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.

A National Registry of Thalassemia in Turkey: Demographic and Disease Characteristics of Patients, Achievements, and Challenges in Prevention.

OBJECTIVE: The Turkish Society of Pediatric Hematology set up a National Hemoglobinopathy Registry to demonstrate the demographic and disease characteristics of patients and assess the efficacy of a hemoglobinopathy control program (HCP) over 10 years in Turkey. MATERIALS AND METHODS: A total of 2046 patients from 27 thalassemia centers were registered, of which 1988 were eligible for analysis. This cohort mainly comprised patients with ß-thalassemia major (n=1658, 83.4%) and intermedia (n=215, 10.8%). RESULTS: The majority of patients were from the coastal areas of Turkey. The high number of patients in Southeastern Anatolia was due to that area having the highest rates of consanguineous marriage and fertility. The most common 11 mutations represented 90% of all ß-thalassemia alleles and 47% of those were IVS1-110(G->A) mutations. The probability of undergoing splenectomy within the first 10 years of life was 20%, a rate unchanged since the 1980s. Iron chelators were administered as monotherapy regimens in 95% of patients and deferasirox was prescribed in 81.3% of those cases. Deferasirox administration was the highest (93.6%) in patients aged <10 years. Of the thalassemia major patients, 5.8% had match-related hemopoietic stem cell transplantation with a success rate of 77%. Cardiac disease was detected as a major cause of death and did not show a decreasing trend in 5-year cohorts since 1999. CONCLUSION: While the HCP has been implemented since 2003, the affected births have shown a consistent decrease only after 2009, being at lowest 34 cases per year. This program failure resulted from a lack of premarital screening in the majority of cases. Additional problems were unawareness of the risk and misinformation of the at-risk couples. In addition, prenatal diagnosis was either not offered to or was not accepted by the at-risk families. This study indicated that a continuous effort is needed for optimizing the management of thalassemia and the development of strategies is essential for further achievements in the HCP in Turkey.

A case of ulcerative colitis with digital arterial thrombosis.

Thromboembolic events are rare in the course of ulcerative colitis and related with the activity of the disease. These complications are especially seen in young patients and cause high mortality and morbidity. Arterial thrombotic complications are less frequent and are usually seen after a surgical procedure. Here, we present a 36-year-old man with active ulcerative colitis presenting via digital arterial thrombosis and digital necrosis that was not associated with a surgical procedure.

Aberrations of chromosomes 9 and 22 in acute lymphoblastic leukemia cases detected by ES-fluorescence in situ hybridization.

A reciprocal translocation between chromosomes 9 and 22 creates oncogenic BCR/ABL fusion in the breakpoint region of the derivative chromosome 22. The aim of this study was to evaluate the importance of atypical fluorescence in situ hybridization (FISH) signal patterns in pediatric and adult acute lymphoblastic leukemia (ALL) cases. We evaluated t(9;22) translocation in 208 cases with ALL (294 tests), including 139 childhood and 69 adult cases by FISH technique using BCR/ABL extra signal (ES) probe. FISH signal patterns observed in pediatric ALL cases were as follows; Major-BCR/ABL (M-BCR/ABL) (1.4%), minor-BCR/ABL (m-BCR/ABL) (3.6%), trisomy 9 (4.3%), trisomy 22 (4.3%), trisomy or tetrasomy of both chromosomes 9 and 22 (2.9%), monosomy 9 (1.4%), monosomy 22 (0.7%), ABL gene amplification (1.4%), derivative chromosome 9 deletion (1.4%), and extra copies of the Philadelphia chromosome (1.4%). FISH signal patterns observed in adult ALL cases were as follows; M-BCR/ABL (5.8%), m-BCR/ABL (11.6%), two different cell clones with major and minor BCR/ABL signal pattern (2.9%), extra copies of Philadelphia chromosome (4.3%), derivative chromosome 9 deletion (1.4%), trisomy 9 (2.9%), tetraploidy (1.4%), monosomy 9 (1.4%), trisomy 22 (1.4%), and coexistence of both trisomy 22 and monosomy 9 (1.4%). Trisomy 9, trisomy 22, and polyploidy of chromosomes 9 and 22 were specific atypical FISH signal patterns for childhood B cell acute lymphoblastic leukemia (B-ALL) patients. However, monosomy 9 and ABL gene amplification were highly specific for childhood T cell acute lymphoblastic leukemia (T-ALL) patients. Our report presents the correlation between atypical FISH signal patterns and clinical findings of a large group of ALL cases.

Array comparative genomic hybridization analysis of adult acute leukemia patients.

We have performed a retrospective array-based comparative hybridization (array-CGH) study on 41 acute leukemia samples [n=17 acute lymphoblastic leukemia (ALL) patients only at diagnosis, n=3 ALL patients both at diagnosis and relapse; n=20 acute myeloid leukemia (AML) patients only at diagnosis and n=1 AML patient both at diagnosis and relapse] using an Agilent 44K array. In addition to previously detected cytogenetic aberrations, we observed cryptic aberrations in 95% of ALL and 90.5% of AML cases. ALL-specific recurrent abnormalities were RB1 (n=3), PAX5 (n=4), and CDKN2B (n=3) deletions; AML-specific recurrent abnormalities were HOXA9 and HOXA10 (n=2) deletions and NOTCH1 duplication (n=2). Recurrent duplication of the ELK1 oncogene was observed in both ALL (n=2) and AML (n=3) cases. Our results demonstrate that oligo-array CGH (oaCGH) is an effective method for defining copy number alterations and identification of novel recurring unbalanced abnormalities. At least for now, however, the use of oaCGH for routine diagnosis still has some restrictions.

Microsatellite instability is a common finding in multiple myeloma.

PURPOSE: Microsatellite instability (MSI) occurs as a result of sliding in the DNA sequences from shortening or elongation of the repeat zones of DNA during replication. Such abnormalities can normally be corrected by the enzymes coded by the DNA mismatch repair (MMR) genes. Therefore, detection of MSI is considered to be a sign of disorder of the MMR genes and is interpreted as a replication error phenotype. PATIENTS AND METHODS: We evaluated the MSI in 5 different loci in the 14q32 region of immunoglobulin heavy chain IgH gene in 26 newly diagnosed patients with multiple myeloma (MM). RESULTS: Fifty-four percent of the patients disclosed MSI and at least 1 locus but no significant association of MSI was found between different clinical stages and the MM subtype. MSI was not found in 5 light-chain myeloma patients. CONCLUSION: Although our case number is small, probably the genomic instability in heavy-chain MM may be a common finding and probably plays a critical role in the MM pathogenesis.

Thrombin activatable fibrinolysis inhibitor and other hemostatic parameters in patients with polycystic ovary syndrome.

OBJECTIVES: To investigate the plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) in women with polycystic ovary syndrome (PCOS) and its correlation with various metabolic, hormonal and hemostatic parameters. METHODS: Forty-eight women with PCOS and 43 age- and BMI-matched ovulatory controls were recruited during a 20-month study period. Blood samples were drawn for all tests, which included plasma lipids and lipoproteins, reproductive hormones, glucose, insulin, TAFI antigen concentration, plasminogen activator inhibitor-1 (PAI-1) activity, fibrinogen concentration, thrombomodulin, thrombin-antithrombin (TAT) complexes, D-dimer, Protein C Antigen, Protein S Antigen, Antithrombin III (AT III) and activated protein C (APC) resistance. RESULTS: Plasma TAFI levels of PCOS patients were found to be significantly higher than in healthy controls (93.8%+/-30.6%vs. 79.8% +/- 22.4%, p < 0.05). Plasma levels of D-dimer, AT III, PAI-1 and thrombomodulin were also significantly higher in women with PCOS compared with healthy controls. All the other hemostatic parameters (including TAT complexes; Protein C; APC; and Protein S) were comparable between the two study groups. CONCLUSION: This study showed that plasma levels of TAFI, PAI-1, D-dimer, AT III and thrombomodulin were significantly increased in women with PCOS compared with age- and BMI-matched controls.

Bleomycin, etoposide and cisplatin (BEP) combination with concurrent imatinib mesylate (GLEEVEC) in chronic myeloid leukemia (CML) patient with mesenchymal tumor.

Imatinib is now indicated as the first line therapy for chronic myeloid leukemia (CML). Treatment of CML with imatinib is generally well tolerated and the risk of severe adverse affects is low. Many new drugs including targeted therapy are combined with antineoplastic agents safely. We here report a patient with CML who developed concurrent mesenchymal tumor while undergoing therapy with imatinib and treated with combination chemotherapy including bleomycin, etoposide, and cisplatin, as well as imatinib without severe toxicity.

Hodgkin's lymphoma initially presenting with polymyalgic symptoms: a case report.

The association of polymyalgic symptoms and lymphoma is a rare event whose pathogenesis remains to be clarified. Here, we describe a case of a 75-year old man with Hodgkin's lymphoma, who had presented with polymyalgic symptoms suggesting polymyalgia rheumatica. An intensive investigation with respect to malignancy was initially negative. Corticosteroid treatment was administered first and a dramatic clinical improvement was achieved. Four months later, when the corticosteroid treatment was tapered off, the initial manifestations reappeared. After the development of lymph node enlargement, the patient was diagnosed by lymph node biopsy as having Hodgkin's lymphoma. The lymphadenopathy and musculoskeletal manifestations all responded well to chemotherapy. Hodgkin's lymphoma should be considered in the differential diagnosis of PMR. These musculoskeletal syndromes should alert the physician to possible paraneoplastic manifestations of an evolving neoplasm.

Unusual extramedullary hematopoiesis in a patient receiving granulocyte colony-stimulating factor.

A 42-year-old woman was diagnosed with myelodysplastic syndrome with fibrosis that developed bilaterally, cervical lymphadenopathy and cutaneous infiltration by trilineage extramedullary hematopoiesis after granulocyte colony-stimulating factor therapy because of severe neutropenia. Hepatosplenomegaly was not observed during her follow-up. Extramedullary hematopoiesis disappeared after growth factor therapy was stopped. Although the neutropenia was alleviated by growth factor administration, the appearance of an unusual involvement of extramedullary hematopoiesis should be kept in mind.

Hypercalcemia and Multiple Pathological Fractures in Chronic Lymphocytic Leukaemia: A Case Report.

Hypercalcemia is common in some lymphoproliferative disorders such as myeloma or T- cell leukaemialymphoma, but is rarely described in B-cell chronic lymphocytic leukaemia (CLL). A CLL patient who have been presented with multiple pathological fractures and widespread osteolytic lesions is reported. He was a 74 year old male with fractures of his bilateral humerus and radii and multiple osteolytic lesions of skull, fibula, femur and costals. On his admission to the hospital for the fractures he has been diagnosed as CLL. Hypercalcemia has also been documented. All the disorders that could be the reason of hypercalcemia have been ruled out. The open biopsy of bone marrow showed lymphocytic infiltration in which increased number of prolymphocytes are observed. Hypercalcemia arising in a patient with CLL may indicate a negative prognosis.

Extramedullary Presentation of Biclonal IgGk and IgAk Multiple Myeloma.

Multiple myeloma is characterized by plasma cell infiltration of the bone marrow and the presence of a monoclonal protein in the plasma or the urine in 90% of cases. Major manifestations of the disease are bone pain, anemia, renal insufficiency and recurrent infections. Less frequent presentations are hepatic and splenic enlargement (5% of cases), lymphadenopathy (4%) and biclonal gammopathy (1%). In this report we describe a biclonal multiple myeloma presenting with cervical lymphadenopathy and sternal mass. The immunohistochemical study of the lymph node and the flow cytometric analysis of the bone marrow showed IgGk and IgAk biclonality. In this report the features of lymph node involvement and biclonality constitute a rare presentation of multiple myeloma.