Response to therapy and prognosis according to molecular characterization in CALR-mutated essential thrombocythemia

Area of Science:

• Hematology
• Molecular Biology
• Oncology

Background:

• Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by elevated platelet counts.
• CALR mutations are common drivers in ET, but their impact on treatment response and clinical outcomes requires further elucidation.
• Previous studies have not comprehensively analyzed the interplay between CALR mutation type, variant allele frequency (VAF), and additional mutations in predicting treatment response and outcomes in ET.

Purpose of the Study:

• To investigate the impact of CALR mutation type, VAF, and co-occurring mutations on cytoreductive therapy response in essential thrombocythemia (ET).
• To analyze the association between molecular profiles and key clinical outcomes, including complete hematological response (CHR), arterial thrombosis, myelofibrosis (MF) progression, and overall survival (OS).

Main Methods:

• Retrospective analysis of 557 CALR-mutated ET patients.
• Next-generation sequencing (NGS) data utilized to determine CALR mutation type, VAF, and additional mutations in 257 patients.
• Multivariate analysis employed to assess the independent prognostic value of molecular factors on treatment response and clinical outcomes.

Main Results:

• CALR Type 2 mutations showed a higher initial rate of CHR, but this significance diminished when VAF was considered.
• High CALR VAF was independently associated with a lower likelihood of achieving CHR (HR=0.482, P=0.003).
• High CALR VAF increased the risk of arterial thrombosis (HR=4.135, P=0.037) and progression to MF (HR=2.631, P=0.049).
• High molecular risk (HMR) mutations, rather than allele burden, were associated with reduced OS (HR=2.114, P=0.031) and increased risk of acute leukemia progression.
• HMR profile did not significantly impact CHR or MF progression rates.

Conclusions:

• CALR VAF and the presence of HMR mutations are more critical determinants of treatment response and clinical outcomes in ET than CALR mutation type.
• High CALR VAF is a significant adverse prognostic factor for achieving hematological response and predicts increased thrombosis and MF progression risk.
• HMR mutations are crucial for predicting overall survival and acute leukemia risk in ET patients.