PHENOTYPIC DIFFERENCES AND TREATMENT RESPONSES IN MOLECULAR SUBGROUPS OF ESSENTIAL THROMBOCYTHEMIA FROM ANALYSIS OF THE PT1 COHORT
(Abstract release date: 05/19/16)
EHA Library. Nangalia J. 06/10/16; 135146; S113
Dr. Jyoti Nangalia
Contributions
Contributions
Abstract
Abstract: S113
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Auditorium 1
Background
Somatically acquired mutations in JAK2, MPL or CALR are found in 85% of patients with essential thrombocythemia (ET) and 15% of patients are ‘triple-negative’ (TN). However, no prospective data exist on the disease characteristics or response to treatment of the different molecular subgroups of ET.
Aims
We aimed to characterise, in the prospective setting, whether baseline clinical characteristics, bone marrow histology, adverse outcomes, and response to treatment are influenced by mutation status in ET.
Methods
Patients aged 18 years or older with newly diagnosed or previously diagnosed ET were enrolled into low, intermediate or high-risk PT-1 studies depending on their risk of vascular complications. Median prospective follow-up duration was 36 months (range, 2-87 months). JAK2, MPL and CALR screening utilised PCR based methods. Clinical and laboratory features were compared between the four molecular subgroups. Time-to-event data was analyzed using Kaplan-Meier curves, log-rank analyses and Cox proportional hazards models. Response to treatment and drug dosage were analyzed using non-parametric regression and linear mixed effects modeling respectively.
Results
JAK2, MPL and CALR mutated ET represented 53%, 4% and 26% of patients and were mutually exclusive in most cases. 1% of patients harbored >1 mutation in these genes and analysis of such patients using individual hematopoietic colonies showed that JAK2, MPL or CALR mutations can be successively acquired within the same tumour subclone. Within the PT-1 cohort, CALR- and MPL-mutated subgroups affected males and females equally, in contrast to the female predominance observed in JAK2-mutated and TN subgroups wherein only 37% and 31% of patients respectively were male (p=0.0008, Chi-squared test). TN patients were significantly younger than any of the other molecular subgroups with a median age of 44 years (p<0.0001 for all comparisons, ANOVA). CALR-mutated patients were also significantly younger than JAK2- (p=0.003, ANOVA) and MPL-mutated (p=0.005, ANOVA) patients, with a median age of 54 years. CALR-mutated trephines had more prominent megakaryocyte atypia (increased cluster frequency, cluster size, tight clusters, paratrabecular megakaryocytes and fibrosis), and TN trephines had relatively milder megakaryocyte abnormalities. CALR-mutated ET patients presented with lower hemoglobin levels and total white cell counts, and higher platelet counts. Whilst the majority of venous thrombotic events occurred in the JAK2-mutated subgroup (21 of 27 events), CALR-mutated ET patients suffered increased rates of myelofibrotic transformation (hazard ratio 3.15 compared to the JAK2-mutated subgroup, p=0.03, Cox proportional hazards model correcting for age, gender and treatment received). No interaction was noted between treatment with either hydroxyurea or anagrelide and the incidence of these adverse outcomes. Patients with CALRins5 mutations presented with higher platelet counts than patients with CALRdel52 mutations but no other differences in disease features or outcome. Platelet control was equivalent between all molecular subgroups following treatment with either hydroxyurea plus aspirin or anagrelide plus aspirin in high-risk patients. However, CALR-mutated and MPL-mutated patients developed lower hemoglobin levels during anagrelide therapy. This observation was not due to differences in anagrelide dosage between molecular subgroups.
Conclusion
These results demonstrate that molecular testing identifies distinct biological subgroups in ET with different clinical outcomes and treatment responses.
Session topic: Myeloproliferative neoplasms - Clinical 1
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Auditorium 1
Background
Somatically acquired mutations in JAK2, MPL or CALR are found in 85% of patients with essential thrombocythemia (ET) and 15% of patients are ‘triple-negative’ (TN). However, no prospective data exist on the disease characteristics or response to treatment of the different molecular subgroups of ET.
Aims
We aimed to characterise, in the prospective setting, whether baseline clinical characteristics, bone marrow histology, adverse outcomes, and response to treatment are influenced by mutation status in ET.
Methods
Patients aged 18 years or older with newly diagnosed or previously diagnosed ET were enrolled into low, intermediate or high-risk PT-1 studies depending on their risk of vascular complications. Median prospective follow-up duration was 36 months (range, 2-87 months). JAK2, MPL and CALR screening utilised PCR based methods. Clinical and laboratory features were compared between the four molecular subgroups. Time-to-event data was analyzed using Kaplan-Meier curves, log-rank analyses and Cox proportional hazards models. Response to treatment and drug dosage were analyzed using non-parametric regression and linear mixed effects modeling respectively.
Results
JAK2, MPL and CALR mutated ET represented 53%, 4% and 26% of patients and were mutually exclusive in most cases. 1% of patients harbored >1 mutation in these genes and analysis of such patients using individual hematopoietic colonies showed that JAK2, MPL or CALR mutations can be successively acquired within the same tumour subclone. Within the PT-1 cohort, CALR- and MPL-mutated subgroups affected males and females equally, in contrast to the female predominance observed in JAK2-mutated and TN subgroups wherein only 37% and 31% of patients respectively were male (p=0.0008, Chi-squared test). TN patients were significantly younger than any of the other molecular subgroups with a median age of 44 years (p<0.0001 for all comparisons, ANOVA). CALR-mutated patients were also significantly younger than JAK2- (p=0.003, ANOVA) and MPL-mutated (p=0.005, ANOVA) patients, with a median age of 54 years. CALR-mutated trephines had more prominent megakaryocyte atypia (increased cluster frequency, cluster size, tight clusters, paratrabecular megakaryocytes and fibrosis), and TN trephines had relatively milder megakaryocyte abnormalities. CALR-mutated ET patients presented with lower hemoglobin levels and total white cell counts, and higher platelet counts. Whilst the majority of venous thrombotic events occurred in the JAK2-mutated subgroup (21 of 27 events), CALR-mutated ET patients suffered increased rates of myelofibrotic transformation (hazard ratio 3.15 compared to the JAK2-mutated subgroup, p=0.03, Cox proportional hazards model correcting for age, gender and treatment received). No interaction was noted between treatment with either hydroxyurea or anagrelide and the incidence of these adverse outcomes. Patients with CALRins5 mutations presented with higher platelet counts than patients with CALRdel52 mutations but no other differences in disease features or outcome. Platelet control was equivalent between all molecular subgroups following treatment with either hydroxyurea plus aspirin or anagrelide plus aspirin in high-risk patients. However, CALR-mutated and MPL-mutated patients developed lower hemoglobin levels during anagrelide therapy. This observation was not due to differences in anagrelide dosage between molecular subgroups.
Conclusion
These results demonstrate that molecular testing identifies distinct biological subgroups in ET with different clinical outcomes and treatment responses.
Session topic: Myeloproliferative neoplasms - Clinical 1
Abstract: S113
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Auditorium 1
Background
Somatically acquired mutations in JAK2, MPL or CALR are found in 85% of patients with essential thrombocythemia (ET) and 15% of patients are ‘triple-negative’ (TN). However, no prospective data exist on the disease characteristics or response to treatment of the different molecular subgroups of ET.
Aims
We aimed to characterise, in the prospective setting, whether baseline clinical characteristics, bone marrow histology, adverse outcomes, and response to treatment are influenced by mutation status in ET.
Methods
Patients aged 18 years or older with newly diagnosed or previously diagnosed ET were enrolled into low, intermediate or high-risk PT-1 studies depending on their risk of vascular complications. Median prospective follow-up duration was 36 months (range, 2-87 months). JAK2, MPL and CALR screening utilised PCR based methods. Clinical and laboratory features were compared between the four molecular subgroups. Time-to-event data was analyzed using Kaplan-Meier curves, log-rank analyses and Cox proportional hazards models. Response to treatment and drug dosage were analyzed using non-parametric regression and linear mixed effects modeling respectively.
Results
JAK2, MPL and CALR mutated ET represented 53%, 4% and 26% of patients and were mutually exclusive in most cases. 1% of patients harbored >1 mutation in these genes and analysis of such patients using individual hematopoietic colonies showed that JAK2, MPL or CALR mutations can be successively acquired within the same tumour subclone. Within the PT-1 cohort, CALR- and MPL-mutated subgroups affected males and females equally, in contrast to the female predominance observed in JAK2-mutated and TN subgroups wherein only 37% and 31% of patients respectively were male (p=0.0008, Chi-squared test). TN patients were significantly younger than any of the other molecular subgroups with a median age of 44 years (p<0.0001 for all comparisons, ANOVA). CALR-mutated patients were also significantly younger than JAK2- (p=0.003, ANOVA) and MPL-mutated (p=0.005, ANOVA) patients, with a median age of 54 years. CALR-mutated trephines had more prominent megakaryocyte atypia (increased cluster frequency, cluster size, tight clusters, paratrabecular megakaryocytes and fibrosis), and TN trephines had relatively milder megakaryocyte abnormalities. CALR-mutated ET patients presented with lower hemoglobin levels and total white cell counts, and higher platelet counts. Whilst the majority of venous thrombotic events occurred in the JAK2-mutated subgroup (21 of 27 events), CALR-mutated ET patients suffered increased rates of myelofibrotic transformation (hazard ratio 3.15 compared to the JAK2-mutated subgroup, p=0.03, Cox proportional hazards model correcting for age, gender and treatment received). No interaction was noted between treatment with either hydroxyurea or anagrelide and the incidence of these adverse outcomes. Patients with CALRins5 mutations presented with higher platelet counts than patients with CALRdel52 mutations but no other differences in disease features or outcome. Platelet control was equivalent between all molecular subgroups following treatment with either hydroxyurea plus aspirin or anagrelide plus aspirin in high-risk patients. However, CALR-mutated and MPL-mutated patients developed lower hemoglobin levels during anagrelide therapy. This observation was not due to differences in anagrelide dosage between molecular subgroups.
Conclusion
These results demonstrate that molecular testing identifies distinct biological subgroups in ET with different clinical outcomes and treatment responses.
Session topic: Myeloproliferative neoplasms - Clinical 1
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30
Location: Auditorium 1
Background
Somatically acquired mutations in JAK2, MPL or CALR are found in 85% of patients with essential thrombocythemia (ET) and 15% of patients are ‘triple-negative’ (TN). However, no prospective data exist on the disease characteristics or response to treatment of the different molecular subgroups of ET.
Aims
We aimed to characterise, in the prospective setting, whether baseline clinical characteristics, bone marrow histology, adverse outcomes, and response to treatment are influenced by mutation status in ET.
Methods
Patients aged 18 years or older with newly diagnosed or previously diagnosed ET were enrolled into low, intermediate or high-risk PT-1 studies depending on their risk of vascular complications. Median prospective follow-up duration was 36 months (range, 2-87 months). JAK2, MPL and CALR screening utilised PCR based methods. Clinical and laboratory features were compared between the four molecular subgroups. Time-to-event data was analyzed using Kaplan-Meier curves, log-rank analyses and Cox proportional hazards models. Response to treatment and drug dosage were analyzed using non-parametric regression and linear mixed effects modeling respectively.
Results
JAK2, MPL and CALR mutated ET represented 53%, 4% and 26% of patients and were mutually exclusive in most cases. 1% of patients harbored >1 mutation in these genes and analysis of such patients using individual hematopoietic colonies showed that JAK2, MPL or CALR mutations can be successively acquired within the same tumour subclone. Within the PT-1 cohort, CALR- and MPL-mutated subgroups affected males and females equally, in contrast to the female predominance observed in JAK2-mutated and TN subgroups wherein only 37% and 31% of patients respectively were male (p=0.0008, Chi-squared test). TN patients were significantly younger than any of the other molecular subgroups with a median age of 44 years (p<0.0001 for all comparisons, ANOVA). CALR-mutated patients were also significantly younger than JAK2- (p=0.003, ANOVA) and MPL-mutated (p=0.005, ANOVA) patients, with a median age of 54 years. CALR-mutated trephines had more prominent megakaryocyte atypia (increased cluster frequency, cluster size, tight clusters, paratrabecular megakaryocytes and fibrosis), and TN trephines had relatively milder megakaryocyte abnormalities. CALR-mutated ET patients presented with lower hemoglobin levels and total white cell counts, and higher platelet counts. Whilst the majority of venous thrombotic events occurred in the JAK2-mutated subgroup (21 of 27 events), CALR-mutated ET patients suffered increased rates of myelofibrotic transformation (hazard ratio 3.15 compared to the JAK2-mutated subgroup, p=0.03, Cox proportional hazards model correcting for age, gender and treatment received). No interaction was noted between treatment with either hydroxyurea or anagrelide and the incidence of these adverse outcomes. Patients with CALRins5 mutations presented with higher platelet counts than patients with CALRdel52 mutations but no other differences in disease features or outcome. Platelet control was equivalent between all molecular subgroups following treatment with either hydroxyurea plus aspirin or anagrelide plus aspirin in high-risk patients. However, CALR-mutated and MPL-mutated patients developed lower hemoglobin levels during anagrelide therapy. This observation was not due to differences in anagrelide dosage between molecular subgroups.
Conclusion
These results demonstrate that molecular testing identifies distinct biological subgroups in ET with different clinical outcomes and treatment responses.
Session topic: Myeloproliferative neoplasms - Clinical 1
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