L24 - MDS and MPN: principles of diagnosis and treatment Flashcards
Spectrum of MDS/MPN?
Myeloproliferative neoplams (MPN)
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)
Myelodysplastic syndromes (MDS)
Definition of MDS? (3 features)
clonal haematological disorder with:
1) ineffective haematopoiesis
2) cytopenia
3) propensity of clonal progression to AML
Define the extent of cytopenia and bone marrow changes in MDS?
cytopenia in ≥ 1 lineage +/- increase in blasts of myeloid lineage
hypercellular bone marrow, significant morphologic dysplasia in ≥ 1 lineage
Explain why hypercullar BM in MDS causes cytopenia?
Hyperproliferative clonal cells undergo premature apoptosis»_space; cytopenia
Epidemiology of MDS?
Male preponderance (2:1)
Increasing incidence after 50s, median age = 75
Spectrum of peripheral blood cytopenia in MDS?
1 lineage: anaemia / neutropenia / thrombocytopenia
2 lineages: bicytopenia
3 lineages: pancytopenia
Name the most common cause of macrocytic anemia in elderly?
MDS = ↑ mean corpuscular volume (MCV)
90% of patients have significant macrocytosis
What is the most common RBC abnormality asso. with MDS?
significant macrocytosis (>100 fl)
Distinguish low grade and high grade MDS?
Low = Dysplasia without excess blasts + Low risk of AML progression
High = Dysplasia with excess blasts + high risk karyotype/ genetics + High risk of progression to AML in 2 years
List the investigative results that confirm MDS? **
Proof of ineffective haematopoesis** and dysplasia +/- increase in blasts by BM and PB
confirm clonality**
List typical blood test results for MDS? (cells involved, vitb12, ldh?)
Red cell Macrocytosis + cytopenia + low reticulocyte count
Normal Vit B12, serum and RBC folate (ddx from B12 and folate dif.)
Usually normal LDH, elev. in high risk
List all the general investigations for suspected MDS?
Blood:
- CBC with D/C and blood film review
- Biochemistry: LDH, Serum active B12, Serum folate
Diagnostic:
- BM aspiration and trephine biopsy to prove clonality and hypercellularity BM***
- Cytogenetic and molecular studies
Main treatment regimen for low-grade MDS with very low to intermediate risk (IPSS-R test)?
Supportive (e.g. transfusion) +/- erythropoietic stimulating factors (e.g. EPO) + Granulocyte-colony stimulating factor (G-CSF)
Main treatment regimen for high grade MDS with intermediate to very high risk (IPSS-R test)?
- Hypomethylating agents (azacitidine, decitabine)
* Allogeneic HSCT in young and transplant-eligible patients
Genetic pathogenesis of MDS?
Aberrant DNA methylation/ inactivation»_space; suppress Tumour suppressant/ physiological genes
MoA of drugs used against high risk MDS?
Hypomethylating agents:
- Azacitidine, Decitabine)
1. Reactivation of silenced genes** (esp. tumour suppressor genes)
2. Cytotoxicity
3. Inhibit cellular proliferation
Describe the blood cell abnormalities in MDS?
RBC:
- Macrocytosis
- Absent polychromasia/ Reticulotcytopenia
WBC:
- Leucopenia
• Hypolobated + hypogranular neutrophils
• No hypersegmented neutrophils (low B12)
(Pseudo PelgerHuët anomaly)
Plt:
- Thrombocytopenia with no platelet clumps
DDx of pancytopenia with significant macrocytosis?
MDS
Pernicious anaemia (B12 def.)
AML or ALL with MDS-related changes
Clinical presentation of MDS on P/E?
Abnormal bleeding tendencies(e.g. abnormal per-rectal bleeding/ menses)
Easy bruising
Fatigue, fever, frequent infections
Anaemic symptoms
LN, liver and spleen are NOT palpable
Typical BM histology in MDS? (think cellularity, erythoid cells, leukaemic cells, megakaryocytic cells appearance)
- Hypercellular marrow* with mulitple lineage dysplasia
- Some leukaemic blasts
- Increased erythropoiesis with Bilobed erythoid cells
- Micromegakaryocytes
- Abnormally lobulated myeloid cells
- Ring sideroblasts* upon iron stain
Is LRFT, LDH levels normal in MDS?
Yes
MDS is not proliferative
Describe the abnormal megakaryocyte morphology in MDS?
Micro-megakaryocytes
Separate nuclei
Define MPN?
• A clonal haematopoietic stem cell disorder
> > proliferation of one or more of the haematopoietic lineages
Molecular pathogenesis of MPN?
Driver mutation/ gene fusion activate tyrosine kinases and cytokine signalling
Define the classes of MPN?
1) Philadelphia chromosome positive:
- CML, BCR-ABL1 positive t(9;22)
2) Philadelphia chromosome negative:
- chronic neutrophilic leukaemia
- Polycythaemia vera
- Essential thrombocythaemia
- Primary myelofibrosis
- Chronic eosinophilic leukaemia, NOS
Genetic hallmark of CML?
BCR-ABL1 t(9;22)
Genetic hallmark of Polycythaemia vera?
JAK2 V617F 9p24
Genetic hallmark of Essential thrombocythaemia and Primary myelofibrosis?
JAK2 V617F 9p24
CALR exon 9 mutation
3 phases of CML and treatment option for each pahse?
chronic phase (CP), accelerated phase (AP) and blast phase (BP)
tyrosine kinase inhibitors: CP
Allo-HSCT = AP and BP
P/E features and clinical presentation of CML in Chronic phase?
50% asymptomatic
Fever, weight loss, night sweat (like lymphoma)
Splenomegaly, Bone pain
CBC findings of CML in Chronic phase?
- Very high leukocytosis
- Anemia
- Thrombocytosis
- Absolute basophilia
- bimodal prominence/ severe increase of neutrophils and myelocytes**
Left shift = highly immature myeloid series in PB
BM findings of CML in Chronic phase?
- Hypercellular with increased M:E ratio, blasts < 10%
- Entire myeloid series hypercellular with bimodal prominence
- Dwarf Megakaryocytes: Increased micromegakaryocytes with hypolobulation
List 2 genetic diagnostic tests for CML?
Cytogenetic and FISH:
identify ch. 9 and 22 translocation by karyotype
Find ABL-1, BCR gene fusion by FISH
MoA of tyrosine kinase inhibitors?
Block ATP binding site on BCR-ABL
Block phosphorylation of effector
Epidemiology of Polycythemia vera?
Median age 55-60
1-3 per 100,000
Clinical presentation of polycythemia vera? What usually precedes the condition?
- typically secondary to vascular disturbances* (e.g. DVT, stroke, thromboembolism) and increased red-cell mass
- Fatigue, aquagenic pruritis*, gout, dizziness and headache
- LOW EPO
- Mild to moderate splenomegaly +/- hepatomegaly
CBC findings of polycythaemia vera? Marrow finding?
Increased RBC, WBC, Plt count
Increased Hb, Hct
Marked trillineage hyperplasia: panmyelosis
pleomorphic, mature megakaryocyte
Epidemiology of essential thromocythaemia?
Median age 50-60
Peak in women in 30
0.5-1.8 per 100,000
Clinical presentation of essential thrombocythaemia? What condition must be excluded in the Ddx?
30-50% asymptomatic: must exclude reactive thrombocytosis
Mostly blood flow abnormalities:
- Headache, Dizziness or lightheadedness,
- Fainting.
- Chest pain
- Temporary vision changes
- Numbness or tingling of the hands and feet
- Redness, throbbing and burning pain in the hands and feet (erythromelalgia)
CBC findings of essential thrombocythaemia?
marked isolated thrombocytosis* with platelet anisocytosis*
Normal Hb, WBC
Marrow findings of essential thrombocythaemia?
proliferation mainly of the megakaryocyte lineage
increased number of large, mature megakaryocytes with hyperlobulated nuclei
What is the most common inherited bleeding disorder?
Inherited von Willebrand disease (VWD)
Epidemiology of Primary myelofibrosis?
Median age at diagnosis 65-70 • Both genders
Clinical presentation of Primary myelofibrosis
Prefibrotic stage or Overt fibrotic phase:
Anaemic symptoms (i.e. lower exercise tolerance, pallor)
Loss appetite, weight loss
Easy bruising, abnormal bleeding
massive splenomegaly, hepatomegaly, portal hypertension from hepatic fibrosis
CBC findings of Primary myelofibrosis?
leucocytosis, anaemia and thrombocytosis
leucoerythoblastic blood picture: increased immature WBC and RBC
tear-drop poikilocytes (RBC deform in spleen)
many giant platelets
Marrow findings of Primary myelofibrosis?
- increased BM cellularity*
- Thickened bony trabeculae,
- Marked coarsening of reticulin fibres
- Increased granulopoiesis and megakaryopoiesis*
- reduced erythropoiesis*
- Megakaryocytes: nuclear atypia, clustering*
Which disease causes must be excluded when investigating PV, ET, MF?
What are the 2 most important investigations for accurate Dx of PV,ET or MF?
Exclusion of CML BCR-ABL1+
Exclusion of reactive causes without somatic mutations
Must Proof clonality by cytogenetic and molecular studies + Morphological Dx by PB & BM
List the 3 diagnostic investigations for MPN?
- BMA and trephine biopsy
- Cytogenetic analysis
- Molecular studies (JAK2, CALR, MPL and BCR-ABL1 to exclude CML)
List the blood metrics tested for MPN?
CBC with differential count and blood film review
- Clotting profile + exclusion of aVWD
- Low EPO level (ddx for PV)
- LRFT, LDH, urate
- Hepatitis B and C serology
3 main risk factors for thrombosis in PV?
High risk:
• Age > 60 OR
• History of thrombosis + CVS risk factors (i.e. hypertension, smoking)
• JAK2V617F
What is assessed to determine Primary myelofibrosis risk?
Various genetic mutations, CBC findings and marrow behavior
Treatment regimen for low risk Polycythaemia vera?
- Low dose aspirin + Phlebotomy to maintain Hct <45%
- Manage CVS risk factors and monitor for bleeding, thrombosis
(Evaluate indications for cytoreductive therapy)
Treatment regimen for high risk Polycythaemia vera?
- Low dose aspirin + Phlebotomy to maintain Hct <45%
- Manage CVS risk factors and monitor for bleeding, thrombosis
- cytoreductive therapy**: Hydroxyurea or Peg-IFNα 2A
Treatment regimen for very low, low risk and intermediate risk essential thrombocythaemia?
- Aspirin
- Monitor for CVS risk factors, new thrombosis, bleeding
- Monitor for acquired vWD
- Cytoredective agents if indicated
Treatment regimen for high risk essential thrombocythaemia?
- Aspirin
- Cytoredective agents: Hydroxyurea or Peg-IFNα 2A +/- anagrelide
- Monitor for acquired vWD
- Monitor for CVS risk factors, new thrombosis, bleeding
Treatment regimen for PMF with low risk of AML and predicted long survival
- Ruxolitinib based on symptoms and organomegaly
- Cytoreduction: Hydroxyurea or Peg-IFNα 2A
- Management of anaemia and cytopenia
Treatment regimen for PMF with high risk of AML and predicted short survival?
- Allo-HSCT if transplant eligible diff. from low risk
- Ruxolitinib based on symptoms and organomegaly
- Cytoreduction: Hydroxyurea or Peg-IFNα 2A
- Management of anaemia and cytopenia
Ddx of genuine erythrocytosis?
Primary = EPO suppressed:
- PV
Secondary = EPO not suppressed:
- Chronic hypoxaemia
- Renal condition with increased EPO production
- Rare paraneoplastic (RCC,HCC)
Ddx of isolated thrombocytosis?
Primary (marrow cause):
- MPN (ET)
Secondary (reactive)
- Bleeding/ Iron deficiency common
- Paraneoplastic phenomena (rare)
- Inflammation (rare)
Explain why increased aPTT is seen in essential thrombocythaemia?
Isolated thrombocytosis:
more platelets = consume more vWB factors
= Reduce binding of factor 8 to VWB
= Reduce t1/2 of factor 8, less react with thromboplastin
= Prolong aPTT
Define MDS/MPN? What is the classical type? What are the 3 blood cell abnormality criteria?
Clonal haematological disorders, classic = CMML
1) proliferation in one lineage (typically leucocytosis),
2) cytopenia in ≥1 other lineage(s) (typically anaemia and/or thrombocytopenia)
3) dysplasia in ≥1 lineage
CBC finding of CMML?
Classical = chronic myelomonocytic leukaemia (CMML)
leucocytosis, monocytosis +/- anaemia +/- thrombocytopenia
occasional promonocytes and dysplastic neutrophils
Presentation of CMML?
anaemic symptoms and easy brusing
Pallor and hepatosplenomegaly.
Marrow finding for CMML?
monocytosis
dysplastic neutrophils (hypogranular with abnormal lobulation)
Hypercellular, dysplastic myeloid series and megakaryocytes
Difference in CBC finding of the 2 phases of PMF?
- Cellular (prefibrotic) phase:
Anaemia
White cell count ↑
Platelet count ↑ - Fibrotic phase: pancytopenia
