MPNs Flashcards
CML, PV, ET, PMF, JMML, CNL, CEL
Dx criteria of PMF
PMF
Major All
- Megakaryocyte atypia with MF2+
- Exclude other MPN criteria
-
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
Dx criteria of ET
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
Dx criteria for PV
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
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Diagnosis of PV requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion
Dx criteria for JMML
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
Molecular diagnosis of CML and pathophysiology of translocation
BCR::ABL1/t(9;22)
- Constitutive activation of BCR::ABL
- Autophosphorylation of substrate
- JAK/STAT -> Cell growth and survival
- PI3K/AKT -> “ and Inhibits Apoptosis
- RAS/MEK -> Activation of TF (NFKB)
BCR::ABL Breakpoints
- p210
- p190
- Denovo ALL
- Monos - p230
- Neutrophilia and Thombocytosis
Phases of CML
- CP
- High Risk Chronic Phase (old AP) - 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
What ACAs (4) and Genes Altered (8) could lead to progression in CML?
- ACAs
- Add pH
- Complex Karyo
- Mono7/del7q
- Tri 8,19, 21 - Genes Altered
- RUNX1
- ASXL1
- TP53
- RB1
- N/KRAS
- IDH 1&2
- TET2
- MYC
Risk scores used in CML and parameters
ELTS and SOKAL
- Age
- Spleen size
- Plt
- Blasts %
EUTOS and HASFORD
- adds Eos and Baso
Treatment options for CML?
- Low Risk:
* TFR Yes = Nilotinib
* TFR No = Imatinib - Int/High Risk:
* 2G TKI
Indications for TFR?
- 18yo
* Lower age and female - Access to RQPCR
* Prev quantifiable RQPCR
* Stable Response MR4 for 2+yrs - Compliance 3+yrs
* No Resistance to 2G TKI
Monitoring for CML TFR patients
- Monthly RQPCR for 6mo
- 2 monhtly for 18mo
Different TKIs
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
Monitoring of CML
- Karyotype (5% sens for MRD
- With FISH (1% sens for MRD)
- RQPCR: BCR::ABL1 to Control gene (GUSB, BCR or ABL1) as %
- Baseline = 100%
- MCyR = 10% (Log 1) - 3mo Early molecular response (Indication for TFR)
- CCyR = 1% (Log 2) - 6mo
- MMR = 0.1% (Log 3) -1yr
- MR4 = 0.01% (Log 4)
- MR4.5 = 0.032% (Log 4.5)
Treatment of CML BP
- Get to CP then HSCT
- Myeloid BP (Denovo) - TKI
- Myeloid BP (transformed) - TKI & Chemo
- Lymphoid BP - TKI & HyperCVAD
