Chronic Myeloid Neoplasms Flashcards
Five overall categories of chronic myeloid neoplasms
Myelodysplastic syndromes
Myeloproliferative neoplasms
MDS/MPN overlap syndromes
Mastocytosis
Myeloid neoplasms associated with eosinophilia and abnormalities of PDGFR(A or B) or FGFR1
MPN-category chronic myeloid neoplasms
Mastocytosis-category chronic myeloid neoplasms
Chronic myeliod or lymphoid neoplasms with eosinophilia and gene rearrangements
Chronic myeloid neoplasms categorized as MDS/MPN overlap
Broad subcategories of chronic myeloid neoplasm characterized by MDS
The patient seems to have a CML-like phenotype, but cytogenetics is negative for t(9;22).
What is the next step?
Orthogonal assessment for BCR-ABL1 rearrangement by FISH or RT-PCR
(preferably RT-PCR)
Types of BCR-ABL1 fusion protein
p210: Most common, classic disease phenotype, BCR exon 14 conjugated to ABL1 exon 3.
p230: Second most common, more prominent neutrophilic maturation and/or thrombocytosis, produced by BCR exon 12 fusion to ABL1 exon 3.
p190: Least common, but is often associated with more monocytic differentiation, produced by BCR exon 13 conjugated to ABL1 exon 2 or 3.
Molecular findings of chronic neutrophilic leukemia
CSF3R mutations
may be accompanied by SETBP or ASXL1 mutations. (only ASXL1 portends a worse prognosis)
Molecular findings of primary myelofibrosis
50-60%: JAK2 mutation
30%: CALR mutation
8%: MPL mutation
Molecular findings of essential thrombocythemia
50-60%: JAK2 mutation
30%: CALR mutation
3%: MPL mutation
Molecular findings of chronic eosinophilic leukemia, NOS
No disease-specific mutation, but demonstration of somatic mutations provides evidence of clonality.
On karyotype, +8, 7-, and Iso17q are common.
Mutations in the ‘general myeloid’ category which may be associated with almost any myeloid neoplasm
ASXL1
EZH2
TET2
IDH1
IDH2
SRSF2
SF3B1
Summary of the MPN genes
Type of JAK2 mutation sometimes found in B-ALL
JAK2 exon 14
Whereas conventional PV is usually JAK2 V617F or less often JAK2 exon 12
Most known pathogenic CALR mutations are. . .
delins-type mutations located in exon 9, giving rise to frameshifts that alter the reading frame.
The most common exon 9 alterations are a 52bp deletion (Type 1) and a 5 bp insertion (Type 2)
MPL hotspot mutation
MPL W515_
Most common KIT hotspot mutation
D816V
Prognosis in chronic myeloid/lymphoid neoplasms with eosinophilia
Good for PDGFRA/B, since imatinib and other TKIs work on these proteins.
Not as good for FGFR1 or JAK2 fusions, which have fewer, more inconsistently effective TKIs.
Non-TKI fusion partners in chronic myeloid/lymphoid neoplasms with eosinophilia
Very variable - eight partners have been reported for PDGFRA, over 30 for PDGFRB, 14 for FGFR1.
So, it is a good rule of thumb to just be suspicious of ANY potential translocation involving PDGFRA/PDGFRB/FGFR1/JAK2 in these clinical scenarios.
Carve-out diagnosis under the umbrella of chronic myeloid/lymphoid neoplasms with eosinophilia
Myeloid/lymphoid neoplasms with JAK2::PCM1 fusion