Myeloproliferative diseases are a collective group of disorders characterized by the clonal proliferation of at least one hematopoietic cell lineage. The ensuing conditions are associated with severe complications.
Myeloproliferative diseases have similar clinical pictures and generally feature nonspecific symptoms such as fatigue, weight loss, and anorexia. Once the condition progresses, the patients develop signs and symptoms. Patients with abnormal blood count are prone to bleeding easily, prolonged hemorrhage, and thrombosis. The latter is more common in ET and PV due to the viscosity of the blood, which also increases the risk for cardiovascular events. Leukocytopenia leads to infection of the sinuses, skin, and genitourinary system. Pain and early satiety caused by an enlarged spleen are particularly observed in CML and PMF.
Further signs such as tinnitus, priapism, and stupor are suggestive of leukostasis. Arthralgia and gout occur secondary to hyperuricemia. Note that the Neoplasm Symptom Assessment Form (MPN-SAF) can be administered to patients suffering from myeloproliferative diseases as a method to assess the patient's clinical picture .
Remarkable findings on the exam include pallor, petechiae, and ecchymoses. Moreover, patients with these conditions exhibit splenomegaly, and pain the left upper quadrant and left shoulder due to splenic infarction.
When in early stages, MPNs may be discovered incidentally on routine tests. In others, the clinical picture will warrant further investigation. Asymptomatic patients with abnormal tests and symptomatic patients should all undergo a clinical assessment that consists of a thorough history, a complete physical exam, and appropriate studies. A CBC with differential, blood smear, bone marrow/aspiration, and genetic analyses are key studies that provide information about the disease and its degree of severity.
In CML, cytogenic testing will demonstrate the presence of the Philadelphia chromosome. Polymerase chain reaction (PCR) and fluorescent in-situ hybridization (FISH) are other diagnostic techniques that can be used as well.
The index of suspicion for PV is high for men with a hemoglobin above 18.5 g/dL and women with a hemoglobin greater than 16.5 g/dL. In addition to the abnormal hemoglobin values, the WHO proposes that the presence of JAK2 mutation on PCR analysis is another major criterion for the diagnosis of PV. Note that the clinician should exclude secondary etiologies of polycythemia.
The workup for ET is comprised of PCR detection of JAK2 V617F mutation or another clonal marker. According to the WHO , the following are the criteria for the diagnosis of ET: 1) a platelet count above or equal to 450 x 109/L, 2) evidence of megakaryocyte proliferation, 3) presence of above mutation, and 4) failure to meet criteria for other myeloid neoplasms. Note that reactive thrombocytosis must be ruled out.
Histologic studies on peripheral blood smear reflect a picture of leukoerythroblastosis im PMF. Moreover, bone marrow biopsy studies reveal increased fibrosis. The WHO  outlines the following diagnostic criteria 1) proliferation of megakaryocytes on bone marrow analysis, 2) presence of JAK2 V617F mutation or other clonal marker, and 3) exclusion of other causes. Also, about half of all patients have cytogenic defects such as various deletions and trisomies .
In CEL, thorough anamnesis and physical examination should be conducted to identify possible triggers of secondary eosinophilia. The latter may be induced by hypersensitivity reactions, infestation with parasites, autoimmune disorders, psoriasis and other skin diseases, among others. These are not necessarily associated with severe clinical symptoms, and if patients are unaware of their condition and don't seek medical attention, they may develop chronic eosinophilia. In case of confirmed primary eosinophilia, blood smears should be prepared because they may reveal important morphological features of distinct cell populations. Results may or may not hint at a malignancy, and they may allow for the distinction of myeloid and lymphoid neoplasms and myelodysplastic syndromes. FIP1L1-PDGFRA fusion has been reported to be the most common chromosomal rearrangement causing CEL. Consequently, patients suspicious of CEL should first be tested to this effect. Nested reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization may be applied to demonstrate the absence of loci physiologically located between those genes encoding for FIP1L1 and PDGFRA. A combined approach may significantly increase the sensitivity of tests. Blood and bone marrow specimens that test negative for FIP1L1-PDGFRA should subsequently be subjected to analysis for PDGFRB or FGFR1 rearrangements. According to the diagnostic guidelines given by the World Health Organization, identification of any of the aforementioned cytogenetic anomalies warrants the diagnosis of an eosinophilic myeloproliferative disorder due to rearrangements of PDGFRA, PDGFRB or FGFR1. However, CEL-NOS is not associated with any of those abnormalities, and other myeloid malignancies should be ruled by the following measures:
If these criteria are not met by a patient presenting with chronic eosinophilia, they are usually diagnosed with IHS.
The main class of drugs used in the treatment of CML targets the tyrosine kinase. Hence, the tyrosine kinase inhibitors (TKIs) such as imatinib, and other new ones are used as first-line agents. Chemotherapy, allogenic stem cell transplantation, and interferon have all been used in the past but are associated with adverse effects.
Patients developing CEL due to rearrangements involving those genes encoding for PDGFRA or PDGFRB generally respond well to treatment with imatinib. Allogeneic stem cell transplantation should be considered in cases of advanced CEL and poor response to drug therapy.
The goals for patients with PV are to reduce the red blood cell count and to decrease the risk of thrombosis. Hence, phlebotomy is the mainstay therapy, as it decreases the hemoglobin level and viscosity of the blood. Furthermore, aspirin 81mg is used for prevention of thrombotic events unless the patient has contraindications. Myelosuppressive drugs such as hydroxyurea, interferon, and JAK inhibitors may be helpful.
Treatment of ET is approached differently for low and high-risk groups. The low risk refers to patients who 1) are younger than the age of 60, 2) possess risk factors for thrombosis or cardiovascular events, and 3) exhibit platelet count of ≤1,500 x 109/L. These individuals can be observed or treated with low dose aspirin. High-risk patients are older than 60 years of age and/or positive for a history of a thrombotic episode. These patients should be treated with cytoreductive therapy.
While allogeneic hematopoietic cell transplantation can reverse the process of this disease, the advanced age of these individuals renders them as poor candidates. The only drug approved for PMF is a selective JAK1/JAK2 inhibitor called ruxolitinib. Other similar agents are currently undergoing clinical trials . Supportive transfusions are very beneficial for these patients.
Many cases of myeloproliferative disorders develop gradually and slowly. With prompt and appropriate management, the outcomes are promising. The prognosis is reflective of numerous factors such as the type of disease, the clinical presentation, percentage of blasts present in the peripheral blood and blood marrow, and existing chromosomal defects.
Patients with PV have a close to normal life expectancy with at least 10 years after diagnosis. Those with ET have a normal lifespan. Furthermore, individuals with PMF have a poor prognosis with a median survival of 3.5 to 5.5 years . The common causes of death in the latter are attributed to infection, cardiovascular events, hemorrhage, and thrombosis.
It is estimated that 1070 patients with CML will die in 2016 . Furthermore, the later stages of CML are difficult to control and associated with increased risk of fatality. Advanced CML is more aggressive that the other proliferative disorders.
There are serious sequelae that can arise from myeloproliferative diseases such as myocardial infarction, stroke, infection, liver failure, renal failure, anemia, hemorrhage, and hepatomegaly/splenomegaly. Additionally, CML has the potential to transform into acute leukemia.
Myeloproliferative disease encompasses a group of neoplasms affecting then proliferation of hematopoietic cell lineages in the bone marrow, and possibly the spleen and liver . The etiology may be multifactorial in which there is genetic and environmental interplay.
More than 90% of all cases of CML occur secondary to the presence of the Philadelphia chromosome, which results from a balanced reciprocal translocation between chromosomes 9 and 22. The new chromosome includes the BCR-ABL fusion oncogene which codes for a constitutively active tyrosine kinase. The latter leads to the overproduction of the progenitor hematopoietic cells.
Certain subtypes of CEL are associated with genetic anomalies provoking constitutive activity of tyrosine kinases. The respective rearrangements of PDGFRA, PDGFRB or FGFR1 have not only been detected in eosinophils, but also in non-eosinophilic granulocytes, monocytes and mast cells, and this observation implies that chromosomal alterations originate from common precursor cells, i.e., from myeloblasts or earlier developmental stages of myeloid cells.
More than 90% of PV cases exhibit a mutation in the Jak2 gene . There are familial cases that have been linked to a mutated erythropoietin (EPO) receptor.
ET emerges due to the hypersensitivity of megakaryocyte progenitor cells to cytokines such as interleukin-3 (IL-3) and IL-6 . Furthermore, about 50% to 65% of individuals with ET have a mutation in the JAK2 kinase, which leads to its overactivity and contribution to the disease.
The underlying mechanism responsible for PMF is the clonal proliferation of hematopoietic stem cells. Approximately half of all cases have a JAK2 mutation. This causes the myeloid cells to increase their response to cytokines. Risk factors for PMF include exposure to radiation and petrochemicals such as toluene and benzene.
The incidence of CML in 2016 is 1.8 per population of 100,000 . Furthermore, the median age at diagnosis is 64 years . There is a gender preference for males. The overall annual incidence of CEL and idiopathic hypereosinophilic syndrome has been estimated to be 0.036 per 100,000 inhabitants.
The prevalence of PV in the United States is approximately 44 to 57 individuals per population of 100,000 . This affects both genders of all ethnicities but is more common in East European Jewish background. It typically presents in the 6th or the 7th decade of life, with a possible predilection for men  .
The prevalence of ET is about 30 to 57 per population of 100,000. . The median age at diagnosis is 60 years old. Furthermore, it is more commonly found in younger women.
The estimated incidence of PMF between 2008 and 2010 was 1 per population of 100,000 . The median age at diagnosis is 67 years. It affects men and women equally and occurs more in Caucasians. This disease may develop in progressive cases of PV and other myeloproliferative neoplasms.
The pathophysiology of CML is explained by the underlying tyrosine kinase that exhibits a gain of function characteristic, which leads to the excessive production of granulocytes as well as red blood cells, megakaryocytes, monocytes, etc. The clinical course of CML evolves over three stages which are the chronic, accelerated, and blast phases. The chronic phase is insidious and may last months to years. The accelerated phase is aggressive and eventually progresses to the blast crisis. It is thought that genetic instability and additional chromosomal defects play a role in the evolution of the disease.
In PV, the pathogenesis emerges from the abnormal proliferation of pluripotent stem cells and their differentiation into granulocytes, red blood cells, and platelets. This occurs as a consequence of progenitor cells projecting a high response to erythropoietin, IL-3, and granulocyte-macrophage-colony-stimulating factor. The majority of cases have a constantly active JAK-STAT pathway. Thrombosis and bleeding are serious sequelae , which manifest as a result of the viscosity caused by the overproduction of red blood cells and platelets.
In ET, megakaryocyte precursors have an increased response to cytokines and maybe even thrombopoietin. The mutations associated with ET are found in JAK2, thrombopoietin receptor (MPL) and/or calreticulin (CALR). Clinical complications include thrombosis and bleeding although the mechanisms are not fully understood.
PMF is characterized by excessive marrow fibrosis as well as extramedullary hematopoiesis. Originating from clonal stem cells, the myeloid cells secrete platelet-derived growth factor (PDGF), transforming growth factor-B (TGF-B), epidermal growth factor (EGF), and basic fibroblastic growth factor (FGF). The resultant bone marrow fibrosis ultimately leads to pancytopenia and extramedullary hematopoiesis.
There is no prevention for myeloproliferative diseases.
The myeloproliferative disorders, currently known as myeloproliferative neoplasms (MPNs), describe a group of conditions caused by the proliferation of clonal hematopoietic stem cells in the bone marrow and occasionally in the spleen and liver . The World Health Organization (WHO) classified chronic myelogenous leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL), not otherwise specified and mastocytosis among the MPNs .
While these disorders have overlapping features, they also vary. CML is the only neoplasm with the characteristic BCR-ABL fusion oncogene that leads to excessive production of blast cells. PV occurs secondary to a Janus kinase 2 (JAK2) mutation that results in an overproduction of red blood cells. Furthermore, ET is defined as the proliferation of megakaryocytes and the ensuing thrombocytosis. PMF is characterized by the marrow fibrosis and extramedullary hematopoiesis.
Myeloproliferative disorders are often slow developing and do not initially present with symptoms. Moreover, the majority of patients are diagnosed incidentally while undergoing routine testing. The clinical picture in early stages is often nonspecific with symptoms including fatigue, weight loss and anorexia. As the disease evolves with the involvement of the bone marrow, more ominous findings and signs manifest. Serious complications such thrombosis and hemorrhage arise.
The diagnosis is achieved through a thorough assessment of the patient's history, physical examination, and pertinent studies. The latter includes the complete blood count (CBC), analysis of peripheral blood smear, bone marrow biopsy and aspiration, and chromosomal studies.
The therapeutic approach depends on the present disorder. The goals aim to prolong survival and improve the quality of life. The treatment ranges from specific target drugs to plasmapheresis.
What are myeloproliferative disorders?
This group of diseases occurs largely due to mutations in the stem cells of the bone marrow causing an overproduction of various types of blood cells. The following are the main myeloproliferative disorders:
What are the signs and symptoms?
These diseases take months to years to progress. In the early stages, there may be no symptoms. As the disease progresses, patients will mostly likely experience the following:
How are they diagnosed?
Most patients with these diseases are diagnosed while undergoing routine blood work. They are usually without symptoms in the early stages. When a patient has an abnormal laboratory finding or symptoms like the above, the clinician should obtain the full history, perform a complete physical exam, and order the appropriate tests such as:
The World Health Organization has set forth guidelines to aid the clinicians in diagnosing the patients accurately.
How are they treated?
The treatment goals aim to prolong survival and improve the quality of life. CML is treated with medications such as imatinib that target the chromosomal defect as well as other options such as chemotherapy. PV is treated with plasmapheresis. ET can be observed in a group of patients. PMF is treated with blood transfusions, stem cell transplantation, and/or other drugs.
What is the prognosis of these diseases?
Many cases of myeloproliferative disorders develop gradually and slowly. With early diagnosis and appropriate management, the prognosis is promising. The prognosis is reflective of numerous factors such as the type of disease, the clinical presentation, percentage of blood cells present in the peripheral blood and blood marrow, existing chromosomal defects.