Contributions
Abstract: PB2277
Type: Publication Only
Background
Classic BCR-ABL1-negative MPNs include PV, ET, and PMF with JAK2V617F as the most common mutation. JAK2V617F can be detected in about 95% of patients with PV while the remaining 5% of PV patients carry a somatic mutation of JAK2 exon 12. Approximately one-third of patients with ET or PMF do not carry any mutation in JAK2 or MPL. In December 2013, mutations were described in CALR in 67–71 and 56–88% of JAK2 and MPL negative patients with ET and PMF, respectively. Various studies have found differences in the clinical features of patients with CALR mutations compared with those harboring JAK2 mutations, such as a lower risk of thrombosis, lower hemoglobin and leukocyte counts, higher platelet count and longer survival for CALR-mutated ET patients. CALR mutations have been reported to be mutually exclusive with JAK2V617F or MPL mutations. However, recently, a few studies have reported the coexistence of JAK2 and CALR mutations in MPN.
Aims
The aim of the study is to evaluate the coexistence of CALR and JAK2 in our center.
Methods
Our series consisted of 122 ET patients, 88 females and 34 males, diagnosed between 1996 and 2017 with a mean age at diagnosis of 56.62±17.65. JAK2 mutation screening was carried out using real time PCR with FRET probes and CALR and MPL analysis using high resolution melting. Mutations were confirmed by Sanger sequencing (ABI 3130 Thermo Fisher).
Results
Among the 115 ET patients studied for the presence of the 3 mutations we found 40.9% (n=47) JAK2+/MPL-/CALR-, 12.2% (n=14) JAK2-/MPL-/CALR+, 44.4% (n=51) JAK2-/MPL-/CALR-, 1.7% (n=2) JAK2+/MPL-/CALR+ and 0.8% (n=1) JAK2-/MPL+/CALR-. Both patients JAK2+/CALR+ presented clinical features similar to the others patients with ET due to a history of gradual elevation of platelet counts. These 2 patients had no associated symptoms, splenomegaly or previous hemorrhagic or thrombotic episodes. The peripheral blood count for one of these patients had a plt count of 1018x106/L, hgb 13.7g/dl, WBC count 12.22x109/L and was considered IP low risk; the other patient had a plt count of 523x106/L, hgb 12.5g/dl and WBC count 6.05x109/L, with a recent diagnosis as IP high risk. Both patients were treated with acetylsalicylic acid. One of them progressed to MF after 7 years of being diagnosed and both are still alive.
Conclusion
Since CALR mutations discovery, their presence has been proposed to be mutually exclusive with JAK2 and MPL mutations. However, CALR and JAK2 co-mutations have been reported in a few MPN cases across different ethnic groups with a frequency of around 1%, which agrees with the incidence of our series (1.64%), although 2 groups have reported frequencies higher than 4% in Asian patients. To date, we have not observed the coexistence of MPL and CALR/JAK mutations in any MPN patient. This discrepancy could either be due to differences in methodology for the detection of CALR mutations, a different mutational spectrum in Caucasian and Asian populations, or the fact that the majority of groups follow a diagnostic workup flow for MPN with the assumption that mutations are mutually exclusive. Co-mutated patients might represent a new subtype in MPNs; in fact, many groups have suggested that JAK2/CALR double positive might have a different phenotype and clinical course, distinct from JAK2-positive or CALR-positive subgroups. Thus identification of the true frequency of these patients is important for defining the prognosis, risk factors and outcomes of these MPN subgroups. Our results suggest that these mutations should be analyzed independently and simultaneously at diagnosis in all MPN patients.
Session topic: 16. Myeloproliferative neoplasms - Clinical
Keyword(s): Essential Thrombocytemia, mutation analysis
Abstract: PB2277
Type: Publication Only
Background
Classic BCR-ABL1-negative MPNs include PV, ET, and PMF with JAK2V617F as the most common mutation. JAK2V617F can be detected in about 95% of patients with PV while the remaining 5% of PV patients carry a somatic mutation of JAK2 exon 12. Approximately one-third of patients with ET or PMF do not carry any mutation in JAK2 or MPL. In December 2013, mutations were described in CALR in 67–71 and 56–88% of JAK2 and MPL negative patients with ET and PMF, respectively. Various studies have found differences in the clinical features of patients with CALR mutations compared with those harboring JAK2 mutations, such as a lower risk of thrombosis, lower hemoglobin and leukocyte counts, higher platelet count and longer survival for CALR-mutated ET patients. CALR mutations have been reported to be mutually exclusive with JAK2V617F or MPL mutations. However, recently, a few studies have reported the coexistence of JAK2 and CALR mutations in MPN.
Aims
The aim of the study is to evaluate the coexistence of CALR and JAK2 in our center.
Methods
Our series consisted of 122 ET patients, 88 females and 34 males, diagnosed between 1996 and 2017 with a mean age at diagnosis of 56.62±17.65. JAK2 mutation screening was carried out using real time PCR with FRET probes and CALR and MPL analysis using high resolution melting. Mutations were confirmed by Sanger sequencing (ABI 3130 Thermo Fisher).
Results
Among the 115 ET patients studied for the presence of the 3 mutations we found 40.9% (n=47) JAK2+/MPL-/CALR-, 12.2% (n=14) JAK2-/MPL-/CALR+, 44.4% (n=51) JAK2-/MPL-/CALR-, 1.7% (n=2) JAK2+/MPL-/CALR+ and 0.8% (n=1) JAK2-/MPL+/CALR-. Both patients JAK2+/CALR+ presented clinical features similar to the others patients with ET due to a history of gradual elevation of platelet counts. These 2 patients had no associated symptoms, splenomegaly or previous hemorrhagic or thrombotic episodes. The peripheral blood count for one of these patients had a plt count of 1018x106/L, hgb 13.7g/dl, WBC count 12.22x109/L and was considered IP low risk; the other patient had a plt count of 523x106/L, hgb 12.5g/dl and WBC count 6.05x109/L, with a recent diagnosis as IP high risk. Both patients were treated with acetylsalicylic acid. One of them progressed to MF after 7 years of being diagnosed and both are still alive.
Conclusion
Since CALR mutations discovery, their presence has been proposed to be mutually exclusive with JAK2 and MPL mutations. However, CALR and JAK2 co-mutations have been reported in a few MPN cases across different ethnic groups with a frequency of around 1%, which agrees with the incidence of our series (1.64%), although 2 groups have reported frequencies higher than 4% in Asian patients. To date, we have not observed the coexistence of MPL and CALR/JAK mutations in any MPN patient. This discrepancy could either be due to differences in methodology for the detection of CALR mutations, a different mutational spectrum in Caucasian and Asian populations, or the fact that the majority of groups follow a diagnostic workup flow for MPN with the assumption that mutations are mutually exclusive. Co-mutated patients might represent a new subtype in MPNs; in fact, many groups have suggested that JAK2/CALR double positive might have a different phenotype and clinical course, distinct from JAK2-positive or CALR-positive subgroups. Thus identification of the true frequency of these patients is important for defining the prognosis, risk factors and outcomes of these MPN subgroups. Our results suggest that these mutations should be analyzed independently and simultaneously at diagnosis in all MPN patients.
Session topic: 16. Myeloproliferative neoplasms - Clinical
Keyword(s): Essential Thrombocytemia, mutation analysis