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

Response to cytoreductive therapy according to CALR mutation type, CALR variant allele frequency (VAF), and additional mutations has not been previously studied in essential thrombocythemia (ET). The impact of the molecular profile on treatment response and the main clinical outcomes was analyzed in 557 CALR ET patients (CALR Type 1, n = 339, median VAF 36%; and CALR Type 2, n = 218, median VAF 35%). NGS data on additional mutations were available for 257 patients. CALR Type 2 showed a significantly higher rate of complete hematological response (CHR) to first-line cytoreduction. However, in the multivariate analysis, the effect of CALR mutation type in response rates was no longer significant once CALR VAF was considered, whereas high VAF remained independently associated with a lower likelihood of achieving CHR (hazard ratio [HR] = 0.482, 95% confidence interval (CI): 0.297-0.781; P = 0.003). Moreover, high VAF was also associated with an increased risk of arterial thrombosis (HR = 4.135, 95% CI: 1.093-15.645; P = 0.037), and progression to MF (HR = 2.631, 95% CI: 1.004-6.890; P = 0.049). Although allele burden affects overall survival (OS) in the entire population, its impact was surpassed by the presence of high molecular risk (HMR) mutations (HR = 2.114, 95% CI: 1.070-4.176; P = 0.031). Furthermore, the HMR profile was also associated with a higher risk of progression to acute leukemia, while it did not influence the probability of CHR or progression to MF. In conclusion, CALR VAF and HMR profile appear to be more important than CALR mutation type regarding treatment response and major clinical outcomes in ET.