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Chronic myeloproliferative neoplasms

Determinants of long-term outcome in type 1 calreticulin-mutated myelofibrosis

Leukemia volume 33, pages 780–785 (2019)Cite this article

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Somatic driver mutations in exon 9 of the calreticulin (CALR) gene were first identified in 2013 [1], with a reported mutational frequency of 15–25% in essential thrombocythemia (ET) [2] and 25–35% in primary myelofibrosis (PMF) [3]. Over 80% of these mutations constitute variants defined as either type 1, a 52 bp deletion (p.L367fs*46), or type 2, a 5 bp TTGTC insertion (p.K385fs*47) [1]. Subsequent reports have exposed these mutants’ differential distribution according to disease subtype [4] in addition to their phenotypic and prognostic disparities in both ET and PMF [5, 6]. Importantly, type 1 CALR variants, which comprise ~70% of all CALR mutations in PMF [1], have emerged as a phenotypically and prognostically distinct mutational subset, clustering with lower dynamic international prognostic scoring system (DIPSS)-plus scores and significantly favorable survival rates compared with both CALR type 2 and JAK2 mutated cohorts [5, 7, 8]. Moreover, molecular interactions between CALR type 1 and additional genetic lesions such as ASXL1 are of proven prognostic relevance [9]. Despite these advances however, little is known about the natural history of CALR type 1-mutated PMF. Firstly, independent clinical, cytogenetic, and molecular predictors of survival have not yet been appraised in a strictly CALR type 1-mutated PMF population. Furthermore, it is not clear whether long-term survival in this strictly molecularly defined subgroup can be reliably assessed using contemporary prognostic models. The current study comprehensively documents the molecular correlates and determinants of long-term outcome, as measured by overall (OS), leukemia-free (LFS), and thrombosis-free (TFS) survival in CALR type 1-mutated primary myelofibrosis.

This study obtained the institutional review board approval from Mayo Clinic, Rochester, MN, USA. Diagnoses were consistent with the World Health Organization (WHO) criteria [10]. Mutation analysis of CALR and designation of type 1/type 1-like and type 2/type 2-like variants were as previously described [7], and detection of additional mutations was based on the availability of next-generation sequencing (NGS)-derived information. Karyotype, DIPSS, and mutation-enhanced international scoring system 70 and 70+ (MIPSS70+) version 2.0 determinations were as previously described [11,12,13]. Definition of high molecular risk mutations (HMR) was consistent with the MIPSS70+ version 2.0 criteria and considered the presence of at least one of ASXL1, SRSF2, EZH2, IDH1/ IDH2, and U2AF1 Q157 [13]. Laboratory and clinical variables considered for statistical analyses corresponded to the time of referral, which coincided in majority with the date of diagnosis/within one year of diagnosis. Sex-adjusted moderate–severe anemia was defined as hemoglobin <10 g/dl in women and <11 g/dl in men [13]. OS was defined by time from the date of referral to date of death (uncensored) or last contact (censored), while LFS and TFS, respectively, considered blast transformation and first thrombotic event as uncensored variables. Recipients of allogeneic stem cell transplant were censored at the time of transplant. Multivariate analysis was performed using a Cox proportional hazards regression model. Survival analysis was performed by the Kaplan–Meier method and differences assessed using the log rank test. All statistical analyses were conducted using JMP® Pro 13.0.0 software package (SAS Institute, Cary, NC, USA) and P values < 0.05 were considered significant.

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Authors and Affiliations

  1. Divisions of Hematology, Mayo Clinic, Rochester, MN, USA

    Natasha Szuber, Terra L. Lasho, Christy Finke, Animesh Pardanani, Naseema Gangat & Ayalew Tefferi

  2. Divisions of Hematopathology, Mayo Clinic, Rochester, MN, USA

    Curtis A. Hanson

  3. Laboratory Genetics and Genomics, Departments of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

    Rhett P. Ketterling

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  1. Natasha Szuber
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Correspondence to Ayalew Tefferi.

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Szuber, N., Lasho, T.L., Finke, C. et al. Determinants of long-term outcome in type 1 calreticulin-mutated myelofibrosis. Leukemia 33, 780–785 (2019). https://doi.org/10.1038/s41375-018-0283-x

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