Driver mutations and prognosis in primary myelofibrosis: Mayo-Careggi MPN alliance study of 1,095 patients

Ayalew Tefferi, Maura Nicolosi, Mythri Mudireddy, Natasha Szuber, Christy M. Finke, Terra L. Lasho, Curtis A. Hanson, Rhett P. Ketterling, Animesh D Pardanani, Naseema Gangat, Carmela Mannarelli, Tiziana Fanelli, Paola Guglielmelli, Alessandro M. Vannucchi

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalAmerican Journal of Hematology
DOIs
StateAccepted/In press - Jan 1 2017

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Calreticulin
Primary Myelofibrosis
Mutation
Survival
Leukemia

ASJC Scopus subject areas

  • Hematology

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Driver mutations and prognosis in primary myelofibrosis : Mayo-Careggi MPN alliance study of 1,095 patients. / Tefferi, Ayalew; Nicolosi, Maura; Mudireddy, Mythri; Szuber, Natasha; Finke, Christy M.; Lasho, Terra L.; Hanson, Curtis A.; Ketterling, Rhett P.; Pardanani, Animesh D; Gangat, Naseema; Mannarelli, Carmela; Fanelli, Tiziana; Guglielmelli, Paola; Vannucchi, Alessandro M.

In: American Journal of Hematology, 01.01.2017.

Research output: Contribution to journalArticle

Tefferi, A, Nicolosi, M, Mudireddy, M, Szuber, N, Finke, CM, Lasho, TL, Hanson, CA, Ketterling, RP, Pardanani, AD, Gangat, N, Mannarelli, C, Fanelli, T, Guglielmelli, P & Vannucchi, AM 2017, 'Driver mutations and prognosis in primary myelofibrosis: Mayo-Careggi MPN alliance study of 1,095 patients', American Journal of Hematology. https://doi.org/10.1002/ajh.24978
Tefferi, Ayalew ; Nicolosi, Maura ; Mudireddy, Mythri ; Szuber, Natasha ; Finke, Christy M. ; Lasho, Terra L. ; Hanson, Curtis A. ; Ketterling, Rhett P. ; Pardanani, Animesh D ; Gangat, Naseema ; Mannarelli, Carmela ; Fanelli, Tiziana ; Guglielmelli, Paola ; Vannucchi, Alessandro M. / Driver mutations and prognosis in primary myelofibrosis : Mayo-Careggi MPN alliance study of 1,095 patients. In: American Journal of Hematology. 2017.
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abstract = "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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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 D

AU - Gangat, Naseema

AU - Mannarelli, Carmela

AU - Fanelli, Tiziana

AU - Guglielmelli, Paola

AU - Vannucchi, Alessandro M.

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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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