GENERAL PRINCIPLES
The myeloproliferative disorders (MPDs) are a group of clonal diseases characterized by overproduction of mature, largely functional cells arising from the transformation of a clonal hematopoietic stem cell. The World Health Organization (WHO) has designated seven conditions as MPDs (Table 9-1). Philadelphia chromosome-positive chronic myeloid leukemia (CML) is discussed in the chapter on leukemias (Chap. 29). Collectively, these disorders are uncommon. They share the signs and symptoms of hepatosplenomegaly, hypercatabolism, clonal marrow hyperplasia without dysplasia, and increased numbers of one or more cell lines. They are typically indolent and chronic in nature but may evolve into acute leukemia. Recent description of the activating Janus kinase 2 (JAK2) mutation V617F in many of these disorders links them with a common pathophysiology. Although of clear clinical importance, this mutation is still being incorporated into diagnostic, prognostic, and treatment algorithms.
POLYCYTHEMIA VERA
GENERAL PRINCIPLES
Definition
Polycythemia vera (PV) is a monoclonal stem cell disease characterized by proliferation of a multipotent stem cell with trilineage hyperplasia resulting primarily in expansion of the RBC line. Recently, the activating JAK2 V617F mutation has been noted in nearly all patients. JAK2 is an essential kinase in the erythropoietin (EPO) receptor signal transduction pathway. Constitutive JAK2 kinase activity results in EPO-independent proliferation of erythrocyte precursors. JAK2 is also involved in the JAK2-STAT5 pathways of the thrombopoietin (TPO) receptor (Mpl) and the granulocyte colony-stimulating factor receptor (GCSF-R). The V617F mutation can thus lead to proliferation of multiple cell lines, and patients with PV often have elevated platelets and leukocytes as well. 1
Epidemiology
PV is the most common of the MPDs, with an incidence of ~2 in 100,000 people. The average age of PV patients is 60 years, but it occurs across all age groups, with a male predominance. Although familial clustering does exist, it is uncommon, and the JAK2 mutation is acquired somatically, suggesting a separate predisposition pathway.
Etiology
Etiology is not clear but the following observations have been made:
Clonal cytogenetic abnormalities are associated with the disorder in ~30% of patients, mainly deletion of long arm of chromosome 20, trisomy of chromo-some 8 or 9, or loss of heterozygosity on short arm of chromosome 9. The JAK2 gene is located on the short arm of chromosome 9.
Up to 97% of patients have an activating mutation in JAK2 (V617F), which is also seen in other MPDs.
There is impaired post-translational processing of the TPO receptor, Mpl, leading to decreased expression on platelets and megakaryocytes. Thus, proliferation of platelet in PV may be independent of TPO.
BCL-XL, an apoptosis-inhibiting oncoprotein, is overexpressed in erythroid cells.
Bone marrow shows erythroid progenitor cell proliferation in the absence of EPO stimulation.
Risk Factors
None known.
Clinical Course
PV is a chronic disorder and may be characterized as having phases during its course. The preerythrocytic phase is generally asymptomatic, with an isolated increase in platelets or RBCs. Patients may experience trivial pruritus and may have mild splenomegaly. This progresses to the erythrocytic phase, characterized by erythrocytosis requiring regular phlebotomy as well as increased granulocytes and platelet counts. Splenomegaly, pruritus, thrombosis, and hemorrhage may be present. This may last for a number of years. The spent phaseis characterized by a reduced need for phlebotomy. Thrombocytosis and leukocytosis persist, and splenomegaly is progressive.
Up to 50% of patients may progress to a clinical picture difficult to differentiate from that of idiopathic myelofibrosis. Anemia develops, and the peripheral smear shows a leukoerythroblastic picture with teardrop poikilocytes, nucleated red cells, and anisocytosis. Immature granulocytes are seen, with a slight increase in basophils, and platelets are often abnormal in morphology. Splenomegaly worsens, and there are increased systemic symptoms. Acute myeloid leukemia (AML) may occur in up to 20% of patients, and the risk is increased in patients treated with alkylating agents. The incidence of progression to AML is higher in patients with myelofibrosis.
Thrombotic risk is present throughout the course of PV and may be linked to elevated, dysfunctional leukocytes or platelets. Reduction of thrombotic risk is a mainstay of therapy, and recurrent thrombosis can be common.
DIAGNOSIS
Clinical Presentation
Patients are often asymptomatic at presentation; however, they may present with symptoms related to increased RBC mass and hyperviscosity. Symptoms may include headache, weakness, peptic ulcer disease, hyperhydrosis, vision changes, tinnitus, and vertigo. In addition, many patients experience pruritus, especially with exposure to hot water. Erythromelalgia, due to microarteriolar occlusion, is characterized by a burning sensation in the digits and may be severe. Patients are also predisposed to thrombosis and, less often, hemorrhage. Many of these symptoms have been attributed to hyperviscosity, but dysfunction of leukocytes and platelets may also play an important role. Physical exam findings include splenomegaly, hepatomegaly, hypertension, and plethora.
Diagnostic Criteria
The Polycythemia Vera Study Group established diagnostic criteria >30 years ago. These are currently in flux, as they include neither EPO levels nor the JAK2 mutation. At Washington University, we have adopted the Campbell-proposed criteria based on JAK2 status, with modifications of the Polycythemia Vera Study Group criteria (Table 9-2).2 Patients with JAK2-positive PV have a hematocrit >52% in men or >48% in women or an increased red cell mass (>25% above predicted) and a documented mutation. Ninety-five percent to 97% of patients with PV test positive either in exon 14 or in exon 12. Patients with suspected PV and negative exon 14 V617F JAK2 mutation should be tested for JAK2 exon 12 mutations.3 JAK2-negative PV is much less common and should prompt a careful examination for secondary causes of polycythemia.
Differential Diagnosis
Patients with secondary polycythemia typically have elevated EPO levels caused by chronic hypoxemia, heavy smoking, renal disease, or malignancies such as renal cell cancer, hepatocellular cancer, and hemangioblastoma. Rare conditions such as congenital polycythemia with augmented hypoxia sensing and high–oxygen affinity hemoglobin mutants should be considered. Relative polycythemia, or pseudopolycythemia, is associated with a normal red cell mass and decreased plasma volume secondary to causes such as dehydration, diuretics, and burns. In cases of JAK2-negative polycythemia with low-normal EPO levels, BCR-ABL rearrangements should be evaluated, as CML may present with many of the same features.
Diagnostic Testing
The diagnosis is suspected when blood counts reveal an elevated hematocrit (Hct). The EPO level is low (<20 mU/mL) and often undetectable. The JAK2 V617F mutation is seen in nearly all patients. Leukocyte alkaline phosphatase scores, vitamin B12, and uric acid levels may be elevated but are nonspecific findings. These patients also have an elevated RBC mass as demonstrated by 51 Cr labeling of RBCs and isotope dilution, although this is rarely tested now. In addition, ~60% of patients have elevated granulocyte counts, and 50% have thrombocytosis.
The peripheral smear may show microcytic, hypochromic RBCs with anisocytosis and poikilocytosis, reflecting exhaustion of iron stores due to increased hemoglobin (Hgb) synthesis. WBCs generally have normal morphology, but there are often increased basophils, eosinophils, and immature forms. Platelets occasionally have an abnormal morphology, with megathrombocytes seen on the smear.
Bone marrow biopsy findings are not diagnostic of PV, but biopsy is frequently performed to evaluate fibrosis and cytogenetics even when the diagnosis is not in question. Findings include hypercellular marrow with trilineage hyperplasia and clustered megakaryocytes with hypolobulated nuclei. Approximately 30% of PV patients will have an abnormal karyotype. Common karyotype changes include trisomy 9 (amplification of JAK2), trisomy 8 (also found in other MPDs, myelodysplastic syndrome, AML), trisomy 1q (unclear significance), del 5q and del 7q (more often seen after cytotoxic therapy), and del 13q (also associated with idiopathic myelofibrosis and chronic lymphocytic leukemia).
TREATMENT
The goals of treatment are to reduce the blood volume to normal and to prevent thrombotic and hemorrhagic complications. Thrombotic risk has been associated with an age >60 years, prior thrombosis, and a platelet count >1000 × 109/L. Thrombocytosis clearly increases thrombotic risk, and this risk appears to be a continuum, with increased risk starting at 400 × 109/L and peaking at 900 × 109/L. Hemorrhagic risk increases with platelet counts >1500 × 109/L. Emerging risk factors include leukocyte counts >15 × 109/L and cardiovascular factors such as smoking, obesity, hypertension, hypercholesterolemia, diabetes, and coronary artery disease (Table 9-3).
Low-risk patients are <60 years old and have no history of thrombosis, no cardiovascular risk factors, and platelet counts <1500 × 109/L. These patients are managed with phlebotomy to an Hct of <45% and low-dose aspirin. Iron deficiency via phlebotomy is a goal of treatment.
High-risk patients are ≥60 years old or have a history of a thrombotic event, or cardiovascular risk factors, or platelet counts >1500 × 10 9/L. These patients typically require cytoreductive agents in addition to phlebotomy, and aspirin is usually held off until platelet counts are <1500 × 109/L.
Treatmentfor intermediate-risk patients must be individualized, as data are insufficient to clearly support either a conservative (low-risk) or an aggressive (high-risk) treatment plan. Typically, these patients are treated with phlebotomy, aspirin, and management of cardiovascular risk factors to limit thrombotic risk. Patients with elevated platelets (>400 × 109 to 600 × 109/L) or elevated leukocytes (>15 × 109/L) may need to be treated more like high-risk patients.
Medications
Hydroxyurea, interferon-alpha, and anagrelide are the most commonly used cytoreductive agents.
Hydroxyurea acts to decrease all three blood lines. It has been particularly useful in patients with extensive pruritus. Long-term use of hydroxyurea has been suggested to increase the risk of leukemogenesis (mean time to transformation ~15 years). This has been difficult to assess in MPD patients, who already have an underlying propensity toward leukemic evolution. However, in other diseases, such as sickle cell anemia, leukemogenic risk has not been seen. Long follow-up of prospective trials will be required to definitively answer this question, and some authors currently prefer its use in the elderly more than in those younger than 60 years. Hydroxyurea is generally well tolerated but may cause erythema, hyperpigmentation, and distal leg ulcers. Gastrointestinal symptoms of nausea, vomiting, constipation, and diarrhea are very common with doses >60 mg/kg.
Interferon-alpha decreases both the red cell number and the frequency of thrombohemorrhagic events. As in CML, it affects the stem cell compartment, and reversal of JAK2 mutational status can be seen. It must be administered subcutaneously and can cause fever, arthralgias, myalgias, alopecia, anorexia, peripheral neuropathies, and depression. ACE inhibitors should be avoided with interferon-alpha, as this may lead to granulocytopenia and thrombocytopenia.
Anagrelide primarily effects platelet production and is more commonly used in PV for thrombocytosis. Side effects include palpitations, tachycardia, nausea, diarrhea, and fluid retention.
Agentssuchas radioactive phosphorus and alkylating agents also are cytoreductive but are associated with increased transformation to AML and are rarely used today. Radioactive 32P may have a role in noncompliant patients with life expectancy <10years.
Additional agents can be useful in symptom management. Hyperuricemiamay be treated with allopurinol. Erythromelalgia may be treated with aspirin or other non-steroidal anti-inflammatory drugs. Hemorrhage should be managed with platelet transfusion, since platelets have abnormal function in PV. Pruritus is often poorly responsive to antihistamines but may respond to cimetidine or cyproheptadine. If these agents fail, cytoreductive agents may be needed.
SPECIAL CONSIDERATIONS
Surgery. Elective surgery should be avoided in patients with poorly controlled polycythemia, as 75% will have hemorrhagic or thrombotic complications, and mortality is high. Platelet counts and Hct should be controlled for at least 2 months before surgery, if possible. Thromboembolic prophylaxis should be used as well. Splenectomy is rarely recommended in PV patients because of the high risk of surgical complications.
Polycythemia vera and pregnancy. There is an increased incidence of premature births, preeclampsia, and hemorrhage in PV patients. Management should include phlebotomy and low-dose aspirin. Aspirin should be discontinued ~5 days prior to delivery to limit hemorrhagic risk. If cytotoxic treatment is needed, interferon-alpha is the agent of choice, as it has not been shown to be teratogenic or leukemogenic.
OUTCOME/PROGNOSIS
Patients with PV who are treated have a mortality rate similar to that of age-matched controls. Death is secondary to thrombosis in 30% to 40% of patients. Myelofibrosis is the cause of death ~5% of patients, and hemorrhage is the cause in 2% to 10% of patients.
ESSENTIAL THROMBOCYTHEMIA OR ESSENTIAL THROMBOCYTOSIS
GENERAL PRINCIPLES
Definition
Essential thrombocythemia or essential thrombocytosis (ET) is a stem cell disorder whose distinguishing characteristic is a markedly elevated platelet count caused by excessive megakaryocyte proliferation. The activating JAK2 V617F mutation is seen in nearly half of patients with ET, and patients also may have other clinical features of PV. Studies of X chromosome inactivation suggest that ET is a heterogeneous disease and both monoclonal and polyclonal evolution has been noted.
Epidemiology
ET occurs at an incidence of between 1.5 and 2.5 cases per 100,000. Most patients are >50 years old, and there is a female predominance.
Pathophysiology
Neither TPO nor its receptor (c-Mpl) has been implicated in the pathogenesis of ET. Mutations involving the c-Mpl gene are only rarely identified in ET,4 and endogenous megakaryocyte colony growth does not appear to be dependent on an autocrine stimulation involving TPO. This is in contrast to autosomal dominant familial ET where activating mutations in the genes for TPO or c-Mpl, or mutations in the genes for other proteins, are responsible for TPO-mediated thrombocytosis.
Serum TPO levels in ET have been reported to be inappropriately normal or elevated. This unexpected finding may be a result of increased bone marrow stromal production of TPO or decreased ligand clearance associated with reduced platelet c-Mpl expression in patients with ET.
DIAGNOSIS
Clinical Presentation
Symptoms generally are related to hemorrhage and vaso-occlusion, although most patients are asymptomatic at diagnosis. Bleeding is commonly from mucous membranes, skin, and GI tract and is rarely life threatening. Vaso-occlusion may cause erythromelalgia (burning pain, increased skin warmth, and erythema of the feet and hands), transient ischemic attacks, visual disturbances, headache, seizures, and dizziness. Large vessel involvement has also been reported with myocardial infarction and cerebrovascular accidents. A small percentage of patients may experience pruritus. Physical exam findings are generally limited to splenomegaly and easy bruising.
Diagnostic Testing
Patients have an elevated platelet count, with large platelets visible on peripheral smear. Granulocytes may be increased, with mild basophilia and rare early forms. Serum B12 and leukocyte alkaline phosphatase scores are generally normal. Iron deficiency must be ruled out. Bone marrow findings are commonly nondiagnostic and include hypercellularity with granulocyte hyperplasia and increased megakaryocytes. The megakaryocytes are large, are often clustered, and may exhibit mild atypia. JAK2 V619F is seen in nearly half of ET patients.
At Washington University, we have begun incorporating JAK2 status into the diagnostic criteria (Table 9-2). Other causes of reactive (secondary) thrombocytosis should be carefully investigated and include splenectomy, trauma, cancer, acute and chronic inflammation, infection, and iron deficiency. C-reactive protein and sedimentation rate can be useful in this evaluation. If iron stores are absent, iron replacement is initiated, which may uncover PV in some patients. Philadelphia chromosome also should be evaluated to rule out CML. Ultimately, bone marrow biopsy may be required to differentiate ET from myelodysplastic syndromes.
TREATMENT
The goals of treatment focus on maintaining platelet counts of <600 × 109/L (<400 × 109 /L if possible) and limiting thrombo-hemorrhagic risk. Thrombotic risk has been linked to age (>60 years old), prior thrombosis, and platelet count >400 × 109 to 600 × 109/L. Other risk factors that are still emerging and being validated include elevated leukocytes (>8.7 × 109 /L), positive JAK2 V617F mutation, and cardiovascular risk factors such as diabetes, obesity, smoking, hypertension, hyperlipidemia, and hypercholesterolemia (Table 9-3).
Low-risk patients are <60 years old, with no prior thrombotic event and a platelet count <400 × 109 to 600 × 109 /L. These patients are managed with low-dose aspirin and observation.
High-risk patients are >60 years old or have a history of thrombosis. These patients require cytoreductive agents such as hydroxyurea, interferon-alpha, and anagrelide, with aggressive treatment of reversible risk factors.
Intermediate-risk patients require individualized therapy.
Aspirin is commonly used to prevent thrombosis but should be withheld once platelet counts are >1500 × 109/L due to bleeding risk. Extreme thrombocytosis may promote the abnormal adsorption of large von Willebrand factor (vWF) multimers and result in a hemostatic defect. Accordingly, such patients should be screened for the presence of acquired von Willebrand disease (vWD). Low-dose aspirin therapy (e.g., <100 mg/d) is acceptable if the ristocetin cofactor level is at least 30%; if <30%, all aspirin should be avoided. As discussed in the PV section above, hydroxyurea has been suggested to increase the risk of leukemic transformation in MPD patients (mean time to transformation ~15 years). In young patients, it is not unreasonable to start with anagrelide, which has not been linked to leukemogenesis. However, the combination of anagrelide and aspirin has been shown to increase the risk of bleeding compared to hydroxyurea and aspirin. In patients who require aspirin, especially those >60 years, hydroxyurea is still typically the first-line agent. In younger patients, alternatives include anagrelide monotherapy and interferon-alpha.
Management of thrombosis typically requires either lifelong aspirin, for arterial thrombosis, or coumadin, for venous thrombosis. In addition, other risk factors should be aggressively managed, including platelet count, leukocyte count, and cardiovascular risk factors.
Rarely, symptomatic, extreme thrombocytosis may be managed with thrombopheresis, although the results are short lived and must be combined with other modalities of therapy.
Symptoms of gout may be managed with allopurinol. Vaso-occlusive symptoms may respond to aspirin alone. Like PV, pruritus may respond to cimetidine or cyproheptadine.
SPECIAL CONSIDERATIONS
Surgery. Splenectomy poses a high risk for patients with ET and an increased platelet count and is contraindicated.
Essential thrombocythemia and pregnancy. Pregnant patients are at higher risk of early miscarriage complications and are often treated with aspirin. As the pregnancy progresses, the platelet count usually decreases toward the normal range but may rebound quickly after delivery. Aspirin should be discontinued ~5 days prior to delivery to limit hemorrhagic risk.
OUTCOME/PROGNOSIS
Patients generally have an excellent prognosis and appear to have median survivals similar to those of age-matched controls. Morbidity and mortality are related to thrombotic and hemorrhagic events. Transformation to AML is relatively rare, but risk is increased in patients treated with multiple cytotoxic drugs.
CHRONIC IDIOPATHIC MYELOFIBROSIS (AGNOGENIC MYELOID METAPLASIA)
GENERAL PRINCIPLES
Definition
Chronic idiopathic myelofibrosis (CIMF) is a clonal disorder thought to arise from a primitive lymphohematopoietic precursor. Patients have clonal circulating red cells, granulocytes, and platelets, and their marrow is fibrotic due to a reactive, polyclonal proliferation of fibroblasts and other mesenchymal cells induced by the neo-plastic cells. The neoplastic cells also emigrate from the marrow and establish sites of extramedullary hematopoiesis (myeloid metaplasia) in various sites throughout the body. One-third of cases of CIMF harbor cytogenetic abnormalities at diagnosis and often transform to AML. Common genetic abnormalities found in CIMF are mutations in JAK2 (35% to 55%), the retinoblastoma susceptibility gene, and the p53 gene, as well as abnormalities of the RAS family of proto-oncogenes. Neoangiogenesis is particularly active in CIMF compared with the other myeloproliferative syndromes.
Epidemiology
CIMF is the least common of the MPDs, with an annual incidence of 0.2 to 1.5 cases per 100,000. The typical case is a male older than age 50 years. The median age at presentation is 67 years, and 70% of cases are diagnosed after age 60 years. No common etiologic factor has been identified, although there are sporadic reports of an association with radiation and benzene exposure.
DIAGNOSIS
Clinical Presentation
Two-thirds of patients are symptomatic at diagnosis from the effects of hypercatabolism, cytopenias, or extramedullary hematopoiesis (Table 9-4). Bone pain may also be a prominent feature. Splenomegaly is very common, with 85% to 100% of patients having it at diagnosis, and it is frequently progressive, with up to 35% of patients developing massive splenomegaly (extending into the pelvis). Two-thirds of patients will have hepatomegaly, and 10% will have peripheral lymphadenopathy. A minority of patients will develop portal hypertension, with the associated signs and symptoms.
Diagnostic Criteria
CIMF is diagnosed when the following are present:
Presence of megakaryocyte proliferation and atypia, usually accompanied by reticulin and/or collagen
WHO criteria for PV, CML, MDS, or other myeloid neoplasm not met
Demonstration of a clonal marker (e.g., JAK2 or MPL)
Leukoerythroblastosis
Palpable splenomegaly
Anemia
Increased serum lactate dehydrogenase level
Other causes of bone marrow fibrosis should be excluded, including cancers metastatic to the marrow, CML, myelodysplasia with fibrosis, other MPDs, infection, autoimmune disorders, secondary hyperparathyroidism associated with vitamin D deficiency, and lymphoma. In addition, the marrow may not be fibrotic early in the course of the disease, further complicating the diagnosis. Careful morphologic exam of the bone marrow, as well as cytogenetic studies, may help to differentiate among disorders. The diagnosis of osteosclerosis is made when sclerotic lesions by x-ray are present along with the criteria for CIMF. These lesions occur in up to 50% of patients and may cause severe pain.
Diagnostic Testing
The complete blood count is usually abnormal in CIMF. Fifty percent to 70% of patients will be anemic at presentation, some severely, with 25% having an Hgb <8 g/dL. Other abnormalities are variably present: leukocytosis (50%), leucopenia (7%), thrombocytosis (28%), and thrombocytopenia (37%). The peripheral smear shows a leukoerythroblastic picture with teardrop poikilocytes, nucleated red cells, and anisocytosis. Abnormalities in immunologic studies are found in 50% of patients and include autoantibodies, polyclonal hyperglobulinemia, a positive Coombs test, and monoclonal antibodies.
During bone marrow biopsy, marrow may not be attainable by aspiration secondary to fibrosis, resulting in a “dry tap.” Findings on marrow exam include increased cellularity, granulocyte hyperplasia, and megakaryocyte dysplasia. Reticulin staining is increased, and variable degrees of fibrosis are present. The diagnosis is usually made by the constellation of increased marrow reticulin or collagen fibrosis, typical leukoerythroblastic peripheral blood findings, and splenomegaly in the absence of other known disorders such as ET, PV, CML, and AML-M7.
TREATMENT
Conventional therapy, including supportive care, does not alter the natural history of CIMF. Low-risk patients with only mild splenomegaly should initially be observed. Those with progressive organomegaly and/or leukocytosis or thrombocytosis should be initially managed with hydroxyurea. Those with painful or massive splenomegaly and those with portal hypertension should be considered for either splenic irradiation or splenectomy. Those who develop anemia in the setting of cytopenias should be treated with androgens, transfusion, and exogenous EPO. Those who develop anemia and increased WBC and/or platelet counts should be managed with corticosteroids and transfusions.
Splenectomy may alleviate mass-related symptoms, portal hypertension, refractory anemia, and thrombocytopenia. Prolonged benefit has been seen; however, serious perioperative complications, including bleeding, thrombosis, and infection, occur in nearly 30% of persons. Therefore, it should be reserved for patients who have not responded to more conservative management for these symptoms. The median survival for patients undergoing splenectomy is 2 years. There is an increased risk for leukemic transformation in those individuals who undergo splenectomy.
Splenic irradiation usually controls pain and other symptoms related to splenomegaly (94% of the time for a median of 6 months), but the associated toxicity is not trivial. Severe cytopenias may develop in up to 43% of irradiated patients, of which 13% may be fatal due to infections and hemorrhage. Toxicity is not related to radiation dose, so blood counts must be monitored closely with treatment. In addition, radiation therapy does not improve the anemia and, therefore, is generally used for patients who are not surgical candidates.
Thalidomide, with or without a tapering course of steroids, has shown some promise in ameliorating both splenomegaly and cytopenias. Unfortunately it is poorly tolerated, with up to two-thirds of persons stopping the medication within 6 months. Lenalidomide may have similar benefits, with better tolerability. These and other targeted therapies have been associated with a hyperproliferative syndrome requiring rescue hydroxyurea for leukocytosis and/or thrombocytosis.
Etanercept (Enbrel, 25 mg SQ twice weekly) has been associated with improvement of constitutional symptoms (e.g., weight loss, night sweats, fatigue, fever).
JAK2 inhibitors are being investigated in patients with myelofibrosis. Reductions in splenic size and relief of symptoms (e.g., pruritus, fatigue) have been reported.
Allogeneic stem cell transplantation is the only therapy that offers the chance to eliminate marrow fibrosis and potentially cure patients. With standard myeloablative conditioning regimens, there is significant morbidity and mortality. Reduced-intensity conditioning regimens may abrogate some of these complications. Transplantation should be considered in young patients with a poor prognosis and a histocompatible donor.
OUTCOME/PROGNOSIS
The course of CIMF is highly variable, and most of the morbidity and mortality is due to progressive marrow failure, thrombosis, hypersplenism, advanced age, and evolution into AML. The rate of progression to acute leukemia is ~20% over 10 years. Approximately 7% of patients will develop portal hyper-tension related to increased portal flow from massive splenomegaly as well as intrahepatic obstruction related to thrombosis in small portal veins. Associated ascites and variceal bleeding may occur. Progressive splenomegaly may lead to splenic infarction, which presents acutely with fever, nausea, and left upper quadrant pain. Patients may develop neutrophilic dermatoses, which appear as tender plaques. Extramedullary hematopoiesis may develop in many sites, including the spleen, liver, lymph nodes, serosal surfaces, paraspinal or epidural spaces, and urogenital system.
CIMF carries the worst prognosis of all the MPDs, with a median survival of ~3.5 to 5.5 years. However, survival is variable and ranges from <3 to >10 years. The International Working Group for Myelofibrosis Research and Treatment has devised a prognostic scoring system (IPSS-PMF) from an evaluation of presenting signs and symptoms in 1054 consecutively studied patients diagnosed with CIMF at seven different centers. The following five adverse prognostic features were noted on multivariate analysis:6
Presence of constitutional symptoms (i.e., weight loss >10%, night sweats, or fever)
Age >65 years
Hemoglobin <10g/dL
Leukocyte count >25,000/µL
Circulating blast cells ≥1%
Subjects with 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2), or ≥3 (high risk) of these variables at presentation had nonoverlapping median survivals of 135, 95, 48, and 27 months, respectively.
The degree of fibrosis does not appear to be related to prognosis. In addition, cytogenetic findings predict either good (sole abnormalities of del(20q), del(13q), trisomy 9) or poor (complex abnormalities, trisomy 8) prognosis. The prognostic value of other cytogenetic findings is unclear because of the small number of patients evaluated. Two studies have shown that a low burden of the JAK 2V617F allele in PMF might indicate the presence of an overriding V617F-negative clone that confers a more aggressive disease phenotype with shortened overall survival, although the biologic mechanisms underlying this correlation remain to be established.
HYPEREOSINOPHILIC SYNDROMES
GENERAL PRINCIPLES
Definition
Two syndromes compose this category: chronic eosinophilic leukemia (CEL) and idiopathic hypereosinophilic syndrome (HES). They should be suspected when the peripheral eosinophil count is persistently >1500/µL. The diagnosis of these disorders requires ruling out other causes of eosinophilia, such as underlying infection, allergy, autoimmune disease, pulmonary disease, clonal lymphoid disorder, and other MPDs. Also, the peripheral eosinophilia should be accompanied by an elevated eosinophil count in bone marrow and characteristic end-organ damage.
Epidemiology
HES is rare and the prevalence is unknown. Most patients are diagnosed between the ages of 20 and 50 years, although HES can develop in children. PDGFRalpha (PDGFRA)-associated HES occurs almost exclusively in males, whereas lymphocytic variant HES and HES of unknown etiology appear to be equally distributed between the sexes.
Pathophysiology
Eosinophils are derived from myeloid progenitors in the bone marrow, through the action of three hematopoietic cytokines: granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5. Of these three, only IL-5 is specific for eosinophil differentiation.
Several mechanisms have been proposed to account for the dysregulated overproduction of eosinophils in patients with HES: 7
Clonal eosinophilic proliferation as a result of a primary molecular defect involving hematopoietic stem cells and/or defects in signal transduction from the receptors that mediate eosinophilopoiesis
Overproduction of eosinophilopoietic cytokines, such as IL-5
Functional abnormalities of the eosinophilopoietic cytokines, related to enhanced or prolonged biologic activity
Defects in the normal suppressive regulation of eosinophilopoiesis or of eosinophil survival and activation
DIAGNOSIS
Clinical Presentation
Ninety percent of patients will have symptoms at diagnosis. Characteristically, patients will complain of various nonspecific constitutional symptoms such as fever, fatigue, cough, pruritus, diarrhea, angioedema, and muscle pains. Infiltrating eosinophils will produce end-organ damage in the majority of patients within 3 years of diagnosis. Cardiac disease is the major cause of death, but virtually every organ system may be involved, leading to protean clinical manifestations (Table 9-5).
Diagnostic Criteria
Diagnosis relies on the exclusion of all possible causes of reactive eosinophilia. Also, patients must be evaluated and ruled out for T-cell lymphomas, Hodgkin lymphoma, mastocytosis, ALL, AML, CML, PV, ET, CIMF, and the myelodysplastic syndromes. If all of these exclusions are met, a diagnosis of HES can be made. If there is a clonal chromosomal abnormality or if there are >2% blasts in the peripheral blood or >5% but <19% blasts on bone marrow aspirate, then the diagnosis is CEL. If there are >20% blasts on bone marrow aspirate, then the diagnosis is AML.
Diagnostic Testing
The diagnosis is usually suspected based on peripheral eosinophilia and some constellation of the symptoms reviewed in Table 9-4. CEL is due to an autonomous proliferation of clonal cells. HES is diagnosed when the diagnostic criteria for CEL are satisfied, but without evidence of clonality or myeloid cell proliferation. A molecular defect has been identified in about half of CEL/HES cases. It is a specific interstitial deletion on chromosome 4 that results in the expression of a FIP1L1-PDGFRA fusion tyrosine kinase. This fusion kinase is sensitive to inhibition by imatinib.
Treatment is aimed at those with end-organ damage. Corticosteroids reduce peripheral eosinophil numbers and the toxicity of the eosinophilic granules. Steroid-resistant patients are treated with various single-agent or combination therapies, including hydroxyurea, interferon, vincristine, and etoposide.
Several recent studies have shown the efficacy of imatinib in the treatment of both CEL and HES. Notably, responses are seen both in patients with recognized mutations of the FIP1L1-PDGFRA kinase, the assumed target of imatinib in this disease, and in those without it. These dramatic responses argue that imatinib should be the first-line therapy for symptomatic CEL and HES. For HES patients (with or without the FIP1L1/PDGFRA fusion) who fail pharmacologic management, allogeneic hematopoietic cell transplant offers a chance of long-term remission.
OUTCOMES/PROGNOSIS
The clinical course of both HES and CEL is markedly variable. Features that portend a better prognosis include the following:
Prolonged eosinopenia in response to prednisone challenge
The absenceoffindings associated with MPDs, including elevated serum vita-min B12, abnormal leukocyte alkaline phosphatase scores, splenomegaly, cytogenetic abnormalities, myelofibrosis, and myeloid dysplasia
The presence of angioedema, although this observation may have been due to the inclusion of patients with the entity of episodic angioedema with eosinophilia (Gleich's syndrome)
Blast transformation may come early or very late in the clinical course. Features that predict a poor prognosis are marked splenomegaly, cytogenetic abnormalities, dysplastic myeloid features, and increased peripheral or marrow blast counts. Long-term survival is possible. In one case series up to 42% of persons were still alive 15 years after diagnosis.
REFERENCES
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