Myeloproliferative Neoplasms Flashcards
1. Describe characteristic molecular abnormalities identified in the classical myeloproliferative neoplasms contribute to disease pathogenesis (MKS 1a and 1b) 2. Describe the distinction between BCR-ABL as a disease specific molecular abnormality, compared to JAK2 V617F, which represents a normal pathway placed into overdrive; recognize the implications regarding treatment (MKS 1a, MKS 1b, MKS 1e) 3. Describe the diagnosis, clinical features, and treatment options for patients with classical M
1
Q
What are myeloproliferative disorders and what are some underlying pathogenetic factors?
A
- The hallmark diseases that are now referred to as Myeloproliferative Neoplasms (MPN), include:
- chronic myeloid leukemia (CML)
- BCR-ABL negative MPN
- essential thrombocytosis (ET)
- polycythemia vera (PV)
- fprimary myelofibrosis (PMF)
- The myeloproliferative neoplasms (MPN) are characterized by:
- clonal proliferation of hematopoietic stem cells
- indolence, with disease durations sometimes measured in decades
- tendencies toward thrombosis
- extramedullary hematopoiesis (usually splenomegaly)
- myelofibrosis
- transition to acute leukemia
- The discovery of the Philadelphia chromosome, due to a translocation of chromosomes 9 and 22, and its product, BCR-ABL, has led to targeted therapy with tyrosine kinase inhibitors (Imatinib, Nilotinib, Dasatinib, Bosutinib, Ponatinib), which have dramatically altered the natural history of CML
- The molecular underpinnings of the BCR-ABL negative MPN have been better understood since the discovery of JAK2 V617F in 2005, and now, the calreticulin gene mutations in 2013
- Though these mutations are prevalent, they may not be the causative lesions or sole abnormalities, and as a result, targeted therapy (JAK-inhibitors) has had less of an effect than hoped in patients with BCR-ABL negative MPN
2
Q
What are some features of MDS that differentiate it from MPN?
A
- The MPN are sometimes confused with myelodysplastic disorders (MDS)
- MDS is typically characterized by:
- decreased (rather than increased) counts of one or more of the myeloid lineages in the peripheral blood
- increase in myeloid cell numbers in the bone marrow
- abnormal myeloid cell morphology termed “dysplasia”—in the case of MDS, hematopoiesis is ineffective
- In some patients, features of MPN and MDS are seen concurrently
- The most recent WHO classification recognizes this category of patients with an overlap syndrome, coined “MDS/MPN”
- The most common overlap is chronic myelomonocytic leukemia (CMML)
3
Q
Describe how the Philadelphia Chromosome (BCR-ABL) contributes to MPN.
A
- The recognition of the Philadelphia (Ph) chromosome in 1960 represented a landmark discovery as it was the first leukemia associated with a consistent and specific chromosomal abnormality, ushering in era of cytogenetic analysis in hematology
- The Ph chromosome (t9;22) is comprised from a translocation of the Abelson (ABL) proto-oncogene from chromosome 22 to the long arm of chromosome 9 (BCR), resulting in a BCR-ABL fusion gene
- This is a tumor specific abnormality
- The Ph chromosome (t9;22) is comprised from a translocation of the Abelson (ABL) proto-oncogene from chromosome 22 to the long arm of chromosome 9 (BCR), resulting in a BCR-ABL fusion gene
- The most common protein expression of this fusion gene, p210, displays tyrosine kinase activity, activating signaling pathways (RAS, PI3-K and c-MYC) that both enhance bone marrow progenitor proliferation and decrease apoptosis (programmed cell death)
- What results is an increase in number of normal appearing granulocytes
- Differentially is initially preserved, until, there is failure, and immature white blood cells, including blasts can appear in the blood
- Almost all patients with typical CML have the BCR-ABL fusion gene
- The targeting of BCR-ABL has been one of the greatest success stories in hematology-oncology
4
Q
Desccribe how the JAK2 V617F mutation contributes to MPN.
A
- The discovery of the JAK2 V617F mutation in 2005 has provided significant insight into the pathogenesis of the BCR-ABL negative MPN, and provides some rationale for the shared clinical features seen in these diseases
- The Janus Kinase receptors (JAK2-wild type) are integral for normal hematopoiesis
- When the appropriate ligand (Epo, GCSF, GM-CSF, thrombopoietin) binds its receptor, JAK2 becomes activated via phosphorylation, and then transmits its signal through phosphorylation of downstream intracellular pathways (STAT), which regulate gene transcription
- What results is the proliferation and differentiation of erythroid, granulocytic, and megakaryocytic precursors
- The JAK2 V617F mutation is characterized by a switch from valine to phenylalanine at position 617 in exon 14 of the JAK2 gene
- What results is a loss of negative regulation—in other words, when mutant, JAK2 is constitutively active
- Therefore, downstream signaling is constitutively active; the drive for proliferation and differentiation through this normal pathway becomes more robust
- JAK-inhibitors are available, but the effects do not compare to those of CML targeted therapy, in part because this is a normal pathway, and the drug effects both normal and mutant signaling
- JAK2 V617F mutations are found in: 95% of PV; 50-60% of ET; and 50-60% of MF
5
Q
How do calreticulin gene mutations contribute to the pathogenesis of PMN?
A
- Approximately 40 to 50% of patients with ET and MF lack JAK2 V617F mutations, but often the clinical phenotype is generally similar
- In late 2013, two groups simultaneously reported the frequent mutation of the calreticulin gene
- This mutation was identified in a substantial proportion of patients who have JAK2 V617F negative ET or MF, filling a diagnostic gap
- This mutation is mutually exclusive from the JAK2 V617F mutation
- Just how the mutation leads to the clinical phenotype of ET or MF is not yet clear, though one group was able to show activation of similar downstream pathways (STAT)
- This mutation can be tested for in the clinic
-
Additional mutations (we can test patients for these as well):
- JAK2 exon 12 (2-3% of PV patients); MPL mutations (5-10% of ET and PMF patients)
6
Q
What are some less common mutations in PMN?
A
- C-KIT (KIT D816V) in Systemic Mastocytosis
- PDGFRA, PDGRFB, and FGFR1 clonal rearrangements in MPNs associated with eosinophilia.
7
Q
What are some common disease features in PMN?
A
- Indolence, initially
- Bone marrow hypercellularity, associated with increased numbers of granulocytes, red blood cells, and/or platelets
- Organomegaly (particularly splenomegaly)
- Thrombotic or hemorrhagic complications
- Initial presence of bone marrow fibrosis, or evolution to fibrotic phase, with eventual marrow failure (ET and PV)
- Transformation to an acute, blast phase
8
Q
What are the uniqe features and epidemiology of Chronic Myeloid Leukemia (CML)?
A
-
Unique features:
- Often marked leukocytosis, with mature and immature granulocytes, along with basophilia
- Hallmark is the Philadelphia chromosome
-
Epidemiology:
- ~1 new cases per 100,000 persons per year (slight male predominance)
- Typically a disease of middle-age (6th decade)
- Possible associations with radiation exposure (increased incidence in survivors of Hiroshima)
9
Q
What is the differential diagnosis, diagnosis, clinical concerns, and natural history of CML?
A
-
Differential diagnosis:
- Exclude other MPN, such as ET and MF which can mimic
- Severe infection causing leukocytosis can mimic as well (leukemoid reaction)
-
Diagnosis:
- Patients present with a pronounced leukocytosis, often with WBC of 50 to 200 x 109/L
- left shifted granulopoiesis (all stages often present in peripheral blood), with metamyelocytes, myelocytes, promyelocytes and even blasts
- Frequent basophilia
- Thrombocytosis can be present
- BCR-ABL can be identified by testing of the peripheral blood (FISH or qPCR) or bone marrow (FISH, conventional cytogenetics, qPCR).
-
Clinical concerns
- Many patients may be asymptomatic, and identified based on a routine blood count
- Others may have fevers, sweats, fatigue, or pain from an enlarged spleen (can be noted on physical)
- Aside from leukocytosis, patients may or may not have anemia, thrombocytopenia, or thrombocytosis
-
Natural history:
- CML exists in 3 phases:
- a chronic phase
- an accelerated phase marked by progressive symptoms, splenomegaly, basophilia, thrombocytosis or thrombocytopenia, and increasing blasts/immaturity of the white cell lineage
- a blast phase, akin to acute leukemia (myeloid or lymphoid)
- CML exists in 3 phases:
10
Q
What is the treatment for CML?
A
- The treatment of CML has been revolutionized by the advent of BCR-ABL tyrosine kinase inhibitor therapy
- The first in this class was imatinib, which now has more the 10 years of follow-up
- 8 year follow-up showed excellent survival (89-95%)
- Prior to the advent of this class, patients almost uniformly progressed to blast phase in 3-5 years without bone marrow transplant
- Currently, TKI’s have dramatically reduced the proportion of patients that accelerate
- There are now second and third generation TKI’s that are quite effective, even if a patient has developed resistance to Imatinib (or intolerance)
- The prognosis is influenced by meeting certain milestones, including cytogenetic remission (disappearance of the Ph chromosome) and molecular remission (decreased minimal residual disease burden, measured by PCR)
- Some patients acquire mutations in the BCR-ABL kinase domain which leads to loss of response to therapy and disease progression
- Previously, the T315I mutation conferred resistance to all TKI’s, but now, patients with this mutation can be treated with ponatinib
11
Q
List the classical BCR-ABL negative Myeloproliferative Neoplasms.
A
- Polycythemia vera
- Essential thrombocytosis
- Primary myelofibrosis
12
Q
What are the unique features and epidemiology of polycythemia vera?
A
-
Unique features:
- Absolute erythrocytosis (increase in red cell mass and plasma volume)
-
Epidemiology:
- 2 new cases per 100,000 persons per year
- Slight male predominance, often in the 6th or 7th decade
13
Q
What is the differential diagnosis, diagnosis, clinical concerns, and prognosis of polycythemia vera?
A
-
Differential diagnosis:
- Exclude secondary causes of erythrocytosis (a high hemoglobin):
- Hypoxia
- High affinity Hemoglobin
- Methemoglobinemia
- Increased Epo production
- Dehydration
- “Stress” erythropoiesis
- Exclude secondary causes of erythrocytosis (a high hemoglobin):
-
Diagnosis (Proposed per the WHO revisions)
-
Major criteria:
- Hb > 18.5 g/dl in men; > 16.5 g/dl in women
- JAK2 V617F mutation or JAK2 exon 12 mutation
-
Minor criteria:
- Leukocytosis/thrombocytosis or hypercellular marrow (& undetectable iron storage)
- Low Epo level (autonomous rbc production in PV)
- Endogenous Erythroid Colony formation (growth w/o epo)
-
Major criteria:
-
Clinical concerns:
- Symptoms from hyperviscosity: Headaches, Malaise, Fatigue, Plethora/Ruddy complexion
- Platelet hypersensitivity: erythromelalgia, pruritus (also due to mast cell and basophil proliferation)
- Thrombotic complications (arterial and/or venous); bleeding problems
- Disease transformation (to myelofibrosis and acute leukemia)
- Prognosis: ~20 years median survival
14
Q
What is the treatment of polycythemia vera?
A
- Aspirin: Lowers vascular risk
- Phlebotomy: Reduction of RBC mass and viscosity, until iron deficient (goal Hct 45% or less)
- Chemotherapy: (Hydroxyurea)-often in those over 60, or w/ prior thrombosis
- JAK-inhibition: Ruxolitinib, a JAK1/JAK2 inhibitor was approved in December 2014
- Pegylated Interferon: Potential disease-modifying effects
15
Q
What are the unique features and epidemiology of essential thrombocytosis?
A
-
Unique features:
- None! Thrombocytosis can be a feature of PV and MF, as well as CML, and other malignancies
-
Epidemiology:
- 0.5 new cases per 100,000 persons per year
- female predominance, often in 6th or 7th decade, though another peak appears in younger women in 3rd to 5th decade
