Agnogenic Myeloid Metaplasia With

Myelofibrosis

Author: Asheesh Lal, MBBS, MD; Chief Editor: Emmanuel C Besa, MD

Updated: Mar 26, 2012Background

Agnogenic myeloid metaplasia with myelofibrosis 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. (See
Etiology.)[5]
The disorder is characterized by anemia, bone marrow fibrosis (myelofibrosis),
extramedullary hematopoiesis, leukoerythroblastosis, teardrop-shaped red blood cells
(RBCs) in peripheral blood, and hepatosplenomegaly (see the image below). (See
Workup.)

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.

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. (See Clinical, Workup, and
Treatment.)
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. (See
Clinical and Treatment.)
Extramedullary hematopoiesis may involve any organ, and symptoms depend on the
organ or site of involvement. It may result in gastrointestinal (GI) tract bleeding, spinal
cord compression, seizures, hemoptysis, and/or effusions. These are easily controlled
with low-dose radiation. (See Treatment.)
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 antiinflammatory drugs (NSAIDs) 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.
For patient education information, see the Cancer Center, as well as Anemia.

Etiology
In patients with agnogenic myeloid metaplasia, the hematopoietic system is most
affected. Other organ systems may be involved via extramedullary hematopoiesis. (See
the image below.)

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.
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-),
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- 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 medullary and extramedullary hematopoiesis. Increased serum
vascular endothelial growth factor levels have been postulated as the underlying
mechanism for increased angiogenesis.

Risk factors
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.[6, 7, 8, 9]
A study by Fredericksen et al found that patients with chronic myeloproliferative
neoplasms have an increased incidence of secondary hematologic and nonhematologic
cancers. Patients with essential thrombocytopenia had a standardized incidence ratio for
developing nonhematologic cancer of 1.2; patients with polycythemia vera had a ratio of
1.6; and patients with CML had a ratio of 1.6.[10]

Epidemiology
Agnogenic myeloid metaplasia is an uncommon disease, with an annual incidence of
approximately 0.5-1.5 cases per 100,000 individuals in the United States. The worldwide
incidence of the disorder is unknown.

Race-, sex-, and age-related demographics

Agnogenic myeloid metaplasia appears to be more common in white people than in
individuals of other races. In addition, an increased prevalence rate of the disorder has
been noted in Ashkenazi Jews.
A slight male preponderance appears to exist for agnogenic myeloid metaplasia; however,
in younger children, girls are affected twice as frequently as boys.
Agnogenic myeloid metaplasia characteristically occurs in individuals over age 50 years,
with the median age at diagnosis being approximately 65 years. However, the disease 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 in children usually occurs in the first 3 years of life.

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.[11] The common
causes of death in patients with agnogenic myeloid metaplasia are infections,
hemorrhage, cardiac failure, postsplenectomy mortality, and leukemic transformation.
Leukemic transformation occurs in approximately 20% of patients with agnogenic
myeloid metaplasia within the first 10 years.
Advanced age and anemia are associated with shorter survival, and renal failure, hepatic
failure, and thrombosis have also been reported as causes of death.
Other poor prognostic factors of agnogenic myeloid metaplasia include the presence of
hypercatabolic symptoms, leukocytosis (leukocyte count of 10,000-30,000/L),
leukopenia, circulating blasts, increased numbers of granulocyte precursors,
thrombocytopenia (platelet count of < 100,000/L), and karyotype abnormalities.
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.

Scoring systems
A simple scoring system to determine the prognosis in agnogenic myeloid metaplasia has
been proposed.[12] This system uses 2 adverse prognostic factors: a hemoglobin value of
less than 10 g/dL and a total white blood cell (WBC) count of less than 4000/L or
greater than 30,000/L. 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 do those with a
normal karyotype (median survival, 50 mo vs 112 mo). Leukocytosis (>30,000/L) and
abnormal karyotype have reportedly been associated with increased risk of
transformation to acute myelogenous leukemia (AML).
The Dynamic International Prognostic Scoring System (DIPSS) for primary
myelofibrosis uses the following 5 risk factors to predict survival:

Age older than 65 years

Hemoglobin level lower than 10 g/dL
Leukocyte count higher than 25 109/L
Circulating blasts of 1% or more
Constitutional symptoms

A 2011 study was carried out to refine the DIPSS by incorporating prognostic
information from karyotype, platelet count, and transfusion status. The study also found
that the presence of either unfavorable karyotype or thrombocytopenia predicted inferior
leukemia-free survival.[13]

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 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 (see the image below). 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.

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.

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 Examination
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 found in 60-70% of patients with agnogenic myeloid metaplasia, and
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%).

Diagnostic Considerations
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.
Performing testing for bcr:abl gene rearrangements is important to exclude CML.
JAK2V617F mutation can be detected in approximately 5060% of patients with
agnogenic myeloid metaplasia.[14, 15, 16]

Differential Diagnoses

Chronic Myelogenous Leukemia

Hairy Cell Leukemia
Histoplasmosis
Myelodysplastic Syndrome
Polycythemia Vera
Thrombocytosis, Essential
Tuberculosis

Complete Blood Count

A complete blood count (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, as depicted in the image
below. Large platelets and megakaryocyte fragments may be observed.

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.

Anemia
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 and leukocytosis

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 and DIC

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.

Imaging Studies
Skeletal radiographs show increased bone density and a prominence of bony trabeculae in
persons 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.

Genetic Testing
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. Fluorescent in situ hybridization (FISH) studies or polymerase chain
reaction (PCR) assay testing for bcr:abl may be helpful in excluding CML (this may also
be performed on peripheral blood). FISH studies for abnormalities associated with
myelodysplastic syndromes, such as del 7, 7q-, and 5q-, may also be helpful.

Procedures and Histologic Findings

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. Biopsy specimens should not be obtained from the
sternum; sternal aspirates are typically not useful because of the high frequency of dry
taps and the inability to obtain a biopsy from this site.

Histology
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.
(See the images below.)

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.
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.
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.

Approach Considerations
Historically, therapy for agnogenic myeloid metaplasia was mainly supportive. Patients
received transfusions as needed. Thrombocytosis could be managed with hydroxyurea
and other palliative agents. Low-risk, asymptomatic patients may be observed without
intervention. Patients with milder disease may still be treated with supportive therapies.

Pharmacologic Therapy
Chemotherapeutics
The JAK1/JAK2 inhibitor, ruxolitinib (Jakafi), is the first chemotherapeutic agent to be
approved by the US Food and Drug Administration (FDA) for the treatment of
myelofibrosis. The November 2011 approval was based on the results of the COMFORTI and COMFORT-II trials. A gain-of-function mutation (VG17F) in JAK2 is present in
50% of all patients with myelofibrosis and contributes to the pathophysiology of the
disease. Thus, inhibition of this target is a potential therapeutic option.

In the COMFORT-1 trial, patients with intermediate-2 or high-risk myelofibrosis were

randomized to either ruxolitinib (either 15 mg or 20 mg PO bid) or placebo. The primary
endpoint was the proportion of patients with 35% or higher reduction in spleen volume at
week 24 of therapy, assessed by MRI or CT. The primary endpoint response rate was
41.9% for ruxolitinib compared with 0.7% for placebo. The most common adverse events
of any grade were abdominal pain (10.3% vs 41.1%), thrombocytopenia (34.2% vs
9.3%), fatigue (25.2% vs 33.8%), anemia (31% vs 13.9%), diarrhea (23.2% vs 21.2%),
and peripheral edema (18.7% vs 22.5%).
The Comfort-II trial was a randomized phase III study that compared the efficacy and
safety of ruxolitinib with best available therapy in patients with intermediate-2 or highrisk primary myelofibrosis, post-polycythemia vera-myelofibrosis, or post-essential
thrombocythemia-myelofibrosis, and palpable splenomegaly. The primary endpoint was
the proportion of patients achieving at least 35% reduction in spleen volume at week 48
as determined by MRI. The response rate was 28% for ruxolitinib compared with 0% for
the control arm. The most common adverse events were thrombocytopenia, anemia,
diarrhea, and edema.
A double-blind placebo-controlled trial by Verstovsek et al randomized patients with
intermediate-2 or high-risk primary myelofibrosis to twice-daily oral ruxolitinib (n=155)
or placebo (n=154). The primary endpoint was the proportion of patients achieving at
least 35% reduction in spleen volume at week 24 as determined by MRI, which was
reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the
placebo group. This reduction in spleen volume was maintained for 48 weeks in 67% of
the patients. Anemia and thrombocytopenia were the most common adverse events, with
2 patients in ruxolitinib group having transformation to acute myeloid leukemia.[17]
A clinical trial by Harrison et al also found reductions in splenomegaly and other diseaserelated symptoms, improvements in quality of life, and modest toxic effects with oral
ruxolitinib versus the best available therapy.[18]
Older chemotherapeutics have mainly been used as cytoreductive therapy to control
leukocytosis, thrombocytosis, or organomegaly. Hydroxyurea is the preferred agent, but
other drugs (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.[19]
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.

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 reduced side effects
in comparison with higher doses of thalidomide. Some patients develop a significant
increase in WBC or platelet counts, usually in the first 4-8 weeks, and may require
additional cytoreductive therapy.[20, 21, 22, 23, 24, 25, 26, 27]
In a study in which low-dose thalidomide and prednisone were administered to 21
symptomatic patients suffering from myelofibrosis with myeloid metaplasia, an objective
clinical response was demonstrated in 13 (62%) patients, all improvements in anemia. [20]
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.[28]

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,[29, 30] tyrosine kinase inhibitors,[15] vascular endothelial growth factor inhibitors,
[31, 32]
and Janus kinase 2 (JAK2) inhibitors.
Although thalidomide and lenalidomide can alleviate anemia in myelofibrosis, their use is
limited by their respective potential to cause peripheral neuropathy and
myelosuppression. Pomalidomide is a second-generation thalidomide analogue with
reduced toxicity and enhanced anticancer and immunological activity.
A study by Tefferi et al found pomalidomide to be effective against myelofibrosisassociated anemia. The investigators conducted a phase II, randomized, multicenter,
double-blind, adaptive study of 4 treatment arms of pomalidomide, including
pomalidomide at a dose of 2 mg/day plus placebo, pomalidomide at a dose of 2 mg/day
plus prednisone, pomalidomide at a dose of 0.5 mg/day plus prednisone, and prednisone
plus placebo.[33] Pomalidomide was administered for as many as 12 treatment cycles
lasting 28 days. During the first 3 cycles, prednisone (30 mg/d) was administered via a
tapering dose schedule. Of 84 patients with myelofibrosis-associated anemia who were
randomized, response in anemia was documented in 20 patients, including 15 who
became transfusion independent.
The response rates were 23%, 16%, 36%, and 19%, respectively. With or without
pomalidomide, the response was durable (range, 3.2-16.9+ mo) and was significantly
better in patients without leukocytosis (37% vs 8%; P =.01). The presence of JAK2
V617F and the cytogenetic status did not affect the response. Toxicities of grade 3 or
higher were infrequent and included neutropenia (9%, 16%, 5%, and 5%, respectively),
thrombocytopenia (14%, 16%, 9%, and 5%, respectively), and thrombosis (9%, 5%, 0%,
and 0%, respectively).
In addition to dysregulated JAK/STAT signaling, activation of the AKT/mTOR pathway
occurs in myelofibrosis. Guglielmelli et al conducted a phase 1/2 study with everolimus,
an mTOR inhibitor, in 39 high-risk or intermediate-risk subjects with primary or
postpolycythemia vera/post-essential thrombocythemia myelofibrosis. [34] Responses were
evaluated in 30 patients of phase 2. No dose-limiting toxicity was observed in doses of as
much as 10 mg/d. The most common toxicity was grade 1-2 stomatitis. Rapid and
sustained splenomegaly reduction of more than 50% and more than 30% was observed in
20% and 44% of subjects, respectively.
A total of 69% and 80% of patients experienced complete resolution of systemic
symptoms and pruritus, respecitvely. Response in leukocytosis, anemia, and
thrombocytosis occurred in 15%-25% of patients. Clinical responses were not associated
with reduced JAK2 V617F burden, circulating CD34+ cells, or cytokine levels, whereas
CCDN1 mRNA and phospho-p70S6K level, known targets of mTOR, and WT1 mRNA
were identified as possible biomarkers associated with response.

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.
Patients with agnogenic myeloid metaplasia who require surgery are best treated under
the supervision of an experienced hematologist, because splenectomy in these patients
has been associated with a significant risk of operative mortality and morbidity from
infections, hemorrhage, and thrombosis. Mortality rates in splenectomized patients of up
to 38% have been reported, although other reports estimate the operative mortality rate to
be approximately 9%. 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.
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 AML. A
study reported a cumulative transformation rate of 55% in splenectomized patients,
compared with 27% in nonsplenectomized patients. Splenectomy was considered to be an
independent risk factor for transformation to AML.

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 radiation is beneficial to patients with symptomatic splenomegaly or splenic
infarction, although the effects are usually temporary (median duration, 6 mo).[35]
After splenic irradiation, prolonged pancytopenia may occur (25% of patients). In
addition, splenectomy after splenic irradiation is associated with a very high risk of intraabdominal hemorrhage. Accordingly, reserve splenic irradiation only for patients in
whom surgery is contraindicated.

Medication Summary
As previously stated, chemotherapeutics have mainly been used as cytoreductive therapy
to control leukocytosis, thrombocytosis, or organomegaly. Hydroxyurea is the preferred
agent, but other drugs (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.
Ruxolitinib is indicated for myelofibrosis and is an effective agent to reduce
splenomegaly. Patients with agnogenic myeloid metaplasia are especially prone to
developing myelotoxicity with these agents, which should therefore be used with caution.

Antineoplastic Agents
Class Summary
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.
View full drug information

Hydroxyurea (Droxia, Hydrea)

Hydroxyurea is an inhibitor of deoxynucleotide synthesis. It is less leukemogenic than
alkylating agents (busulfan) are. Hydroxyurea's myelosuppressive effects last a few days
to a week and are easier to control than those associated with alkylating agents. It is lethal
to cells in the S phase and is cell-cycle specific.
This agent is used mainly to control counts and alleviate constitutional symptoms or
symptoms resulting from hepatic enlargement. It can be administered at higher doses in
patients with extremely high WBC counts (>300,000/L) and adjusted accordingly as
WBC and platelet counts fall. Hydroxyurea can be administered as a single daily dose or
divided into 2-3 doses at a higher dose range.
View full drug information

Busulfan (Myleran, Busulfex)

Hydroxyurea is an inhibitor of deoxynucleotide synthesis. It is less leukemogenic than
alkylating agents (busulfan) are. Hydroxyurea's myelosuppressive effects last a few days
to a week and are easier to control than those associated with alkylating agents. It is lethal
to cells in the S phase and is cell-cycle specific.

This agent is used mainly to control counts and alleviate constitutional symptoms or
symptoms resulting from hepatic enlargement. It can be administered at higher doses in
patients with extremely high WBC counts (>300,000/L) and adjusted accordingly as
WBC and platelet counts fall. Hydroxyurea can be administered as a single daily dose or
divided into 2-3 doses at a higher dose range.
View full drug information

Cladribine (Leustatin)
Cladribine is a synthetic antineoplastic agent for continuous intravenous (IV) infusion.
The enzyme deoxycytidine kinase phosphorylates this compound into active 5'triphosphate derivative, which then breaks DNA strands and inhibits DNA synthesis.
Cladribine disrupts cell metabolism, causing death to resting and dividing cells.
View full drug information

Ruxolitinib (Jakafi)
JAK1/JAK2 kinase inhibitor indicated for treatment of patients with intermediate or highrisk myelofibrosis, including primary myelofibrosis, post-polycythemia vera
myelofibrosis, and post-essential thrombocythemia myelofibrosis. Janus-associated
kinases (JAKs) JAK1 and JAK2 mediate the signaling of a number of cytokines and
growth factors that are important for hematopoiesis and immune function.

Biological Response Modulators

Class Summary
Immunotherapy (biotherapy) currently used to treat patients with melanoma includes IFN
and IL-2.
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Interferon alfa-2b (Intron A)

This is a protein product manufactured by recombinant DNA technology. Its mechanism
of antitumor activity is not clearly understood; however, direct antiproliferative effects
against malignant cells and modulation of host immune response may play important
roles. Its immunomodulatory effects include suppression of tumor cell proliferation,
enhancement of macrophage phagocytic activity, and augmentation of lymphocyte
cytotoxicity.

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Peginterferon alfa-2b (Pegintron, Pegintron Redipen, Sylatron)

This is a protein product manufactured by recombinant DNA technology. Its 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.

Androgens
Class Summary
Androgens improve symptoms of anemia and decrease transfusion requirements in
patients with agnogenic myeloid metaplasia.
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Oxymetholone (Anadrol-50)
Oxymetholone is used to manage anemias resulting from deficient RBC production.

Corticosteroids
Class Summary
Corticosteroids have anti-inflammatory properties and cause profound and varied
metabolic effects. These agents modify the body's immune response to diverse stimuli.
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Prednisone
Prednisone inhibits phagocytosis of platelets and may improve RBC survival.
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Prednisolone (Orapred ODT, Prelone, Millipred)

Prednisolone decreases autoimmune reactions, possibly by suppressing key components
of the immune system. This agent does not need to undergo hepatic metabolism.

Immunomodulators
Class Summary
Agents in this category may have antiangiogenesis and immunomodulatory effects.
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Thalidomide (Thalomid)
Thalidomide's mechanism of action not clearly known, but the drug is thought to work by
immunomodulatory effects and antiangiogenesis.
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Lenalidomide (Revlimid)
A thalidomide analogue, lenalidomide is an immunomodulatory agent with
antiangiogenic and antineoplastic properties.