Page 881 - Hematology_ Basic Principles and Practice ( PDFDrive )

764 Part VII Hematologic Malignancies

TABLE Components in the Routine Clinical Evaluation of TABLE Tyrosine Kinase Involvement in Myeloproliferative
55.1 Myeloid Diseases 55.3 Neoplasms
Current Disease Tyrosine Kinase Involvement
• Accurate clinical history, including family history and physical Chronic myeloid leukemia, ABL1 (100%)
examination findings BCR-ABL1+
• General laboratory findings, including CBC, and other specific tests
(e.g., EPO) when appropriate Myeloid and lymphoid neoplasms PDGFRA, PDGFRB, or FGFRA
• Evaluation of well-prepared and stained peripheral blood smear with with eosinophilia TK
200 cell differential count abnormalities
• Review of BM aspirate, including iron stain, and 500 cell Polycythemia vera JAK2 V617F (≈95%), JAK exon
differential count 12 (≈4%)
• Evaluation of H&E sections of BM biopsy of sufficient length and Primary myelofibrosis JAK2 V6174 (≈50%), MPL W515
reticulin stain K/L (5–9%), CALR (35%)
• Phenotyping studies, including cytochemical reactions (nonspecific Essential thrombocythemia JAK2 V617F (≈50%), MPL W515
and specific esterase reactions and myeloperoxidase) and flow K/L (≈1%), CALR (35%)
cytometric analysis of peripheral blood or BM for phenotype of
blasts or other cells when appropriate Chronic neutrophilic leukemia CSF3R (83–90%)
• Cytogenetic analysis, including karyotype, and FISH for specific Chronic eosinophilic leukemia, —
abnormalities when appropriate not otherwise specified
• Single-nucleotide polymorphism array karyotyping Mastocytosis KIT D816V (≈95%)
• Genetic analysis for particular genetic rearrangements or mutations,
including gene sequencing when appropriate MPN, unclassified —
• Next-generation sequencing MPN, Myeloproliferative neoplasm; TK, tyrosine kinase.
Potential Future Clinical Studies
• Gene expression arrays
• Genome-wide epigenetic studies successfully lead to the rational targeted therapy (i.e., imatinib and
other TK inhibitors). 9
BM, Bone marrow; CBC, complete blood count; EPO, erythropoietin; FISH,
fluorescence in situ hybridization; H&E, hematoxylin and eosin. The MPNs also include BCR-ABL1–negative entities, essential
thrombocythemia (ET), polycythemia vera (PV), and primary myelo-
fibrosis (MF) (see Chapters 68–70). These MPNs share common
TABLE WHO Classification of Myeloid Neoplasms features including multipotential hematopoietic stem cell origin,
55.2 clonal proliferation, and chronic nature. Although they seem to be
distinctive, they can present a diagnostic challenge, and they can have
The MPNs, including the myeloid and lymphoid neoplasms with subtle and overlapping presentations. Recent discoveries in the
eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFRA underlying molecular pathology of these entities have demonstrated
The AML that, similar to CML and eosinophilic disorders, they too share TK
The MDS signaling dysregulation, at least to some degree. This is attributable
The MDS/MPN (“overlap”) syndromes to an associated mutation in the TK, JAK2 (JAK2 V617F), which is
AML, Acute myelogenous leukemia; MDS, myelodysplastic syndromes; MPN, present in about 50 to 95% of cases of Ph-negative MPNs. Variants
myeloproliferative neoplasm. of JAK2 mutations involving exon 12 are also observed in 2% to 3%
of PV patients. This association has led to significant revisions in the
2008 WHO criteria for diagnosis, but it also has raised questions as
name and in the components of the disorders. However, refinements to how a single mutation can be associated with such heterogeneous
have led to an increased understanding of the clinical, pathologic, phenotypic characteristics. Proposed revisions in 2016 WHO classi-
and genetic basis of the diseases and ultimately serve, or at least strive fications for the diagnosis of the Ph-negative MPNs include suggested
to, improve diagnosis, treatment and outcome. The current classifica- modifications of lower hemoglobin thresholds for PV. BM biopsy
tion of myeloid neoplasms include the categories of myeloproliferative results and the presence of JAK2 mutations will represent major
neoplasms (MPNs), acute myeloid leukemias (AMLs), myelodysplas- criteria. A subnormal erythropoietin level will become a minor crite-
tic syndromes (MDS), and MDS/MPNs, which is a category with rion, and the endogenous erythroid colony assay will no longer be
features that are intermediate between MDS and MPN (Table 55.2). included in the next revision of the WHO diagnostic criteria for
10
This generally accepted classification system was derived from a MPNs. These changes are intended to capture patients with subtle
5
number of earlier classification systems, and represents the working presentations, such as those with masked PV. Experts also have rec-
4,6
system of WHO as of 2008. The recent proposal to update the ommended inclusion of mutations in calreticulin and the thrombo-
2008 classification is based on the newer information from molecular poietin receptor, MPL, which is identified in 20% to 30% of ET and
testing modalities that further impact the classification and categori- MF cases, and the colony-stimulating factor 3 receptor mutations in
zation of these neoplasms. 7 the next revision. 10–12
JAK2 V617F inhibitors are among several agents under investiga-
tion for use in patients with MPNs. In 2011 the US Food and Drug
The Myeloproliferative Neoplasms Administration (FDA) approved ruxolitinib for the treatment of
patients with intermediate or high-risk MF. Subsequently, the FDA
The MPNs, formerly referred to as myeloproliferative disorders also designated ruxolitinib as an orphan product, as it demonstrated
(MPDs), are a group of clonal multipotential hematopoietic stem cell potentially significant improvement in safety and efficacy over other
disorders that have a proliferative nature, presenting frequently with available therapies for PV. A number of novel agents that target
hypercellular BMs, and an elevation of one or more myeloid cell types various pathways are currently being investigated and will be further
in the blood. The MPNs are insidious in onset and chronic in course discussed in detail later (see Chapters 68–70).
but have a variable tendency to terminate in BM failure or acute Chronic neutrophilic leukemia (CNL) and mast cell disease are
8
leukemia. The MPNs include CML (Table 55.3), which illustrates currently included in the category of MPNs. CNL is now better
how the elucidation of pathways involved in the molecular pathogen- defined with the integration of CSF3R mutation as a diagnostic tool,
esis (i.e., dysregulation of ABL1 tyrosine kinase [TK] signaling) can and is distinct from atypical CML. 13