eMedicine Specialties > Hematology > Stem Cells and Disorders

Agnogenic Myeloid Metaplasia With Myelofibrosis

Asheesh Lal, MBBS, MD, Physician, Department of Internal Medicine, Lexington Medical Center

Updated: Oct 8, 2008

Introduction

Background

Agnogenic myeloid metaplasia (AMM), first described by Heuck in 1879, is a clonal disorder arising from the neoplastic transformation of early hematopoietic stem cells.^1,2,3,4 Agnogenic myeloid metaplasia is categorized as a chronic myeloproliferative disorder, along with chronic myelogenous leukemia (CML), polycythemia vera, and essential thrombocytosis.⁵ The disorder is characterized by anemia, bone marrow fibrosis, extramedullary hematopoiesis, leukoerythroblastosis, teardrop-shaped red blood cells (RBCs) in peripheral blood, and hepatosplenomegaly.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Cancer and Tumors Center. Also, see eMedicine's patient education article Anemia.

Pathophysiology

In patients with agnogenic myeloid metaplasia, the hematopoietic system is most affected. Other organ systems may be involved by extramedullary hematopoiesis.

Clonality studies in patients with agnogenic myeloid metaplasia demonstrate that myeloid cells arise from clonal stem cells; however, bone marrow fibroblasts and, sometimes, T cells are polyclonal. The cause of the excessive marrow fibrosis observed in agnogenic myeloid metaplasia remains unclear. Platelets, megakaryocytes, and monocytes are thought to secrete several cytokines, such as transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), interleukin-1 (IL-1), epidermal growth factor (EGF), and basic fibroblast growth factor (bFGF), which may result in fibroblast formation and extracellular matrix proliferation. In addition, endothelial proliferation and growth of capillary blood vessels in the bone marrow are observed and may be a result of TGF-β and bFGF production.

Neoangiogenesis is a hallmark feature of chronic myeloproliferative disorders. Approximately 70% of patients with agnogenic myeloid metaplasia have substantial increases in bone marrow microvessel density. Neoangiogenesis in agnogenic myeloid metaplasia is noted in both medullary and extramedullary hematopoiesis. Increased serum vascular endothelial growth factor levels have been postulated as the underlying mechanism for increased angiogenesis.

Frequency

United States

Agnogenic myeloid metaplasia is an uncommon disease, with an annual incidence of approximately 0.5-1.5 cases per 100,000 individuals.

International

The worldwide incidence of agnogenic myeloid metaplasia is unknown.

Mortality/Morbidity

The main causes of death in patients with agnogenic myeloid metaplasia are infection, hemorrhage, cardiac failure, postsplenectomy complications, and transformation to acute leukemia.

• Leukemic transformation occurs in approximately 20% of patients with agnogenic myeloid metaplasia within the first 10 years. Renal failure, hepatic failure, and thrombosis have also been reported as causes of death.
• The median length of survival is approximately 3.5-5.5 years from diagnosis, with a range of 1-15 years.
• The 5-year survival rate is approximately half that expected for age- and sex-matched controls. Less than 20% of patients are expected to be alive at 10 years.⁶

Race

• Agnogenic myeloid metaplasia appears to be more common in white people than in individuals of other races.
• An increased prevalence rate of agnogenic myeloid metaplasia has been noted in Ashkenazi Jews.

Sex

A slight male preponderance appears to exist for agnogenic myeloid metaplasia; however, in younger children, girls are affected twice as frequently as boys.

Age

• Agnogenic myeloid metaplasia characteristically occurs in individuals older than 50 years. The median age at diagnosis is approximately 65 years.
• Agnogenic myeloid metaplasia has been reported in persons in all phases of life, from neonates to octogenarians.
• Approximately 22% of affected patients are younger than 56 years. Agnogenic myeloid metaplasia usually occurs in children in the first 3 years of life.

Clinical

History

One fourth of patients with agnogenic myeloid metaplasia are asymptomatic, and the diagnosis is made as a result of detecting splenomegaly or checking blood cell counts for an unrelated cause. Symptoms may occur as a result of anemia, splenomegaly, hypermetabolic states, extramedullary hematopoiesis, bleeding, bone changes, portal hypertension, and immune abnormalities.

• Anemia may occur as a result of ineffective erythropoiesis, erythroid hypoplasia, and hypersplenism. Anemia may cause easy fatigability, weakness, dyspnea, and palpitations.
• Splenomegaly may result in early satiety and left upper quadrant discomfort. Splenic infarcts, perisplenitis, or subcapsular hematoma may occur, causing severe left upper quadrant or left shoulder pain. Occasionally, patients may have diarrhea related to pressure on the colon.
• A hypermetabolic state occurs and can result in weight loss, night sweats, and low-grade fever. Gout and urate kidney stones may develop.
• Bleeding is observed in one fourth of patients with agnogenic myeloid metaplasia and varies in severity from insignificant cutaneous petechiae to severe, life-threatening gastrointestinal (GI) tract bleeding. Platelet dysfunction, acquired factor V deficiency, thrombocytopenia, disseminated intravascular coagulation (DIC), esophageal varices, and peptic ulcer disease may occur, contributing to bleeding.
• Extramedullary hematopoiesis may cause symptoms, depending on the organ or site of involvement. The condition may result in GI tract hemorrhage, spinal cord compression, focal seizures, symptoms related to brain tumors, ascites, hematuria, pericardial effusion, pleural effusion, hemoptysis, and respiratory failure.
• Portal hypertension may occur as a result of markedly increased splenoportal blood flow and decreased hepatic vascular compliance. Ascites, esophageal and gastric varices, GI tract bleeding, and hepatic encephalopathy may occur. Hepatic or portal vein thrombosis may also arise as complications.
• Patients with agnogenic myeloid metaplasia develop osteosclerosis. This may cause severe joint and bone pain.
• One half of patients with agnogenic myeloid metaplasia have abnormalities of humoral immunity. A variety of autoantibodies and circulating immune complexes may be detected, and amyloidosis may develop. Infections, commonly pneumonia, may occur as a result of immune deficiency.

Physical

• Splenomegaly is the most common finding in patients with agnogenic myeloid metaplasia, and it is present in approximately 90% of patients. Spleen size may vary from barely palpable to massive (observed in 35% of patients).
• Hepatomegaly is also observed in 60-70% of patients with agnogenic myeloid metaplasia.
• Pallor is observed in 60% of patients.
• Other physical findings include petechiae and ecchymosis (20%), lymphadenopathy (10-20%), signs of portal hypertension (10-18%), and gout (6%).

Causes

No specific risk factors can be identified in most patients with agnogenic myeloid metaplasia, although exposure to radiation, Thorotrast contrast agents, and industrial solvents (eg, benzene, toluene) have been associated with an increased risk.^7,8,9,10

Differential Diagnoses

Other Problems to Be Considered

Chronic myelomonocytic leukemia
Malignancies with bone marrow fibrosis

Diagnose agnogenic myeloid metaplasia with caution in patients with another malignancy. The bone marrow involvement in carcinomas or lymphomas may be associated with marrow fibrosis. In these situations, the fibrosis reverses after effective treatment of the underlying disease. Similarly, marrow fibrosis may result in cases of granulomatous involvement of the bone marrow, as in histoplasmosis and tuberculosis.

Workup

Laboratory Studies

• Complete blood cell (CBC) count
  • A CBC panel with careful examination of the peripheral smear is essential in patients thought to have agnogenic myeloid metaplasia.
  • Peripheral blood reveals leukoerythroblastosis with teardrop poikilocytosis. Large platelets and megakaryocyte fragments may be observed.
  • Anemia is present in most patients with agnogenic myeloid metaplasia, with more than 60% having a hemoglobin concentration of less than 10 g/dL. Causes of anemia include hemodilution, ineffective erythropoiesis, and shortened RBC survival. Approximately 15% of patients also experience a major hemolytic episode during the course of the illness. This may result from an erythrocyte defect similar to that observed in paroxysmal nocturnal hemoglobinuria or from antibodies to RBCs. Anemia resulting from blood loss or folate deficiency (because of increased consumption) may also occur.
  • Leukopenia is observed in up to one fourth of patients with agnogenic myeloid metaplasia, whereas leukocytosis may be observed in one third. A small number of blasts and Pelger-Huet cells are observed.
  • Thrombocytosis is more common than thrombocytopenia. DIC is observed in 15% of patients. The condition is usually clinically silent, but changes in the form of decreased platelets, decreased clotting factors, and increased fibrin degradation products may be observed. Such changes may result in excessive bleeding at the time of surgery. Obtaining a preoperative DIC panel may therefore be prudent.
• JAK2V617F mutation can be detected in approximately 50–60% of patients with agnogenic myeloid metaplasia.^11,12,13

Imaging Studies

• Skeletal radiographs show increased bone density and a prominence of bony trabeculae in those with agnogenic myeloid metaplasia. Increased bone density may be patchy, resulting in a mottled appearance.
• Magnetic resonance imaging (MRI) may help the clinician to assess the severity and progression agnogenic myeloid metaplasia. Marrow patterns observed on an MRI examination of the proximal femur appear to correlate with clinical severity.
• Liver and splenic enlargement is observed on ultrasonograms and computed tomography (CT) scans.

Other Tests

• Cytogenetic studies of bone marrow are helpful in excluding CML, myelodysplastic syndrome, or other chronic myeloid disorders. However, these may be difficult to obtain due to "dry tap" on bone marrow aspirates in over 50% of patients with agnogenic myeloid metaplasia. FISH studies or PCR testing for bcr:abl may be helpful to exclude CML (this my be performed on peripheral blood also). Fluorescent in situ hybridization (FISH) studies for abnormalities associated with myelodysplastic syndromes, such as del 7, 7q–, 5q– etc may be helpful.

Procedures

• Obtaining bone marrow aspirate and biopsy specimens is important to help establish the diagnosis of agnogenic myeloid metaplasia. This is usually performed over the posterior iliac crest, using specialized needles. Aspirate may also be obtained from over the sternum, although most physicians prefer the posterior iliac crest. Biopsy specimens should not be obtained from the sternum. Sternal aspirates are typically not useful because of the high frequency of dry taps and an inability to obtain a biopsy from this site. Obtaining studies for bcr:abl gene rearrangement is also important to exclude CML.

Histologic Findings

Bone marrow aspirates are dry in up to 50% of patients with agnogenic myeloid metaplasia. Performing a bone marrow biopsy is essential for confirming the diagnosis. Biopsy specimens reveal hypercellular marrow with increased megakaryocytes. Characteristic features of agnogenic myeloid metaplasia include patchy hematopoietic cellularity and reticular fibrosis. The amount of reticulin deposition varies from field to field. Megakaryocytes may be present in clusters and may show dysplasia. Distended marrow sinusoids, frequently containing intravascular hematopoiesis, are also observed.

Cytogenetic studies reveal chromosomal abnormalities in 50-60% of patients. The presence of an abnormal karyotype is associated with a poorer prognosis.

Liver biopsy specimens usually reveal normal histology or minimal portal fibrosis. Thrombotic lesions may occur in portal veins. Hepatic vein thrombosis may occur.

Treatment

Medical Care

Therapy for agnogenic myeloid metaplasia is mainly supportive. None of the current treatments has been shown to consistently prolong survival. Asymptomatic patients may be observed without intervention. Anemia and thrombocytopenia may be severe and require transfusional support. Use allopurinol to keep uric acid levels within the reference range. Patients agnogenic myeloid metaplasia who have hemolysis should receive folic acid supplementation. The anemia is usually unresponsive to the administration of exogenous erythropoietin.

• Chemotherapeutics
  • Chemotherapeutics have mainly been used as cytoreductive therapy to control leukocytosis, thrombocytosis, or organomegaly.
  • Hydroxyurea is the preferred agent, but other agents (eg, interferon, cladribine) have also been used. Busulfan has been used, but it is not a preferred agent in view of the lesser toxicity of hydroxyurea. Patients with agnogenic myeloid metaplasia are especially prone to developing myelotoxicity with these agents, which should therefore be used with caution.
  • Interferon alfa is a viable alternative to hydroxyurea therapy, especially in young patients (<45 y), who have a long life expectancy. Response rates of 50% have been observed, with improvement in splenomegaly and blood cell counts. Results are best in patients with elevated counts.¹⁴
  • Aggressive chemotherapy to induce remissions has been used; however, despite aggressive chemotherapy, hematologic remissions are rare and do not change the overall course of the disease.
• Radiation therapy
  • Radiation may be used to treat symptomatic extramedullary hematopoiesis. This therapy is also beneficial for bone pain resulting from tumors or periostitis.
  • Splenic irradiation may be considered for patients in whom splenectomy is contraindicated. Splenic radiation is beneficial to patients with symptomatic splenomegaly or splenic infarction. The effects are usually temporary (median duration, 6 mo).¹⁵
  • After splenic irradiation, prolonged pancytopenia may occur (25% of patients). Splenectomy after splenic irradiation is associated with a very high risk of intra-abdominal hemorrhage; accordingly, reserve this therapy only for patients in whom surgery is contraindicated.
• Androgens and corticosteroids: These agents have been used to treat patients with severe anemia and are administered to improve symptoms and to decrease transfusional requirements. Approximately 30% of patients respond to therapy.
• Thalidomide with prednisone: Studies using low-dose thalidomide (50 mg) and prednisone showed lesser side effects than higher doses of thalidomide.^{16,17,18,19,20,21,22,23} Some patients develop significant increase in white blood cell (WBC) or platelet counts usually in first 4-8 weeks and may require additional cytoreductive therapy. In a study of 21 symptomatic patients an objective clinical response was demonstrated in 13 (62%) patients, all improvements in anemia.¹⁶ Among 10 patients who were dependent on erythrocyte transfusions, 7 (70%) improved and 4 (40%) became transfusion independent. Among 8 patients with thrombocytopenia (platelet count < 100 × 10⁹/L), 6 (75%) experienced a 50% or higher increase in their platelet count. In 4 of 21 patients (19%), spleen size decreased by more than 50%.
• Lenalidomide is a thalidomide analogue that is much more potent than thalidomide. It is approved for treatment of multiple myeloma and for patients with 5q– syndrome myelodysplastic syndrome. A study of 68 patients with symptomatic myelofibrosis and myeloid metaplasia revealed overall response rates of 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia.²⁴
• High-dose chemotherapy: This modality combined with autologous transplantation has been shown to slow disease progression. In a small study, evidence of improvement in fibrosis was noted.
• Allogeneic stem cell transplantation
  • Allogeneic stem cell transplantation is a potentially curative therapy in patients with agnogenic myeloid metaplasia. Long-lasting, complete remissions have been reported. Regression of marrow fibrosis occurs following successful allogeneic transplantation.
  • Patients with hemoglobin values below 10 g/dL, karyotypic abnormalities, osteomyelosclerosis, and older age appear to have poorer outcomes. The 1-year mortality rate for persons receiving human leukocyte antigen (HLA)-identical sibling transplants is approximately 30%.
  • Newer nonmyeloablative transplantations may improve the overall outcome by decreasing the early mortality observed after conventional high-dose chemotherapy – based transplantation regimens.
• Investigational drugs: Several new investigational drugs are being studied, including farnesyl transferase inhibitors,^25,26 tyrosine kinase inhibitors,¹² vascular endothelial growth factor inhibitors,^27,28 and also JAK2 inhibitors.

Surgical Care

Patients with agnogenic myeloid metaplasia who require surgery are best treated under the supervision of an experienced hematologist. Patients with agnogenic myeloid metaplasia are prone to developing problems with bleeding, infections, and thromboses. A high risk of perioperative mortality has been reported in patients undergoing splenectomy. No clear data are available for optimal preoperative management.

Obtain CBC and platelet counts, and order studies to assess for subclinical DIC. Consider patients with significant thrombocytosis for cytoreductive therapy to decrease platelet counts to the reference range. Patients with agnogenic myeloid metaplasia who experience problems with bleeding may require platelet transfusions and infusions of cryoprecipitate, based on coagulation parameters.

• Splenectomy
  • Splenectomy may be considered for patients with overt portal hypertension, progressive anemia requiring transfusions, or symptomatic splenomegaly refractory to hydroxyurea.
  • Splenectomy has also been used in patients with severe thrombocytopenia; however, one review reported a lack of a sustained benefit in this situation.
  • Splenectomy has been associated with a significant risk of operative mortality and morbidity from infections, hemorrhage, and thrombosis. Mortality rates of up to 38% have been reported, although other reports estimate the operative mortality rate to be approximately 9%.
  • Patients with agnogenic myeloid metaplasia may develop marked hepatomegaly and thrombocytosis after splenectomy, which may be minimized by close monitoring and the appropriate use of cytoreductive therapy. Aplastic crises do not occur following splenectomy because bone marrow continues to be the predominant site of hematopoiesis.
  • Splenectomy is reportedly associated with a higher rate of transformation to acute myelogenous leukemia (AML). A study reported a cumulative transformation rate of 55% in splenectomized patients compared with 27% in nonsplenectomized patients. Splenectomy was considered an independent risk factor for transformation to AML.

Consultations

Consultation with a hematologist may be helpful when caring for patients with agnogenic myeloid metaplasia.

Medication

Therapy for agnogenic myeloid metaplasia is mainly supportive and is used to control symptoms and decrease transfusion requirements. No treatment for agnogenic myeloid metaplasia consistently prolongs survival.

Antineoplastic Agents

Antineoplastic agents are predominantly used as cytoreductive therapy to control leukocytosis, thrombocytosis, and organomegaly. Patients with agnogenic myeloid metaplasia are especially prone to developing myelotoxicity with these agents; therefore, use them with caution.

Hydroxyurea (Droxia, Hydrea)

Inhibitor of deoxynucleotide synthesis. Less leukemogenic than alkylating agents (busulfan). Myelosuppressive effects last a few days to a week and are easier to control than those associated with alkylating agents. Lethal to cells in the S phase and is cell-cycle specific.

Used mainly to control counts and alleviate constitutional symptoms or symptoms resulting from hepatic enlargement. Can be administered at higher doses in patients with extremely high WBC counts (>300,000/µL) and adjusted accordingly as WBC and platelet counts fall. Can be administered as a single daily dose or divided into 2-3 doses at a higher dose range.

Dosing

Adult

Not established; initial suggested dose, 500 mg PO qd, not to exceed 800 mg/m² q4h; allow 3-4 d for change in blood cell counts; best administered under the guidance of an experienced hematologist/oncologist

Pediatric

Not established; initial suggested dose, 15 mg/kg/d PO qd; allow 3-4 d for change in blood cell counts

Interactions

Coadministration with fluorouracil can increase neurotoxicity.

Contraindications

Documented hypersensitivity; leukopenia (<2500 WBC/µL); thrombocytopenia (<100,000 WBC/µL); severe anemia

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

Therapy requires close supervision; complete blood cell status (bone marrow examination and kidney and liver function) should be determined before and repeatedly during treatment; monitor the patient's hemoglobin level and total leukocyte and platelet counts at least qwk; if the WBC count decreases to <2500/µL or the platelet count is <100,000/µL, therapy should be interrupted until the reference range levels return; if anemia occurs, manage with whole blood replacement without interrupting hydroxyurea therapy.

Busulfan (Myleran, Busulfex)

Potent cytotoxic drug that, at the recommended dosage, causes profound myelosuppression. As an alkylating agent, the mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Dosing

Adult

Not established; suggested dose, 2 mg/d PO and adjusted based on blood cell counts; best administered under the guidance of an experienced hematologist/oncologist

Pediatric

Not established

Interactions

CYP3A3/4 enzyme substrate; acetaminophen, cyclophosphamide, itraconazole, and thioguanine may increase toxicity; phenytoin may decrease levels

Contraindications

Documented hypersensitivity; severely depressed bone marrow function; women who are breastfeeding; failure to respond to previous treatment

Precautions

Pregnancy

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

Precautions

Regularly examine the patient's hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; may cause pulmonary fibrosis; if the WBC count is high, hydration and allopurinol should be used to prevent hyperuricemia

Cladribine (Leustatin)

Synthetic antineoplastic agent for continuous IV infusion. The enzyme deoxycytidine kinase phosphorylates this compound into active 5'-triphosphate derivative, which then breaks DNA strands and inhibits DNA synthesis. Disrupts cell metabolism, causing death to both resting and dividing cells.

Dosing

Adult

Not established; suggested dose, 0.05 mg/kg/d IV for 7 d; may repeat cycle if needed; best administered under the guidance of an experienced hematologist/oncologist

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

Caution in patients with a history of hematologic or immunologic dysfunctions; neurotoxicity may occur

Interferon alfa-2a and interferon alfa-2b (Roferon-A and Intron A)

Protein product manufactured by recombinant DNA technology. The mechanism of antitumor activity is not clearly understood, but direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Dosing

Adult

Not established; suggested dose, 5 million U SC/IM 3-5 times/wk for maintenance may decrease to 3 million U SC/IM 3 times/wk; adjust dose based on the blood cell counts

Pediatric

Not established

Interactions

Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity.

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

Caution patients with in brain metastases, severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, or a compromised CNS.

Androgens

Androgens improve symptoms of anemia and decrease transfusion requirements in patients with agnogenic myeloid metaplasia.

Oxymetholone (Anadrol-50)

Used to manage anemias resulting from deficient RBC production.

Dosing

Adult

2-4 mg/kg/d PO

Pediatric

Neonates: 0.175 mg/kg/d PO

>1 month: 1-2 mg/kg/d PO

Interactions

May increase the sensitivity of anticoagulants

Contraindications

Documented hypersensitivity; males with prostate or breast cancer; females with breast cancer with hypercalcemia, those who are pregnant, and those who are breastfeeding; nephrosis; severe hepatic dysfunction

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Anabolic steroid; may cause virilization in women; may cause hepatotoxicity, decrease HDL-C level, and increase LDL-C level

Corticosteroids

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Sterapred, Meticorten)

Inhibits phagocytosis of platelets and may improve RBC survival.

Dosing

Adult

1 mg/kg/d PO initial

Pediatric

Administer as in adults.

Interactions

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

Contraindications

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

Precautions

Pregnancy

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

Precautions

Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible.

Immunomodulators

Agents in this category may have antiangiogenesis and immunomodulatory effects.

Thalidomide (Thalomid)

The mechanism of action not clearly known, but it is thought to work by immunomodulatory effects and antiangiogenesis.

Dosing

Adult

Doses from 50-800 mg PO have been used; for agnogenic myeloid metaplasia, lower doses may be better tolerated and have similar efficacy.

Pediatric

<12 years: Not established

>12 years: Administer as in adults.

Interactions

Increases the risk of thromboembolism with darbepoetin alfa and docetaxel; may increase the sedative effects of alcohol, barbiturates, chlorpromazine, and reserpine

Contraindications

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

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

In the late 1950s, up to 12,000 birth defects, primarily phocomelias, were associated with the use of thalidomide during pregnancy; exposure resulted in eye disorders in 46 (54%) patients and included ocular mobility defects, facial palsy, and abnormal lacrimation; other abnormalities observed following exposure included facial hemangioma and esophageal or duodenal atresia, anomalies of the heart, kidney, external ears, central nervous system, and GI tract have also been reported; avoid hazardous tasks, such as operating motor vehicles or dangerous machinery; can cause severe birth defects; concomitant use of substances associated with peripheral neuropathy; severe skin reactions during therapy may indicate hypersensitivity; may cause moderate to severe peripheral neuropathy that may be irreversible; may increase HIV viral load in HIV-seropositive patients, neutropenic patients; patients with a history of seizures or risk factors for seizures; increased incidence of thrombotic events

Lenalidomide (Revlimid)

A thalidomide analogue, is an immunomodulatory agent with anti-angiogenic and anti-neoplastic properties.

Dosing

Adult

10 mg PO qd; start at 5 mg PO qd for patients with platelet counts <100,000

Pediatric

Not established

Interactions

May increase digoxin levels (monitor digoxin levels if coadministered)

Contraindications

Documented hypersensitivity to drug or components; 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 (the program requires mandatory pregnancy testing and limits prescription to a 1-mo supply via mail); male patients, including those with vasectomy, must use latex condoms 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 the decrease dose); not break, chew, or open the cap

Follow-up

Complications

• Portal hypertension occurs in approximately 7% of patients with agnogenic myeloid metaplasia and may be related to increased portal flow resulting from marked splenomegaly and to intrahepatic obstruction resulting from thrombotic obliteration of small portal veins. This may result in variceal bleeding or ascites. Hepatic or portal vein thrombosis may occur. Symptomatic portal hypertension is managed by splenectomy, with or without the creation of a portosystemic shunt.
• Splenic infarction may occur and results in an acute or subacute onset of severe pain in the left upper quadrant that may be associated with nausea, fever, and referred left shoulder discomfort. The episode is usually self-limited and may last several days. Treat patients with hydration and opiate analgesics. Individuals with refractory cases of agnogenic myeloid metaplasia may require splenectomy or splenic irradiation.
• Extramedullary hematopoiesis may involve any organ, and symptoms depend on the organ or site of involvement. Extramedullary hematopoiesis may result in GI tract bleeding, spinal cord compression, seizures, hemoptysis, and/or effusions. These are easily controlled with low-dose radiation.
• Patients with agnogenic myeloid metaplasia are also prone to developing infectious complications because of defects in humoral immunity.
• Osteosclerosis, hypertrophic osteoarthropathy, and periostitis may occur, resulting in significant pain and discomfort. This may require the administration of nonsteroidal anti-inflammatory drugs or opioid analgesics.
• Gout or urate stones may develop as a result of uric acid overproduction. Allopurinol should be used to keep uric acid in the reference range.

Prognosis

• The median length of survival for patients with agnogenic myeloid metaplasia is 3.5-5.5 years. The 5-year survival rate is about half of that expected for age- and sex-matched controls. Less than 20% of patients are expected to be alive at 10 years. The common causes of death in those with agnogenic myeloid metaplasia are infections, hemorrhage, cardiac failure, postsplenectomy mortality, and leukemic transformation.
• Advanced age and anemia are associated with shorter survival.
• Other poor prognostic factors of agnogenic myeloid metaplasia include the presence of hypercatabolic symptoms, leukocytosis (leukocyte count, 10,000-30,000/μL), leukopenia, circulating blasts, increased numbers of granulocyte precursors, thrombocytopenia (platelet count, <100,000/μL), and karyotype abnormalities.
• A simple scoring system to determine the prognosis in agnogenic myeloid metaplasia has been proposed.²⁹ This system uses 2 adverse prognostic factors: a hemoglobin value less than 10 g/dL and a total WBC count less than 4000/μL or greater than 30,000/μL. Patients with no risk factors are at low risk, those with both the risk factors are at high risk, and those with a single risk factor are at intermediate risk. Median survival times for low-risk groups are 93 months; intermediate-risk groups, 26 months; and high-risk groups, 13 months.
• Low-risk patients with an abnormal karyotype have a worse outcome than those with a normal karyotype (median survival, 50 mo vs 112 mo).
• Leukocytosis (>30,000/μL) and abnormal karyotype have reportedly been associated with increased risk of transformation to AML.
• Bone marrow vascularity is significantly increased in patients with agnogenic myeloid metaplasia. Increased bone marrow microvascular density has also been reported in approximately 70% of patients with agnogenic myeloid metaplasia, and it is an independent poor prognostic factor for survival.

Miscellaneous

Medicolegal Pitfalls

• A diagnosis of agnogenic myeloid metaplasia must be carefully considered, especially in patients with other malignancies or granulomatous disorders. These patients may have findings of marrow fibrosis as observed in agnogenic myeloid metaplasia. A misdiagnosis of agnogenic myeloid metaplasia in a patient with a potentially curable disorder could result in a lawsuit. Performing testing for bcr:abl gene rearrangements is important to exclude CML.
• Patients with agnogenic myeloid metaplasia who require a splenectomy should be well counseled regarding the risks and benefits of the procedure. Splenectomy has been associated with a significant risk of perioperative mortality and complications. Careful preoperative counseling may help avoid legal problems.

Multimedia

Media file 1: Peripheral smear from a patient with agnogenic myeloid metaplasia. This image shows the presence of teardrop red blood cells (RBCs) and a leukoerythroblastic picture with the presence of nucleated RBC precursors and immature myeloid cells. Courtesy of Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.

Media file 2: Bone marrow biopsy from a patient with agnogenic myeloid metaplasia. This image shows extensive fibrosis. Courtesy of Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.

Media file 3: Reticulin stain on a bone marrow biopsy from a patient with agnogenic myeloid metaplasia. This image shows extensive fibrosis. Courtesy of Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.

Media file 4: Extramedullary hematopoiesis in the spleen of a patient with agnogenic myeloid metaplasia. Courtesy of Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.

References

1. Heuck G. Zwei Falle von Leukemie mit eigenthumlichen Blutresp. Knockenmarksbefund. Arch Pathol Anat Physiol Virchows. 1879;78:475-96.

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Keywords

agnogenic myeloid metaplasia with myelofibrosis, AMM, agnogenic myeloid metaplasia, myeloid metaplasia, idiopathic myelofibrosis, aleukemic myelosis, nonleukemic myelosis, myelosclerosis, leukoerythroblastic anemia with diffuse osteosclerosis, megakaryocytic splenomegaly, anemia, bone marrow fibrosis, extramedullary hematopoiesis, leukoerythroblastosis, hepatosplenomegaly, hematopoietic system, chronic myeloid leukemia, CML, chronic myelogenous leukemia, chronic myelocytic leukemia, polycythemia vera, essential thrombocytosis

Contributor Information and Disclosures

Author

Asheesh Lal, MBBS, MD, Physician, Department of Internal Medicine, Lexington Medical Center
Asheesh Lal, MBBS, MD is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching

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Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
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Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Related eMedicine Topics

• Myelodysplastic Syndrome
• Myeloproliferative Disease

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