Myeloproliferative Disease

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Practice Essentials

Myeloproliferative diseases are a heterogeneous group of disorders characterized by cellular proliferation of one or more hematologic cell lines in the peripheral blood, distinct from acute leukemia. The peripheral smear below shows leukoerythroblastosis and giant platelets in a patient with myelofibrosis.



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Peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows leukoerythroblastosis. This photomicrograph also shows giant pla....

Patients are at risk for thrombotic and hemorrhagic events. They are also at risk of developing secondary acute leukemia from their underlying disorder, as well as from their treatment.

Signs and symptoms

Patients may have a history of the following:

Clinical symptoms can include the following:

See Presentation for more detail.

Diagnosis

Laboratory studies

The following laboratory studies can be used in the diagnosis of myeloproliferative disease:

Biopsy

Bone marrow aspiration and biopsy with cytogenetic studies are required in most, but not all, patients. Cytogenetic studies detect the presence or absence of the Philadelphia chromosome and help to differentiate myeloproliferative disorders from myelodysplastic syndrome.

Bone marrow histology shows hypercellularity in most of these disorders. In the case of myelofibrosis, bone marrow fibrosis is demonstrated on the reticulin stain. Bone marrow fibrosis is also detected in the spent phase of chronic myelogenous leukemia and polycythemia vera.

See Workup for more detail.

Management

Chronic myelogenous leukemia

Hematopoietic stem cell transplantation can be considered in young patients with chronic myelogenous leukemia in chronic phase if a human leukocyte antigen (HLA)-matched donor is available.

Agents used in the treatment of the disease include the following:

Polycythemia vera

Treatment for this disease is palliative. Young (< 40 y), asymptomatic patients with polycythemia vera can be considered for therapeutic phlebotomies alone to maintain a hematocrit level of less than 45%. Other patients can undergo myelosuppressive therapy with hydroxyurea. Radioactive phosphorous can be used as an alternative therapy in older patients.

Essential thrombocythemia

No curative treatment is available. The aim of therapy is to maintain the patient’s platelet count within the reference range. This usually can be achieved with hydroxyurea or anagrelide.

Myelofibrosis

Asymptomatic patients can be monitored clinically until symptomatic. Hydroxyurea is useful to suppress the number of circulating cells.

Patients with painful, massively enlarged spleens refractory to myelosuppressive therapy are occasionally treated with radiation therapy, but they may ultimately require splenectomy.

In November 2011, a JAK1/JAK2 inhibitor, ruxolitinib (Jakafi), became the first US Food and Drug Administration (FDA)–approved drug for patients with intermediate- or high-risk myelofibrosis.

Allogeneic hematopoietic stem cell transplantation (ASCT) is curative for primary myelofibrosis (PMF) and may be an alternative for selected patients whose disease is refractory to conventional therapies. 

See Treatment and Medication for more detail.

Background

Myeloproliferative diseases (MPDs) are a heterogeneous group of disorders characterized by cellular proliferation of one or more hematologic cell lines in the peripheral blood, distinct from acute leukemia.

According to the French-American-British (FAB) classification, chronic myeloproliferative diseases consist of the following four diseases:



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Peripheral smear of a patient with chronic myelogenous leukemia (CML) shows leukocytosis with extreme left shift and basophilia.

In 2002, the World Health Organization (WHO) proposed an alternate classification schema for these diseases, adding chronic neutrophilic leukemia (CNL) and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES).[2] The WHO updated its classification in 2008 and changed the nomenclature from “chronic myeloproliferative disease” to “myeloproliferative neoplasms”.[3]  In 2016, the WHO further revised its classification of hematopoietic tumors and now recognizes several major categories of myeloid malignancies including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap, mastocytosis, eosinophilia‐associated myeloid/lymphoid neoplasms with specific mutations (e.g., PDGFR) and myeloid neoplasms with germline predisposition.[4] For a comparison of the FAB and 2016 WHO classification systems, see the table below.

Table. Comparison of FAB and WHO Classifications of Myeloproliferative Neoplasms (MPN)



View Table

See Table

In some patients, conditions overlap, and clear categorization may be difficult. Myeloproliferative disease may evolve into one of the other myeloproliferative conditions, transform to acute leukemia, or both.

Some evidence indicates that myeloproliferative diseases arise from malignant transformation of a single stem cell. Involvement of erythropoiesis, neutrophilopoiesis, eosinophilopoiesis, basophilopoiesis, monocytopoiesis, and thrombopoiesis occurs in the chronic phase of CML. Some evidence also indicates that lymphocytes are derived from primordial malignant cells. This is based on observations that a single isoenzyme for glucose-6-phosphate dehydrogenase (G6PD) is present in some T and B lymphocytes in women with CML who are heterozygous for isoenzymes A and B.

Pathophysiology

Data from glucose-6-phosphate dehydrogenase (G6PD) studies, cytogenetic analyses, and molecular methods have established the clonal origin of myeloproliferative diseases; this clonality potentially occurs at different stem cell levels. An attribute common to these disorders appears to be an acquired activating mutation in the gene coding for various tyrosine kinases.

In chronic myelogenous leukemia, the tyrosine kinase activity of the bcr-abl hybrid gene is increased. In polycythemia vera, essential thrombocythemia, and myelofibrosis (see the following images), the prevalent genetic lesion appears to be a valine to phenylalanine substitution at amino acid position 617 (V617F) within the Janus kinase 2 (JAK2) gene.[5, 6, 7, 8] This produces hypersensitivity to erythropoietin. At least in myelofibrosis patients the leukemic transformation is probably not related to JAK-2 (V617F) mutation status.[9]



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Peripheral smear of a patient with essential thrombocythemia (ET) shows markedly increased number of platelets. Some of the platelets are giant (arrow....



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Peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows leukoerythroblastosis. This photomicrograph also shows giant pla....

A study by Anand et al found that JAK2 mutations generate expansion of later myeloid differentiation compartments, in which homozygous expression of the mutation confers an added proliferative advantage at the single-cell level. The findings suggest that JAK2 inhibitors may control myeloproliferation; however, they may have limited efficacy in eradicating leukemic stem cells.[10]

Systemic mastocytosis has been linked with the D816 mutation of the KIT gene. The FIP1L1-PDGFR mutation has been identified in a subgroup of people with systemic mastocytosis with eosinophilia (SM-eos).[11]

Nangalia et al reported that somatic mutations in the CALR gene exist in the majority of patients without JAK2 and MPL mutations, who comprise about 68% of patients with essential thrombocythemia and 88% of patients with primary myelofibrosis. On clonal analyses, CALR mutations were found in the earliest phylogenetic node, a finding consistent with its role as a possible initiating mutation.[12, 13, 14]

Etiology

As with other malignant disorders, the precise cause of myeloproliferative disease is unknown. The etiology is complex, incompletely understood, and likely a multistep process involving more than one gene.

Philadelphia chromosome, t(9:22), is found in most patients who have chronic myelogenous leukemia. Even when Philadelphia chromosome testing is negative, the gene bcr-abl, formed as result of t(9:22), tests positive in patients with chronic myelogenous leukemia using molecular techniques. Bcr-abl encodes a fusion protein with tyrosine kinase activity, which is constitutively expressed and is regarded as the central mechanism that underlies the chronic phase of chronic myelogenous leukemia.[15]

In a retrospective study of 11,000 patients in Sweden with myeloproliferative neoplasm, the authors reviewed the incidence of acute myeloid leukemia (AML) and myelodysplastic syndrome that were secondary to treatment; the study found that treatment with radioactive phosphorus but not hydroxyurea increased the risk of myelodysplastic syndrome and AML.[16]

Epidemiology

The American Cancer Society estimates that 8990 new cases of chronic myelogenous leukemia (CML) will be diagnosed in the United States in 2019.[17]  CML accounts for more than half of myeloproliferative disease cases. The incidence of polycythemia vera in the United States is approximately 5-17 cases per 1 million population per year. True incidences of essential thrombocythemia and myelofibrosis are not known because epidemiological studies on these disorders are inadequate.

The incidence of polycythemia vera is 0.02-2.8 per 100,000 per year[18, 19] ; Japan has the lowest incidence. Essential thrombocythemia has an incidence of 0.1-1.5 per 100,000 per year. Myelofibrosis has an international incidence of 0.4-0.9 per 100,000 per year.

CML appears to affect all races with approximately equal frequency. In a study from northern Israel, the incidences of polycythemia vera, essential thrombocythemia, and myelofibrosis in Ashkenazi Jews were 10-fold higher than in Sephardic Jews, and 20-fold higher than in Arabs.[3]

The female-to-male ratio is 1:1.4. The American Cancer Society estimates that new cases of CML will be diagnosed in 5250 males and 3740 females in 2019.[17]

Most cases encountered in clinical practice are in patients aged 40-60 years. Myeloproliferative diseases are uncommon in people younger than 20 years and are rare in childhood.

Prognosis

The current (2008-2014) 5-year relative survival rate for adults (ages 20 and older) is 67% for CML. Survival rates for CML hav more than tripled, up from 22% in the mid-1970s, in large part due to the discovery and use of targeted drugs over the past two decades. The American Cancer Society estimates that 1040 deaths from chronic myelogenous leukemia (CML) will occur in 2019.[17]  

Exact mortality and morbidity rates of other myeloproliferative diseases are unknown.

Patients are at risk of both thrombotic and hemorrhagic events. Thrombotic and hemorrhagic events are particularly common in polycythemia vera (PV) and essential thrombocythemia (ET). Thrombosis is the cause of death in 30-40% of patients. A particularly serious thrombotic event that may be associated with polycythemia vera is Budd-Chiari syndrome, which is due to hepatic venous or inferior venal caval thrombosis.

Patients are at risk of developing secondary acute leukemia from their underlying disorder as well as their treatment.

History

Presenting complaints in patients with myeloproliferative neoplasms include the following:

A study by Scherber et al assessed the use of an 18-item assessment form called the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), which is completed by the patient and is designed to assess symptoms of myelofibrosis, essential thrombocythemia, and polycythemia vera. The study found that the MPN-SAF is a comprehensive and reliable instrument that correlated well with physicians’ blinded opinion of patient symptoms.[20]

Physical Examination

Physical examination findings in patients with myeloproliferative disease may include the following:

Laboratory Studies

Laboratory studies for the diagnosis of myeloproliferative disease include the following:

Imaging Studies

Imaging studies are not routinely required. However, a liver-spleen scan may occasionally be helpful to assess the size of these organs in the diagnosis of difficult cases.

Procedures

Bone marrow aspiration and biopsy with cytogenetic studies are required in most, but not all, patients. Cytogenetic studies detect presence or absence of the Philadelphia chromosome and help to differentiate these disorders from myelodysplastic syndrome. PCR testing on bone marrow for JAK2 is available for suspected cases of polycythemia vera, essential thrombocythemia, or myelofibrosis.

Histologic Findings

Bone marrow histology shows hypercellularity in most myeloproliferative disorders. In the case of myelofibrosis, bone marrow fibrosis is demonstrated on the reticulin stain. Bone marrow fibrosis is also detected in the spent phase of chronic myelogenous leukemia and polycythemia vera.

Approach Considerations

Treatment of myeloproliferative neoplasms varies by disease subtype. For full discussion, see the following Medscape articles:

Treatment of Chronic Myelogenous Leukemia

Imatinib mesylate (Gleevec), a bcr-abl –specific tyrosine kinase inhibitor (TKI), is approved for use in Philadelphia chromosome–positive chronic myelogenous leukemia (CML) in chronic phase. In one study at 18 months, the complete response rate was 76.2% and the major cytogenetic response rate was 87.1%. Imatinib is also indicated for CML in blast crisis, accelerated phase, or in chronic phase after interferon alfa therapy failure. This is the treatment of choice for most patients.[1]

Interferon alfa, usually administered as a subcutaneous daily injection in a dose of 5 million U, produces hematologic and molecular remissions in some patients with CML. In these patients, evidence shows that it prolongs survival. Several patients who achieved molecular remissions have survived for more than 10 years. Addition of low-dose cytosine arabinoside to interferon alfa has been reported to achieve higher remission rates. Patients with CML who are intolerant of interferon alfa therapy can be treated with hydroxyurea.

Dasatinib (Sprycel) is a TKI indicated for the treatment of adults patients with CML in chronic, accelerated, or myeloid or lymphoid blast phase who are resistant or intolerant to prior therapy including imatinib. Nilotinib (Tasigna) is a TKI indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive CML in adult patients resistant to or intolerant to prior therapy including imatinib.

Hematopoietic stem cell transplantation can be considered in young patients with CML in chronic phase, if a human leukocyte antigen (HLA)-matched donor is available.

When the disease progresses to the blast phase (see the image below), it is treated as acute leukemia, though the outcome is usually grave.



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Peripheral smear of a patient with chronic myelogenous leukemia (CML) in blastic phase shows several blasts.

 

Treatment of Polycythemia Vera

Treatment of polycythemia vera (PV) is palliative. Young (< 40 y), asymptomatic patients with PV can be considered for therapeutic phlebotomies alone to maintain hematocrit level below 45%.

High-risk patients with systemic symptoms, history of thrombosis or bleeding, or high rate of phlebotomies or patients older than 69 years are best treated with myelosuppressive therapy in the form of hydroxyurea.[23] In December 2014, the US Food and Drug Administration (FDA) expanded the approval of the JAK1/JAK2 inhibitor, ruxolitinib (Jakafi) for the treatment of PV in patients who have an inadequate response to or cannot tolerate hydroxyureaAn alternative therapy.[24]

In older patients, radioactive phosphorus (32P) can be used for treatment of PV. However, this is unsuitable for younger patients because of the potential for causing secondary leukemia.

Treatment of Essential Thrombocythemia

Treatment of essential thrombocythemia (ET) is meant to relieve symptoms and to prevent complications because no curative modality is available at present. The aim of treatment is to maintain the platelet count within the reference range. This usually can be achieved with hydroxyurea or anagrelide.

There remains a question of the efficacy of ruxolitinib vs other conventional therapies. In ET patients resistant or intolerant to hydroxycarbamide therapy, ruxolitinib significantly improved some disease-related symptoms, but rates of thrombosis, hemorrhage, or transformation were no different when compared to best available therapy in the randomized phase 2 MAJIC trial.[25]

Treatment of Primary Myelofibrosis

Asymptomatic patients can be monitored clinically until symptoms develop. Treatment options for symptomatic MF include the following:

In November 2011, the JAK1/JAK2 inhibitor, ruxolitinib (Jakafi), became the first US Food and Drug Administration (FDA)–approved drug for patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Approval was expedited in accordance with the US Orphan Drug Act and based on US and international data from the COMFORT-1 and COMFORT-2 trials. Results from the COMFORT-1 trial showed patients (n=309) who received ruxolitinib had a significant reduction in spleen volume (at least 35%) at 24 weeks when assessed by MRI or CT compared with placebo (41.9% vs 0.7%).[27] ​

Allogeneic hematopoietic stem cell transplantation (ASCT) is curative for primary myelofibrosis (PMF) and may be an alternative for selected patients whose disease is refractory to conventional therapies[26]  However, less than 10% of patients with MF are even referred for ASCT due to high transplant-related mortality (20%-40%). ASCT is limited to small proportion of MF patients, usually for those at younger age at transplant, without significant co-morbidities and at higher prognostic categories.[28]

Performing a pretransplantation splenectomy in patients with myelofibrosis (MF) is a matter of debate. While the procedure improves hematological recovery, it may lead to severe morbidities. Robin and colleagues retrospectively analyzed data from 85 consecutive patients who underwent transplantation for MF, including 39 patients who underwent splenectomy before their transplantation. The majority had PMF (78%), were considered high-risk patients (84% dynamic international prognostic scoring system intermediate-2 or higher), and had received transplants from HLA-matched sibling donors (56%) after a reduced-intensity conditioning regimen (82%). One-half of all splenectomized patients presented surgical or postsurgical morbidities, most frequently thrombosis and hemorrhage. However, retransplantation splenectomy was not associated with nonrelapse mortality or post-transplantation relapse but with an improved overall survival (OS) and event-free survival (EFS).[29]

Consultations

Surgical consultation for permanent central venous access device placement may be required for patients in whom repeated blood draws, blood transfusions, and/or chemotherapy is anticipated.

A radiation oncologist may need to be involved in selected cases, when splenic radiation is considered appropriate.

Diet and Activity

Massive splenomegaly is usually associated with epigastric and left upper quadrant discomfort and early satiety. Patients with these symptoms are encouraged to eat frequent, small meals rather than 3 large meals.

Individuals with myeloproliferative diseases are not encouraged to restrict their daily activities, but they are encouraged to refrain from physical activities that might expose them to abdominal trauma because massively enlarged spleens are likely to rupture, sometimes in response to minimal trauma.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Medication classes used include interferons, antimetabolites, and tyrosine kinase inhibitors (TKIs).

Interferon alfa-2a and interferon alfa-2b (Roferon-A, Intron A)

Clinical Context:  Naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha-, beta-, and gamma-interferons may be administered topically, systemically, and intralesionally. Interferon alfa is recommended for the initial management of low-risk CML. In low-risk CML, significant numbers of patients achieve hematological and molecular remissions. These patients have prolonged survival.

Class Summary

Interferons are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha-, beta-, and gamma-interferons may be given topically, systemically, and intralesionally.

Hydroxyurea (Hydrea)

Clinical Context:  Antineoplastic agent provides effective palliative treatment that primarily controls symptoms associated with leukocytosis, thrombocytosis, or hepatosplenomegaly due to MPD. Inhibitor of deoxynucleotide synthesis and DOC for inducing hematologic remission in CML. Less leukemogenic than alkylating agents such as busulfan, melphalan, or chlorambucil. Myelosuppressive effects last a few days to a week and are easier to control than alkylating agents. Busulfan has prolonged marrow suppression and can cause pulmonary fibrosis as well. Can be administered at higher doses in patients with extremely high WBC counts (>300,000) and adjusted accordingly as counts fall and platelet counts drop. Dose can be administered as a single daily dose or divided into 2 or 3 doses at higher dose ranges.

Anagrelide (Agrylin)

Clinical Context:  Reduces elevated platelet count in patients with essential thrombocythemia and polycythemia vera.

Ruxolitinib (Jakafi)

Clinical Context:  JAK1/JAK2 kinase inhibitor indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Janus-associated kinases (JAKs) JAK1 and JAK2 mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function.

Class Summary

Antimetabolites inhibit cell growth and proliferation.

Imatinib mesylate (Gleevec)

Clinical Context:  Specifically designed to inhibit tyrosine kinase activity of the bcr-abl kinase in Ph+ leukemic CML cell lines. Used to treat newly diagnosed adult patients with CML or those in blast crisis, accelerated phase, or in chronic phase after failure to interferon alfa therapy. Also indicated to treat pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell transplant or who have demonstrated interferon alfa resistance. Well absorbed after oral administration, with maximum concentrations achieved within 2-4 hours. Elimination is primarily in feces in form of metabolites.

Dasatinib (Sprycel)

Clinical Context:  Multiple tyrosine kinase inhibitor. Inhibits growth of cell lines overexpressing BCR/ABL. Orphan drug indicated for chronic myeloid leukemia (CML) in individuals resistant to or intolerant of prior therapy (eg, imatinib [Gleevec]). Has been able to overcome imatinib resistance resulting from BCR/ABL kinase domain mutations.

Nilotinib (Tasigna)

Clinical Context:  Inhibits BCR/ABL kinase. In vitro, inhibits BCR/ABL –mediated proliferation of murine leukemic cell lines and human cell lines derived from Philadelphia chromosome–positive chronic myeloid leukemia. Under the conditions of the assays, was able to overcome imatinib resistance resulting from BCR/ABL kinase mutations in 32 of 33 mutations tested. In vivo, shown to reduce tumor size in a murine BCR/ABL xenograft model. Indicated for Philadelphia chromosome–positive chronic myeloid leukemia in adults whose disease has progressed or who cannot tolerate other therapies that include imatinib.

Class Summary

These agents inhibit the activity of bcr-abl tyrosine kinase, resulting in decreased proliferation and increased apoptosis in Ph-positive cell lines.

Author

Haleem J Rasool, MD, FACP, Chair, Department of Oncology, Mayo Clinic Health System, La Crosse, WI

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Additional Contributors

Koyamangalath Krishnan, MD, FRCP, FACP, Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine, James H Quillen College of Medicine at East Tennessee State University

Disclosure: Nothing to disclose.

References

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Peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows leukoerythroblastosis. This photomicrograph also shows giant platelets.

Peripheral smear of a patient with chronic myelogenous leukemia (CML) shows leukocytosis with extreme left shift and basophilia.

Peripheral smear of a patient with essential thrombocythemia (ET) shows markedly increased number of platelets. Some of the platelets are giant (arrow).

Peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows leukoerythroblastosis. This photomicrograph also shows giant platelets.

Photomicrograph of a peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows findings of leukoerythroblastosis, giant platelets, and few teardrop cells.

Peripheral smear of a patient with chronic myelogenous leukemia (CML) in blastic phase shows several blasts.

Peripheral smear of a patient with chronic myelogenous leukemia (CML) shows leukocytosis with extreme left shift and basophilia.

Peripheral smear of a patient with chronic myelogenous leukemia (CML) in blastic phase shows several blasts.

Peripheral smear of a patient with essential thrombocythemia (ET) shows markedly increased number of platelets. Some of the platelets are giant (arrow).

Peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows leukoerythroblastosis. This photomicrograph also shows giant platelets.

Photomicrograph of a peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows findings of leukoerythroblastosis, giant platelets, and few teardrop cells.

FAB WHO
Chronic myelogenous leukemiaChronic myelogenous leukemia, BCR/ABL1 positive
Polycythemia veraPolycythemia vera
Essential thrombocythemiaEssential thrombocythemia
Agnogenic myeloid metaplasia/myelofibrosisPrimary myelofibrosis*
...Chronic neutrophilic leukemia, not otherwise specified
...MPN, unclassified
*The 2016 WHO classification system distinguishes prefibrotic (prePMF) from overtly fibrotic PMF [4]