MPNs

Question 1

Dx criteria of PMF

PMF

Answer 1

Major All

1. Megakaryocyte atypia with MF2+
2. Exclude other MPN criteria
3. JAK2 MPL CALR
   or
   Other clinical marker (ASXL1, TET2, EZH1, SRSF2, SF3B1)
   or
   Exclude reactive MF

**Minor** 1+ on 2 occasions

Leukoerythroblastic
Leukocyte >11
Anaemia 
Palpable splenomegaly
LDH 

Prefirbrotic PMF
1. MF 1
2. Not leucoerythroblastic

Question 2

Dx criteria of ET

Answer 2

Major criteria

 1. Platelet count ≥450 × 109/L
 2. BM biopsy: proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and MF1
 3. Exclude other
 4. Presence of JAK2, CALR, or MPL mutation

Minor criterion

 Presence of a clonal marker or absence of evidence for reactive thrombocytosis

Diagnosis of ET requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion

Question 3

Dx criteria for PV

Answer 3

Major criteria
1. Hb >16.5 g/dL or Hct >49% in men
Hb >16.0 g/dL or Hct >48% in women
2. BM - hypercellularity for age with panmyelosis with pleomorphic, mature megakaryocytes (differences in size)
3. Presence of JAK2V617F or JAK2 exon 12 mutation

~~~
Minor criterion

 Subnormal serum erythropoietin level
```

Diagnosis of PV requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion

Question 4

Dx criteria for JMML

Answer 4

I. Clinical and hematologic features (all 4 features mandatory)
* PB monocyte count ≥1 × 109/L
* Blast/ProMonos < 20%
* Splenomegaly
* Absence of BCR/ABL1 or KMT2A

AND

II. **Genetic studies **(1 finding sufficient) Mutation of:
* PTPN11
* K/NRAS
* NF1
* CBL

OR

III. For patients without genetic features, besides the clinical and hematologic features listed under I, 2+ of the following criteria must be fulfilled:
* > Hemoglobin F
* LE Reaction
* GM-CSF hypersensitivity
* TCP with Hypercellular BM and < Megs

Question 5

Molecular diagnosis of CML and pathophysiology of translocation

Answer 5

BCR::ABL1/t(9;22)
- Constitutive activation of BCR::ABL
- Autophosphorylation of substrate

1. JAK/STAT -> Cell growth and survival
2. PI3K/AKT -> “ and Inhibits Apoptosis
3. RAS/MEK -> Activation of TF (NFKB)

Question 6

BCR::ABL Breakpoints

Answer 6

1. p210
2. p190
   - Denovo ALL
   - Monos
3. p230
   - Neutrophilia and Thombocytosis

Question 7

Phases of CML

Answer 7

1. CP
   - High Risk Chronic Phase (old AP)
2. BP (due to ACAs and Genes altered)
   - ≥20% blasts in PB or BM
   - Extramedullary proliferation of blasts
   - Lymphoblasts in PB or BM (even if <10% - 1/3 of BP and 1/3 of these are T)
   - Sheets of blasts in BM

Question 8

What ACAs (4) and Genes Altered (8) could lead to progression in CML?

Answer 8

1. ACAs
   - Add pH
   - Complex Karyo
   - Mono7/del7q
   - Tri 8,19, 21
2. Genes Altered
   - RUNX1
   - ASXL1
   - TP53
   - RB1
   - N/KRAS
   - IDH 1&2
   - TET2
   - MYC

Question 9

Risk scores used in CML and parameters

Answer 9

ELTS and SOKAL
- Age
- Spleen size
- Plt
- Blasts %
EUTOS and HASFORD
- adds Eos and Baso

Question 10

Treatment options for CML?

Answer 10

1. Low Risk:
   * TFR Yes = Nilotinib
   * TFR No = Imatinib
2. Int/High Risk:
   * 2G TKI

Question 11

Indications for TFR?

Answer 11

1. 18yo
   * Lower age and female
2. Access to RQPCR
   * Prev quantifiable RQPCR
   * Stable Response MR4 for 2+yrs
3. Compliance 3+yrs
   * No Resistance to 2G TKI

Question 12

Monitoring for CML TFR patients

Answer 12

• Monthly RQPCR for 6mo
• 2 monhtly for 18mo

Question 13

Different TKIs

Answer 13

1G
Imatinib
* 400mg dly with food

2G
Nilotinib
* 300mg BD empty stomach
* +: < risk of kinase domain mutations
* -: Clots
Dasatinib
* 100mg dly
* -: > risk of kinase domain mutations and Cardiac/Resp disease
Bosutinib
* 400mg dly

3G
Ponatinib
* +: Only TKI for T315I mutation
* -: Clots
Asciminnib
* Failed on 2 TKIs
* ABL Myristoyl pocket

Question 14

Monitoring of CML

Answer 14

• Karyotype (5% sens for MRD
• With FISH (1% sens for MRD)
• RQPCR: BCR::ABL1 to Control gene (GUSB, BCR or ABL1) as %

1. Baseline = 100%
2. MCyR = 10% (Log 1) - 3mo Early molecular response (Indication for TFR)
3. CCyR = 1% (Log 2) - 6mo
4. MMR = 0.1% (Log 3) -1yr
5. MR4 = 0.01% (Log 4)
6. MR4.5 = 0.032% (Log 4.5)

Question 15

Treatment of CML BP

Answer 15

• Get to CP then HSCT
• Myeloid BP (Denovo) - TKI
• Myeloid BP (transformed) - TKI & Chemo
• Lymphoid BP - TKI & HyperCVAD

Question 16

Pathogenesis of PV

Answer 16

• JAK2V617F (5% exon 12)
• +++ RBC mass (but also panmyelosis) = EPO independant erythropoiesis

Question 17

Clinical Symptoms of PV (9)

Answer 17

MPN SST LGH

• MF
• Pruritis (Acquagenic)
• Neurological (Hyperviscosity)
• Skin (erythromyalgia)
• Splenomegaly
• Thrombosis (Unusual sites)
• Leukaemic transf.
• Gout (>UA)
• HPT

Question 18

Prognosis in PV

Answer 18

MIPPS-PV
* Age
* WCC
* Abn Karyotype
* SRSF2 mutation

V2 adds
* Hb
* Blast%
* Const Sx

Question 19

Treatment of PV

Answer 19

Venesection - Hct < 45%
ASA

Risk (Hx of Thrombosis and Age < 60yo):

Low Risk
* ASA BD
* Peg-INF-a

High Risk
* Hydrea start 500mg BD
* a. thrombosis - ASA BD
* v. thombosis - Anticoag

New Drugs
* Hepcidin mimetic (< Hct, improve splenomeg and thrombocytosis)
* TP53 Stabiliser (< Hct, symptoms, JAK2 allelic burden)
* JAK mutant target (Givinostat - “)

Question 20

Mutations in ET

Answer 20

• JAK - 55% (similar fts as PV)
• CALR - 30% (T1 - 52bp del & T2 - 5bp ins) >er Plt
• MPL - 5% (isolated > plt and risk of thrombosis)
• Triple Neg - 15% (?germline mut)

Question 21

Clinical Fts of ET

Answer 21

T2SH

• Transform to MF, PV, Leukaemia
• Thrombosis
• Splenomeg
• Haemorrage

Question 22

Prognostic score of ET

Answer 22

IPSET
(Thrombosis Hx, Age, JAK2)

• Very low: - / < 60yo / -
• Low: JAK2 +
• Int: > 60yo
• High: + or > 60yo and JAK

Question 23

Treatment of ET

Answer 23

Very Low & Low:
* CVS risk: ASA
* No: Observe

Int & High risk:
* HU
* Prev thrombosis - a: ASA and v: Anticoag

Question 24

Clinical symptoms of PMF

Answer 24

• ASx = 1/3 of pts
• Const Sx
• Anaemia
• Thrombosis
• Bleeding
• Splenomegaly

Question 25

Treatment of PMF

Answer 25

**Very Low and Low Risk** ASx = Observe Sx: * TCP = Pacritinib * Anaemia and No splenomeg = Danazol, Pred, IMID and ESA * Anaemia and spleen = Momelotinib * Spleen and > counts = HU / Ruxolitinib **Int, High and Very High Risk** Transplant eligible = HSCT Non transplant eligible = Sx (above)

Question 26

Prognosis of PMF (6)

Answer 26

IPPS, DIPPS&Plus, MIPPS70&v2, GIPPS * Const Sx * Hb * Blast% * Karyotype - Very > risk/unfavourable * CALR Neg * HMR Mutations

Question 27

Diagnostic criteria of CNL

Answer 27

I. **Excluded** reactive neutrophilia, MPNs or Overlaps II. **WCC > 25** * Mature/Bands > 80% * Precursors < 10% * Monos < 10% * Rare blasts * Hypercellular bone marrow with Normal maturation * No dysplasia * HSM III. Negative BCR::ABL1, PV, ET, PMF WITH **CSF3R**

Question 28

Diagnostic criteria of CEL

Answer 28

I. HE > 1.5 2x over4 wks II. Clonality III. Abnormal morphology IV. Exclude other Myeloid neoplasms * AML inv16 * CML * M/L with Eos * B-ALL (5;14) * Mastocytosis

Question 29

What is an atypical presentation for CML ?

Answer 29

A **marked thrombocytosis without leukocytosis** this mimics ET or other MPNs Note: ~5% cases are diagnosed in accelerated or blast phase

Question 30

What is important to remember when increased neutrophils are present ?

Answer 30

Increased frequency with **plasma cell neoplasms and MGUS** to produce a neutrophilic leukamoid reaction.