Real world results of venetoclax combined with hypomethylating agents in relapsed/refractory AML.

OBJECTIVE: Relapsed/refractory AML cases are much more resistant to chemotherapy. Venetoclax is a highly sensitive BCL-2 inhibitor. It was aimed to evaluate the effects of venetoclax therapy on real-world R/R AML survival outcomes, the effects of the cytogenetic characteristics of the patients and previous clinical applications on treatment response, and venetoclax treatment toxicity. PATIENTS AND METHODS: The study included patients who only received a venetoclax-based salvage on R/R AML patients from Turkey. The study included a total of 62 patients from 6 different centers in Turkey. Response to 2 cycles of venetoclax treatment was assessed by bone marrow blast rate. The demographic data, cytogenetic characteristics, AML type, MDS type, response rates and overall survival of the patients after venetoclax combination treatment were assessed. Median age of the patients was 65 (19-85). Mean number of prior treatments was 2.67 ±1.75. RESULTS: 13 patients (21%) had a history of allogenic stem cell transplantation. 58 (93.5%) had received HMA therapy before venetoclax. 36 patients (58.1%) had de-novo AML, and 25 (40.3%) previously had MDS. Treatment response was evaluated as complete remission (n = 21, 33.9%), partial response (n = 17, 27.4%), and treatment failure (n = 24, 38.7%). Patients in the TF group were significantly more likely to have poor cytogenetic and to have received allogeneic transplants. The mean estimated overall survival after the venetoclax treatment was 9.13 ± 0.75 months. CONCLUSIONS: The study population consisted of a group of patients who had relapsed or primary refractory disease with poor prognosis, despite numerous rounds of chemotherapy. It is our belief that the high response rates obtained with the combination of venetoclax/HMA, and having obtained positive results with poor risk patients, indicated a promising perspective for R/R AML patients.

Prognostic significance of flow cytometry findings in Turkish adult acute leukemia patients.

OBJECTIVE: Several factors are known to affect prognosis of acute leukemia such as age, high leukocyte count, cytogenetic abnormality, performance status and recurrent leukemia. We aimed to investigate the association between cell surface markers and prognostic determinants such as recurrence at 6 and 12 months and survival at 6, 12 and 18 months in acute leukemia patients. PATIENTS AND METHODS: A total of 142 patients, 101 with acute myeloid leukemia (AML) and 41 with B-cell acute lymphoblastic leukemia (B-ALL) were included. The effects of surface markers on survival and recurrence rates were evaluated retrospectively. RESULTS: In AML patients, CD5+ and CD34+ immunophenotypes and in ALL patients cCD22+, CD34+ and CD49f + CD19+ immunophenotypes were positive prognostic indicators. In AML patients CD7 expression, and in ALL patients CD5+, CD7+ and CD117+ immunophenotypes and >90% CD45 expression were negative prognostic indicators. CONCLUSIONS: This study demonstrates that flow cytometry, a common diagnostic tool in acute leukemia, may also have prognostic value in acute leukemia in the future.

Association of the PTPN22 gene polymorphism with autoantibody positivity in Turkish rheumatoid arthritis patients.

The PTPN22 C1858T gene polymorphism has been recently reported to be associated with rheumatoid arthritis (RA) in European and North American ancestry. In contrast, the frequency of PTPN22 C1858T polymorphism is extremely rare in Asian and African populations. As the genetic heterogeneity between populations is clearly present in RA, we wanted to investigate whether the PTPN22 C1858T polymorphism is associated with RA in Turkey and with autoantibody positivity. A total of 323 RA patients and 426 healthy controls were genotyped by polymerase chain reaction restriction fragment length polymorphism for the PTPN22 C1858T polymorphism (rs2476601). The frequencies of heterozygote genotype (CT) were 8.4% in RA patients and 5.4% in the healthy controls, respectively [odds ratio (OR): 1.6, P = 0.14]. The homozygote genotype (T/T) was absent in both RA patients and the healthy controls. When compared with the healthy controls, we found the significant associations between the frequency of PTPN22 heterozygote (CT) polymorphism and RA patients with RF positivity and anti-CCP positivity, respectively (OR: 2.05, P = 0.04 and OR: 2.1, P = 0.03, respectively). Our study suggests that the PTPN22 C1858T polymorphism acts as a susceptibility gene for autoantibody-positive RA in Turkey.

Coagulopathy parameters in patients with Crimean-Congo hemorrhagic fever and its relation with mortality.

BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is an acute illness affecting multiple organ systems and characterized by ecchymosis, visceral bleeding, and hepatic dysfunction. In this study, we aimed to investigate the profile of coagulopathy markers (platelet count, activated partial tromboplastin time (aPTT), prothrombin time (PT), international normalized ratio (INR), fibrinogen, protein C, protein S, antithrombin III, activated protein C resistance (APCR), and D-dimer) and their clinical significance in 83 CCHF-infected patients. SUBJECTS AND METHODS: We studied 83 CCHF patients who were admitted to Ankara Numune Education and Research Hospital during the spring and summer of2007. We compared the coagulopathy markers of fatal CCHF patients (n=9) with nonfatal cases (n=74). RESULTS: Platelet count, PT, aPTT, INR, and fibrinogen were prognostic factors associated with mortality for CCHF. Especially, platelet count<20 x 10(9) cells/l and aPTT>60 sec were important. Protein C, protein S, APCR, and antithrombin III levels were not associated with mortality. CONCLUSION: Laboratory tests including classical parameters (platelet count, PT, aPTT, INR, and fibrinogen) of coagulopathy seem to be enough for the followup of CCHF. Protein S, protein C, APCR, and D-dimer levels were not associated with mortality.

Effects of imatinib mesylate on renin-angiotensin system (RAS) activity during the clinical course of chronic myeloid leukaemia.

The renin-angiotensin system (RAS) is involved in cell growth, proliferation and differentiation in bone marrow in an autocrine-paracrine manner, and it modulates normal and neoplastic haematopoietic cell proliferation. This study aimed to assess expressions of the RAS components, renin, angiotensinogen and angiotensin-converting enzyme (ACE), during imatinib mesylate treatment of patients with chronic myeloid leukaemia (CML). Expressions of RAS components were studied in patients with CML at the time of diagnosis (n = 83) and at 3, 6 and 12 months after diagnosis (n = 35) by quantitative real-time polymerase chain reaction. De novo CML patients had increased ACE, angiotensinogen and renin mRNA levels and these expression levels decreased following administration of imatinib. The RAS activities were significantly different among Sokal risk groups of CML, highlighting the altered biological activity of RAS in neoplastic disorders. The results of this study confirm that haematopoietic RAS affects neoplastic cell production, which may be altered via administration of tyrosine kinase inhibitors such as imatinib mesylate.

The relation between plasminogen activator inhibitor activity and disease activation in acute myeloblastic leukaemia patients.

Coagulation and fibrinolytic abnormalities are common in patients with acute myeloblastic leukaemia (AML) like other forms of leukaemias. In this study, we investigated if total plasminogen activator inhibitor (PAI) activity, which is believed to increase in initial diagnosis and relapse in AML patients could be accepted as a relapse criterion or not. Total of 34 AML patients and 18 healthy volunteers were included in this study. The patients' diagnosis were based on clinical criteria as well as morphological, cytochemical, immunuphenotypic examinations of peripheral blood and bone marrow specimens. Total PAI activity was measured with Dade Behring Bericrom PAI reagent in BCS system. Total PAI activity was higher than 3.5 U/ml in 11 AML patients while it was normal (0.3-3.5 U/ml) in control group (P < 0.01). There was no significant difference in total PAI activity between AML subgroups (P > 0.05). We found significant difference in total PAI activity between patients who have active disease and remission. In conclusion, the total PAI activity could be accepted as a relapse and an initial diagnosis criterion of AML patients during follow up.

Plasma levels of thrombin-activatable fibrinolysis inhibitor in primary and secondary thrombocytosis.

An elevated platelet count is a common finding in both hospitalized and ambulatory patients. Thrombosis and bleeding complications are more frequently observed in patients with clonal thrombocytosis than secondary thrombocytosis. The aim of this study was to investigate the behaviors of thrombin-activatable fibrinolysis inhibitor (TAFI) activity, the inhibitor of fibrinolysis, and also prothrombin time (PT), active partial thromboplastin time, and D-dimer and fibrinogen levels in 21 patients affected with clonal thrombocytemia as compared with 21 patients with reactive thrombocytosis and 21 healthy controls. In the clonal thrombocytemia group, plasma levels of TAFI activity were significantly higher than in both the reactive thrombocytosis and the control group. Plasma levels of leukocyte and platelet counts were significantly higher in the clonal thrombocytemia group than in the other two groups and also higher in the reactive thrombocytosis group than in the control group, which was also significant. Fibrinogen and D-dimer levels were higher in patients than in the control group but showed no significant difference between the clonal and secondary thrombocytosis groups. Plasma levels of PT and aPTT were higher in secondary thrombocytosis group than the clonal thrombocytosis group. The results of this study showed for the first time that TAFI activity is increased in patients with clonal thrombocytosis. These increased levels in clonal thrombocytosis can be considered a factor to explain the thrombotic tendency in myeloproliferative disorders.

High-dose thiotepa, melphalan and carboplatin (TMCb) followed by autologous stem cell transplantation in patients with advanced breast cancer: a retrospective evaluation.

This study was conducted to evaluate the efficacy of high-dose thiotepa, melphalan and carboplatin (TMCb) regimen in 27 patients undergoing autologous stem cell transplantation (ASCT) for metastatic breast cancer. A total of 27 patients with stage IV breast cancer underwent ASCT following thiotepa (500 mg/m(2)), melphalan (100 mg/m(2)) and carboplatin (1200-1350 mg/m(2)). Of 27 patients, 17 had refractory relapse, eight had responding relapse, and two had no evidence of disease (NED) at the time of transplant. In all, 11 patients had only bone disease, nine had bone plus visceral disease, three had only visceral disease, and two had locoregional recurrent disease. The median time from diagnosis to transplant was 1081 days (range 180-2341). Staging for evaluation of response was performed 4-6 months after transplantation. Five patients were not evaluable (NE) for response because of NED at transplant (n=2) or early death due to transplant-related complications (n=3) (two of viral pneumonia and one of regimen-related toxicity) occurring at a median of 4 days (range 11-46) post-transplant. One of the two patients who was NED at the time of transplant is still NED on day 760 post-transplant. Seven of 15 refractory (47%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft-tissue disease with at least improvement in bone lesions. Of 27 patients (37%),(10) are alive and progression-free, a median of 582 days (range 410-1380) after treatment, 6/17 (35%) with refractory disease and 4/10 (40%) with responsive disease. The probability of progression-free survival (PFS) for all patients was 0.50. The probabilities of PFS at 2 years for patients with refractory (n=17) and responsive (n=10) disease were 0.42 and 0.60, respectively. PFS at 2 years for the 14 patients who were NED or achieved CR/PR(*) following-HDC was 0.67. PFS at 2 years for patients who did not achieve CR/PR(*) following-DHC was 0.33. These preliminary data suggest that high-dose TMCb followed by autologous stem cell transplantation is an effective regimen for patients with advanced breast cancer and may be comparable to some previously used regimens.

Mobilization of peripheral blood stem cells with chemotherapy and recombinant human granulocyte colony-stimulating factor (rhG-CSF): a randomized evaluation of different doses of rhG-CSF.

To date, no randomized study has compared different doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF) following submyeloablative mobilization chemotherapy. Therefore, we evaluated the effect of different doses of rhG-CSF following mobilization chemotherapy on yields of CD34+ peripheral blood stem cells (PBSC). Fifty patients were randomized to receive 8 (n = 25) versus 16 microg/kg/d (n = 25) of rhG-CSF following mobilization chemotherapy. The median number of CD34+ cells collected after 8 microg/kg/d of rhG-CSF was 2.36 x 10(6)/kg (range, 0.21-7.80), compared with 7.99 (2.76-14.89) after 16 microg/kg/d (P < 0.001). Twenty out of 25 (80%) patients in the low-dose and 23 out of 25 (92%) in the high-dose rhG-CSF arm underwent high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Median days to white blood cell engraftment in patients mobilized with 8 microg/kg and 16 microg/kg of rhG-CSF were 12 (10-20) and 9 (8-11) respectively (P < 0.001). There was no difference between the two groups regarding the other parameters of peritransplant morbidity: days to platelet engraftment (P = 0.10), number of red blood cell (P = 0.56) and platelet transfusions (P = 0.22), days of total parenteral nutrition requirement (P = 0.84), fever (P = 0.93) and antibiotics (P = 0.77), and number of different antibiotics used (P = 0.58). These data showed that higher doses of rhG-CSF following submyeloablative mobilization chemotherapy were associated with a clear dose-response effect based on the collected cell yields. Based on the parameters of peritransplant morbidity, 8 microg/kg/d was as effective as 16 microg/kg/d except for a rapid neutrophil engraftment in the high-dose arm. Therefore, in routine clinical practice, despite some advantage in the use of higher doses of rhG-CSF, lower doses may be used for PBSC collections following chemotherapy-based mobilization regimens in this cost-conscious era.

Primary non-Hodgkin's lymphoma of the liver (case report).

Primary non-Hodgkin's lymphoma of the liver is very uncommon, and fewer than 100 cases have been reported in the literature. Most reports describe either solitary or multiple mass lesions in the liver. A diffuse lesion without nodule formation is a relatively rare form of the disease. The histologic feature of the disease is a predominantly large cell lymphoma of B-cell lineage. We report a case of primary B-cell non-Hodgkin's lymphoma which had diffusely infiltrated the liver without nodule formation.

Massive Intraabdominal Relapse in a Patient with Acute Lymphocytic Leukemia.

Abdominal involvement in an isolated extramedullary relapse region in patients with acute lymphocytic leukemia (ALL) is a rare event, especially in patients in hematological remission. The literature related to this subject is very limited. In this study, a 23-year-old male patient, is presented who had been in remission for 4 years, was admitted because of an enlarged testis, and was found to have an abdominal bulky mass during physical examination. An early diagnosis of abdominal involvement is extremely important and must be kept in mind for ALL patients who are admitted for testicular relapse.

Protein C and protein S activities in Behçet's disease as risk factors of thrombosis.

BACKGROUND: In Behçet's disease (BD), there is a marked increase in vascular complications. Approximately 30% of patients with BD suffer from thrombosis of the arteries and veins, varices, aneurysms, and thrombophlebitis of superficial or deep veins. Protein C and Protein S are major inhibitors of coagulation, and it is well known that the deficiency of Protein C and Protein S causes thrombotic disorders. METHODS: Protein C and Protein S activities were measured in 23 patients with BD and in a control group consisting of 23 age- and sex-matched healthy volunteers. Patients who had received anticoagulant or oral contraceptive drugs, or who had liver disease or active thrombosis, were not included in the study. RESULTS: Of the 23 patients with BD (age, 13-55 years), the mean Protein S activities (94.2 +/- 11.3%) were slightly lower than the means of the control group (109.1 +/- 8.4%), but not statistically significant differences could be demonstrated (p > 0.05). Compared with the means of the control group (103.5 +/- 6.9%), the Protein C activities were not lower in BD (106.3 +/- 8.4%). No statistical difference was determined. CONCLUSIONS: Protein C and Protein S deficiencies are not a probable cause of thrombotic manifestations in BD. We do not recommend the measurement of these activities routinely in BD unless thrombosis is the major and primary manifestation of BD.

Development of hyperthyroidism during long term interferon therapy in a patient with chronic myelogenous leukemia: case report.

In this case report a patient with thyroid dysfunction who received chronic treatment with interferon-alpha (INF-alpha) following a diagnosis of chronic myelogenous leukemia (CML) is described. Generally INF-alpha induced dysthyroidism develops in the earlier phase of INF-alpha treatment. This is a case report of thyroid dysfunction which occurred 4 years after the patient began to receive INF-alpha administration. In addition, INF-alpha was administered to this patient for a longer period than those reported in the literature.