MDS/MPN Syndromes Flashcards
What are the basic diagnostic criteria
of CMML ?
- persistent absolute monocytosis
- > 1 x 10^9/L or >1,000/uL
- marrow dysplasia
- usually dysgranulopoiesis
- must be in > 10% of cells
- < 20% blasts including promonocytes
- absence of Philadelphia chromosome
What is the morphology of the
monocytes in CMML ?
- can be normal to atypical
- may have a concomitant reactive Blastic Plasmacytoid Dendritic Cell Infiltrate
- Positive: CD2, CD4, CD5, CD14, CD56, CD68, CD123
What genetic alterations must be excluded if
there is significant eosinophilia seen in a
case of CMML ?
- eosinophilia: > 1.5 x 10^9/L
- Must exclude rearrangements of:
- PDGRFB
- FGFR1
- PCM-JAK2 (mutations)
What are common genes that are mutated
in CMML ?
- TET2
- SRSF2
- SETBP1
- ASXL1
What is the definition of atypical CMML ?
- Leukocytosis > 13 x 10^9/L
- composed of a spectrum of mature neutrophils, metamyelocytes, myelocytes and promyelocytes
- marrow dysplasia
- <20% of blasts
- no Philadelphia chromosome
What genes are often mutated in
atypical CMML ?
- SETBP1
- ETNK1
- note: some may have JAK2 mutations
What is the definition of Juvenile Myelomonocytic Leukemia ?
- affects children
- presents with a monocytosis ( >1 x 10^9/L) and/or granulocytosis
- hepatosplenomegaly
- constitutional symptoms
What are other findings often seen in JMML ?
- anemia, thrombocytopenia
- increased HbF
- clonal chromosomal abnormalities:
- monosomy 7 in 25%
What is the test used to diagnose JMML ?
- In vitro spontaneous formation of granulocyte-macrophage colonies
- hypersensitive to GM-CSF
- confirmatory
What genetic alterations can be seen
in JMML ?
- 10% of patients have NF-1
- can have elevated HgF
- Recurrent mutations in:
- PTPN11
- KRAS
- NRAS
- CBL
What is the definition of Chronic myeloid leukemia (CML)?
- defined by presence of Philadelphia chromosome
- t(9;22) , produces a BCR-ABL fusion gene
- translocation occurs: in major breakpoint cluster (M-BCR)
- produces p210 fusion protein
- rare cases translocation occurs in different region
- produces p230 fusion protein
- associated with marked thrombocytosis, neutrophil maturation
What is the third known breakpoint of CML
and when would you expect to have it ?
- M-BCR breakpoint
- p190 fusion protein
- associated with monocytosis
- also the breakpoint of Ph+ ALL
- B-ALL in kids with this translocation is poor prognosis
What can be seen at presentation of CML?
- splenomegaly can be seen
- platelet aggregation defects
- impaired aggregation in response to epinephrine
How is the chronic phase of CML defined ?
- leukocytosis due to increased neutrophils in all stages of maturation
- proportion of myelocytes exceeds that of the other mature forms
- Myelocyte bulge
- Basophilia, eosinophilia, thrombocytosis
- Absolute monocytosis in most cases
- Blasts usually <1%
- low LAP score
What are the bone marrow findings in
Chronic Myeloid Leukemia ?
- Hypercellular
- Increased M:E ratio and myelocyte bulge
- similar to that seen in the blood
- Increased megakaryocytes
- often small, hypolobated (Dwarf megas)
- Immature myeloids are away from the trabeculae
- thickening of trabecular cuff of immature cells
- Increased histiocytes
- gray-green crystal containing, Gaucher like, sea-blue histiocytes
- indicative of increased cell turnover
- Dyspoiesis is UNUSUAL in CML
What characterizes the accelerated phase
of CML?
Marked by the emergence of 1 or more of the following:
- progressive basophilia ( >20%)
- thrombocytopenia ( <100 x10^9/L)
- thrombocytosis (>1000 x10^9) or leukocytosis
- clonal cytogenetic progression
- Philadelphia chromosome with +8, i(17q), +19 or another Ph chromosome
- increasing blasts >10%
- but less than 20%
- clusters of abnormal megakaryocytes
- LAP score tends to rise
What characterizes the blast phase of
CML ?
- >20% blasts in the marrow or blood or infiltrate into the tissue (chloroma) OR
- prominent focal accumulation of blasts in the marrow biopsy (fills an intertrabecular space)
- in blast phase:
- 70% are AML type
- 30% are ALL type (often coexpression of myeloid antigens)
- additional cytogenetic abnormalities
- most common: duplication of Ph chromosome
- +8, i(17q)
What is the treatment for CML ?
- Imatinib
- tyrosine kinase inhibitor
- second line: nilotinib, desatinib
- result in prolonged survival
What is the most key prognostic factor in CML?
- response to the tyrosine kinase inhibitor
- measured by quantitative reverse transcriptase real time PCR (RT-PCR)
- 3 log reduction in first 8-12 months is good response
Note: Imatinib functions through competitive inhibition of the ATP binding site of BCR-ABL
What are the modes of development of resistance
to Imatinib ?
- Imatinib also functions against: PDGFR and c-KIT
- Resistance is present initially in 5% of cases
- result of distinct mutations in the BCR-ABL gene
- esp. TK domain: P loop (T315I) - KNOW
- early treatment with Imatinib lessens the chances of development of resistance
IMP: accelerated or blast phase are more likely to develop resistance to Imatinib
What are secondary/other mechanisms of
resistance development in CML ?
- P-glycoprotein (MDR) overexpression
- Amplification of BCR-ABL leading to bcr-abl kinase
- acquisition of additional non-Bcr-Abl genetic anomolies (clonal evolution)
What is the definition of
minimal residual disease in CML?
- Clinical remission: ~10^9-10^10 leukemic cells (about 2-3 log reduction)
- MRD generally refers to leukemic cells < 10^9-10^10
- Complete cytogenetic response:
- undetectable Philadelphia chromosome in 20 metaphased by conventional cytogenetics
- generally achieved when the number of leukemic cells is <10^9
- or a log of 3 reduction
In CML, what predicts 0% chance of disease progression
over the course of 2 years?
- a true log of 3 reduction at 12 months
- confirmed by quantitative PCR for the BCR-ABL transcript
- BCR-ABL quantitative PCR is used to establish baseline for future MRD monitoring at diagnosis
- Quantitative PCR (RT-PCR) considered the method of chose for MRD detection
- esp in patients who have achieved complete cytogenetic remission
What is the presentation of patient’s with
polycythemia vera?
- hypertension, thrombosis, pruritis, plethora, erythromelalgia, and or headache
- spleen is typically enlarged at presentation
- Budd-Chiari in 10% of cases
- Most common cause of death:
- thrombosis (31%)
- acute leukemia (19%)
What are the diagnostic criteria for
Polycythemia Vera?
IMP: must differentiate PV from relative polycythemia, secondary polycythemia and CML
Must have 2 major and 1 minor criteria as the minimum:
- Major:
- Hgb > 16.5 (men) >16 (women), or Hct: >25%
- JAK2 V617F or JAK2 exon12 mutation
- Minor:
- subnormal serum erythropoitin (EPO)
What are causes of relative and secondary
polycythemia ?
- Relative:
- stress or dehydration
- called Gaisboch syndrome
- Secondary:
- Low PaO2 states (smoking, living at high altitudes)
- high oxygen affinity hemoglobin variants
- Neoplasms
- RCC, Cerebellar hemangioblastoma
- produce excess EPO
What is characteristic of the
Proliferative Phase of Polycythemia Vera?
- erythrocytosis, neutrophilia
- sometimes basophilia and or thrombocytosis
- marrow is hypercellular with a low M:E ratio
- megakaryocyte hyperplasia is often prominent
- stainable iron is usually decreased or absent
What is characteristic of the spent
phase of PV ?
- post polycythemic myelofibrosis with myeloid metaplasia
- peripheral myelopthisic pattern (marrow replacement)
- marrow reticulin fibrosis
- extramedullary hematopoiesis
What is endogenous colony formation
used to assess?
- used to evaluate Polycythemia vera
- use a culture of the patient’s marrow
- PV
- spontaneous formation of erythroid colonies
- without addition of EPO
- in other conditions, colony formation requires the addition of EPO
- spontaneous formation of erythroid colonies
What is the characteristic JAK2 mutation
identified in many MPNs ?
- JAK2 V617F
- present in >90% of PV
- 50% of ET and 50% of PMF
- present in >90% of PV
- the second most common activating mutation is within JAK2 exon 12, which is seen in a small proportion of PV cases
In what MPNs would you see mutations
in MPL ?
- small subset of PMF and ET
- MPL W515L or W515K
- IMP: these are not seen in PV
When would you expect to see a
CALR mutation in an MPN?
- Calreticulin exon 9 mutations
- seen in JAK2 negative PMF (25-35%)
- ET (15-24%)
- CALR type 1 mutation results from a 52 bp deletion
- type 2 mutations result from a 5 bp insertion
What are the diagnostic criteria of
Essential Thrombocythemia ?
Need all major or first 3 major and minor criteria
- Major:
- sustained thrombocytosis >450 x10^9/L
- bone marrow megakaryocytic hyperplasia, no panmyelosis
- no significant increase in granulocytic/erythroid precursors
- fails to meet criteria for PV, PMF, CML and MDS
- JAK2 V617F, MPL or CALR mutation
- Minor:
- presence of clonal marker or absence of reactive thrombocytosis
What is the clinical presentation
of ET?
- bimodal age distribution: peaks at age 30 and 60
- female predominance, esp for JAK2 mutations
- men tend to have more of the CALR
- presents as isolated thrombocytosis
- some patients can present with thrombosis or mucosal hemorrhages
What are the histological findings of
Essential Thrombocythemia?
- increase in mature appearing, large, hyperlobated megakaryocytes (stag-horn like)
- paratrabecular in distribution
- may have emperipolesis
- unlike PV and PMF megakaryocyte topography is not altered
- no significant megakaryocyte clumping
- stainable iron is present
- helps rule out iron deficiency
- significant reticulin fibrosis is not present
What conditions must be ruled out
before making a diagnosis of ET?
- Reactive thrombocytopenia
- seen in iron deficiency
- chronic inflammation
- asplenia
- other hematolymphoid malignancies
- CML
What is the morphology of the cellular
or prefibrotic phase of PMF ?
Presentation: anemia, mild leukocytosis, and thrombocytosis
- marrow is hypercellular with increased granulocytic precursors and increased megakaryocytes
- erythroid precursors
- relatively diminished with maturation arrest
- helps differentiate it from Panmyelosis
- granulocytes have normal distribution and lack a myelocyte bulge (different than CML)
What is the morphology of
PMF megakaryocytes ?
- morphologically abnormal
- aberrantly lobulated with clumped, hyperchromatic chromatin/ink like
- clusters are prominent
- found adjacent to sinuses and trabeculae
What is characteristic of the fibrotic
phase of PMF ?
- Leukoerythroblastic pattern in the peripheral blood
- dacrocytosis and anisocytosis
- bone marrow cant be aspirated
- Key findings:
- reticulin/collagen fibrosis
- intrasinusoidal hematopoiesis
- morphologically abnormal clusters of megakaryocytes
What is the clinical presentation of
Chronic Eosinophilic Leukemia (CEL) ?
- predominantly a disease of men 9:1 ratio
- peripheral blood eosinophilia
- >1.5 x 10^9/L
- often with evidence of tissue infiltration and damage
- Common sites involved:
- heart, GI tract, lung and CNS
- endomyocardial fibrosis can be seen in the heart
- Eosinophil Morphology
- hypogranular with cytoplasmic vacuolization
- if no clonality seen blasts must be >2% in PB and >5% in BM but <20% overall
What must be excluded in order
to diagnose Chronic Eosinophilic Leukemia ?
- No identifiable cause of secondary eosinophilia
- No evidence of a defined syndrome associated with eosinophilia: PDGFRA, PDGFRB and FGFR1
- If there is evidence of clonality by cytogenetics or increased blasts (must be <20%)
- can make the diagnosis of CEL
- IF these are lacking you call it hypereosinophilic syndrome
What are common causes of
Hypereosinophilia ?
- allergic reactions
- parasitic infections
- collagen vascular diseases
- mastocytosis
- other hematolymphoid neoplasms
What are the 3 myeloid neoplasms with
associated eosinophilia ?
- PDGFRa rearrangment
- PDGFRb rearrangment
- FGFR1 rearrangment
Note: endomyocardial fibrosis can occur with any of these conditions.
PDGFRa and PDGFRb rearrangements are responsive to Imatinib and other Tyrosine Kinase inhibitors
What is known about the PDGFRa
neoplasm?
- presents like Chronic eosinophilic leukemia
- also can be AML with eos and T-ALL with eos
- epidemiology:
- M:F 17:1 (median 40 years)
- No abnormal karyotype
- Usual gene rearrangements:
- NFIP1L1/PDGFRa
- cryptic del(4q12)
- NFIP1L1/PDGFRa
