A Multi-Center Study on the Efficacy of Eltrombopag in Management of Refractory Chronic Immune Thrombocytopenia: A Real-Life Experience

Objective: The aim of the present study was to evaluate the efficacy and safety of eltrombopag, an oral thrombopoietin receptor agonist, in patients with chronic immune thrombocytopenia (ITP). Materials and Methods: A total of 285 chronic ITP patients (187 women, 65.6%; 98 men, 34.4%) followed in 55 centers were enrolled in this retrospective cohort. Response to treatment was assessed according to platelet count (/mm3) and defined as complete (platelet count of >100,000/mm3), partial (30,000-100,000/mm3 or doubling of platelet count after treatment), or unresponsive (<30,000/mm3). Clinical findings, descriptive features, response to treatment, and side effects were recorded. Correlations between descriptive, clinical, and hematological parameters were analyzed. Results: The median age at diagnosis was 43.9±20.6 (range: 3-95) years and the duration of follow-up was 18.0±6.4 (range: 6-28.2) months. Overall response rate was 86.7% (n=247). Complete and partial responses were observed in 182 (63.8%) and 65 (22.8%) patients, respectively. Thirty-eight patients (13.4%) did not respond to eltrombopag treatment. For patients above 60 years old (n=68), overall response rate was 89.7% (n=61), and for those above 80 years old (n=12), overall response rate was 83% (n=10). Considering thrombocyte count before treatment, eltrombopag significantly increased platelet count at the 1st, 2nd, 3rd, 4th, and 8th weeks of treatment. As the time required for partial or complete response increased, response to treatment was significantly reduced. The time to reach the maximum platelet levels after treatment was quite variable (1-202 weeks). Notably, the higher the maximum platelet count after eltrombopag treatment, the more likely that side effects would occur. The most common side effects were headache (21.6%), weakness (13.7%), hepatotoxicity (11.8%), and thrombosis (5.9%). Conclusion: Results of the current study imply that eltrombopag is an effective therapeutic option even in elderly patients with chronic ITP. However, patients must be closely monitored for response and side effects during treatment. Since both response and side effects may be variable throughout the follow-up period, patients should be evaluated dynamically, especially in terms of thrombotic risk factors.

FAS/FASL gene polymorphisms in Turkish patients with chronic myeloproliferative disorders.

INTRODUCTION: Chronic myeloproliferative disorders (CMPD) are chronic myeloid hematological disorders, characterized by increased myeloid cell proliferation and fibrosis. Impaired apoptotic mechanisms, increased cell proliferation, uncontrolled hematopoietic cell proliferation and myeloaccumulation may contribute to the pathogenesis of CMPD. The aim of our study was to show the possible role of FAS/FASL gene polymorphisms in CMPD pathogenesis and investigate the association with clinical parameters and susceptibility to disease. MATERIAL AND METHODS: We included 101 (34 polycythemia vera (PV), 23 primary myelofibrosis (PMF), 44 essential thrombocythemia (ET)) CMPD patients diagnosed according to the WHO classification criteria and 95 healthy controls in this study. All the patients and the controls were investigated for FAS/FASL gene expression, allele frequencies and phenotype features, and also FAS mRNA levels were analyzed. RESULTS: Chronic myeloproliferative disorders patients showed increased FAS-670AG + GG genotype distribution compared with the control group (p < 0.05). While the A allele was more frequent in both groups, AG genotype was more frequent in CMPD patients. There was no association between FAS-670A>G gene polymorphism and some clinical parameters such as splenomegaly and thrombosis (p > 0.05). No statistically significant difference in FASL+843C>T genotype or allele frequency was found between groups (p > 0.05). Moreover, no statistically significant difference was detected in FASL and JAK2V617F mutations (p > 0.05). FAS mRNA expression was 1.5-fold reduced in patients compared to healthy subjects. CONCLUSIONS: According to our findings, FAS/FASL gene expression may contribute to the molecular and immunological pathogenesis of CMPD. More investigations are needed to support these data.

The effect of the additional cytogenetic abnormalities on major molecular response and BCR-ABL kinase domain mutations in long-term follow-up chronic myeloid leukemia patients, a cross sectional study.

The aim of the study was to examine the relation between additional chromosomal aberrations (ACAs) with major molecular response (MMR) and BCR-ABL kinase domain (KD) mutations in the long-term follow-up of the chronic myeloid leukemia (CML) disease. The study design was cross-sectional observational and used the CML patients' data of Izmir Ataturk Education and Research Hospital from 2011 to 2015. Conventional cytogenetic, fluorescence in situ hybridization (FISH), quantitative real-time polymerase chain reaction (RQ-PCR) test results from 89 CML patients' and pyrosequencing analysis results from 17 patients' were set up for comparison analysis. The chi-square test was used in statistical analysis of the experimental data. There were no statistically significant correlations between ACAs and MMR (p = .361, p > .05) groups or BCR-ABL KD mutations (p = .576, p > .05) groups observed in the study. This study has revealed that MMR and BCR-ABL KD mutations did not correlate with ACAs.

Multicenter Retrospective Analysis of Turkish Patients with Chronic Myeloproliferative Neoplasms.

OBJECTIVE: Chronic myeloproliferative neoplasms (CMPNs) that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are Philadelphia-negative malignancies characterized by a clonal proliferation of one or several lineages. The aim of this report was to determine the demographic features, disease characteristics, treatment strategies, and survival rates of patients with CMPNs in Turkey. MATERIALS AND METHODS: Across all of Turkey, 9 centers were enrolled in the study. We retrospectively evaluated 708 CMPN patients' results including 390 with ET, 213 with PV, and 105 with PMF. RESULTS: The JAK2V617F mutation was found positive in 86% of patients with PV, in 51.5% of patients with ET, and in 50.4% of patients with PMF. Thrombosis and bleeding at diagnosis occurred in 20.6% and 7.5% of PV patients, 15.1% and 9% of ET patients, and 9.5% and 10.4% of PMF patients, respectively. Six hundred and eight patients (85.9%) received cytoreductive therapy. The most commonly used drug was hydroxyurea (89.6%). Leukemic and fibrotic transformations occurred at rates of 0.6% and 13.2%. The estimated overall survival in PV, ET, and PMF patients was 89.7%, 85%, and 82.5% at 10 years, respectively. There were no significant differences between survival in ET, PV, and PMF patients at 10 years. CONCLUSION: Our patients' results are generally compatible with the literature findings, except for the relatively high survival rate in PMF patients. Hydroxyurea was the most commonly used cytoreductive therapy. Our study reflects the demographic features, patient characteristics, treatments, and survival rates of Turkish CMPN patients.

Effectiveness of Quantitative Real Time PCR in Long-Term Follow-up of Chronic Myeloid Leukemia Patients.

OBJECTIVE: To determine the use of the Quantitative Real Time PCR (RQ-PCR) assay follow-up with Chronic Myeloid Leukemia (CML) patients. STUDY DESIGN: Cross-sectional observational. PLACE AND DURATION OF STUDY: Izmir Ataturk Education and Research Hospital, Izmir, Turkey, from 2009 to 2013. METHODOLOGY: Cytogenetic, FISH, RQ-PCR test results from 177 CMLpatients' materials selected between 2009 - 2013 years was set up for comparison analysis. Statistical analysis was performed to compare between FISH, karyotype and RQ-PCR results of the patients. Karyotyping and FISH specificity and sensitivity rates determined by ROC analysis compared with RQ-PCR results. Chi-square test was used to compare test failure rates. RESULTS: Sensitivity and specificity values were determined for karyotyping 17.6 - 98% (p=0.118, p > 0.05) and for FISH 22.5 - 96% (p=0.064, p > 0.05) respectively. FISH sensitivity was slightly higher than karyotyping but there was calculated a strong correlation between them (p < 0.001). RQ-PCR test failure rate did not correlate with other two tests (p > 0.05); however, karyotyping and FISH test failure rate was statistically significant (p < 0.001). CONCLUSION: Besides, the situation needed for karyotype analysis, RQ-PCR assay can be used alone in the follow-up of CMLdisease.

Eltrombopag for the Treatment of Immune Thrombocytopenia: The Aegean Region of Turkey Experience.

OBJECTIVE: Immune thrombocytopenia (ITP) is an immune-mediated disease characterized by transient or persistent decrease of the platelet count to less than 100x109/L. Although it is included in a benign disease group, bleeding complications may be mortal. With a better understanding of the pathophysiology of the disease, thrombopoietin receptor agonists, which came into use in recent years, seem to be an effective option in the treatment of resistant cases. This study aimed to retrospectively assess the efficacy, long-term safety, and tolerability of eltrombopag in Turkish patients with chronic ITP in the Aegean region of Turkey. MATERIALS AND METHODS: Retrospective data of 40 patients with refractory ITP who were treated with eltrombopag in the Aegean region were examined and evaluated. RESULTS: The total rate of response was 87%, and the median duration of response defined as the number of the platelets being over 50x109/L was 19.5 (interquartile range: 5-60) days. In one patient, venous sinus thrombosis was observed with no other additional risk factors due to or related to thrombosis. Another patient with complete response and irregular follow-up for 12 months was lost due to sudden death as the result of probable acute myocardial infarction. CONCLUSION: Although the responses to eltrombopag were satisfactory, patients need to be monitored closely for overshooting platelet counts as well as thromboembolic events.

The prognostic significance of bone marrow metastases: evaluation of 58 cases.

BACKGROUND: Bone marrow biopsy is widely used method for diagnosis, follow-up and staging of hemato-oncologic diseases. This procedure is also used for determining the bone marrow metastasis in patients with solid tumors. In this study, clinical, hematological, and pathological features of 58 patients with bone marrow metastases diagnosed by bone marrow biopsies were examined retrospectively MATERIALS AND METHODS: Among 3345 bone marrow biopsies performed in our hospital between January 2006 and August 2013, 58 cases with solid tumor metastasized to bone marrow were included in this study. RESULTS: Among 58 cases with solid organ carcinoma metastasis in bone marrow, mean age was 59.9. Thirty-nine cases were found to have a known primary tumor focus. The most common tumors metastasized to bone marrow were breast carcinomas (23 patients, 59%), gastric carcinomas (6 patients, 15.3%), prostate carcinomas (4 patients, 10,2%), and lung carcinomas (3 patients, 7.7%), respectively. Nineteen patients were firstly diagnosed from bone marrow biopsies as metastatic carcinomas. The median overall survival after bone marrow metastasis was 28 days (95% confidence interval: 7.5-48.4). The median overall survival difference was not statistically significant between patients with primary known and unknown tumor (P = 0.973). Statistically significant difference was observed between the survival of breast cancer and gastric cancer (P = 0.028). The most common hematologic symptom was the coexistence of anemia and thrombocytopenia (31%), thrombocytopenia (27.6%) and anemia (20.7%) alone. The median overall survival difference was statistically significant between patients who have anemia and thrombocytopenia (P < 0.005). CONCLUSION: Bone marrow biopsy is an easily accessible, easily applied, a useful procedure for diagnosing metastatic diseases in patients with hematologic symptoms such as anemia and thrombocytopenia besides being an uncomfortable procedure for patients. Furthermore, it is useful in predicting the prognosis and short survey after diagnosing bone marrow metastasis.

JAK2 V617F mutation status of 232 patients diagnosed with chronic myeloproliferative neoplasms.

INTRODUCTION/BACKGROUND: The aim of this study was to investigate the presence of Janus kinase 2 (JAK2) V617F mutation in patients with break point cluster region-abelson negative chronic myeloproliferative neoplasms (CMPNs) in our center. PATIENTS AND METHODS: We compared patients with and without the mutation, and also patients with the homozygous and heterozygous mutation, in terms of different clinical and laboratory features. RESULTS: The JAK2 V617F mutation was detected in 77 (95%), 88 (68%), and 17 (77%) of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) patients, respectively. Among JAK2 V617F-positive patients, the homozygous genotype was found in 39 (50.6%) of the 77 PV, 23 (26.1%) of the 88 ET, and 11 (64.7%) of the 17 PMF patients. Bleeding was seen in 14 (6%) of all patients. Upper gastrointestinal bleeds were the most common, seen in 11 patients. Out of 232 CMPN patients, 44 (19%) had thrombosis. The most common thrombotic event was transient ischemic attack (52%). Progression to myelofibrosis was seen in 1 (1.2%) PV and 3 (2.3%) ET patients, and progression to acute leukemia was seen in 2 (2.5%) PV and 3 (2.3%) ET patients. Three patients with PV (3.7%), 3 with ET (2.7%), and 5 with PMF (2.7%) died during follow-up. CONCLUSION: JAK2 V617F mutation frequencies in our PV and ET patients were similar to those reported previously. JAK2 V617F mutation frequency in our PMF patients was greater than in previous reports. All of our PV patients with thrombosis and most of our ET patients with thrombosis (76.1%) were JAK2 V617F mutation-positive. This mutation seems to be correlated with thrombosis risk.

Soluble CD40 ligand, high sensitive C-reactive protein and fetuin-A levels in patients with essential thrombocythemia.

BACKGROUND: CD40 ligand (CD40L) is expressed on the surface of activated platelets and activated T lymphocytes. Circulating soluble CD40 ligand (sCD40L) is formed from these molecules proteolytically. Fetuin-A is a potent antiinflammatory cytokine. AIM OF THE STUDY: In this study, we aim to investigate sCD40L levels to determine whether there is platelet activation and to measure high sensitive C-reactive protein (hs-CRP) levels to demonstrate if this leads to an inflammatory process and also to study fetuin-A levels to see if there is any concomitant antiinflammatory event in patients with essential thrombocythemia (ET). METHODS: We compared 30 patients with essential thrombocythemia with 30 control subjects and in these patients we measured levels of sCD40L, hs-CRP and fetuin-A. RESULTS: sCD40L levels were significantly higher in the ET group compared to the control group (30.6±14.4 vs. 18.5±8.9, p=0.001). Although fetuin-A levels showed a slight trend to be increased in ET patients, the difference did not reach significance (4.5±4.2 vs. 3.2±2.1, p=0.158). There were no statistically significant differences in hs-CRP levels (24.6±4.9 vs. 25.0±5.2, p=0.750). CONCLUSION: sCD40L was significantly higher in patients with an ET without any association with an inflammatory process and we believe this may be a marker of platelet regeneration.