Myeloproliferative Neoplasms

Indications for Testing

Along with medical history, symptom assessment, and physical examination, the following nonspecific laboratory tests are recommended as part of the initial evaluation in the diagnostic workup of MPNs: CBC, peripheral blood smear, comprehensive metabolic panel (including lactate dehydrogenase [LDH], liver function, and serum uric acid tests), serum erythropoietin (EPO), and serum iron level measurements.  If the results of these tests suggest the possibility of MPN, molecular testing, chromosome analysis, and bone marrow staining are indicated.

Classification

The following are the major MPN subtypes, not including CML.

Diagnostic Criteria

The diagnosis of MPN should be based on the 2017 WHO diagnostic criteria.  Criteria include specific findings from the CBC, blood smear, and bone marrow analysis, correlated with clinical history as well as the presence of certain molecular markers and the exclusion of other disorders.  

Laboratory Testing

Diagnosis

Molecular Testing

Testing for BCR-ABL1 Mutation

Testing of peripheral blood or bone marrow by fluorescence in situ hybridization (FISH) is best for initial screening because it will detect rare breakpoints that may not always be detected by molecular methods. Multiplex reverse transcriptase polymerase chain reaction (RT-PCR) can also be used to confirm and monitor the BCR-ABL1­ fusion gene, the presence of which is diagnostic for CML in the appropriate context; the absence of BCR-ABL1 by FISH essentially excludes CML, and testing for other MPN mutations should be performed.  For testing specific to CML, see the Chronic Myelogenous Leukemia topic.

Testing for Other Mutations

Molecular testing is used to assess clonality and to detect MPN-specific mutations.  Molecular testing of blood should be performed first for the JAK2 V617F mutation in all patients because it is the most common mutation and occurs in most patients (>95%) with PV.   If the JAK2 V617F mutation is not detected, testing for CALR and then MPL mutations should follow for patients with ET or PMF.  If PV is still suspected in those with negative JAK2 V617F mutation results, testing should be performed for JAK2 exon 12 mutations. In those with ET or PMF but without JAK2, MPL, or CALR mutations (triple-negative MPNs), testing for mutations in ASXL1, CBL, CSF3R, DNM3TA, EZH2, IDH1, IDH2, LINK/SH2B3, SF3B1, SRSF2, TET2, TP53, and U2AF1 genes should then be considered. A comprehensive next generation sequencing (NGS) myeloid panel can be useful for this testing. 

Patients with molecular evidence of PDGFRA, PDGFRB, FGRF1, or PCM1-JAK2 rearrangements are considered to have myeloid/lymphoid neoplasms of a different classification from MPN.

Testing using a multigene NGS panel that includes JAK2, CALR, and MPL may be used instead of single-gene tests.  NGS provides the benefit of identifying additional mutations that may have prognostic importance.

Cytogenetics

Cytogenetic analysis is important in distinguishing MPN subtypes. The chromosome analysis also serves to provide evidence of clonality and clonal evolution over time, and to assess the success of treatment. Chromosomal evaluation (eg, karyotype) is performed with or without FISH and should be done with bone marrow biopsy when possible.  The Philadelphia chromosome, which results from a reciprocal translocation of chromosomes 9 and 22 and affects the BCR-ABL1 fusion gene, is the hallmark of CML. Although specific chromosomal abnormalities have not been identified for MPNs other than CML, abnormalities range from <5-30% and are varied.  Complex karyotypes are defined as three or more unrelated chromosomal abnormalities, or one or two abnormalities that include trisomy 8, 7/7q-, i(17q), 5/5q-, 12p-, inv(3), or 11q23 rearrangement. These abnormalities have prognostic significance and may predict the transformation of MPN to acute myeloid leukemia (AML). 

Bone Marrow Staining

Bone marrow evaluation is used to confirm a diagnosis of MPN and to assess the blast percentage and any evidence of fibrosis, which help to determine the prognosis. Trichrome and reticulin staining of bone marrow aspirate or biopsy is necessary to accurately assess the degree of fibrosis.  Bone marrow histology should be assessed to rule out disease progression to MF before starting cytoreductive therapy. 

Prognosis

The overall survival of patients with MPNs is variable depending on the subtype.  Several scoring systems and prognostic models have been developed for the risk stratification of patients with MPNs. See the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Myeloproliferative Neoplasms  for recommendations on risk stratification.

Monitoring

Monitoring of Treatment Effects

Ruxolitinib has been associated with increased levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides; thus, assessment of lipid profiles should be performed 8-12 weeks following initiation of ruxolitinib.  Patients with high lipid levels should be monitored and treated according to clinical guidelines for hyperlipidemia.  See Atherosclerotic Cardiovascular Disease Risk Markers for information on screening and testing for dyslipidemia.

Patients should be monitored for additional risks associated with ruxolitinib use, including :

• Renal impairment
• Hepatic impairment
• Bacterial, mycobacterial, fungal, and viral infections
• Tuberculosis
• Hepatitis B
• Progressive multifocal leukoencephalopathy
• Herpes zoster
• Nonmelanoma skin cancer

Patients receiving danazol for the management of MF-associated anemia should be screened for prostate cancer and monitored with liver function tests.