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MBBS II HIS > L24 - MDS and MPN: principles of diagnosis and treatment > Flashcards

L24 - MDS and MPN: principles of diagnosis and treatment Flashcards

1
Q

Spectrum of MDS/MPN?

A

Myeloproliferative neoplams (MPN)

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)

Myelodysplastic syndromes (MDS)

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2
Q

Definition of MDS? (3 features)

A

clonal haematological disorder with:

1) ineffective haematopoiesis
2) cytopenia
3) propensity of clonal progression to AML

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3
Q

Define the extent of cytopenia and bone marrow changes in MDS?

A

cytopenia in ≥ 1 lineage +/- increase in blasts of myeloid lineage

hypercellular bone marrow, significant morphologic dysplasia in ≥ 1 lineage

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4
Q

Explain why hypercullar BM in MDS causes cytopenia?

A

Hyperproliferative clonal cells undergo premature apoptosis&raquo_space; cytopenia

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5
Q

Epidemiology of MDS?

A

Male preponderance (2:1)

Increasing incidence after 50s, median age = 75

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6
Q

Spectrum of peripheral blood cytopenia in MDS?

A

 1 lineage: anaemia / neutropenia / thrombocytopenia

 2 lineages: bicytopenia

 3 lineages: pancytopenia

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7
Q

Name the most common cause of macrocytic anemia in elderly?

A

MDS = ↑ mean corpuscular volume (MCV)

90% of patients have significant macrocytosis

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8
Q

What is the most common RBC abnormality asso. with MDS?

A

significant macrocytosis (>100 fl)

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9
Q

Distinguish low grade and high grade MDS?

A

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

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10
Q

List the investigative results that confirm MDS? **

A

Proof of ineffective haematopoesis** and dysplasia +/- increase in blasts by BM and PB

confirm clonality**

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11
Q

List typical blood test results for MDS? (cells involved, vitb12, ldh?)

A

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

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12
Q

List all the general investigations for suspected MDS?

A

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
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13
Q

Main treatment regimen for low-grade MDS with very low to intermediate risk (IPSS-R test)?

A

Supportive (e.g. transfusion) +/- erythropoietic stimulating factors (e.g. EPO) + Granulocyte-colony stimulating factor (G-CSF)

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14
Q

Main treatment regimen for high grade MDS with intermediate to very high risk (IPSS-R test)?

A
  • Hypomethylating agents (azacitidine, decitabine)

* Allogeneic HSCT in young and transplant-eligible patients

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15
Q

Genetic pathogenesis of MDS?

A

Aberrant DNA methylation/ inactivation&raquo_space; suppress Tumour suppressant/ physiological genes

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16
Q

MoA of drugs used against high risk MDS?

A

Hypomethylating agents:

  • Azacitidine, Decitabine)
    1. Reactivation of silenced genes** (esp. tumour suppressor genes)
    2. Cytotoxicity
    3. Inhibit cellular proliferation
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17
Q

Describe the blood cell abnormalities in MDS?

A

RBC:

  • Macrocytosis
  • Absent polychromasia/ Reticulotcytopenia

WBC:
- Leucopenia
• Hypolobated + hypogranular neutrophils
• No hypersegmented neutrophils (low B12)
(Pseudo PelgerHuët anomaly)

Plt:
- Thrombocytopenia with no platelet clumps

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18
Q

DDx of pancytopenia with significant macrocytosis?

A

MDS

Pernicious anaemia (B12 def.)

AML or ALL with MDS-related changes

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19
Q

Clinical presentation of MDS on P/E?

A

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

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20
Q

Typical BM histology in MDS? (think cellularity, erythoid cells, leukaemic cells, megakaryocytic cells appearance)

A
  • 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
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21
Q

Is LRFT, LDH levels normal in MDS?

A

Yes

MDS is not proliferative

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22
Q

Describe the abnormal megakaryocyte morphology in MDS?

A

Micro-megakaryocytes

Separate nuclei

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23
Q

Define MPN?

A

• A clonal haematopoietic stem cell disorder

> > proliferation of one or more of the haematopoietic lineages

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24
Q

Molecular pathogenesis of MPN?

A

Driver mutation/ gene fusion activate tyrosine kinases and cytokine signalling

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25
Q

Define the classes of MPN?

A

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

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26
Q

Genetic hallmark of CML?

A

BCR-ABL1 t(9;22)

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27
Q

Genetic hallmark of Polycythaemia vera?

A

JAK2 V617F 9p24

28
Q

Genetic hallmark of Essential thrombocythaemia and Primary myelofibrosis?

A

JAK2 V617F 9p24

CALR exon 9 mutation

29
Q

3 phases of CML and treatment option for each pahse?

A

chronic phase (CP), accelerated phase (AP) and blast phase (BP)

tyrosine kinase inhibitors: CP
Allo-HSCT = AP and BP

30
Q

P/E features and clinical presentation of CML in Chronic phase?

A

50% asymptomatic
Fever, weight loss, night sweat (like lymphoma)
Splenomegaly, Bone pain

31
Q

CBC findings of CML in Chronic phase?

A
  • Very high leukocytosis
  • Anemia
  • Thrombocytosis
  • Absolute basophilia
  • bimodal prominence/ severe increase of neutrophils and myelocytes**

Left shift = highly immature myeloid series in PB

32
Q

BM findings of CML in Chronic phase?

A
  • Hypercellular with increased M:E ratio, blasts < 10%
  • Entire myeloid series hypercellular with bimodal prominence
  • Dwarf Megakaryocytes: Increased micromegakaryocytes with hypolobulation
33
Q

List 2 genetic diagnostic tests for CML?

A

Cytogenetic and FISH:

identify ch. 9 and 22 translocation by karyotype

Find ABL-1, BCR gene fusion by FISH

34
Q

MoA of tyrosine kinase inhibitors?

A

Block ATP binding site on BCR-ABL

Block phosphorylation of effector

35
Q

Epidemiology of Polycythemia vera?

A

Median age 55-60

1-3 per 100,000

36
Q

Clinical presentation of polycythemia vera? What usually precedes the condition?

A
  • 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
37
Q

CBC findings of polycythaemia vera? Marrow finding?

A

Increased RBC, WBC, Plt count
Increased Hb, Hct

Marked trillineage hyperplasia: panmyelosis
pleomorphic, mature megakaryocyte

38
Q

Epidemiology of essential thromocythaemia?

A

Median age 50-60
Peak in women in 30
0.5-1.8 per 100,000

39
Q

Clinical presentation of essential thrombocythaemia? What condition must be excluded in the Ddx?

A

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)
40
Q

CBC findings of essential thrombocythaemia?

A

marked isolated thrombocytosis* with platelet anisocytosis*

Normal Hb, WBC

41
Q

Marrow findings of essential thrombocythaemia?

A

proliferation mainly of the megakaryocyte lineage

increased number of large, mature megakaryocytes with hyperlobulated nuclei

42
Q

What is the most common inherited bleeding disorder?

A

Inherited von Willebrand disease (VWD)

43
Q

Epidemiology of Primary myelofibrosis?

A

Median age at diagnosis 65-70 • Both genders

44
Q

Clinical presentation of Primary myelofibrosis

A

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

45
Q

CBC findings of Primary myelofibrosis?

A

leucocytosis, anaemia and thrombocytosis

leucoerythoblastic blood picture: increased immature WBC and RBC

tear-drop poikilocytes (RBC deform in spleen)

many giant platelets

46
Q

Marrow findings of Primary myelofibrosis?

A
  • increased BM cellularity*
  • Thickened bony trabeculae,
  • Marked coarsening of reticulin fibres
  • Increased granulopoiesis and megakaryopoiesis*
  • reduced erythropoiesis*
  • Megakaryocytes: nuclear atypia, clustering*
47
Q

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?

A

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

48
Q

List the 3 diagnostic investigations for MPN?

A
  • BMA and trephine biopsy
  • Cytogenetic analysis
  • Molecular studies (JAK2, CALR, MPL and BCR-ABL1 to exclude CML)
49
Q

List the blood metrics tested for MPN?

A

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
50
Q

3 main risk factors for thrombosis in PV?

A

High risk:
• Age > 60 OR
• History of thrombosis + CVS risk factors (i.e. hypertension, smoking)
• JAK2V617F

51
Q

What is assessed to determine Primary myelofibrosis risk?

A

Various genetic mutations, CBC findings and marrow behavior

52
Q

Treatment regimen for low risk Polycythaemia vera?

A
  1. Low dose aspirin + Phlebotomy to maintain Hct <45%
  2. Manage CVS risk factors and monitor for bleeding, thrombosis

(Evaluate indications for cytoreductive therapy)

53
Q

Treatment regimen for high risk Polycythaemia vera?

A
  1. Low dose aspirin + Phlebotomy to maintain Hct <45%
  2. Manage CVS risk factors and monitor for bleeding, thrombosis
  3. cytoreductive therapy**: Hydroxyurea or Peg-IFNα 2A
54
Q

Treatment regimen for very low, low risk and intermediate risk essential thrombocythaemia?

A
  1. Aspirin
  2. Monitor for CVS risk factors, new thrombosis, bleeding
  3. Monitor for acquired vWD
  4. Cytoredective agents if indicated
55
Q

Treatment regimen for high risk essential thrombocythaemia?

A
  1. Aspirin
  2. Cytoredective agents: Hydroxyurea or Peg-IFNα 2A +/- anagrelide
  3. Monitor for acquired vWD
  4. Monitor for CVS risk factors, new thrombosis, bleeding
56
Q

Treatment regimen for PMF with low risk of AML and predicted long survival

A
  1. Ruxolitinib based on symptoms and organomegaly
  2. Cytoreduction: Hydroxyurea or Peg-IFNα 2A
  3. Management of anaemia and cytopenia
57
Q

Treatment regimen for PMF with high risk of AML and predicted short survival?

A
  1. Allo-HSCT if transplant eligible diff. from low risk
  2. Ruxolitinib based on symptoms and organomegaly
  3. Cytoreduction: Hydroxyurea or Peg-IFNα 2A
  4. Management of anaemia and cytopenia
58
Q

Ddx of genuine erythrocytosis?

A

Primary = EPO suppressed:
- PV

Secondary = EPO not suppressed:

  • Chronic hypoxaemia
  • Renal condition with increased EPO production
  • Rare paraneoplastic (RCC,HCC)
59
Q

Ddx of isolated thrombocytosis?

A

Primary (marrow cause):
- MPN (ET)

Secondary (reactive)

  • Bleeding/ Iron deficiency common
  • Paraneoplastic phenomena (rare)
  • Inflammation (rare)
60
Q

Explain why increased aPTT is seen in essential thrombocythaemia?

A

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

61
Q

Define MDS/MPN? What is the classical type? What are the 3 blood cell abnormality criteria?

A

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

62
Q

CBC finding of CMML?

A

Classical = chronic myelomonocytic leukaemia (CMML)

leucocytosis, monocytosis +/- anaemia +/- thrombocytopenia

occasional promonocytes and dysplastic neutrophils

63
Q

Presentation of CMML?

A

anaemic symptoms and easy brusing

Pallor and hepatosplenomegaly.

64
Q

Marrow finding for CMML?

A

monocytosis

dysplastic neutrophils (hypogranular with abnormal lobulation)

Hypercellular, dysplastic myeloid series and megakaryocytes

65
Q

Difference in CBC finding of the 2 phases of PMF?

A
  1. Cellular (prefibrotic) phase:
     Anaemia
     White cell count ↑
     Platelet count ↑
  2. Fibrotic phase: pancytopenia

MBBS II HIS (30 decks)

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