A GREATER UNDERLYING MUTATIONAL COMPLEXITY MAY CONTRIBUTE TO THE DIFFERENTIAL PROGNOSTIC IMPACT OF PHENOTYPIC-DRIVER MUTATION IN PRIMARY MYELOFIBROSIS
(Abstract release date: 05/19/16)
EHA Library. Guglielmelli P. 06/10/16; 135147; S114
Dr. Paola Guglielmelli
Contributions
Contributions
Abstract
Abstract: S114
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:30 - 12:45
Location: Auditorium 1
Background
In primary myelofibrosis (PMF), JAK2/CALR/MPL mutational status is prognostically informative, with “triple-negative” (TN) patients (pts) displaying the worst survival (Rumi E, Blood 2014). Also, survival was significantly shorter in CALR type 2/like (Ty2) vs type 1/like (Ty1) mutated pts (Tefferi A, Blood 2014; Guglielmelli P, BCJ. 2015). A high-molecular risk category (HMR) identifies pts with reduced survival if harboring any one of ASXL1, EZH2, IDH1/2 and SRSF2 mutated genes (Vannucchi A, Leukemia 2013; Guglielmelli P, Leukemia 2014).
Aims
To analyze the molecular landscape of PMF pts categorized according to their driver mutation status and correlate with clinical endpoints and outcome.
Methods
All PMF pts (WHO-2008) provided informed consent. Established methods were used for JAK2, MPL and CALR mutations. NGS analysis with Ion Torrent platform was used to genotype 18 genes (referred as subclonal, SC): all coding sequence of c-KIT, TET2, RUNX1, NRAS, KRAS, DNAMT3A, IKZF1, EZH2, TP53; hot spot of IDH1/2 and SRSF2 and selected exons of CBL, IDH2, ASXL1, SF3B1, NFE2, SH2B3, U2AF1. The nonparametric Wilcoxon rank-sum test, Kaplan-Meier estimate of survival and log-rank test were used as appropriate.
Results
We analyzed 126 pts: 43 were JAK2+ (34.1%), 42 TN ( 33.3%) and 41 CALR mut (32.6%; 26 (63.4%) Ty1 and 15 (36.6%) Ty2. Overall, 17 pts (13.5%) progressed to AML. Death occurred in 69 pts (43.4%) after a median follow up of 3.8y. There was no difference between Ty1 and Ty2 for common hematologic and clinical variables; conversely, both Ty1 and Ty2 differed from JAK2+ counterpart for younger age, lower leukocyte and higher platelet counts; males were more represented among Ty1 pts that other genotypes. More deaths occurred among Ty2 (45.8%), JAK2+ (37.0%) and TN (72.7%) pts compared to Ty1 (20.0%) (P<.0001). Median survival of CALR Ty1 was 26.4y vs 8.59y for CALR Ty2, 10.3y for JAK2+ and 2.1 for TN (P<.0001). The corresponding hazard ratio, taking CALR Ty1 pts as reference, was 3.0 (95%CI, 1.2-7.6), 2.4 (95%CI, 1.0-5.7) and 11.1 (95%CI, 5.0-25.01) for CALR Ty2, JAK2+ and TN pts, respectively. HMR status was associated with shortened survival ((HR 3.3, 95%CI 1.9-5.8; P<.001) as it was the number of HMR mutations (HR 5.4, 95%CI 2.8-10.6; P<.001). Considering the individual mutations, only EZH2, ASXL1 and SRSF2 predicted for shorter survival (2.7y, 1.93y and 1.03y respectively; P=.001; P=.01 and P<.0001). Pts harboring any one of SC mutations were similarly distributed among groups: Ty1 61%, Ty2 67%, JAK2+ 77%, TN 74%; exceptions were SRSF2 mutations (n=26) that were 0% Ty1, 6.7% Ty2, 14% JAK2+, 45% TN (P<.0001), and SF3B1 that was mutated in 3 Ty2 (20%) vs 1 pts in both Ty1 (4%) and JAK2+ (2%) and no TN pt (P=.009). Conversely, the proportion of pts with >2 SC mutations was significantly higher in TN (52%) vs the others (Ty1 15%, Ty2 20%, JAK2+ 42%)(P= .02). The proportion of HMR was significantly higher in TN (67%) and JAK2+ (54%) pts compared with CALR subtypes (35% in Ty1, 27% in Ty2) (P=.01), as it was the percentage of pts having >2 HMR mutations (P=.006).
Conclusion
Overall, our findings support previous reports that the prognostic advantage of CALR mutation in PMF regards only Ty1 mutation; however, we did not find evidence that such difference might be ascribed to a greater molecular complexity of Ty2. Conversely, the dismal outcome of TN pts might be explained, at least in part, by occurrence of greater number of prognostically negative HMR mutations, particularly of SRSF2 mutations.
Session topic: Myeloproliferative neoplasms - Clinical 1
Keyword(s): Molecular, Myelofibrosis, Prognosis
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:30 - 12:45
Location: Auditorium 1
Background
In primary myelofibrosis (PMF), JAK2/CALR/MPL mutational status is prognostically informative, with “triple-negative” (TN) patients (pts) displaying the worst survival (Rumi E, Blood 2014). Also, survival was significantly shorter in CALR type 2/like (Ty2) vs type 1/like (Ty1) mutated pts (Tefferi A, Blood 2014; Guglielmelli P, BCJ. 2015). A high-molecular risk category (HMR) identifies pts with reduced survival if harboring any one of ASXL1, EZH2, IDH1/2 and SRSF2 mutated genes (Vannucchi A, Leukemia 2013; Guglielmelli P, Leukemia 2014).
Aims
To analyze the molecular landscape of PMF pts categorized according to their driver mutation status and correlate with clinical endpoints and outcome.
Methods
All PMF pts (WHO-2008) provided informed consent. Established methods were used for JAK2, MPL and CALR mutations. NGS analysis with Ion Torrent platform was used to genotype 18 genes (referred as subclonal, SC): all coding sequence of c-KIT, TET2, RUNX1, NRAS, KRAS, DNAMT3A, IKZF1, EZH2, TP53; hot spot of IDH1/2 and SRSF2 and selected exons of CBL, IDH2, ASXL1, SF3B1, NFE2, SH2B3, U2AF1. The nonparametric Wilcoxon rank-sum test, Kaplan-Meier estimate of survival and log-rank test were used as appropriate.
Results
We analyzed 126 pts: 43 were JAK2+ (34.1%), 42 TN ( 33.3%) and 41 CALR mut (32.6%; 26 (63.4%) Ty1 and 15 (36.6%) Ty2. Overall, 17 pts (13.5%) progressed to AML. Death occurred in 69 pts (43.4%) after a median follow up of 3.8y. There was no difference between Ty1 and Ty2 for common hematologic and clinical variables; conversely, both Ty1 and Ty2 differed from JAK2+ counterpart for younger age, lower leukocyte and higher platelet counts; males were more represented among Ty1 pts that other genotypes. More deaths occurred among Ty2 (45.8%), JAK2+ (37.0%) and TN (72.7%) pts compared to Ty1 (20.0%) (P<.0001). Median survival of CALR Ty1 was 26.4y vs 8.59y for CALR Ty2, 10.3y for JAK2+ and 2.1 for TN (P<.0001). The corresponding hazard ratio, taking CALR Ty1 pts as reference, was 3.0 (95%CI, 1.2-7.6), 2.4 (95%CI, 1.0-5.7) and 11.1 (95%CI, 5.0-25.01) for CALR Ty2, JAK2+ and TN pts, respectively. HMR status was associated with shortened survival ((HR 3.3, 95%CI 1.9-5.8; P<.001) as it was the number of HMR mutations (HR 5.4, 95%CI 2.8-10.6; P<.001). Considering the individual mutations, only EZH2, ASXL1 and SRSF2 predicted for shorter survival (2.7y, 1.93y and 1.03y respectively; P=.001; P=.01 and P<.0001). Pts harboring any one of SC mutations were similarly distributed among groups: Ty1 61%, Ty2 67%, JAK2+ 77%, TN 74%; exceptions were SRSF2 mutations (n=26) that were 0% Ty1, 6.7% Ty2, 14% JAK2+, 45% TN (P<.0001), and SF3B1 that was mutated in 3 Ty2 (20%) vs 1 pts in both Ty1 (4%) and JAK2+ (2%) and no TN pt (P=.009). Conversely, the proportion of pts with >2 SC mutations was significantly higher in TN (52%) vs the others (Ty1 15%, Ty2 20%, JAK2+ 42%)(P= .02). The proportion of HMR was significantly higher in TN (67%) and JAK2+ (54%) pts compared with CALR subtypes (35% in Ty1, 27% in Ty2) (P=.01), as it was the percentage of pts having >2 HMR mutations (P=.006).
Conclusion
Overall, our findings support previous reports that the prognostic advantage of CALR mutation in PMF regards only Ty1 mutation; however, we did not find evidence that such difference might be ascribed to a greater molecular complexity of Ty2. Conversely, the dismal outcome of TN pts might be explained, at least in part, by occurrence of greater number of prognostically negative HMR mutations, particularly of SRSF2 mutations.
Session topic: Myeloproliferative neoplasms - Clinical 1
Keyword(s): Molecular, Myelofibrosis, Prognosis
Abstract: S114
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:30 - 12:45
Location: Auditorium 1
Background
In primary myelofibrosis (PMF), JAK2/CALR/MPL mutational status is prognostically informative, with “triple-negative” (TN) patients (pts) displaying the worst survival (Rumi E, Blood 2014). Also, survival was significantly shorter in CALR type 2/like (Ty2) vs type 1/like (Ty1) mutated pts (Tefferi A, Blood 2014; Guglielmelli P, BCJ. 2015). A high-molecular risk category (HMR) identifies pts with reduced survival if harboring any one of ASXL1, EZH2, IDH1/2 and SRSF2 mutated genes (Vannucchi A, Leukemia 2013; Guglielmelli P, Leukemia 2014).
Aims
To analyze the molecular landscape of PMF pts categorized according to their driver mutation status and correlate with clinical endpoints and outcome.
Methods
All PMF pts (WHO-2008) provided informed consent. Established methods were used for JAK2, MPL and CALR mutations. NGS analysis with Ion Torrent platform was used to genotype 18 genes (referred as subclonal, SC): all coding sequence of c-KIT, TET2, RUNX1, NRAS, KRAS, DNAMT3A, IKZF1, EZH2, TP53; hot spot of IDH1/2 and SRSF2 and selected exons of CBL, IDH2, ASXL1, SF3B1, NFE2, SH2B3, U2AF1. The nonparametric Wilcoxon rank-sum test, Kaplan-Meier estimate of survival and log-rank test were used as appropriate.
Results
We analyzed 126 pts: 43 were JAK2+ (34.1%), 42 TN ( 33.3%) and 41 CALR mut (32.6%; 26 (63.4%) Ty1 and 15 (36.6%) Ty2. Overall, 17 pts (13.5%) progressed to AML. Death occurred in 69 pts (43.4%) after a median follow up of 3.8y. There was no difference between Ty1 and Ty2 for common hematologic and clinical variables; conversely, both Ty1 and Ty2 differed from JAK2+ counterpart for younger age, lower leukocyte and higher platelet counts; males were more represented among Ty1 pts that other genotypes. More deaths occurred among Ty2 (45.8%), JAK2+ (37.0%) and TN (72.7%) pts compared to Ty1 (20.0%) (P<.0001). Median survival of CALR Ty1 was 26.4y vs 8.59y for CALR Ty2, 10.3y for JAK2+ and 2.1 for TN (P<.0001). The corresponding hazard ratio, taking CALR Ty1 pts as reference, was 3.0 (95%CI, 1.2-7.6), 2.4 (95%CI, 1.0-5.7) and 11.1 (95%CI, 5.0-25.01) for CALR Ty2, JAK2+ and TN pts, respectively. HMR status was associated with shortened survival ((HR 3.3, 95%CI 1.9-5.8; P<.001) as it was the number of HMR mutations (HR 5.4, 95%CI 2.8-10.6; P<.001). Considering the individual mutations, only EZH2, ASXL1 and SRSF2 predicted for shorter survival (2.7y, 1.93y and 1.03y respectively; P=.001; P=.01 and P<.0001). Pts harboring any one of SC mutations were similarly distributed among groups: Ty1 61%, Ty2 67%, JAK2+ 77%, TN 74%; exceptions were SRSF2 mutations (n=26) that were 0% Ty1, 6.7% Ty2, 14% JAK2+, 45% TN (P<.0001), and SF3B1 that was mutated in 3 Ty2 (20%) vs 1 pts in both Ty1 (4%) and JAK2+ (2%) and no TN pt (P=.009). Conversely, the proportion of pts with >2 SC mutations was significantly higher in TN (52%) vs the others (Ty1 15%, Ty2 20%, JAK2+ 42%)(P= .02). The proportion of HMR was significantly higher in TN (67%) and JAK2+ (54%) pts compared with CALR subtypes (35% in Ty1, 27% in Ty2) (P=.01), as it was the percentage of pts having >2 HMR mutations (P=.006).
Conclusion
Overall, our findings support previous reports that the prognostic advantage of CALR mutation in PMF regards only Ty1 mutation; however, we did not find evidence that such difference might be ascribed to a greater molecular complexity of Ty2. Conversely, the dismal outcome of TN pts might be explained, at least in part, by occurrence of greater number of prognostically negative HMR mutations, particularly of SRSF2 mutations.
Session topic: Myeloproliferative neoplasms - Clinical 1
Keyword(s): Molecular, Myelofibrosis, Prognosis
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:30 - 12:45
Location: Auditorium 1
Background
In primary myelofibrosis (PMF), JAK2/CALR/MPL mutational status is prognostically informative, with “triple-negative” (TN) patients (pts) displaying the worst survival (Rumi E, Blood 2014). Also, survival was significantly shorter in CALR type 2/like (Ty2) vs type 1/like (Ty1) mutated pts (Tefferi A, Blood 2014; Guglielmelli P, BCJ. 2015). A high-molecular risk category (HMR) identifies pts with reduced survival if harboring any one of ASXL1, EZH2, IDH1/2 and SRSF2 mutated genes (Vannucchi A, Leukemia 2013; Guglielmelli P, Leukemia 2014).
Aims
To analyze the molecular landscape of PMF pts categorized according to their driver mutation status and correlate with clinical endpoints and outcome.
Methods
All PMF pts (WHO-2008) provided informed consent. Established methods were used for JAK2, MPL and CALR mutations. NGS analysis with Ion Torrent platform was used to genotype 18 genes (referred as subclonal, SC): all coding sequence of c-KIT, TET2, RUNX1, NRAS, KRAS, DNAMT3A, IKZF1, EZH2, TP53; hot spot of IDH1/2 and SRSF2 and selected exons of CBL, IDH2, ASXL1, SF3B1, NFE2, SH2B3, U2AF1. The nonparametric Wilcoxon rank-sum test, Kaplan-Meier estimate of survival and log-rank test were used as appropriate.
Results
We analyzed 126 pts: 43 were JAK2+ (34.1%), 42 TN ( 33.3%) and 41 CALR mut (32.6%; 26 (63.4%) Ty1 and 15 (36.6%) Ty2. Overall, 17 pts (13.5%) progressed to AML. Death occurred in 69 pts (43.4%) after a median follow up of 3.8y. There was no difference between Ty1 and Ty2 for common hematologic and clinical variables; conversely, both Ty1 and Ty2 differed from JAK2+ counterpart for younger age, lower leukocyte and higher platelet counts; males were more represented among Ty1 pts that other genotypes. More deaths occurred among Ty2 (45.8%), JAK2+ (37.0%) and TN (72.7%) pts compared to Ty1 (20.0%) (P<.0001). Median survival of CALR Ty1 was 26.4y vs 8.59y for CALR Ty2, 10.3y for JAK2+ and 2.1 for TN (P<.0001). The corresponding hazard ratio, taking CALR Ty1 pts as reference, was 3.0 (95%CI, 1.2-7.6), 2.4 (95%CI, 1.0-5.7) and 11.1 (95%CI, 5.0-25.01) for CALR Ty2, JAK2+ and TN pts, respectively. HMR status was associated with shortened survival ((HR 3.3, 95%CI 1.9-5.8; P<.001) as it was the number of HMR mutations (HR 5.4, 95%CI 2.8-10.6; P<.001). Considering the individual mutations, only EZH2, ASXL1 and SRSF2 predicted for shorter survival (2.7y, 1.93y and 1.03y respectively; P=.001; P=.01 and P<.0001). Pts harboring any one of SC mutations were similarly distributed among groups: Ty1 61%, Ty2 67%, JAK2+ 77%, TN 74%; exceptions were SRSF2 mutations (n=26) that were 0% Ty1, 6.7% Ty2, 14% JAK2+, 45% TN (P<.0001), and SF3B1 that was mutated in 3 Ty2 (20%) vs 1 pts in both Ty1 (4%) and JAK2+ (2%) and no TN pt (P=.009). Conversely, the proportion of pts with >2 SC mutations was significantly higher in TN (52%) vs the others (Ty1 15%, Ty2 20%, JAK2+ 42%)(P= .02). The proportion of HMR was significantly higher in TN (67%) and JAK2+ (54%) pts compared with CALR subtypes (35% in Ty1, 27% in Ty2) (P=.01), as it was the percentage of pts having >2 HMR mutations (P=.006).
Conclusion
Overall, our findings support previous reports that the prognostic advantage of CALR mutation in PMF regards only Ty1 mutation; however, we did not find evidence that such difference might be ascribed to a greater molecular complexity of Ty2. Conversely, the dismal outcome of TN pts might be explained, at least in part, by occurrence of greater number of prognostically negative HMR mutations, particularly of SRSF2 mutations.
Session topic: Myeloproliferative neoplasms - Clinical 1
Keyword(s): Molecular, Myelofibrosis, Prognosis
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