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In 2013, the landscape of myeloproliferative neoplasms (MPN) was altered dramatically by the identification of somatic mutations in the calreticulin (CALR) gene. With this discovery molecular information, in addition to the JAK2V617F mutation, can be implemented as an affirmative variable for discrimination of MPNs from reactive myeloid proliferations for the first time. Previously, the clinical course of essential thrombocythemia (ET) or primary myelofibrosis (PMF) in patients carrying the CALR mutation has been reported to be more indolent than in JAK2 positive patients and was associated with increased survival.

Our aim was to investigate the different impacts of CALR mutations on the prognosis and clinical outcome in prefibrotic PMF (prePMF) and WHO-classified ET (WHO-ET). Additionally, the same investigations were made concerning ASXL1 (exon12) mutations, with ASXL1 being one of the most common bystander mutated genes in MPNs.

In a cohort of 348 patients with the clinical diagnosis of either WHO-ET or PMF, mutational analysis for CALR was available.  For study entry, the following eligibility criteria had to be fulfilled: a) availability of mutation analysis for JAK2, MPL and CALR; b) availability of representative, treatment-naive bone marrow biopsy; c) availability of a histological and clinical consensus on the diagnosis; d) complete long-term documentation of clinical data and outcome.

Consenting clinico-pathological findings were consistent with 115 cases of WHO-ET and 85 patients with prePMF. In contrast to the most recent publications, the present study revealed a different CALR mutation frequency in ET (table 1). This discrepancy in the frequencies of CALR positivity in our ET cohort may be due to our strict adherence to the WHO criteria for diagnosis of ET. Regarding prePMF, we observed CALR mutations in 39% of the patients. 92% of the JAK2/MPL wt subgroup carried the CALR mutation, with JAK2, MPL and CALR wt being observed in only 3% of prePMF. The most striking differences between WHO-ET and prePMF were seen in the comparison of the overall survival (figure 1A, 1B). While the CALR mutation did not have any beneficial influence on survival in WHO-ET, it was associated with a superior overall survival in prePMF. Such a difference was not seen in the time to transformation into overt MF, and there was only a slightly shorter time to progression to fibrosis in CALR wt prePMFs. There was a trend showing that CALR mutated prePMF patients have shorter thrombosis-free survival compared to CALR wt prePMF patients. No impact of the CALR mutations on thrombosis-free survival in WHO-ET was observed. ASXL1 (exon12) mutations revealed no impact on overall survival (figure 1C).

The present data confirm that WHO-ET and prePMF are biologically different sub-entities of MPNs. In prePMF, almost all patients are now associated with known disease-causing mutations. Our data support the classical approach in the diagnosis of thrombocytosis, using BM histology to differentiate WHO-ET from prePMF and more accurately estimate the outcome of the disease.