WORKUP	Section 5 of 11
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Lab Studies:

• CBC count

• A CBC panel with careful examination of the peripheral smear is essential in patients thought to have AMM.

• Peripheral blood reveals leukoerythroblastosis with teardrop poikilocytosis. Large platelets and megakaryocyte fragments may be observed.

• Anemia is present in most patients, 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 a fourth of patients, whereas leukocytosis may be observed in a third. A small number of blasts and Pelger-Huët cells are observed.

• Thrombocytosis is more common than thrombocytopenia.

• RBC mass and plasma volume studies may help determine the cause of anemia.

• 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.

Imaging Studies:

• Skeletal radiographs show increased bone density and a prominence of bony trabeculae. Increased bone density may be patchy, resulting in a mottled appearance.

• MRIs may help assess the severity and progression of disease. 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 CT scans.

Other Tests:

• Cytogenetic studies of bone marrow are helpful in excluding CML, myelodysplastic syndrome, or other chronic myeloid disorders. Various chromosomal abnormalities may occur. A recent review reported cytogenetic abnormalities in approximately 61% of patients with AMM.

Procedures:

• Obtaining bone marrow aspirate and biopsy specimens is important to help establish the diagnosis. 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. Performing a bone marrow biopsy is essential for confirming the diagnosis. Biopsy specimens reveal hypercellular marrow with increased megakaryocytes. Characteristic features 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	Section 6 of 11
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Medical Care: Therapy for AMM mainly is supportive. None of the 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 who have hemolysis should receive folic acid supplementation. 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 AMM 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 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.

• 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).

• 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: This drug is one of the most promising being investigated for AMM. Small studies have reported some improvement in anemia, thrombocytopenia, and splenomegaly. Improvements were associated with significant adverse effects, resulting in high drop-out rates. Marked increases WBC counts and/or platelets were also reported. More recent studies using low-dose thalidomide (50 mg) and prednisone showed thalidomide to be better tolerated than higher doses.

• Imatinib: Administration of imatinib mesylate has been reported to cause improvement in splenomegaly, but it is also associated with marked increases in WBC or platelet counts.

• 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.

• Investigational drugs: Several new investigational drugs are being studied, including farnesyl transferase inhibitors, tyrosine kinase inhibitors, and vascular endothelial growth factor inhibitors.

Consultations: Consultation with a hematologist may be helpful when caring for patients with AMM.

	MEDICATION	Section 7 of 11
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Therapy for AMM is mainly supportive and is used to control symptoms and decrease transfusion requirements. No treatment consistently prolongs survival.

Drug Category: Antineoplastic agents -- Predominantly used as cytoreductive therapy to control leukocytosis, thrombocytosis, and organomegaly. Patients with AMM are especially prone to developing myelotoxicity with these agents; therefore, use them with caution.

Drug Name	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 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/mL) 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.
Adult Dose	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 guidance of experienced hematologist/oncologist
Pediatric Dose	Not established; initial suggested dose, 15 mg/kg/d PO qd; allow 3-4 d for change in blood cell counts
Contraindications	Documented hypersensitivity; leukopenia (<2500 WBC/mL); thrombocytopenia (<100,000 WBC/mL); severe anemia
Interactions	Coadministration with fluorouracil can increase neurotoxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Therapy requires close supervision; complete blood status (bone marrow examination and kidney and liver function) should be determined prior to and repeatedly during treatment; monitor hemoglobin level and total leukocyte and platelet counts at least qwk; if WBC count decreases to <2500/mL or platelet count is <100,000/mL, therapy should be interrupted until reference range levels return; if anemia occurs, manage with whole blood replacement without interrupting hydroxyurea therapy

Drug Name	Busulfan (Myleran, Busulfex) -- Potent cytotoxic drug that, at recommended dosage, causes profound myelosuppression. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Adult Dose	Not established; suggested dose, 2 mg/d PO and adjusted based on blood cell counts; best administered under guidance of experienced hematologist/oncologist
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severely depressed bone marrow function; women who are breastfeeding; failure to respond to previous treatment
Interactions	CYP3A3/4 enzyme substrate; acetaminophen, cyclophosphamide, itraconazole, and thioguanine may increase toxicity; phenytoin may decrease levels
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; may cause pulmonary fibrosis; if WBC count is high, hydration and allopurinol should be used to prevent hyperuricemia

Drug Name	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.
Adult Dose	Not established; suggested dose, 0.05 mg/kg/d for 7 d; may repeat cycle if needed; best administered under guidance of experienced hematologist/oncologist
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients with history of hematologic or immunologic dysfunctions; neurotoxicity may occur

Drug Name	Interferon alfa-2a and interferon alfa-2b (Roferon-A and Intron A) -- Protein product manufactured by recombinant DNA technology. 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.
Adult Dose	Not established; suggested dose, 5 million U 3-5 times/wk for maintenance may decrease to 3 million U 3 times/wk; adjust dose based on blood cell counts
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in brain metastases, severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, or compromised CNS

Drug Category: Androgens -- Improve symptoms of anemia and decrease transfusion requirements.

Drug Name	Oxymetholone (Anadrol-50) -- Used to manage anemias resulting from deficient RBC production.
Adult Dose	2-4 mg/kg/d PO
Pediatric Dose	Neonates: 0.175 mg/kg/d PO >1 month: 1-2 mg/kg/d PO
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
Interactions	May increase sensitivity of anticoagulants
Pregnancy	X - Contraindicated in pregnancy
Precautions	Anabolic steroid; may cause virilization in women; may cause hepatotoxicity, decrease HDL-C, and increase LDL-C

Drug Category: Corticosteroids -- Have anti-inflammatory properties and cause profound and varied metabolic effects. Modify the body's immune response to diverse stimuli.

Drug Name	Prednisone (Deltasone) -- Inhibits phagocytosis of platelets and may improve RBC survival.
Adult Dose	1 mg/kg/d PO initial
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective-tissue infections; fungal or tubercular skin infections; GI tract disease
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
Pregnancy	B - Usually safe but benefits must outweigh the risks.
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

Drug Category: Immunosuppressant agents -- Interfere in processes that promote immune reactions.

Drug Name	Thalidomide (Thalomid) -- Mechanism of action not clearly known but thought to work by immunomodulatory effects and antiangiogenesis.
Adult Dose	Doses from 50-800 mg have been used; for AMM, lower doses may be better tolerated and have similar efficacy
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
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
Interactions	Increases risk of thromboembolism with darbepoetin alfa and docetaxel; may increase sedative effects of alcohol, barbiturates, chlorpromazine, and reserpine
Pregnancy	X - Contraindicated in pregnancy
Precautions	In late 1950s, up to 12,000 birth defects, primarily phocomelias, were associated with 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; void 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

Drug Category: Tyrosine kinase inhibitors -- Inhibit tyrosine kinase, which in turn inhibits activation of intracellular pathways that can promote deregulated cell proliferation.

Drug Name	Imatinib mesylate (Gleevec) -- Specifically designed to inhibit tyrosine kinase activity of the bcr-abl kinase in Ph+ CML cell lines. Well absorbed after oral administration, with maximum concentrations achieved within 2-4 h. Elimination is primarily in feces in form of metabolites.
Adult Dose	400-800 mg/d PO
Pediatric Dose	260 mg/m2/d
Contraindications	Documented hypersensitivity
Interactions	CYP3A4 inhibitors (ketoconazole increases distribution of imatinib); CYP3A4 substrates (simvastin increases maximum concentration of imatinib by a 2- to 3.5-fold factor); CYP3A4 inducers (phenytoin decreases AUC by approximately one fifth of typical AUC); likely to increase blood levels of drugs that are substrates of CYP2C9, CYP2D6, and CYP3A4/5
Pregnancy	D - Unsafe in pregnancy
Precautions	Liver or renal impairment (pharmacokinetic data are lacking; imatinib mesylate is potentially hepatotoxic); myelosuppression (exacerbation, risk of sepsis); patients at risk from fluid retention/edema (eg, congestive heart failure, hypertension); viral or bacterial infection (risk of worsening); dose must be reduced or interrupted if edema or anemia occur, transaminases or bilirubin become elevated, or grade 3-4 neutropenia or thrombocytopenia develop; pediatric patients commonly experience musculoskeletal pain

	FOLLOW-UP	Section 8 of 11
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Complications:

• Portal hypertension occurs in approximately 7% of patients and may be related to both 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. Refractory cases 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 AMM 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:

• Median length of survival for patients with AMM 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 are infections, hemorrhage, cardiac failure, postsplenectomy mortality, and leukemic transformation.

• Advanced age and anemia are associated with shorter survival.

• Other poor prognostic factors include the presence of hypercatabolic symptoms, leukocytosis (leukocyte count, 10,000-30,000/mL), leukopenia, circulating blasts, increased numbers of granulocyte precursors, thrombocytopenia (platelet count, <100,000/mL), and karyotype abnormalities.

• A simple scoring system to determine prognosis has been proposed. This system uses 2 adverse prognostic factors: hemoglobin value less than 10 g/dL and total WBC count less than 4000/mL or greater than 30,000/mL. 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-, intermediate-, and high-risk groups are 93, 26, and 13 months, respectively.

• Low-risk patients with an abnormal karyotype have a worse outcome than those with a normal karyotype (median survival, 50 mo versus 112 mo).

• Leukocytosis (>30,000/mL) and abnormal karyotype have reportedly been associated with increased risk of transformation to AML.

• Bone marrow vascularity is significantly increased in patients with AMM. Increased bone marrow microvascular density has also been reported in approximately 70% of patients and is an independent poor prognostic factor for survival.

	MISCELLANEOUS	Section 9 of 11
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Medical/Legal Pitfalls:

• A diagnosis of AMM must be carefully considered, especially in patients with other malignancies or granulomatous disorders. These patients may have findings of marrow fibrosis as observed in AMM. A misdiagnosis of AMM 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 AMM 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.

	PICTURES	Section 10 of 11
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Caption: Picture 1. Peripheral smear in agnogenic myeloid metaplasia showing the presence of teardrop RBCs and a leukoerythroblastic picture with the presence of nucleated RBC precursor and immature myeloid cells. Courtesy of Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.
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Caption: Picture 2. Bone marrow biopsy in agnogenic myeloid metaplasia showing extensive fibrosis. Courtesy of Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.
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Caption: Picture 3. Reticulin stain on bone marrow biopsy in agnogenic myeloid metaplasia showing extensive fibrosis. Courtesy of Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.
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Caption: Picture 4. Extramedullary hematopoiesis in the spleen in a patient with agnogenic myeloid metaplasia. Courtesy of Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.
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	BIBLIOGRAPHY	Section 11 of 11
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Agnogenic Myeloid Metaplasia With Myelofibrosis excerpt