Clinical manifestations and diagnosis of primary myelofibrosis

Author
Ayalew Tefferi, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Rebecca F Connor, MD
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(Spouse previously owned): Pharmacyclics [B cell lymphomas (Ibrutinib)].
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All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Aug 2014. | This topic last updated: Jan 13, 2014.
INTRODUCTION Primary myelofibrosis (PMF) [1,2], previously called chronic idiopathic
myelofibrosis (CIMF) in the 2001 WHO classification [3] and also previously known as agnogenic
myeloid metaplasia (AMM), is one of the chronic myeloproliferative disorders, which are
collectively characterized by clonal proliferation of myeloid cells with variable morphologic maturity
and hematopoietic efficiency (figure 1) [1,4].
Acute myelofibrosis, a term that has been applied to the clinical picture occasionally seen in
patients with acute megakaryoblastic leukemia (FAB M7), is discussed separately. (See
"Classification of acute myeloid leukemia".)
The clinical manifestations and diagnosis of PMF will be reviewed here [5,6]. The pathogenetic
mechanisms, prognosis, and treatment of this disorder are discussed separately. (See
"Pathogenetic mechanisms in primary myelofibrosis" and "Prognosis and treatment of primary
myelofibrosis".)
EPIDEMIOLOGY Primary myelofibrosis (PMF) is the least frequent among the chronic
myeloproliferative diseases. One study reported an estimated incidence of 1.5 per 100,000 per
year in Olmsted County, Minnesota [7]. This incidence figure is higher than those reported from
western Australia and northern Israel.
PMF occurs mainly in middle aged and elderly patients. The median age at presentation is 67
years [7]. Approximately 5 and 17 percent of the patients are diagnosed before the age of 40 and
50 years, respectively [8]. The condition is rare in childhood [9]; a familial occurrence has been
reported in several kindreds. Both the familial and the idiopathic forms in childhood may be
associated with congenital anomalies and chromosome abnormalities [10,11].
CLINICAL MANIFESTATIONS
Signs and symptoms The most common presenting complaint in primary myelofibrosis (PMF)
is that of severe fatigue, occurring in 50 to 70 percent of patients (table 1) [7,8,12-15]. Symptoms
due to an enlarged spleen have been described in 25 to 50 percent of patients, while a smaller
number note weight loss and 5 to 20 percent experience other signs of a hypermetabolic state
such as low-grade fever, bone pain, and night sweats [8,14]. Approximately 15 to 30 percent are
asymptomatic, with the diagnosis being made during investigation of splenomegaly (occurring in at
least 90 percent of patients), hepatomegaly (40 to 70 percent), or abnormal blood findings
[8,14,15]. Enlargement of the spleen and liver are due to the marked extramedullary
hematopoiesis associated with PMF.
Pulmonary hypertension Pulmonary hypertension has been detected in patients with PMF;
while often asymptomatic, it has been associated with reduced overall survival [16-18].
Pruritus In our series of 566 consecutive patients with PMF, pruritus was documented in 16
percent [19]. This symptom did not correlate with karyotype, risk category, overall survival,
leukemic transformation, or plasma levels of 20 cytokines known to be abnormally expressed in
PMF.
A symptom assessment form has been devised for measuring clinical improvement in therapeutic
trials [20].
Thrombotic events The incidence of arterial and venous thrombotic events in PMF (2 per 100
patient-years) is approximately the same as that seen in essential thrombocythemia (ET) (1 to
3/100 patient-years), and significantly lower than that seen in polycythemia vera (PV) (5.5/100
patient-years) [21]. In a retrospective analysis of 205 patients with PMF, 13.2 percent had
experienced a thrombotic event at or prior to their diagnosis, and 10.7 percent developed post-
diagnosis thrombosis at a median follow-up of 31 months [22]. On multivariate analysis, a history
of thrombosis was the only predictive variable; 71 percent of the venous events were temporally
associated with other exogenous risk factors for thrombosis (eg, surgery, central line placement,
hormonal therapy).
Splenomegaly Splenomegaly, often marked, is the hallmark of PMF [23]. The spleen may be
so large that its lower border is below the pelvic brim and its right border extends across the
midline. In two series, 38 percent of patients had splenomegaly that extended more than 10 cm
below the left costal margin [24] and 23 percent had massive splenomegaly that extended over 16
cm below the left costal margin [8].
Symptoms due to splenic disease often figure prominently in PMF. Patients may note a dragging
sensation in the left upper abdomen, and the spleen may compress the patient's stomach, leading
to early satiety. Severe left upper quadrant pain, with or without left shoulder pain, may result from
multiple and/or recurrent episodes of splenic infarction or perisplenitis.
Hepatomegaly Palpable hepatomegaly is present in 40 to 70 percent of patients. Portal
hypertension may develop as a result of increased splanchnic flow due to splenomegaly and/or
intrahepatic obstruction associated with extramedullary hematopoiesis [25]. Complications include
ascites, esophageal and gastric varices, gastrointestinal bleeding and hepatic encephalopathy.
Portal vein thrombosis is a recognized complication of PMF and other chronic myeloproliferative
disorders [25] and may precede the clinical onset of the disease [26]. (See "Risk and prevention of
venous thromboembolism in adults with cancer".)
Extramedullary hematopoiesis Foci of extramedullary hematopoiesis (EMH) may occur in
almost any organ [27-29]. Organ involvement may present as splenomegaly, hepatomegaly,
lymphadenopathy, pleural, pericardial or abdominal effusions, or involvement of the
gastrointestinal or genitourinary tracts or lung, leading to symptoms such as dysuria and
respiratory distress [30-34]. Involvement of the central nervous system may be associated with
increased intracranial pressure, altered sensorium, motor and sensory impairment, including cord
compression [35,36].
Involvement of the skin is rare, but may present as erythematous plaques, nodules, erythema,
ulcers or bullae [37,38]. In a literature review of 13 such cases, nine showed that all three
hematopoietic cell lines (myeloid, erythroid, and megakaryocytic) were present in these lesions
[39].
In our series of 27 patients with an antemortem diagnosis of extramedullary hematopoiesis other
than in the liver or spleen, involved sites were as follows [29]:
In or surrounding the vertebral column (especially thoracic) 7
Lymph nodes 4
Retroperitoneum 4
Lungs or pleura 3
Genitourinary system 2
Skin 2
Other sites (thalamus, right atrium, mouth, muscle, bowel) 5
Foci of EMH may develop and/or enlarge significantly after splenectomy, perhaps due to the loss
of filtering function of the spleen [40,41]. This may be especially critical in the liver [32,42]. As an
example, a study of 10 patients with PMF undergoing splenectomy found hepatic EMH in all those
in whom an intraoperative liver biopsy was performed [42]. Following splenectomy, a significant
increase in liver size and in serum concentrations of alkaline phosphatase, bilirubin, and/or
gamma-glutamyl transpeptidase were seen in all patients. Two patients developed acute liver
failure and died three and four weeks postsplenectomy. In contrast, no liver changes were
observed in 10 patients with chronic myeloid leukemia who also underwent splenectomy. (See
"Prognosis and treatment of primary myelofibrosis", section on 'Splenectomy'.)
Bone and joint involvement A number of skeletal changes may accompany the marrow
fibrosis in PMF. These abnormalities may be asymptomatic but can cause severe bone and joint
tenderness or pain, especially in the lower extremities, that is difficult to treat.
Osteosclerosis is characterized by a diffuse or patchy increase in bone density on radiologic
studies and increased prominence of bony trabeculae. A mottled radiographic appearance of the
bone has been described in 25 to 66 percent of patients with PMF [14]. This pattern may be
confused with metastatic carcinoma.
Periostitis can lead to debilitating bony pain.
Cortical bone blood flow is considerably increased in PMF, resulting in a "superscan"
phenomenon on bone scintigraphy. It is often clinically evident as an increase in warmth over the
tibiae and knees.
Secondary gout due to chronic overproduction of uric acid can lead to acute monoarticular or
chronic polyarticular arthritis. (See "Clinical manifestations and diagnosis of gout".)
Osteolytic lesions are rare, and usually reflect the presence of a solitary myeloid sarcoma, also
called granulocytic sarcoma or chloroma [43]. (See "Clinical manifestations, pathologic features,
and diagnosis of acute myeloid leukemia", section on 'Myeloid sarcoma'.)
LABORATORY FINDINGS
Anemia Anemia with hemoglobin less than 10 g/dL is seen in approximately 50 percent of
patients with primary myelofibrosis (PMF) and 20 percent present with a hemoglobin less than 8
g/dL [8]. The causes are multiple and include:
Reduction in medullary erythropoietic sites
Ineffective erythropoiesis associated with extramedullary sites of red blood cell (RBC) production
Splenic sequestration and destruction of circulating RBCs
Bleeding due to thrombocytopenia or other complications such as varices resulting from portal
vein thrombosis
Autoimmune hemolysis
Dilutional "anemia" may be present in patients with large spleens and expanded plasma
volumes, but normal red blood cell mass.
Influence of thrombopoietin receptor (Mpl) mutations [44]
One or more of the above mechanisms may be responsible for anemia in any particular patient. A
number of isotopic techniques are available for assessment of these mechanisms but are rarely
used [45].
After the onset of anemia, most patients experience a progressive decline in the hemoglobin
concentration, requiring frequent red blood cell transfusions. The peripheral smear is quite
characteristic, showing anisocytosis (ie, red cells of varying size), poikilocytosis (ie, red cells of
varying shape), teardrop-shaped red blood cells (dacrocytes), nucleated red blood cells, and
variable degrees of polychromasia (picture 1 and picture 2). Why dacrocytes form in PMF is not
understood; splenectomy and chemotherapy reduce, but do not eliminate, the number of such
cells in the circulation [46,47].
Platelet and white blood cell abnormalities The platelet and white blood cell (WBC) counts
are variable in PMF. Marked leukocytosis (WBC >30,000/microL) and thrombocytosis (platelet
count >500,000/microL) occur at diagnosis in approximately 11 and 13 percent of patients,
respectively, while leukopenia and thrombocytopenia are seen in 8 and 26 percent, respectively
[8,24]. The variable leukocyte count reflects variation in the number of neutrophils. Immature cells
from the neutrophilic series are always present as part of the leukoerythroblastic blood picture and
myeloblasts may be seen in the peripheral smear, usually amounting to less than 5 percent of the
total WBC count (picture 1). Hypersegmented neutrophils may also be seen (picture 3).
Thrombocytopenia becomes more common with disease progression. Platelets may be
abnormally large with altered granulation; in addition, fragmented megakaryocytes are also seen
on the peripheral smear. Abnormal platelet function is common [48] although the correlation
between these abnormalities and clinical bleeding is weak.
Bleeding complications are usually associated with thrombocytopenia, esophageal or gastric
varices, the use of nonsteroidal antiinflammatory drug, and/or acquired deficiency of factor V [49].
A few patients have mild prolongation of the prothrombin and partial thromboplastin times along
with decreased levels of factor V and VIII. Laboratory features of disseminated intravascular
coagulation (DIC) may accompany these abnormalities and may not be apparent until surgery is
performed.
Circulating CD34+ cells In an Italian multicenter study, the median absolute number of
circulating CD34+ hematopoietic precursor cells in 84 consecutive patients with PMF (92 CD34+
cells/microL; range: 0 to 2460) was 400 times that of healthy normal subjects (normal range: 0.15
to 0.35 cells/microL) [50]. A value of 15 CD34+ cells/microL in patients not on therapy could be
used diagnostically to separate patients with PMF from those with Ph chromosome-negative
chronic myeloproliferative diseases, with positive and negative predictive values of 98 and 85
percent, respectively.
In this study, CD34+ counts progressively increased as disease severity increased; overall survival
and the interval to blast crisis were significantly shorter in patients with >300 CD34+ cells/microL.
However, our serial studies in 94 patients did not support an independent prognostic value for
peripheral blood CD34 counts in PMF [51].
Circulating endothelial progenitor cells with CD34, CD133, and VEGF receptor-2 positivity have
also been detected in patients with PMF [52]. Their significance is unclear.
Abnormal laboratory tests Patients with PMF may have nonspecific abnormalities in a variety
of laboratory tests. These include: elevations in the serum concentrations of alkaline phosphatase,
lactate dehydrogenase, uric acid, leukocyte alkaline phosphatase, and vitamin B12 [53,54]. The
increase in alkaline phosphatase may be due to liver involvement or bone disease, the increase in
lactate dehydrogenase may result from ineffective hematopoiesis, hyperuricemia is due to
enhanced turnover of hematopoietic tissue and can cause gout or uric acid stones, and the
increase in serum vitamin B12 reflects an increased neutrophil mass.
Bone marrow examination There are a number of methodologies available for evaluation of
marrow involvement in patients with PMF; although, as will be described in the next section, the
diagnosis is often strongly suspected from the clinical presentation alone. Furthermore, the bone
marrow may not reveal extensive replacement of the marrow by fibrosis, which has classically
been considered to be the hallmark of the disease.
Marrow can be aspirated and/or biopsied directly, and it can be imaged with magnetic resonance
imaging (MRI) or scintigraphy. These techniques can be used for initial diagnosis and prognosis,
and for monitoring the course of the disease.
Bone marrow aspiration The bone marrow in PMF is often difficult to aspirate, usually yielding
a "dry" tap. In addition, the results of aspiration alone, if successful, are not diagnostic. The most
common findings are neutrophilic and megakaryocytic hyperplasia.
Megakaryocytes are often morphologically abnormal with both micro- and macro-megakaryocytes.
Granulocytes may show hyperlobulation, and erythroid precursors may be normal or increased.
These morphologic changes in megakaryocytes help to distinguish early/prefibrotic PMF from
essential thrombocythemia. (See 'Other chronic myeloproliferative disorders' below.)
Bone marrow biopsy Bone marrow biopsy is necessary to demonstrate fibrosis (picture 4) [55-
57]. Some degree of fibrosis is seen in almost all patients; the fibrosis is typically extensive and
visualized better with a silver stain (reticulin) or a trichrome stain (mature collagen) (picture 5).
Bone marrow sinusoids are expanded and there is intravascular hematopoiesis. The fibrosis is
generally associated with atypical megakaryocytic hyperplasia and thickening and distortion of the
bony trabeculae (osteosclerosis).
In some patients, however, the bone marrow is markedly hypercellular with scant bone marrow
fibrosis; this is called the cellular phase of PMF. The diagnosis of PMF in this setting is made from
the clinical and peripheral smear findings after chronic myeloid leukemia and polycythemia vera
have been excluded.
Bone marrow imaging with MRI The major source of the magnetic resonance imaging (MRI)
signal from bone is the fat and water content of bone marrow, with little or no signal arising from
bone or normal marrow cells. Thus, MRI can demonstrate conversion of fatty marrow (intense or
bright signal) to cellular and/or fibrotic marrow (markedly low intensity signal) [58,59]. However,
the value of this technique for replacing bone marrow biopsy or for staging or prognostic purposes
is not clear [60].
Isotopic marrow imaging Erythropoietically-active marrow can be directly imaged using
isotopes of iron (Fe-52 or Fe-59) or indium (In-111) [61]. These techniques may be useful for
determining patterns of marrow loss, extension into the long bones, or sites of extramedullary
erythropoiesis.
JAK2 gene mutation In multiple reports, 43 to 63 percent of patients with PMF have shown
presence of the JAK2 V617F gene mutation, a mutation also seen in virtually all patients with
polycythemia vera (PV) and in approximately 50 percent of those with essential thrombocythemia
(ET). (See "Overview of the myeloproliferative neoplasms", section on 'Mutations in PV, ET, and
PMF'.)
Presence of this mutation and its allele burden, and their relationship to clinical manifestations,
overall survival, and leukemic transformation are under active investigation [62-69]. (See
"Prognosis and treatment of primary myelofibrosis", section on 'JAK2, calreticulin, and MPL
mutational burden'.)
TRANSFORMATION TO ACUTE LEUKEMIA Acute leukemia occurs as a terminal event in a
minority of patients with primary myelofibrosis (PMF), many of whom have not had prior treatment
with alkylating agents or radiotherapy [70-74]. Most of the leukemic transformations have been of
myeloid origin; however, lymphoid, erythroid, megakaryocytic, and mixed lineage leukemias have
occasionally been described. Localized foci of leukemic blasts (ie, myeloid sarcoma, also called
granulocytic sarcoma or chloroma) are rarely seen in PMF.
The largest reported experience comes from our series of 2333 consecutive patients with PMF, 91
of whom (3.9 percent) fulfilled criteria for acute leukemic transformation; all were myeloid in origin
[70]. A clonal abnormality was present in 49 of the 51 patients in whom cytogenetic studies were
performed, and karyotypic evolution was documented in the majority of patients with serial studies.
In a separate analysis of 311 patients with PMF, the following two factors at the time of diagnosis
were independent predictors of leukemic transformation [75]:
Circulating blasts 3 percent
Platelet count <100,000/microL
In this series, 77, 19, and 4 percent of patients had none, one, or both of these risk factors,
respectively, with rates of leukemic transformation of 6, 18, and 18 percent, respectively.
Treatment-related factors included use of an erythropoiesis-stimulating agent and danazol.
Establishing the presence of leukemic transformation in PMF is often difficult, primarily because
abnormal cell counts and immature cells in the peripheral blood are part of the disease process.
Furthermore, bone marrow biopsy may not reveal clear evidence of leukemia. In such patients, the
diagnosis is established from tissue leukemic deposits or at autopsy.
Leukemic transformation is associated with a poor prognosis. In our series of 91 patients,
treatment with AML-like induction therapy yielded a complete remission rate of zero and a
treatment-related mortality of 33 percent [70]. Overall survival was dismal, with a median survival
of 2.6 months (range: 0 to 24 months), and was similarly poor for patients receiving induction
chemotherapy, low-intensity chemotherapy, or supportive care alone. (See "Prognosis and
treatment of polycythemia vera", section on 'Acute leukemia/MDS'.)
DIAGNOSIS Patients with primary myelofibrosis (PMF) first come to medical attention with
some constellation of the following findings: nonspecific systemic symptoms, splenomegaly,
hepatomegaly (both due to extramedullary hematopoiesis [EMH]), anemia, and either high or low
platelet and white blood cell (WBC) counts (table 1). The peripheral smear provides the first clue
to the diagnosis of PMF. The characteristic features include teardrop-shaped RBCs and the
characteristic leukoerythroblastic findings of myelophthisis (replacement of normal marrow
elements by fibrosis or tumor), nucleated erythrocytes and granulocyte precursors (myelocytes,
metamyelocytes, and blasts) (picture 1).
However, a similar blood picture can be produced by bone marrow infiltration by metastatic cancer
(especially prostate or breast) or infectious granulomata. Thus, bone marrow biopsy is required for
demonstration of fibrosis and the absence of clusters of malignant cells (picture 6) or granulomata.
Primary myelofibrosis: WHO criteria There is no "gold standard" for the diagnosis of PMF,
although criteria have been proposed by the Italian Society of Hematology (table 2), the World
Health Organization, and others [56,76-78].
The 2008 WHO criteria include a combination of the following findings (table 3) [2,56,79]:
Presence of megakaryocyte proliferation and atypia, usually accompanied by reticulin and/or
collagen
WHO criteria for polycythemia vera (PV), chronic myeloid leukemia (CML), myelodysplastic
syndrome (MDS), or other myeloid neoplasm not met
Demonstration of a clonal marker (eg, JAK2 or MPL)
Leukoerythroblastosis
Palpable splenomegaly
Anemia
Increased serum lactate dehydrogenase level
Myelofibrosis following PV or ET An International Working Group for Myelofibrosis Research
and Treatment has proposed criteria for the diagnosis of post-PV and post-ET myelofibrosis,
which includes a combination of the following major (first two, both required) and minor (last five,
at least two required) findings [80]:
Documentation of a previous diagnosis of either PV or ET as defined by WHO criteria
Presence of increased bone marrow fibrosis
Progressive anemia or loss of phlebotomy requirement
Leukoerythroblastic blood picture
Increasing degree of splenomegaly
Development of constitutional symptoms (ie, weight loss, night sweats, unexplained fever)
Increased serum lactate dehydrogenase (post-ET myelofibrosis only)
DIFFERENTIAL DIAGNOSIS There are several other causes of bone marrow fibrosis that
should be considered before the diagnosis of primary myelofibrosis (PMF) is confirmed (table 4).
The diagnosis of PMF is generally tenable if and only if the patient shows all of the following
features on initial presentation (table 2):
Nucleated RBCs in the peripheral blood
Teardrop RBCs in the peripheral blood smear
Early WBC forms in the peripheral blood
Palpable splenomegaly
Other chronic myeloproliferative disorders PMF must be distinguished from the other
chronic myeloproliferative neoplasms (MPNs) (figure 1). Chronic myeloid leukemia (CML),
myelodysplastic syndrome (MDS), and mast cell disease may be accompanied by substantial
bone marrow fibrosis [53,81-85]. It is therefore imperative that careful morphologic and cytogenetic
examination be carried out before a diagnosis of PMF is made [56,57]:
Demonstration of the Philadelphia (Ph) chromosome by conventional cytogenetics or the bcr/abl
fusion signal by fluorescence in situ hybridization (FISH) mandates a diagnosis of CML. (See
"Molecular genetics of chronic myeloid leukemia".)
The presence of dyserythropoiesis (dysplastic bone marrow hyperplasia or even occasional
hypoplasia, associated with variable degrees of peripheral blood cytopenia with or without
monocytosis) suggests a diagnosis of MDS, especially in the absence of splenomegaly [82,83].
Chronic myelomonocytic leukemia (CMML), has features of both MDS and MPN, with dysplastic
changes, monocytosis, hepatosplenomegaly, and lymphadenopathy. (See "Clinical manifestations
and diagnosis of the myelodysplastic syndromes", section on 'Chronic myelomonocytic leukemia'.)
The traditional group of Ph-negative chronic myeloproliferative neoplasms includes PMF,
polycythemia vera (PV), and essential thrombocythemia (ET) [86]. Among these three disorders,
PV is readily identified by the presence of an increased red cell mass. The differentiation between
PMF and ET is dependent primarily on bone marrow morphology, the degree of bone marrow
fibrosis and splenomegaly, and the presence of peripheral blood leukoerythroblastosis in PMF
[87]. (See "Clinical manifestations and diagnosis of polycythemia vera".)
Prefibrotic PMF Early/prefibrotic PMF can mimic ET in its presentation; careful morphologic
examination is necessary for distinguishing between the two. Megakaryocytes are large and
mature-appearing in ET, while those in prefibrotic PMF display abnormal maturation with
hyperchromatic and irregularly folded nuclei [6,88]. This distinction is important since, in two
studies, thrombotic complications, overall survival, leukemic transformation, and rates of
progression to overt myelofibrosis were significantly worse in prefibrotic PMF [89,90].
Acute myelofibrosis Acute myelofibrosis is a syndrome characterized by severe bone marrow
fibrosis associated with fever and pancytopenia, teardrop RBCs, and a leukoerythroblastic blood
picture [91,92]. However, unlike PMF, the spleen is often not palpable in acute myelofibrosis and
in some instances the bone marrow may show excess megakaryoblasts, suggesting a diagnosis
of acute megakaryoblastic leukemia (FAB classification M7). This distinction is critical since the
appropriate treatment for acute myelofibrosis is antileukemic chemotherapy with or without
hematopoietic cell transplantation. (See "Classification of acute myeloid leukemia".)
Secondary forms of myelofibrosis A number of hematologic and non-hematologic conditions
have been associated with the development of marrow fibrosis. These are discussed below.
Myeloproliferative neoplasms other than PMF Hematologic diseases that commonly develop
changes characteristic of myelofibrosis other than primary myelofibrosis include the two other
major myeloproliferative neoplasms: postpolycythemic myeloid metaplasia (PPM) and post-
thrombocythemic myeloid metaplasia (PTM). In a study of 37 patients with PPM and 29 with PTM
<60 years of age, adverse prognostic indicators included older age, anemia, a prior history of PV,
and adverse cytogenetics (ie, presence of cytogenetic abnormalities other than 13q- or 20q-) [93].
(See 'Other chronic myeloproliferative disorders' above and "Prognosis and treatment of
polycythemia vera", section on 'Myelofibrosis'.)
Other hematologic conditions Other hematologic conditions associated with bone marrow
fibrosis include hairy cell leukemia, lymphoma, and multiple myeloma [94-97].
A small percent of patients with immune thrombocytopenia (ITP) will develop marrow fibrosis after
treatment with the thrombopoiesis-stimulating agents romiplostim and eltrombopag [98]. (See
"Immune thrombocytopenia (ITP) in adults: Second- and third-line therapies", section on
'Thrombopoietin receptor agonists'.)
Non-hematologic conditions Nonhematologic causes of bone marrow fibrosis are rare and
include the following:
Malignancy metastatic to the bone marrow [99-101]
Autoimmune disorders (eg, systemic lupus erythematosus, scleroderma, mixed connective tissue
disease, polymyositis) and primary pulmonary hypertension [102-106]
Secondary hyperparathyroidism associated with vitamin D deficiency [107,108] or renal
osteodystrophy [109-111].
SUMMARY AND RECOMMENDATIONS
Suspecting the diagnosis Primary myelofibrosis (PMF, chronic idiopathic myelofibrosis,
agnogenic myeloid metaplasia) should be suspected in a patient presenting with splenomegaly
along with immature cells of the granulocyte series, nucleated red cells, and tear drop-shaped red
cells in the peripheral blood. (See 'Clinical manifestations' above and 'Laboratory findings' above.)
Making the diagnosis PMF is diagnosed when combinations of the following are present (table
3) (see 'Diagnosis' above):
Presence of megakaryocyte proliferation and atypia on bone marrow examination, usually
accompanied by reticulin and/or collagen
WHO criteria for polycythemia vera (PV), chronic myeloid leukemia (CML), myelodysplastic
syndrome (MDS), or other myeloid neoplasm not met
Demonstration of a clonal marker (eg, JAK2 or MPL)
Leukoerythroblastosis
Palpable splenomegaly
Anemia
Increased serum lactate dehydrogenase level