Mutations and prognosis in primary myelofibrosis

Abstract

Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; P<0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P=0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations. Mutational profiling for ASXL1, EZH2, SRSF2 and IDH identifies PMF patients who are at risk for premature death or leukemic transformation.

CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients

“…In multivariable analysis that included all prognostically relevant mutations, 3 absence of CALR (hazard ratio (HR), 2.6; 95% confidence interval (CI), 1.8-3.9), presence of ASXL1 (HR, 2.0; 95% CI, 1.5-2.7) and presence of SRSF2 (HR, 1.7; 95% CI, 1.1-2.8) mutations were significantly associated with shortened survival; EZH2 (P ¼ 0.07) or IDH (P ¼ 0.48) mutations were not significant. Absence of CALR (HR, 2.3; 95% CI, 1.5-3.5) and presence of ASXL1 (HR, 1.5; 95% CI, 1.1-2.1) mutations remained significant when DIPSS-plus risk stratification was added into the multivariable model.…”

“…7 Before the discovery of CALR mutations in ET and PMF, we had identified mutant ASXL1 as dynamic international prognostic scoring system (DIPSS)-plus 10 and IPSS 11 independent risk factor for survival in PMF. 3 More recently, we discovered the prognostic synergism between CALR and ASXL1 mutations in PMF and highlighted the inferior survival associated with 'CALR À ASXL1 þ ' mutational status. 7 The main objective of the current study was to further explore the prognostic interaction between CALR and ASXL1 mutations in PMF with the intent to derive (using a patient cohort from the Mayo Clinic, USA) and validate (using a patient cohort from the University of Florence, Italy) a molecular prognostic model, in the context both DIPSS-plus and IPSS.…”

“…The latter is also the preferred treatment of choice in AML associated with FLT3-ITD, whereas chemotherapy alone might be adequate for AML patients expressing NPM1 mutations without FLT3-ITD. 1 Similarly, the prognostic relevance of mutations in myelodysplastic syndromes 2 and primary myelofibrosis (PMF) 3 has been recognized but not yet implemented in clinical practice.…”

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

“…Specific genes affected in this regard include those relevant to epigenetic (e.g., ASXL1, TET2, EZH2, IDH1, IDH2, DNMT3A), RNA splicing (e.g., SRSF2, U2AF1, SF3B1) or transcriptional (TP53, IKZF1, NF-E2, CUX1) regulation. Mutations other than JAK2, CALR or MPL, which have been shown to have prognostic relevance in PMF, include ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1 [51,52]. In addition, TP53, IDH2, SRSF2, and SH2B3 mutations have been reported to be over-represented in blastphase MPN, suggesting their relevance in disease progression [48,50,53].…”

“…More recently, a number of DIPSS-plus-independent risk factors in PMF were identified and they include driver mutations other than type 1 or type 1-like CALR variants [44], monosomal karyotype [74], nullizygosity for JAK2 46/1 haplotype [75], low JAK2V617F allele burden [76,77], presence or number [78] of IDH1/2 [51], EZH2 [51], SRSF2 [51], or ASXL1 mutations [51], and increased serum IL-8 [79], IL-2R [79] or serum free light chain levels [80]. In a recent international study of 570 patients with PMF [81], the authors reported the longest …”