Is CALR-Mutated Essential Thrombocythemia Really ‘Lower Risk’?

All patients with essential thrombocythemia (ET) have an increased risk of thrombosis, though patients with CALR mutations are known to have a lower risk relative to patients with JAK2 mutations. Recent data has suggested that CALR mutations increase the risk of progression to myelofibrosis (MF) or acute leukemia. Investigators compared retrospective records to further define rates of thrombosis, disease progression, and survival between patients with ET with different driver mutations.

According to the study’s lead author, Katie Erdos, and colleagues from the Myeloproliferative Neoplasms Center of Weill Cornell Medicine in New York, their findings further established that, “although patients with CALR-mutated ET have lower thrombosis risk, they experience higher risk of progression to MF.” The study data were presented at the 15^th International Congress on Myeloproliferative Neoplasms in Brooklyn, New York.

Lower Thrombosis but Higher Progression Risk with CALR Mutations

Erdos and colleagues identified 751 patients with ET treated at their center, of which 338 met WHO criteria and had bone marrow diagnostics and annotated driver mutations. Of the 751 patients, 216 (64%) had JAK2 mutations, 85 (25%) had CALR mutations, 19 (6%) had MPL mutations, and 18 (5%) were triple negative.

Kaplan-Meier analyses were used to estimate overall survival (OS), MF-free survival (MFS), and thrombosis-free survival (TFS), and Cox hazards models were used to estimate risks of post-ET MF, thrombosis, and mortality per IPSET-thrombosis risk categories.

Authors estimated that 20-year TFS was 71% for JAK2, 100% for CALR, 90% for MPL, and 83% for triple negative groups (P=.0027); 20-year MFS was 87% for JAK2, 48% for CALR, 65% for MPL, and 94% for TN (P=.00053) groups; and 20-year OS was 76% for JAK2, 86% for CALR, 89% for MPL, and 90% for triple negative (P=.66).

Based on multivariable analysis, CALR-mutated ET was associated with a significantly increased risk of post-ET MF compared with JAK2-mutated disease (hazard ratio [HR], 11.52; 95% CI, 1.88-70.51; P=.008) regardless of age, sex, white blood cells, and thrombosis history. The study’s analysis did verify that CALR mutations were associated with a reduced risk of thrombosis (HR, 0.08; 95% CI, 0.01-0.58; P=.013) when adjusting for sex and revised IPSET-thrombosis parameters.

Ultimately, Erdos suggested the study’s findings “reinforce the need for long-term data to guide therapy for ET based not only on the near-term thrombotic risk, but also on the long-term risk of progression.”

Reference

Erdos K, Lee N, Lebbe A, et al. Low thrombosis risk CALR mutations confer higher risk of ET progression. Abstract 107. 15^th International Congress on Myeloproliferative Neoplasms.  November 2-3, 2023; Brooklyn, New York.