Myelofibrosis
Rami Komrokji
Eric Padron
Srdan Verstovsek
DEFINITION
Myelofibrosis (MF) is a rare, serious myeloid malignancy classified as one of the Philadelphia chromosome negative [Ph(-)] myeloproliferative neoplasms (MPNs).1
MF is subdivided into primary MF (PMF) and secondary MF.2 Secondary MF may arise from polycythemia vera (PV) or essential thrombocythemia (ET).3
Terms frequently used synonymously with PMF include chronic idiopathic myelofibrosis ([CIMF; World Health Organization [(WHO]), agnogenic myeloid metaplasia, MF with myeloid metaplasia, and idiopathic MF.4,5
The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) has defined MF as either PMF (de novo presenting disease), or post-PV or ET MF (MF transformation from prior PV or ET). Furthermore, patients with transformation to acute leukemia are referred to as PMF in blast phase (PMF-BP) or post-PV/ET MF in blast phase.5
The hallmark of MF neoplasm is an increase in mature blood cells, which arise from clonal expansion driven by genetic mutations in pluripotent cells of the bone marrow compartment. The response to this malignant myeloproliferative process is the secretion of multiple profibrogenic, -angiogenic, and -inflammatory cytokines that eventually results in polyclonal bone marrow fibrosis. MF is typically associated with progressive splenomegaly and in many cases with hepatomegaly, which can lead to other complications such as portal hypertension or splenic infarcts, cytopenias, and an increased likelihood of transforming to a blast phase.6,7
HISTORICAL PERSPECTIVE
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EPIDEMIOLOGY
PMF is a rare disease. The annual incidence of MF has been estimated to be 0.41 to 1.46 cases per 100,000 individuals.21,22 The prevalence of MF in the United States has been estimated as 16,000 to 18,500 patients. MF is slightly more common in males and more common in older patients.21 The median age of patients at the time of diagnosis is 67 years.21 Among the Philadelphia chromosome negative MPNs (e.g., MF, PV, ET), MF is the most symptomatic and carries the worst prognosis.
PATHOGENESIS
Current understanding suggests that PMF occurs secondary to acquired mutations that target the hematopoietic stem cell.1,12,27 As a result, ineffective hematopoeisis and proliferation of dysfunctional megakaryocytes are commonly seen in MF. The hallmark of the disease pathologically is bone marrow reticulin and collagen fibrosis, ineffective extramedullary hematopoiesis (EMH), and deregulated cytokine production.
The disease-initiating mutations remain unknown. Cytogenetic abnormalities originating on the progenitor cell level are well described in MF. In general, approximately half of patients with PMF display cytogenetic abnormalities that include del(20) (q11;q13), del(13)(q12;q22), trisomy 8, trisomy 9, del(12) (p11;p13), monosomy or deletions chromosome 7, and partial trisomy 1q. None of these abnormalities is specific to PMF, although the presence of either del(13)(q12;q22) or der(6)t(1;6)(q21-23;p21-23) is strongly suggestive of PMF diagnosis. Molecular cytogenetics using FISH did not reveal additional karyotypically occult cytogenetic lesions, but comparative genomic hybridization (CGH) studies have disclosed gains of chromosome 9p as the most frequent abnormality occurring in 50% of patients.28,29, 30 and 31
Deregulation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is the key contributor to the clinical phenotype of the disease regardless of the presence or absence of the JAK2 V617F mutation. The mutation described is not a disease initiating abnormality. The JAK-STAT pathway plays a pivotal role in the differentiation and development of hematopoietic cells and the functioning of the immune system.32 The JAK family comprises JAK1, JAK2, JAK3, and TYK2.33 Cytokines and growth factors activate the extracellular portion of their cognate receptors,33,34 which promote the recruitment of JAK proteins to associate closely with the intracellular portion of these receptors and the activation of
the JAK proteins via phosphorylation (Fig. 83.1). Phosphorylation of JAK proteins, in turn, leads to the phosphorylation and activation of several intracellular downstream signaling proteins, such as STAT proteins.35 Phosphorylated STATs translocate to the nucleus and act as inducible nuclear transcription factors, which lead to transcriptional modulation and eventual expression of cellular, molecular, and (patho) physiologic actions that were promoted by the initial signal (ligand).
the JAK proteins via phosphorylation (Fig. 83.1). Phosphorylation of JAK proteins, in turn, leads to the phosphorylation and activation of several intracellular downstream signaling proteins, such as STAT proteins.35 Phosphorylated STATs translocate to the nucleus and act as inducible nuclear transcription factors, which lead to transcriptional modulation and eventual expression of cellular, molecular, and (patho) physiologic actions that were promoted by the initial signal (ligand).
The dysregulation of the JAK-STAT signaling pathway in hematopoietic progenitor cells has been implicated in the pathogenesis of MF. JAK-STAT signaling in the pathogenesis of MF also relates to its role in mediating signaling from proinflammatory cytokines. These cytokines are elevated in environments of myeloproliferative disease and contribute to the debilitating symptoms of MPNs.36 Somatic mutations that contribute to this dysregulated JAK-STAT activity include gain-of-function mutations directly in JAK2, or upstream signaling mutations such as the mutation of the thrombopoietin receptor (MPL W515L),18 and loss of JAK regulation by mutations in the gene for the lymphocyte-specific adaptor protein (LNK exon 2 mutations).37 Mutations in JAK2 that lead to the constitutive activation of the JAK-STAT pathway, namely the JAK2 V617F14, 15 and 16 and JAK2 exon 12 mutations, have been identified, although this latter mutation was primarily identified in patients with PV.38 JAK2 V617F is the most common mutation occurring in a large proportion (50% to 60%) of patients with PMF.14,15 With JAK2 activating mutations, the pathway becomes cytokine- and growth-factor-independent; therefore, even in the absence of these ligands, the intracellular signaling proteins are constitutively active. Clonal expansion leads to an increased JAK2 V617F allele burden and homozygosity influencing disease phenotype and differentiation of PV and ET.
 FIGURE 83.1. The JAK-STAT signaling pathway. Cytokines and growth factors bind to the extracellular receptor and induce a series of intracellular changes: (1) JAK proteins associate with the intracellular portion of the receptor and are phosphorylated; (2) phosphorylated-JAK proteins in turn phosphorylate STAT proteins, which then phosphorylate other downstream proteins; and (3) phosphorylated-STAT translocates into the nucleus and promotes the transcription of genes. Other proteins also regulate this signaling pathway, such as SOCS1, which prevents activation of this pathway. (With permission from Quintas-Cardama A, Kantarjian H, Cortes J, et al. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov 2011;10:127-140.) |
Megakaryocyte-derived transforming growth factor-β1 (TGF-β1) has been identified as the primary cytokine that mediates many of the bone marrow stromal changes (i.e., collagen fibrosis, osteosclerosis, angiogenesis) in PMF.39,40 In mice, the PMF phenotype has been induced either by systemic overexpression of thrombopoietin (TPOhigh mice) or by megakaryocyte lineage-restricted underexpression of the transcription factor GATA-1 (GATA-1low mice). In both instances, the megakaryocytes display abnormal distribution of P-selectin that is believed to promote a pathologic interaction between megakaryocytes and neutrophils, resulting in the release of both fibrogenic and angiogenic cytokines including TGF-β, platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), tissue inhibitors of matrix metalloproteinases, and neutrophilderived elastase and other proteases.41, 42
Another characteristic feature in PMF that accompanies the aberrant bone marrow stromal reaction involves peripheral blood expansion of both CD34-positive myeloid progenitors and endothelial cells.43,44 Current consensus implicates both circulating progenitor cell trapping and abnormal cytokine stimulation of embryonic hematopoietic sites as mechanisms of hepatosplenic EMH in PMF.45,46 Such a contention is supported by the high concordance between bone marrow and splenic tissue cytogenetic findings in PMF.47
Disease progression to blast phase (acute myeloid leukemia [AML]) is probably driven by additional clonal evolution and acquired mutations (see section “Disease Course”).
CLINICAL FEATURES
Splenomegaly is a well-established clinical feature of MF with 85% or more of MF patients presenting with palpable splenomegaly at the time of diagnosis. One third of patients will have marked splenomegaly (Fig. 83.2) and 50% of patients will also have hepatomegaly.48,49 Spleen-related symptoms include abdominal discomfort, early satiety, and pain under the left ribs. Portal hypertension and variceal bleeding can be morbid complications of splenomegaly. Some patients may experience severe pain secondary to splenic infarcts.50
Constitutional symptoms are common and often debilitating. Disease burden due to those symptoms often interfere with daily quality of life. These symptoms include fatigue, pruritus, night sweats, fever and bone/muscle pain, and cachexia. Presence of those symptoms is associated with worse outcome.
Cytopenias can dominate the course of the disease especially at the advanced stages. Two thirds of patients may have anemia at diagnosis and 20% are transfusion-dependent.51,52 Thrombocytopenia may be present in 21% to 37% and leukopenia in 7% to 22%.53
Some patients present with leukocytosis (41% to 49% incidence), and/or thrombocytosis (13% to 31%). Furthermore, >10% of patients may present with extreme thrombocytosis (platelet count >1,000 × 109/L), whereas >20% present with marked leukocytosis (leukocyte count >20 × 109/L).53 Patients with MF are also at risk for developing thrombo-hemorrhagic complications secondary to leukocytosis and/or thrombocytosis.54
Other potential symptoms and complications include ascites, portal hypertension, lymphadenopathy, pleural effusions, and nerve or cord compression secondary to EMH.55
 FIGURE 83.2. Splenomegaly due to extramedullary hematopoiesis in a patient with myelofibrosis. A: Massive splenomegaly. B: Chronic idiopathic myelofibrosis in the spleen. The red pulp shows extensive involvement by maturing myeloid and erythroid cells, as well as atypical megakaryocytes. Some of this abnormal extramedullary hematopoiesis is in a sinus at the lower right side of the figure. |
Characteristic laboratory findings in MF may include peripheral blood leukoerythroblastosis, dacryocytosis, teardrop-shaped red blood cells (see Fig. 80.9), circulating immature myeloid cells, increased serum lactate dehydrogenase, increased vitamin B12 levels, and hyperuricemia. The characteristic bone marrow aspirate and biopsy findings may be limited by the inability to collect an adequate bone marrow aspirate (so-called dry tap). The clustering of atypical megakaryocytes, which may often be mistaken as dysplasia by an inexperienced pathologist, is a pathologic hallmark of myeloproliferative syndromes.56 Reticulin staining demonstrates an increased deposition of reticulin fibers. Collagen fibrosis can be appreciated and may be more disease-specific compared to reticulin staining. In some early cases of MF, the bone marrow could only be hypercellular with no evidence of fibrosis.7 Figure 83.3 illustrates typical bone marrow findings in MF. Circulating levels of CD34+, hematopoietic stem cells and progenitors are high in patients with MF compared with healthy patients as well as patients with other Philadelphia chromosome negative MPNs.42
DIAGNOSIS
The differential diagnosis of MF should include bone marrow fibrosis associated with nonneoplastic and neoplastic conditions (Table 83.1) including but not limited to chronic myeloid leukemia (CML), MDS, chronic myelomonocytic leukemia (CMML), lymphoma, or AML. Presence of JAK2 or MPL mutation is a reliable screen to rule out reactive bone marrow fibrosis or a nonmyeloid malignancy. The diagnosis of PMF is facilitated using the WHO criteria, whereas post-PV or post-EF MF diagnosis is based on the IWG-MRT criteria (Table 83.2).3,57
PMF is typically characterized by the presence of morphologically bizarre megakaryocytes in clusters. However, it is important to note that the presence of apparent reticulin fibrosis is not essential for the diagnosis of PMF. Accordingly, there are two histologic variants of PMF: fibrotic and cellular (prefibrotic) phases.58 Reticulin fibrosis is either absent or minimal in cellular-phase PMF, and it is thus possible to confuse cellular-phase PMF with ET. However, bone marrow is markedly hypercellular, with both granulocytic and megakaryocytic proliferation in PMF, as opposed to often normocellular bone marrow with only megakaryocytic hyperplasia in ET. Further distinction is facilitated by the appreciation of subtle differences in megakaryocyte
morphology; PMF megakaryocytes display defective maturation with prominent “cloudlike” hyperchromatic nuclei, whereas ET megakaryocytes appear mature although large in size, with well-lobulated (i.e., staghornlike) nuclei.59 Other distinguishing features between cellular-phase PMF and ET include the presence of myelophthisis and/or increased LDH in the former but not the latter. One distinct WHO category of AML (i.e., acute MF) can sometimes be confused with PMF. Patients with fibrotic AML, either AML M7 or other AML subtype, usually present with severe constitutional symptoms, pancytopenia, mild or no splenomegaly, and feature an increase in blood and bone marrow blasts that might not necessarily fulfill the required threshold for AML diagnosis.
morphology; PMF megakaryocytes display defective maturation with prominent “cloudlike” hyperchromatic nuclei, whereas ET megakaryocytes appear mature although large in size, with well-lobulated (i.e., staghornlike) nuclei.59 Other distinguishing features between cellular-phase PMF and ET include the presence of myelophthisis and/or increased LDH in the former but not the latter. One distinct WHO category of AML (i.e., acute MF) can sometimes be confused with PMF. Patients with fibrotic AML, either AML M7 or other AML subtype, usually present with severe constitutional symptoms, pancytopenia, mild or no splenomegaly, and feature an increase in blood and bone marrow blasts that might not necessarily fulfill the required threshold for AML diagnosis.
 FIGURE 83.3. Bone marrow in myelofibrosis. A: Hypercellular bone marrow biopsy with megakaryocytic atypia. B: Reticulin stain demonstrating presence of myelofibrosis. |
TABLE 83.1 DIFFERENTIAL DIAGNOSIS FOR BONE MARROW FIBROSIS | |||||||||||||||||||||||||||||||||||||||
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TABLE 83.2 WHO CRITERIA FOR DIAGNOSIS OF PRIMARY AND POST-ET/PV MYELOFIBROSIS | ||||||
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DISEASE COURSE
MF is a progressive disease. Patients develop progressive splenomegaly and its related complications, and suffer from debilitating disease burden symptoms such as cachexia, bone pain, and/or profound fatigue. Cytopenias can worsen during the course of the disease with more patients becoming red blood cell transfusion dependent and developing thrombocytopenia and neutropenia. The rate of secondary AML transformation (or better termed blast phase-PMF) is 10% to 15%. Blast phase-PMF is very difficult to manage, and response to intensive chemotherapy is poor.60 The major causes of death in PMF include infections (26% to 29%), bleeding (11% to 22%), heart failure (7% to 15%), liver failure (3% to 8%), and portal hypertension (6%).61,62
RISK STRATIFICATION AND PROGNOSIS
MF is a progressive hematologic disease and its prognosis is dependent on several factors. The International Prognostic Scoring System (IPSS) estimates survival from the time of diagnosis using the following risk factors: (1) age 65 years or older; (2) anemia (hemoglobin <10 g/dl); (3) presence of constitutional symptoms; (4) leukocytosis (white blood cell count >25 × 109/L); and (5) circulating blasts of at least 1%.63 Patients presenting with more than two of the aforementioned prognostic factors of MF have a median survival of less than 3 years, whereas patients without any of the factors have a median survival of more than 10 years. The presence of 0, 1, 2, and ≥3 factors using IPSS define low, intermediate-1, intermediate 2, and high-risk disease, respectively.
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