TY - JOUR
T1 - Driver mutations and prognosis in primary myelofibrosis
T2 - Mayo-Careggi MPN alliance study of 1,095 patients
AU - Tefferi, Ayalew
AU - Nicolosi, Maura
AU - Mudireddy, Mythri
AU - Szuber, Natasha
AU - Finke, Christy M.
AU - Lasho, Terra L.
AU - Hanson, Curtis A.
AU - Ketterling, Rhett P.
AU - Pardanani, Animesh
AU - Gangat, Naseema
AU - Mannarelli, Carmela
AU - Fanelli, Tiziana
AU - Guglielmelli, Paola
AU - Vannucchi, Alessandro M.
N1 - Publisher Copyright:
© 2017 Wiley Periodicals, Inc.
PY - 2018/3
Y1 - 2018/3
N2 - The 2013 discovery of calreticulin (CALR) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple-negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2, 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple-negative. Survival was longer with type 1/like CALR, compared to JAK2 (HR 2.6, 95% CI 1.9-3.5), type 2/like CALR (HR 2.5, 95% CI 1.4-4.5), MPL (HR 1.8, 95% CI 1.1-2.9) and triple-negative mutational status (HR 2.4, 95% CI 1.6-3.6), but otherwise similar between the non-type 1/like CALR mutational states (P =.41). In multivariable analysis, the absence of type 1/like CALR (P <.001; HR 2, 95% CI 1.4-2.7), presence of ASXL1/SRSF2 mutations (P <.001; HR 1.9, 95% CI 1.5-2.4) and DIPSS-plus (P <.001) were each predictive of inferior survival. Furthermore, among 210 patients with ASXL1/SRSF2 mutations, survival was significantly longer in the presence vs. absence of type 1/like CALR mutations (median 5.8 vs. 2.9 years; P <.001). Triple-negative status did not disclose additional prognostic information for overall or leukemia-free survival. The observations regarding the prognostic distinction between CALR mutation variants were validated in an external cohort of 386 patients from the University of Florence Careggi hospital. We conclude that type 1/like CALR mutations in PMF not only predict superior survival, but also partially amend the detrimental effect of high molecular risk mutations.
AB - The 2013 discovery of calreticulin (CALR) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple-negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2, 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple-negative. Survival was longer with type 1/like CALR, compared to JAK2 (HR 2.6, 95% CI 1.9-3.5), type 2/like CALR (HR 2.5, 95% CI 1.4-4.5), MPL (HR 1.8, 95% CI 1.1-2.9) and triple-negative mutational status (HR 2.4, 95% CI 1.6-3.6), but otherwise similar between the non-type 1/like CALR mutational states (P =.41). In multivariable analysis, the absence of type 1/like CALR (P <.001; HR 2, 95% CI 1.4-2.7), presence of ASXL1/SRSF2 mutations (P <.001; HR 1.9, 95% CI 1.5-2.4) and DIPSS-plus (P <.001) were each predictive of inferior survival. Furthermore, among 210 patients with ASXL1/SRSF2 mutations, survival was significantly longer in the presence vs. absence of type 1/like CALR mutations (median 5.8 vs. 2.9 years; P <.001). Triple-negative status did not disclose additional prognostic information for overall or leukemia-free survival. The observations regarding the prognostic distinction between CALR mutation variants were validated in an external cohort of 386 patients from the University of Florence Careggi hospital. We conclude that type 1/like CALR mutations in PMF not only predict superior survival, but also partially amend the detrimental effect of high molecular risk mutations.
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U2 - 10.1002/ajh.24978
DO - 10.1002/ajh.24978
M3 - Article
C2 - 29164670
AN - SCOPUS:85038081747
SN - 0361-8609
VL - 93
SP - 348
EP - 355
JO - American journal of hematology
JF - American journal of hematology
IS - 3
ER -