Impact of CALR and JAK2V617F Mutations on Clinical Course and Disease Outcomes in Essential Thrombocythemia: A Multicenter Retrospective Study in Turkish Patients

Abstract

Objective:

In this study, we investigated the effects of calreticulin (CALR) and JAK2V617F mutational status on clinical course and disease outcomes in Turkish patients with essential thrombocythemia (ET).

Materials and Methods:

Seventeen centers from Türkiye participated in the study and CALR- and JAK2V617F-mutated ET patients were evaluated retrospectively.

Results:

A total of 302 patients were included, of whom 203 (67.2%) and 99 (32.8%) were JAK2V617F- and CALR-positive, respectively. CALR-mutated patients were significantly younger (51 years vs. 57.5 years, p=0.03), with higher median platelet counts (987x10⁹/L vs. 709x10⁹/L, p<0.001) and lower median hemoglobin levels (13.1 g/dL vs. 14.1 g/dL, p<0.001) compared to JAK2V617F-mutated patients. Thromboembolic events (TEEs) occurred in 54 patients (17.9%), 77.8% of which were arterial. Compared to CALR mutation, JAK2V617F was associated with a higher risk of thrombosis (8.1% vs. 22.7%, p=0.002). Rates of transformation to myelofibrosis (MF) and leukemia were 4% and 0.7%, respectively, and these rates were comparable between JAK2V617F- and CALR-mutated cases. The estimated overall survival (OS) and MF-free survival of the entire cohort were 265.1 months and 235.7 months, respectively. OS and MF-free survival durations were similar betweenJAK2V617F- and CALR-mutated patients. Thrombosis-free survival (TFS) was superior in CALR-mutated patients compared to JAK2V617F-positive patients (5-year TFS: 90% vs. 71%, respectively; p=0.001). Age at diagnosis was an independent factor affecting the incidence of TEEs.

Conclusion:

In our ET cohort, CALR mutations resulted in higher platelet counts and lower hemoglobin levels than JAK2V617F and were associated with younger age at diagnosis. JAK2V617F was strongly associated with thrombosis and worse TFS. Hydroxyurea was the most preferred cytoreductive agent for patients with high thrombosis risk.

Introduction

Essential thrombocythemia (ET) is a Philadelphia-negative myeloproliferative neoplasm (MPN) characterized by high platelet counts due to the clonal proliferation of the megakaryocytic lineage within the bone marrow. Patients with ET may display molecular markers such as Janus kinase 2 (JAK2; 9p24), calreticulin (CALR; 19p13.2), or myeloproliferative leukemia virus (MPL oncogene; 1p34) in a mutually exclusive manner [1,2]. The valine-to-phenylalanine (V617F) alteration constitutively activates JAK2, resulting in overproduction of myeloid cells. The JAK2V617F mutation is present in approximately 55% of patients with ET, 25% of patients with CALR, and 3% of patients with MPL [1,3]. The statuses of these driver mutations are relevant not only for their diagnostic contribution but also for their prognostic significance [4].

Frameshift mutations in the CALR gene encoding molecular chaperones in the endoplasmic reticulum are the second most common somatic mutation in ET. Two mutations of the CALR gene, type 1 (c.1092_1143del; L367fs*46) and type 2 (c.1154_1155insTTGTC; K385fs*47), represent more than 80% of CALR mutations [1,2,5]. The mutant CALR protein interacts with the thrombopoietin receptor, MPL, via its extracellular domain, activating the downstream JAK-STAT pathway and resulting in cytokine-independent growth [6,7].

In patients with ET, the presence of JAK2V617F is associated with an increased risk of thrombosis and a lower risk of post-ET myelofibrosis (MF) [8]. Compared to JAK2V617F, mutant CALR is associated with younger age, male sex, higher platelet count, lower hemoglobin level, lower leukocyte count, and lower incidence of thrombotic events. In addition, patients with the type 2 CALR mutation tend to have higher platelet counts than patients with type 1 [9,10].

Previous studies have shown that in patients with ET, median survival is approximately 20 years [11,12], although life expectancy in ET is inferior to that of the general population, regardless of mutational status [12]. Young ET patients have clearly longer survival compared to their older counterparts, which requires appropriate action during patient management [13]. Risk factors for survival in ET are advanced age, leukocytosis, and thrombosis history. Mutational status does not seem to affect survival in patients with ET [14].

The prevalence of JAK2V617F and CALR mutations in Turkish patients with ET and the relationships of these driver mutations with clinical outcomes remain undetermined. In this study, we aim to investigate the effects of CALR and JAK2V617F mutation status on the clinical course and disease outcomes of Turkish ET patients.

Materials and Methods

JAK2V617F- and CALR-mutated ET patients aged ^>18 years were included in the study. MPL-mutated and triple-negative ET patients were excluded. Demographic data, clinical and laboratory characteristics, treatment modalities, and disease outcomes were evaluated retrospectively. Bone marrow aspiration and biopsy were performed for all patients to exclude those with pre-fibrotic MF according to the 2016 revision of the World Health Organization’s classification of myeloid neoplasms and acute leukemia [15].

JAK2V617F mutations were detected by quantitative polymerase chain reaction and CALR mutations were detected by next-generation sequencing of CALR exon 9. The 52-bp deletion (p.L367fs*46) was defined as CALR type 1 and the 5-bp TTGTC insertion (p.K385fs*47) as CALR type 2, while the others were grouped as “other.” CALR subgroup analyses were performed, excluding patients with unknown CALR type.

At diagnosis, the International Prognostic Score of Thrombosis in Essential Thrombocythemia (IPSET-thrombosis) and the revised IPSET-thrombosis were used to define the risk of thromboembolic events (TEEs). The revised IPSET-thrombosis defines four risk categories according to three adverse variables (thrombosis history, age >60 years, and JAK2V617F): very low (no adverse features), low (presence of JAK2V617F), intermediate (age >60 years), and high (presence of thrombosis history or presence of both advanced age and JAK2V617F) [3,16]. Deep vein thrombosis (DVT), pulmonary thromboembolism (PTE), pulmonary arterial hypertension (PAH) due to chronic PTE, and TEEs occurring in any venous vessel were considered as venous-type TEEs. Myocardial infarction (MI), angina pectoris (AP), transient ischemic attack, ischemic stroke or cerebrovascular accident (CVA), thrombosis in the carotid artery, peripheral arterial occlusive disease, and TEEs in any arterial vessel were classified as the arterial type.

All procedures were performed in accordance with the ethical standards of the relevant institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Ethical approval was obtained from the Local Ethics Committee of İzmir Bozyaka Training and Research Hospital with approval number 2022/127 on August 10, 2022.

Statistical Analysis

IBM SPSS Statistics 22 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. The conformity of the variables to normal distribution was examined using visual (histogram and probability graphs) and analytical (Kolmogorov-Smirnov/Shapiro-Wilk test) methods. Descriptive statistics were presented as mean ± standard deviation, median (minimum-maximum), frequency distribution, and percentage. Comparisons between groups were made by chi-square, Fisher exact, and Mann-Whitney U tests as appropriate. Two major outcomes were assessed accordingly: overall survival (OS) and MF-free survival, calculated from the time of development of fibrosis in the bone marrow. Survival estimations were assessed by Kaplan-Meier method and the log-rank test was used for comparisons of survival distributions among groups. Thrombosis-free survival (TFS) was calculated from the date of diagnosis to date of thrombosis (uncensored) or last contact (censored). A Cox proportional hazard regression model was used for multivariable analysis. Values of p<0.05 were considered statistically significant.

In a one-way analysis of variance (ANOVA) study, sample sizes of 53, 33, and 9 were obtained from the 3 CALR-positive groups whose means were to be compared. According to the one-way ANOVA test, the total sample of 95 subjects achieved 100% power to detect differences among the means versus the alternative of equal means using an F-test with a 0.05000-significance level.

Results

Entire Patient Cohort

Patients with ET from 17 centers in Türkiye, diagnosed between January 1999 and July 2022, were included in the study. A total of 302 patients, 203 of whom had JAK2V617F-mutated ET and 99 of whom had CALR-mutated ET, were analyzed. While 174 (57.6%) of the patients were female, 128 (42.4%) were male. The median age was 55 years (range: 20-88 years). Median follow-up was 41.7 months (range: 0.17-278.3 months). Two hundred and three (67.2%) and 99 (32.8%) patients were JAK2V617F- and CALR-positive, respectively. At the time of diagnosis, 24.8% (n=74) of the patients had splenomegaly and 4 patients (1.3%) had splenectomy secondary to trauma. Median platelet count was 784x10⁹/L (range: 452-2635x10⁹/L), median hemoglobin level was 13.8 g/dL (range: 8.2-17.8 g/dL), and median leukocyte count was 9.6x10⁹/L (range: 3.4-33.4x10⁹/L) (Table 1).

Table 1. Demographic and biological features of patients with essential thrombocythemia.

According to the IPSET-thrombosis risk score, 84 (27.8%) patients were in the low-risk group, 81 (26.8%) patients were in the intermediate-risk group, and 137 (45.4%) patients were in the high-risk group. When we evaluated the revised IPSET-thrombosis risk score, 70 (23.2%) patients were in the very low-risk group, 99 (32.8%) were in the low-risk group, 25 (8.3%) were in the intermediate-risk group, and 108 (35.7%) were in the high-risk group.

Including the period before diagnosis, the time of diagnosis, and follow-up, TEEs occurred in 17.9% (n=54) of the patients, 77.8% of which were in arterial sites, while 14.8% were in venous sites and 7.4% were in both venous and arterial sites. Thirty-two patients (59.3%) had MI or AP, 2 patients (3.7%) experienced both MI and PTE, and thrombosis in the carotid artery occurred in 2 cases (3.7%). While 2 patients (3.7%) had both CVA and PAH due to chronic PTE, 7 (13%) had CVA. DVT occurred in 4 cases (7.4%), cerebral venous sinus thrombosis in 3 cases (5.6%), PTE in 1 case (1.9%), and portal vein thrombosis in 1 case (1.9%).

During the follow-up of 258 patients with no history of TEEs prior to or at the time of diagnosis, the TEE rate was 3.9% (n=10). Six of those patients were JAK2V617F-mutated and in the high IPSET-thrombosis risk group at the time of diagnosis, while 4 of them were CALR-mutated and in the low-risk group. Multivariate analysis was performed for analyzing the effects of hemoglobin levels, platelet counts, and age at diagnosis on TEE occurrence. Only age was found to be a factor independently affecting the cumulative TEE incidence (p=0.008) (Table 2).

Table 2. Multivariate analysis for factors that may influence the incidence of thromboembolic events.

Sixty-five (21.5%) female patients were of reproductive age and a total of 3 pregnancies occurred in 2 of those cases. While 2 of them resulted in delivery with the use of interferon alpha (IFN-α), 1 pregnancy resulted in intrauterine fetal death in the 6^th gestational week. Demographic and biological features of patients according to mutational status are presented in Table 1.

Characteristics and Treatments of the JAK2V617F- and CALR-Mutated Subgroups

CALR-mutated patients were significantly younger (median age at diagnosis: 51 years [range: 20-88 years] vs. 57.5 years [range: 20-87 years], p=0.03) than patients harboring the JAK2V617F mutation. Compared to JAK2V617F-mutated cases, patients with CALR mutations had higher median platelet counts (987x10⁹/L [range: 458-2449x10⁹/L] vs. 709x10⁹/L [range: 452-2635x10⁹/L], p<0.001) and significantly lower hemoglobin levels (13.1 g/dL [range: 8.2-17.2 g/dL] vs. 14.1 g/dL [range: 8.3-17.8 g/dL], p<0.001). The leukocyte counts of patients with CALR mutations were lower than those of patients with JAK2V617F mutations, but the difference did not reach statistical significance (8.9x10⁹/L [range: 3.4-20.6x10⁹/L] vs. 9.8x10⁹/L [range: 3.9-33.3x10⁹/L], p=0.06).

Regarding the IPSET-thrombosis risk stratification, 34.5% of JAK2V617F-mutated patients were in the intermediate-risk group and 65.5% in the high-risk group, while 84.8% of the CALR-mutated patients were in the low-risk group, 11.1% in the intermediate-risk group, and 4% in the high-risk group (p<0.001). According to the revised IPSET-thrombosis risk score, 48.8% of JAK2V617F-mutated patients were in the low-risk group and 51.2% in the high-risk group, while 70.7% of the CALR-mutated patients were in the very low-risk group, 25.3% in the intermediate-risk group, and 4% in the high-risk group (p<0.001). Compared to CALR mutations, JAK2V617F mutations were associated with a higher incidence of TEEs (8.1% vs. 22.7%, p=0.002). The incidence of thrombosis in arterial sites was higher than the incidence of thrombosis in venous sites in both groups, although the difference was not statistically significant (Table 1).

All patients received acetylsalicylic acid (ASA) for thromboprophylaxis. The percentage of patients treated with ASA alone was significantly higher in the JAK2V617F-mutated group compared to patients with CALR mutations (25.1% vs. 16.2%, p<0.001). Similarly, hydroxyurea (HU) therapy was found to be more commonly used for patients with JAK2V617F than CALR-mutated patients (64% vs. 48.5%, p<0.001). Other treatment modalities including anagrelide monotherapy, IFN-α, and the combination of HU and anagrelide were more common among CALR-mutated patients than patients harboring JAK2V617F (p<0.001) (Table 1).

There was no difference between the two groups in terms of median follow-up duration, sex distribution, splenomegaly rate, median leukocyte count, comorbidities, or rates of MF progression and leukemia (Table 1).

Patients with CALR Mutations

CALR-mutated patients were further analyzed according to subgroups as type 1, type 2, and others. There was no difference between cases of type 1, type 2, and other CALR mutations in terms of sex, splenomegaly, hemoglobin, platelet and leukocyte counts, comorbidities, IPSET-thrombosis score, revised IPSET-thrombosis score, treatment modalities, incidence of thrombotic events, or leukemic transformation (Table 3).

Table 3. Clinical and biological features of patients with CALR-mutated essential thrombocythemia.

The median ages of patients with type 1, type 2, and other CALR mutations were 54.5, 50, and 37 years, respectively (p=0.005). The rate of progression to MF was higher in the others group than in cases of type 1 and type 2 CALR mutations (22.2%, 1.9%, and 0%, respectively; p=0.02). Similarly, the median follow-up of the others group was significantly longer than the median follow-up durations of patients with type 1 and type 2 mutations (68.5, 49.1, and 45 months, respectively; p=0.04) (Table 3).

Survival

Progression to MF was observed in 4% (n=12) of the entire cohort and leukemic transformation occurred in 0.7% (n=2) of the patients. One patient with leukemic transformation harbored a TP53 mutation with a complex karyotype.

The estimated median OS for the entire cohort was 265.1 months (range: 255.8-274.3 months). There was no difference in OS between CALR- and JAK2V617F-mutated ET cases (254.9 months [range: 235.1-274.7 months] vs. 234.6 months [range: 228.1-241.2 months], p=0.1) (Figure 1). Estimated MF-free survival was 235.7 months (range: 205.7-265.8 months). Like OS, the MF-free survival duration was also similar between the CALR- and JAK2V617F-mutated groups (247.5 months [range: 213.9-281.2 months] vs. 199.7 months [range: 165.7-233.7 months], p=0.4) (Figure 1). In CALR-mutated patients, OS and MF-free survival were similar between the subgroups established according to CALR type (p=0.4 and p=0.2, respectively) (Figure 2). OS and MF-free survival were also similar between men and women (p=0.4 and p=0.06, respectively).

Figure 1.

Overall (A) and myelofibrosis-free (B) survival according to the mutational statuses of the patients.

Figure 2.

Overall (A) and myelofibrosis (MF)-free (B) survival of CALR-mutated patients according to CALR subtypes.

The 2-year and 5-year TFS rates were respectively 93% and 90% in CALR-mutated patients, while TFS was 77% and 71% at 2 years and 5 years in JAK2V617F-mutated patients, respectively. CALR-mutated patients thus had significantly longer TFS compared to JAK2V617F-mutated patients (p=0.001) (Figure 3).

Figure 3.

Thrombosis-free survival according to mutational status.

Discussion

ET is a type of MPN characterized by an increased rate of TEEs, a varying burden of symptoms, and an intrinsic risk of progression to MF and acute leukemia; however, survival is only modestly reduced in most cases. In this study, we have presented the retrospective analysis of 302 patients with ET according to their JAK2V617F and CALR mutational statuses. Furthermore, we compared the clinical courses and disease outcomes of the CALR-mutated patients according to the CALR subtypes of type 1, type 2, and others.

There is growing evidence that CALR-mutated ET cases are phenotypically different from other molecular types of ET, including JAK2V617F-mutated, MPL-mutated, and triple-negative cases, in terms of both clinical and hematological presentations and survival outcomes [17,18,19,20]. Moreover, Alvarez-Larrán et al. [17] underlined the need for new treatment modalities for CALR-mutated ET, arguing that conventional cytoreductive agents are less effective in these patients compared to other ET cases. However, in this study, we compared the outcomes of CALR-mutated patients with only those who were JAK2V617F-positive. Triple-negative ET is a heterogeneous group of diseases and may harbor additional non-driver mutations that affect disease outcome. For this reason, we excluded triple-negative patients from our study due to the heterogeneous nature of the disease and we also excluded MPL cases due to their low frequency.

Nangalia et al. [2] reported that patients with CALR-mutated MPNs presented with higher platelet counts and lower hemoglobin levels than patients carrying the JAK2V617F mutation. Among Han Chinese patients, CALR mutations were associated with younger age and higher platelet counts compared to JAK2V617F mutations [21]. In addition, patients with CALR mutations in Tunisian and Belgian cohorts had higher platelet counts and lower hemoglobin levels and leukocyte counts than patients with JAK2V617F mutations [18,22]. Ceylan et al. [23] showed that patients with CALR mutations presented with higher platelet counts and lactate dehydrogenase levels compared to JAK2- and MPL-mutated patients. Similarly, in our patient cohort, CALR-mutated patients had significantly higher platelet counts and lower hemoglobin levels (p<0.001). In addition, these patients tended to have lower leukocyte counts (p=0.06).

In patients with ET, the risk for thrombotic complications may exceed 20% [7,24], and previous studies have shown that the risk of thrombosis is higher in JAK2V617F-mutated cases [25]. Among the 300 patients with ET reported by Gangat et al. [26], 106 (35%) experienced arterial (n=75) or venous (n=43) events. In univariate analysis, compared to JAK2V617F-mutated cases, CALR-mutated patients had better TFS (hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.30-0.92). However, the authors concluded that the favorable effect of CALR mutations might be confined to younger patients [26]. Guglielmelli et al. [27] reported thrombosis (arterial or venous) in 152 (30%) of 502 ET patients, and of those cases, 96 (19%) were arterial and 82 (16%) were venous. In multivariate analysis, venous thrombosis risk at any time was significantly higher in JAK2V617F-mutated patients than that observed in CALR-mutated cases. This study confirmed the prothrombotic influence of JAK2V617F [28] as opposed to CALR mutations [27]. In a study that included 168 ET patients, 51 (30.35%) experienced thrombotic events, 60% of which were arterial [29], and JAK2V617F-mutated cases exhibited a 1.5-fold higher risk of developing thrombotic events. In our study, the total incidence of thrombotic complications was 17.9%, and most of them (77.8%) were arterial. In the literature, similar to our study, TEEs in ET patients are more common in arterial sites than venous sites, but the incidence of TEEs is generally reported to be higher than that of our patient cohort. Although many factors such as age, comorbidities, and smoking might have an impact on the incidence of TEEs in ET patients, the ASA use in all cases of our cohort might have contributed positively to the low incidence of thrombosis in our study. We also showed in multivariate analysis that age was the only factor independently affecting the incidence of TEEs. Since patients with CALR mutations were younger, age may have contributed positively to the lower incidence of TEEs in these patients. Like previous studies, in our cohort the incidence of all TEEs was significantly higher in JAK2V617F-mutated cases than CALR-mutated cases. Furthermore, JAK2V617F-mutated patients had high risk scores for both IPSET-thrombosis and the revised IPSET thrombosis scoring system compared to CALR-positive patients. The 2-year and 5-year TFS rates were superior in CALR-mutated patients compared to JAK2V617F-positive patients (p=0.001, HR: 0.71, 95% CI: 0.68-0.74). In a Japanese population, JAK2V617F mutations were related to more thrombotic events and more splenomegaly than CALR mutations [30]. In our population, the incidence of splenomegaly was similar between JAK2V617F- and CALR-mutated cases.

In ET, the leukemic transformation rates at 10 years are estimated to be <1% while those at 20 years average 5%, and the rates of developing MF are slightly higher [25]. Historical data about the probability of MF transformation in ET patients revealed rates of 2.7% (95% CI: 2.4-2.9) at 5 years, 8.3% (95% CI: 7.8-8.9) at 10 years, and 15.3% (95% CI: 6.1-24.5) at 15 years [31]. Barbui et al. [8] revealed that leukemic transformation rates at 10 and 15 years were 0.7% and 2.1%, respectively, and progression rates to overt MF at 10 and 15 years were 0.8% and 9.3%, respectively. They claimed that the absence of JAK2V617F was a risk factor for overt MF progression. The rate of leukemic transformation in our cohort (0.7%) is comparable to those mentioned in the literature, while the rate of progression to MF (4%) is slightly higher than the previously published values. The presence of JAK2V617F and CALR mutations had no impact on progression to MF and leukemic transformation in our study.

Among our patient cohort, OS and MF-free survival rates were similar between JAK2V617F- and CALR-mutated patients. In CALR subgroup analysis, the rates of MF occurrence were significantly higher in patients with other (non-type 1 and non-type 2) CALR mutations, but OS and MF-free survival were similar among all CALR-mutated patients. Our results support previous data suggesting that driver mutations do not have an impact on survival in ET [25]. In a study of 1494 ET patients, the independent adverse effect of male sex on survival was confirmed with multivariable analysis (HR: 1.6, 95% CI: 1.1-2.5, p=0.02), and in the context of the IPSET, the HRs (95% CI) were 1.6 (1.1-2.5) for male sex, 7.5 (3.1-18.3) for high-risk IPSET scores, and 4.1 (1.8-9.5) for intermediate-risk IPSET scores. Tefferi et al. [32] suggested that women with ET live longer than their male counterparts and that sex might supersede thrombosis history as a risk factor for OS. However, in our study, sex had no effect on survival outcomes, similar to previous findings in a Romanian cohort [29].

Recent studies revealed the adverse impact on survival of non-driver mutations such as ASXL1, SF3B1, SRSF2, and TP53 [25,33]. TP53 mutations were highly predictive for leukemic transformation in previous studies [33,34]. In our population, one of the two patients who experienced acute myeloid leukemia progression had TP53 mutation with a complex karyotype.

The management of ET mainly focuses on reducing the risk of thrombosis, controlling myeloproliferation, and managing disease-related symptoms and complications [35]. HU is recommended as a front-line cytoreductive therapy for patients with high-risk ET [25]. In the UK-PT1 study, HU was superior to anagrelide in reducing arterial thrombosis, major bleeding, and fibrotic progression [36]. However, in the ANAHYDRET study, HU and anagrelide were found to be similar in the prevention of thrombotic end points [37]. The majority of our patients (77.8%) were treated with cytoreductive agents. In our study, the overall cytoreduction rate was comparable to that of a Romanian cohort (77.8% vs. 76.8%, respectively), although approximately half of the Romanian patients received cytoreductive therapy without ASA/antiplatelets or anticoagulants [23]. HU was the most preferred cytoreductive treatment in both patient cohorts.

In our study, the percentage of patients receiving HU was higher among JAK2V617F-mutated patients than those with CALR mutations (64% vs. 48.5%), but the overall cytoreduction rate was higher among CALR-mutated patients (74.9% vs. 83.8%). The higher rate of HU use among patients with JAK2V617F was probably due to the higher incidence of thrombosis observed in this patient population. In addition, CALR mutations causing higher platelet counts seem to have prompted more cytoreductive therapy initiation. Although most of these patients had a low IPSET-thrombosis score, their exposure to cytoreductive treatment may be considered over-treatment in ET [38]. In contrast, extreme thrombocytosis has previously been associated with CALR mutations [10] and a lower risk of arterial thrombosis [39].

Guglielmelli et al. [27] confirmed the prothrombotic influence of JAK2 as opposed to CALR mutations and suggested that extreme thrombocytosis might also play a part in contributing to the observed decreased risk of arterial thrombosis in CALR-mutated ET.

Study Limitations

Since our study was retrospective in nature, covering approximately 20 years, it has some limitations. The major limitations are the lack of comprehensive data regarding non-driver mutations and different median follow-up periods for different CALR mutation types. While acknowledging the limitations, we anticipate that our study may contribute to the literature as it includes a large number of Turkish patients and provides real-life data.

Conclusion

This is the first multicenter study investigating the disease characteristics and clinical courses of CALR-mutated ET patients in a Turkish population. Our results proved that JAK2V617F was strongly associated with thromboembolic complications and HU was the most preferred cytoreductive agent for patients with high thrombosis risk. Mutant CALR resulted in higher platelet counts and lower hemoglobin levels than mutant JAK2V617F and was related to younger ages at the time of diagnosis. We suggest that ET cases should be managed meticulously considering the disease characteristics caused by driver and non-driver mutations.