Yogen Saunthararajah
Chronic myeloproliferative neoplasms (MPNs) are clonal diseases of myeloid precursors that stand out clinically because of an increase in at least one peripheral blood count or a substantial increase in bone marrow fibrosis. The World Health Organization (WHO) recognizes the following entities (Table 26.1):
1.Chronic myelogenous leukemia (CML), BCR-ABL positive
2.Chronic neutrophilic leukemia
3.Polycythemia vera (PV)
4.Primary myelofibrosis (MF)
5.Essential thrombocythemia (ET)
6.Chronic eosinophilic leukemia, not otherwise specified
7.Mastocytosis
8.MPNs, unclassifiable
CML is discussed in Chapter 25 because of its unique treatment paradigm. This chapter is limited to a discussion of the three “classical” and more common MPNs: PV, ET, and MF. These three neoplasms share clinical characteristics, including propensities to thrombosis and hemorrhage, splenomegaly, debilitating systemic symptoms, cytopenias of some lineages, and a risk of leukemic transformation. The overlap in clinical features, which sometimes confounds attempts at disease classification, reflects overlap at the level of causative mutations, illustrated by a common high frequency of the JAK2 V617F mutation. Common biologic strands are revealed also by evolution of both PV and ET into MF in some patients, and a common risk for transformation into acute myeloid leukemia (AML). Overlap can also occur with myelodysplastic syndromes (MDS), and MDS/MPN overlap neoplasm is a classification recognized by the WHO.
PATHOPHYSIOLOGY AND DIAGNOSIS
Molecular Mechanism
The MPNs are clonal diseases driven by combinations of molecular abnormalities, most of which can be found in all the MPN subtypes, although individual mutations do have specific clinicopathologic associations. For example, the JAK2 mutation that substitutes phenylalanine for valine at position 617 (V617F) causes cytokine-independent (constitutive) activation of downstream messengers through the JAK-STAT, PI3K, and AKT pathways and is found in 95% of patients with PV and 50% to 60% with ET or idiopathic myelofibrosis. Mutated JAK2 is found in >50% of patients with Budd-Chiari syndrome suggestive of a masked myeloproliferative disorder. Inactivating mutations in EZH2 (a polycomb repressor complex component which is also deleted by chromosome 7q loss) are more evenly distributed, but do have an association with increased platelet counts. Inactivating mutations in another polycomb repressor component ASXL1 are highly associated with MF, and interestingly, with transformation of PV or ET into MF. Thus, the improving knowledge regarding the molecular basis of MPNs is useful for diagnosis and prognosis (Table 26.2), and hopefully increasingly useful in guiding therapy. Testing for the JAK2 V617F mutation by different techniques (PCR, restriction enzyme digestive pyrosequencing) is sensitive and specific, and readily available as a diagnostic tool.
Diagnosis and Distinguishing between the MPNs
The clinical presentation of MPNs can be with incidentally noted abnormal blood counts with patterns that vary depending on the particular MPN (Table 26.3). Distinctive clinical features relate to these lineage changes and splenomegaly.
■Increased red blood cell (RBC) mass and thus viscosity in PV can produce symptoms such as headaches, vertigo, tinnitus, and blurred vision. Another characteristic of PV in some patients is pruritus (histamine release) aggravated by hot water.
■Increased number of abnormal platelets in ET can cause arterial thrombotic events such as cerebrovascular ischemia, digital ischemia/erythromelalgia, and spontaneous abortions.
■Anemia in patients with MF may cause fatigue and shortness of breath, and splenomegaly can cause abdominal discomfort or early satiety. Hypermetabolic symptoms such as weight loss and sweating can be seen in MF but also in the other MPNs.
As outlined earlier, there is overlap in the molecular underpinnings of MPNs, and thus, not surprisingly, in clinical behaviors. Nonetheless, the various MPN classifications do have differing risks and prognoses; thus, the diagnostic approach prioritizes not mistakenly classifying an MPN into a category with less urgent prognostic or treatment implications. Accordingly, ET is diagnosed after excluding PV, and MF is diagnosed after excluding PV and ET (because marrow fibrosis can be a sequela of the other MPNs with their greater thrombo-hemorrhagic implications). CML should be ruled out by performing a fluorescence in situ hybridization (FISH) analysis for BCR-ABL in JAK2mutation-negative thrombocytosis or bone marrow fibrosis. Even with a positive JAK2 mutation or other clinical and peripheral blood observations to favor a particular MPN classification, bone marrow biopsy with cytogenetic analysis is recommended, to not miss a diagnosis of CML or MDS with accompanying prognostic and treatment implications. Platelet function tests or bleeding times are of little use in diagnosing or in guiding the management of MPNs.
PROGNOSIS
Median Survivals
■Patients with PV have a median survival of 1.5 to 13 years. In a recent multicountry prospective study of 1,638 patients with PV, the 5-year event-free survival was 82%, with a relatively low risk of death from cardiovascular disease and a high risk of death from noncardiovascular causes (mainly hematologic transformations).
■Patients with ET have a median survival of more than 10 years.
■Patients with MF have a median survival between 3 and 5 years.
Rate of Transformation to Acute Leukemia
■The estimated incidence of acute leukemia in 1,638 patients with PV prospectively followed in the ECLAP study was 1.3%, with an estimated annual incidence of 0.5 per 100,000 per year. Older age and exposure to P32, busulfan, or pipobroman were independent risk factors.
■The cumulative rate of transformation for patients with ET is 2% to 4%, respectively, at 10 and 20 years from diagnosis.
■The cumulative rate of transformation for patients with MF is 10% at 10 years (please also see discussions on treatment regarding transformation risk).
Transformation of PV or ET into MF
Both PV and ET may progress to post-PV MF or post-ET MF, previously referred to as the spent phase, which clinically resembles primary MF and is characterized by progressive cytopenias, splenomegaly, and marrow fibrosis. The cumulative rate of transformation is 5% and 10% at 10 years to 20 years, respectively, for ET and 10% to 20% for the same time line for PV.
Risk Factors for Thrombosis
In two prospective studies, the ECLAP study and the MRC-PT1, the cumulative rate of cardiovascular events in patients with PV ranged from 2.5% to 5% per patient-year and from 1.9% to 3% per patient-year for patients with ET. Arterial thrombosis accounts for 60% to 70% of the events, and is the major cause of death.
■In PV, older age (>60), a hematocrit ≥45%, and a previous history of thrombosis are risk factors. Surgery should be avoided in patients until a hematocrit <45% has been maintained for more than 2 months.
■In ET, age over 60 years and the presence of other cardiovascular risk factors (e.g., smoking and previous thrombosis) increase the risk for thrombosis.
In ET, an association between platelet count and thrombosis has not been established, but platelet cytoreduction on treatment with hydroxyurea (HU) has been associated with a reduced risk.
Risk Factors for Hemorrhage
■In ET, a platelet count >2 × 106/μL is a risk factor for hemorrhage (please also see recommendations regarding treatment).
TREATMENT
As a general principle, treatment for PV, ET, MF, or overlaps thereof is aimed at (i) alleviating the particular symptoms present in the individual patient (e.g., symptoms from splenomegaly, or symptoms from cytopenia) and (ii) anticipating and preventing potential life-threatening complications such as thrombosis or hemorrhage. Bone marrow transplantation is a potentially curative option that should be considered for some patients with MF. Following is a definition of risk categories and recommended treatments, with an overview provided in Table 26.4.
Polycythemia Vera
■Low risk: Age <60 years with no personal history of vascular events and who do not have additional risk factors for cardiovascular disease. Recommended treatment: phlebotomy alone with or without low-dose aspirin.
■Intermediate risk: Age <60 years with no personal history of vascular events and who do have additional cardiovascular risk factors. Recommended treatment: phlebotomy alone is adequate therapy; use of low-dose aspirin is encouraged.
■High risk: Age ≥60 years with a positive history of thrombosis. Recommended treatment: HU (with or without concomitant phlebotomy) and low-dose aspirin.
Maintaining a hematocrit <45% dramatically decreases the incidence of thrombotic complications. This is important, since in PV, 35% of initial thrombotic events are fatal. A randomized study of 518 patients with PV has shown that treatment with low-dose aspirin (100 mg per day) lowers the risk of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.
■Post-PV/ET MF: Options to alleviate cytopenia associated with massive splenomegaly include HU, IFN-α, and EPO (please see treatments for MF). Analgesia may be required for splenic infarct pain. It is difficult to treat cytopenia associated with marrow fibrosis and massive splenomegaly, since agents that reduce splenomegaly may not necessarily relieve cytopenia. Splenectomy can be followed by progressive hepatomegaly and can eventually transform to acute leukemia. In selected patients, allogeneic transplantation can be curative.
■Pruritus: Intractable pruritus responds to IFN-α in up to 81% of patients. In low-risk patients in whom IFN-α is not indicated, paroxetine, a selective serotonin reuptake inhibitor, can alleviate symptoms in most cases.
■Hyperuricemia: Allopurinol should be started before chemotherapy to decrease the risk of urate nephropathy (300 mg per day given orally; dose reduction needed in renal insufficiency).
Essential Thrombocythemia
■Low risk: Age <60 years, and no history of thrombosis, and platelet count <1,000 × 109/L. Recommended treatment: observation or low-dose aspirin, especially if there are symptoms or cardiovascular risk factors (e.g., smoking). If platelet count is ≥1,000 × 109/L, clinically significant acquired von Willebrand syndrome (ristocetin cofactor activity <30%) should be excluded before initiation of low-dose aspirin therapy.
■High risk: Age ≥ 60 years and/or a previous history of thrombosis. Recommended treatment: cytoreduction with HU and low-dose aspirin therapy.
Treatment in ET must consider the fact that life expectancy is nearly normal and that platelet reduction with HU may be associated with an increased risk for transformation to leukemia. Treatment is directed at preventing thrombosis and hemorrhage in those patients deemed to be at risk for these complications, because of an actual history of thrombosis, cardiovascular risk factors such as smoking or age more than 60 years, or a platelet count >1,500 × 109/L. Increased WBC (≥15 × 109/L) might be an additional risk factor for thrombosis.
A randomized trial of HU versus placebo in 114 high-risk patients showed a significant reduction of thrombotic events in the treatment arm (3.6% vs. 24%). The HU dose was adjusted to achieve a platelet count of <600 × 109/L. Anagrelide is a nonmutagenic orally active agent that produces selective platelet cytoreduction by interfering with megakaryocyte maturation. In a randomized study of 809 patients with high-risk ET, HU plus low-dose aspirin was superior to anagrelide plus low-dose aspirin. IFN-α can also effectively cause platelet cytoreduction. The therapeutic target platelet count in this trial was <400 × 109/L. Plateletpheresis is used as an emergency therapy when ongoing thrombosis cannot be adequately managed with chemotherapy and antithrombotic agents.
Myelofibrosis
■Risk stratification by the Dynamic International Prognostic Scoring System Plus (DIPSS Plus): one point each for age >65 years, white blood cell count >25 × 109/L, circulating blast cells ≥1%, presence of constitutional symptoms, unfavorable karyotype, platelet count <100 × 109/L, and transfusion dependence, and two points for hemoglobin <10 g/dL.
Low risk: 0 points, median survival 20 years. Intermediate risk-1: 1 point, median survival 6.5 years. Intermediate risk-2: 2 to 3 points, median survival 2.9 years. High risk: 4 to 6 points, median survival 1.7 years.
■Palliative therapy for MF is directed toward alleviating symptoms which are generally related to anemia, splenomegaly, or systemic symptoms such as severe fatigue.
Anemia: Androgens (e.g., danazol) combined with prednisone (prednisone is tapered after a few weeks), or thalidomide combined with prednisone, or erythropoietin replacement therapy in patients with inappropriately low erythropoietin levels can be considered, although results have been mixed. Transfusion needs may diminish after splenectomy (see below). Transfusion support (with iron chelation when indicated) may be necessary. Lenalidomide should be considered to treat MF with a 5q– chromosome abnormality. Experimental therapies that are being evaluated include pomalidomide and DNMT1-depleting drugs (5-azacytidine and decitabine).
Splenomegaly: Options include JAK2 inhibitor (e.g., ruxolitinib), although the currently approved dosages may be unnecessarily high, and it may be appropriate to start with lower than standard dosages with an escalation if necessary. The main cautions are potential for exacerbating cytopenia with associated risk for hemorrhage, and for rebound disease growth and inflammatory symptoms if the drugs are discontinued abruptly (dosage should be tapered off rather than abruptly discontinued). Lenalidomide should be considered to treat MF with a 5q– abnormality. HU can be considered, with dose modifications depending on cytopenias. Splenectomy is an option to alleviate pain and early satiety, depending on local surgical experience and thus surgical risk. Secondary hepatomegaly is a potential long-term complication of splenectomy. Increasing white blood cell counts and platelet counts after splenectomy may necessitate HU therapy. Experimental therapy options include IFN-α, pomalidomide, and DNMT1-depleting drugs.
■Curative therapy: Allogeneic transplantation should be considered for patients younger than 55 years who have MF.
Five-year survivals with a related or an unrelated matched transplant are 54% and 48%, respectively, as determined by the European Group for Blood and Marrow Transplantation (EBMT). A recommendation for transplantation is not clear-cut in asymptomatic patients without cytogenetic abnormalities and no cytopenia because the median survival in this group is >14 years with palliative therapy alone. In other words, risk classification should be considered, and although the outcome with transplantation is adversely affected by risky characteristics, risk factors such as hemoglobin level <10 g/dL; white blood cell count <4 × 103/μL or >30 × 103/μL; more than 10% of circulating blasts, promyelocytes, or myelocytes; or abnormal cytogenetics should prompt consideration for transplantation. Pretransplantation splenectomy, although not necessary in every patient, is associated with faster engraftment and can be considered in those with massive splenomegaly. Marrow fibrosis is reversible with transplantation.
REVIEW QUESTIONS
Mr. Jones is a 47-year-old active Caucasian male seen in the office of the internist Dr. Brown. His main complaint is increasing fatigue. He has noticed a decrease in his exercise tolerance, and a sense of fatigue that has been progressive in the 3 months preceding his visit to the clinic. He enjoys playing soccer, and usually participates in a “40 years and older” pick-up game every Saturday. For the past 2 months, he has not felt like playing.
Upon questioning, he states that he gets winded easily and feels fatigued after physical effort. It takes him longer to recover from effort than ever before. He denies any chest or abdominal pain and he has not had a change in his bowel habit or noticed any change in the color of his stool. His weight has not changed and his appetite remains good. He has not noticed blood in the toilet bowl after bowel movements. He has not experienced any recent colds, and he has not had recent cough, sore throat, fever, body ache, or headache. He denies night sweats, too. He has noticed some blood when rinsing after brushing his teeth, but, has noticed some bruises, although he wonders if these are from his soccer games. He has not had any bleeding from the nose.
He does not have any significant past medical history and initially he denied taking any medications. However, upon specific questioning regarding use of over-the-counter medications including pain medications, he mentions that he does use naproxen occasionally for pain and swelling in the knees after playing soccer. He has not used naproxen for more than 4 weeks.
He is a lawyer for a local law firm and has not had any unusual chemical exposures. He drinks alcohol only occasionally and in small amounts, and has not noticed swelling around the ankles, although his knees do swell after his soccer games, requiring use of postgame icel-packs. He did travel to Thailand 5 years ago, had a good time, and was not unwell during or after the trip.
He has two siblings, one of whom was born before the patient, “was deformed at birth,” and died as an infant. His other sibling, a brother aged 44, is alive and well without medical problems.
On examination, he is a fit-appearing Caucasian male. Although alert, he does appear fatigued and is pale without icterus. Bruises are noted on his lower extremities. There was no palpable lymphadenopathy. A spleen tip is palpated 12 cm below the left costal margin in the mid-clavicular line. There was no palpable hepatomegaly.
1.What is the diagnosis, or what are the differential diagnoses, for Mr. Jones’ condition?
A.MDS
B.MF
C.Post-PV MF
D.Post-ET MF
E.All of the above
2.What additional investigations are indicated to establish a definitive diagnosis?
A.Reticulocyte count and lactate dehydrogenase
B.Evaluation for JAK2 V617F mutation
C.Bone marrow aspirate and biopsy for morphology and karyotype evaluation
D.FISH studies to detect the BCR-ABL fusion
E.All of the above
3.The JAK2 V617 test was positive, and the bone marrow evaluation demonstrated an increase in reticulin fibrosis, and an increase in the myeloid:erythroid ratio, without an increase in megakaryocyte numbers. A 20q– chromosome abnormality was detected in 20 of 20 metaphases. Liver and renal function tests were normal. What are appropriate therapies for Mr. Jones?
A.Allogeneic stem cell transplant
B.JAK2 inhibitor
C.HU
D.Erythropoietin
E.Iron supplements
Suggested Readings
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2.Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353:33-45.
3.Hoffman R, Mesa RA, Vannucchi AM. Myeloproliferative disorders. In: Hematology 2007 (American Society of Hematology Education Program Book), American Society of Hematology; 2007.
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7.Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. 2007;110(4):1092-1097.
8.Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937-951.