CALR Mutation in Myelofibrosis Associated with Greater Risk of Anemia

By Kerri Fitzgerald - Last Updated: December 19, 2022

A study presented at the 2022 American Society of Hematology Annual Meeting found that CALR mutation in patients with myelofibrosis (MF) may be associated with a more anemic phenotype at diagnosis and an increased risk of developing anemia.

CALR mutations occur in approximately 20% to 30% of patients with essential thrombocythemia (ET) and 25% to 35% of patients with primary MF. Most patients have CALR variant allele frequency (VAF) <50%. Researchers sought to characterize the hematologic and clinical correlates of higher CALR VAF in patients with CALR-mutated primary MF and primary ET MF.

The study included 121 patients with CALR mutation who were identified from a database—42 with pre-primary MF (34.7%), 36 with overt primary MF (29.8%), and 43 with primary ET MF (35.5%). Most patients (71.9%; n=87) had type 1/like mutation. Mutation analysis of a panel of 40 myeloid neoplasm-associated genes was performed by next-generation sequencing (NGS).

Median CALR VAF was 51.4+10.4%. For this analysis, high VAF was defined as ≥55% and was observed in 28 patients (23.1%).

There was a significant trend of increased representation of high VAF CALR patients from pre-primary MF (n=6; 14.3%) to overt primary MF (n=8; 22.2%) and primary ET MF (n=14; 32.6%). ASXL1 mutations were enriched in high VAF CALR patients (n=13/28; 46.4%) compared with lower VAF (n=24/87; 27.6%; P=.04), as was the presence of any one or more mutations in a NGS panel of myeloid genes (82.5% vs 57.5%; P=.02).

When comparing those with high versus lower VAF, there was no significant difference in gender, age, International Prognostic Scoring System, karyotype abnormalities, bone marrow fibrosis grade, constitutional symptoms, splenomegaly, thrombosis, and bleeding events at diagnosis.

However, high VAF patients had lower hemoglobin levels (10.8 g/dL vs 12.1 g/dL; P=.02) and platelet counts (466×109/L vs 661×109/L; P=.02), as well as higher peripheral blood CD34-positive cell counts (62.2×106/L vs 16.9×106/L; P=.01). A greater proportion of high VAF patients developed anemia during follow-up (median, 5.5 years; range, 0.3-33 years).

Anemia-free survival (defined as hemoglobin <10 g/dL) was 7.9 years in the high VAF group versus 22.1 years in the lower VAF group (HR, 3.1; 95% CI, 1.4-7.0; P=.004). Leukocytosis-free survival (defined as leukocytes >25×109/L) was shorter in high VAF patients (HR, 2.55; 95% CI, 1.0-6.6; P=.04).

Despite the findings, “overall survival was not significantly impacted in the different disease categories. Whether a high VAF CALR has different impact in ET remains to be assessed in a separate study,” the authors concluded.


Maccari C, Sordi B, Guglielmelli P, et al. Impact of higher calreticulin gene mutation variant allele frequency in patients with myelofibrosis. Abstract #1720. Presented at the 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana.

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