Final Diagnosis
Essential thrombocythemia with progression to secondary myelofibrosis
Discussion
This is a case of essential thrombocythemia (ET) with progression to secondary myelofibrosis (MF). The International consensus conference and WHO 5th edition share criteria for the diagnosis of post-essential thrombocythemia myelofibrosis(Arber et al. 2022; Holchaus et al. 2022). The diagnosis of post-ET MF is established by all required criteria and at least 2 additional criteria:
In this case, the patient met both of the required criteria, with a fibrosis grade of 3, as well as several of the additional criteria - anemia, leukoerythroblastosis, and elevated LDH.
Next generation sequencing was performed on the specimen with the following results:
- CALR mutation p.Q365Rfs*50 c.1093_1138del
- ASXL1 mutation p.G646Wfs*12 c.1934dup
Myeloproliferative neoplasms (MPN), which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by several classic driver mutations. While PV is almost exclusively associated with JAK2 mutations, common mutations found in ET and PMF include JAK2, MPL, and CALR. In the case of ET, JAK2 V617F mutation is found in 50-60% of cases, while CALR variants are found in 25-35%, and MPL variants are found in the remaining 5-10% (Holchaus et al. 2022). Patients with CALR variants tend to have a higher platelet counts, lower thrombotic risk, and a more indolent course with longer overall survival versus those with triple negative or JAK2 positive ET (Rumi et al. 2014).
CALR is the gene that codes for calreticulin, which is a soluble protein that binds Ca2+ ions, rendering them inactive and incapable of acting as second messengers. Variants in CALR produce alterations in the overall charge of the molecule, and may lead to impaired Ca2+ binding (Kim et al. 2022).
The two most common CALR variants are termed Type 1 and Type 2:
- Type 1 is a 52 base pair deletion which eliminates almost all negatively charged amino acids.
- Type 2 is a 5 base pair insertion which results in retention of approximately half of the negatively charged amino acids.
In both ET and PMF, there is a slight propensity for Type 1 variants. In addition, nonclassical CALR variants have been characterized as either “Type 1-like" or “Type 2-like" based on the resulting alteration of the C-terminal and isoelectric point of the protein. The patient’s CALR mutation was a 46 base pair deletion which is considered a “Type 1-like" variant.
Among patients with CALR mutations, those with “Type 1-like" mutations have a higher risk of transformation to myelofibrosis, whereas those with “Type 2-like" mutations have a more indolent course (Pietra et al. 2016).
References
1. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850
2. Holchaus A, Khoury JD, Harrison CN, et al. Essential Thrombocythaemia. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. Lyon (France): International Agency for Research on Cancer; 2022. (WHO classification of tumours series, 5th ed.; vol. 11). Available from: https://tumourclassification.iarc.who.int/chapters/63.
3. Rumi E, Pietra D, Ferretti V, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014;123(10):1544-1551. doi:10.1182/blood-2013-11-539098
4. Kim H-Y, Han Y, Jang JH, Jung CW, Kim S-H, Kim H-J. Effects of CALR-Mutant Type and Burden on the Phenotype of Myeloproliferative Neoplasms. Diagnostics (Basel). 2022;12(11). doi:10.3390/diagnostics12112570
5. Pietra D, Rumi E, Ferretti VV, et al. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia. 2016;30(2):431-438. doi:10.1038/leu.2015.277