis, osteomyelofibrotic syndrome, agnogenic myeloid metaplasia with myelofibrosis, AMMM, acute myelofibrosis of childhood, C-AMF, primary MF, idiopathic MF, IMF, fibrosis of the bone marrow, acute megakaryoblastic leukemia, AMKL, chronic myeloproliferative disorders, clonal hematopoiesis, splenomegaly, erythroblastic peripheral blood smear, myeloid metaplasia, thrombopoiesis, tuberculosis, visceral leishmaniasis, anemia, neutropenia, thrombocytopenia, hepatosplenomegaly, bacterial sepsis, rickets, systemic lupus erythematosus, histiocytosis, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin disease, Langerhans cell histiocytosis, sickle cell disease, Fanconi anemia, vitamin D deficiency, osteodystrophy, juvenile rheumatoid arthritis, osteopetrosis, hyperparathyroidism, hypoparathyroidism, pernicious anemia, Gaucher disease, treatment, diagnosis

Contributor Information and Disclosures

Author

J Martin Johnston, MD, Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Pediatric Hematology/Oncology, Backus Children's Hospital; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital
J Martin Johnston, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

Medical Editor

Sharada A Sarnaik, MBBS, Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children's Hospital of Michigan
Sharada A Sarnaik, MBBS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
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Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

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