Umit Yavuz Malkan

Management of De Novo CML and Imatinib-Induced Acute Rhabdomyolysis With the Second-Generation TKI, Dasatinib

The aim of this report is to describe a newly diagnosed chronic myeloid leukemia (CML) patient who had imatinib mesylate (IM)-induced rhabdomyolysis and tolerated the second-generation tyrosine kinase inhibitor (TKI) dasatinib that controlled CML disease progression without precipitating the already present muscle damage. A 42-year-old man was admitted to the local hospital with left lumbar region pain. He had polycystic kidney disease, and leukocytosis in the routine tests had been observed. The patient admitted to our hematology outpatient unit for the evaluation of leukocytosis. After the investigations, he had been diagnosed as de novo chronic phase CML. In June 2014, he had been given IM 400 mg once a day. He was not taking any other drug. Pain began in both lower extremities 15 days after the start of medication. The patient’s baseline creatinine level was 1.5 mg/dL before the admission. The laboratory tests were as follows: creatinine 1.4 mg/dL, serum calcium and phosphorus levels in normal range, and creatine kinase (CK) levels 1533 U/L. Therefore, the patient was diagnosed as having rhabdomyolysis. The urine was clear in appearance, yellow colored, with a pH of 5, density 1010, protein glucose bilirubin ketone nitrite negative, and urobilinogen normal, with a few erythrocytes and leukocytes. Other causes of rhabdomyolysis (trauma or direct injury, excessive muscle activity, hereditary muscle enzyme defects, drugs and toxins, muscle hypoxia, metabolic and endocrine disorders, infections, temperature alterations, myocardial infarction, and stroke) were ruled out, and rhabdomyolysis was considered to have been caused by IM. We performed the Naranjo algorithm, and the score was 9 points. Therefore, IM treatment was stopped and secondgeneration TKI (dasatinib) was given instead. We preferred dasatinib because there are trials that confirmed the efficiency of dasatinib in patients with imatinib intolerance. Nilotinib could have also been used; however, its molecular mimicry cast doubts that it might cause the same intolerance and/or adverse events in terms of rhabdomyolysis. Two weeks after IM withdrawal, the pain in the patient’s extremities decreased, and CK levels were 195 U/L. His real-time polymerase chain reaction (PCR) analysis revealed that the disease was controlled with dasatinib treatment, and CK levels remained in normal ranges (Figure 1). He is still on follow-up with dasatinib in our clinic, without any sign of rhabdomyolysis. CML is a slowly progressive clonal malignant disease characterized by myeloid neoplastic expansion with heterogeneous clinical manifestations. CML could be functionally cured by the TKI drugs. IM is the first TKI to be used widely for CML treatment. Diarrhea, edema, myalgia, and skin reactions are common side effects of IM. In one previous study, myalgia occurred in 39% versus 22% of newly diagnosed chronic-phase CML patients who were treated with imatinib and dasatinib, respectively. Rarely, IM-induced rhabdomyolysis cases have been reported. Myalgia is a common side effect of IM. However, rhabdomyolysis with CK elevations is quite rare. In such a patient with CML, IM should be discontinued, and second-generation TKIs (such as dasatinib) should be administered. Because rhabdomyolysis recurs with the reintroduction of IM, the patient should be followed up while under secondgeneration TKIs. Dasatinib treatment could be used as an alternative TKI, so that CML remains under control during the rhabdomyolysis phase, and dasatinib does not precipitate the muscle damage with imatinib already present. It would have been better if we had investigated the plasma levels of imatinib in our patient; however, we failed to perform the plasma analyses. The interrelationships between IM and CK elevations are not well known. Some researchers suggest that IM-induced electrolyte imbalance is the reason for CK elevations. However, although our patient had polycystic kidney disease and creatinine levels of 1.4 mg/dL, he had no electrolyte imbalance. Monitoring the CML disease and TKI drug off-target risks are vital in clinical practice. Expected hematological, cytogenetic, and molecular responses to those drugs during the monitoring of CML vary based on some parameters. These parameters are the disease phase, mutational status, resistance profile, molecular BCR-ABL dynamics, compliance, patient drug adherence, and drug adverse effects. If there is myalgia with muscle weakness after the initiation of IM, rhabdomyolysis should be considered. No reports of rhabdomyolysis occurred during the clinical trial conducted for imatinib approval; however, postmarketing surveillance has captured some case reports of rhabdomyolysis. We have compared such cases in Table 1. In these cases, CK; complete blood count, including differential and platelet count; blood urea nitrogen; creatinine; routine electrolytes, including potassium, calcium, 579425 AOPXXX10.1177/1060028015579425Annals of PharmacotherapyMalkan et al research-article2015

Clinical associations, biological risk factors and outcomes of cerebral venous sinus thrombosis.

Objective Cerebral venous sinus thrombosis (CVST) is a rare cerebrovascular disease affecting young adults. The majority of the patients are female. The aim of this study is to assess the clinical associations, risk factors and outcomes of the patients with CVST. Methods The data of 75 patients with CVST admitted to our hospital between 2006 and 2016 were reviewed. Demographic and clinical features and the thrombophilic risk factors of the patients were recorded. The localizations of the thrombi were determined and modified Rankin score at the time of onset and discharge were calculated. Results The majority of our patients (78.7%) were female. Median age was 35 years (16–76). The most common symptom was headache (86.7%). In 82.6% of our patients, inherited or acquired risk factors for thrombosis were detected. Transverse sinus was the most common site of thrombosis followed by sigmoid and superior sagittal sinuses. Two thirds of the patients had involvement of multiple sinuses. The patients with the involvement of sagittal sinus had better disability at the time of admittance (p = 0.013) while the number of involved sinuses was correlated worse disability (p = 0.015). The neurologic states in the majority of the patients were improved by the end of the hospitalization period (p = 0.001). There was no significant difference in disability score at discharge between men and women (p = 0.080). No patient with CVST died in the hospitalization period. Conclusions This study is one of the largest cohort studies on CVST in our region. The results of the study disclosed that CVST had wide range of clinical manifestations and non-specific symptoms at the beginning. For that reason, in especially high risk groups for thrombosis, the diagnosis of CVST should be kept in mind.

Growth inhibitory activity of Ankaferd hemostat on primary melanoma cells and cell lines

Objective: Ankaferd hemostat is the first topical hemostatic agent about the red blood cell–fibrinogen relations tested in the clinical trials. Ankaferd hemostat consists of standardized plant extracts including Alpinia officinarum, Glycyrrhiza glabra, Thymus vulgaris, Urtica dioica, and Vitis vinifera. The aim of this study was to determine the effect of Ankaferd hemostat on viability of melanoma cell lines. Methods: Dissimilar melanoma cell lines and primary cells were used in this study. These cells were treated with different concentrations of Ankaferd hemostat to assess the impact of different dosages of the drug. All cells treated with different concentrations were incubated for different time intervals. After the data had been obtained, one-tailed T-test was used to determine whether the Ankaferd hemostat would have any significant inhibitory impact on cell growth. Results: We demonstrated in this study that cells treated with Ankaferd hemostat showed a significant decrease in cell viability compared to control groups. The cells showed different resistances against Ankaferd hemostat which depended on the dosage applied and the time treated cells had been incubated. We also demonstrated an inverse relationship between the concentration of the drug and the incubation time on one hand and the viability of the cells on the other hand, that is, increasing the concentration of the drug and the incubation time had a negative impact on cell viability. Conclusion: The findings in our study contribute to our knowledge about the anticancer impact of Ankaferd hemostat on different melanoma cells.

Chimeric antigen receptor T cell treatment in hematologic malignancies.

Adoptive transfer of T cells that have genetically engineered chimeric antigen receptors (CARs) is an encouraging treatment modality in the hematological malignancies. These T cells are capable of selectively recognizing tumor-associated antigens. There are a variety of reported, as well as ongoing studies on the utilization of CAR-T cells in the treatment of leukemia, myeloma, as well as B and T cell lymphomas. In this review, we aimed to highlight current understanding of this promising treatment modality, including its efficacy and adverse effects.

Rebound Thrombocytosis following Induction Chemotherapy is an Independent Predictor of a Good Prognosis in Acute Myeloid Leukemia Patients Attaining First Complete Remission.

There are very few data about the relationship between acute myeloid leukemia (AML) prognosis and bone marrow recovery kinetics following chemotherapy. In this study, we aimed to assess the prognostic importance and clinical associations of neutrophil and platelet recovery rates and rebound thrombocytosis (RT) or neutrophilia (RN) in the postchemotherapy period for newly diagnosed AML patients. De novo AML patients diagnosed between October 2002 and December 2013 were evaluated retrospectively. One hundred patients were suitable for inclusion. Cox regression analysis using need for reinduction chemotherapy as a stratification parameter revealed RT as the only parameter predictive of OS, with borderline statistical significance (p = 0.06, OR = 7; 95% CI 0.92-53), and it was the only parameter predictive of DFS (p = 0.024, OR = 10; 95% CI 1.3-75). In order to understand whether RT or RN was related to a better marrow capacity or late consolidation, we considered neutrophil recovery time and platelet recovery time and nadir-first consolidation durations in all patients in the cohort. Both the marrow recovery duration and the time between marrow aplasia and first consolidation were shorter in RT and RN patients. To our knowledge, this is the first study to report a correlation between RT/RN and prognosis in AML.

Lipotoxicity-Related Hematological Disorders in Obesity

Lipotoxicity can mediate endothelial dysfunction in obesity. Altered endothelial cell phenotype during the pathobiological course of the lipotoxicity may lead to the hemostatic abnormalities, which is a hallmark of several hematological disorders. Impaired hemostasis could also be directly related to the numerous metabolic diseases such as hypertension, diabetes and atherosclerosis. On the other hand, local hematopoietic bone marrow (BM) renin-angiotensin system (RAS) contributes to the development of atherosclerosis via acting on the lipotoxicity processes. Local BM RAS, principally an autocrine/ paracrine/ intracrinehematological system, is located at the crossroads of cellular regulation, molecular interactions and the lipotoxicity-mediated vascular endothelial dysfunction. The positive regulatory role of plasma LDL on AT1 receptor-mediated hematopoietic stem cell (HSC) differentiation and the production of pro-atherogenic monocytes had been described. LDL-regulated HSC function may explain in part hypercholesterolemia-induced inflammation as well as the anti-inflammatory and anti-atherosclerotic effects of AT1 receptor blockers. The role of local adipose tissue RAS is directly related to the pathogenesis of metabolic derangements in obesity. There may be a crosstalk between local BM RAS and local adipose tissue RAS at the genomics and transcriptomics levels. The aim of this chapter is to review hematological alterations propagating the pathological influences of lipotoxicity on the vascular endothelium.

Treatment of pyoderma gangrenosum with thalidomide in a myelodysplastic syndrome case.

Thalidomide may be used as a treatment option for pyoderma gangrenosum (PG) and myelodysplastic syndrome (MDS). Herein, we aimed to report a patient who was treated well with thalidomide and whose diagnosis was PG with MDS. A 61-year-old man with painless ecchymotic lesions in his right upper extremity was admitted to the hospital in Isparta, Turkey, in January 2015. The lesions were diagnosed as PG. In his anamnesis, it was found that he was diagnosed with MDS 6 years ago and had been treated with cyclosporine at 2×100 mg for 5 years, which was stopped in January 2015. Aspiration from liver lesion revealed the presence of Mycobacterium tuberculosis, so antituberculosis treatment was started. Bone marrow investigation revealed MDS-refractory anemia with excess blasts (7%). For lesions in bilateral upper extremities, thalidomide treatment was started at 50 mg/d. After 1 month from the initiation of thalidomide treatment, the lesions in upper extremities had disappeared. In the literature, there are some reports of patients with PG who were successfully treated with thalidomide. Our patient is a complicated case who simultaneously has MDS, PG, and tuberculosis infection. The reason for thalidomide usage in our patient was the need of immune modulation without immune suppression. Our patient has tolerated the drug well, and excellent response was obtained after 1 month of initiation of thalidomide treatment. To conclude, thalidomide is a very effective drug acting as an immune modulator, which is useful in the clinical management of both MDS and PG.

Qualitative/Chemical Analyses of Ankaferd Hemostat and Its Antioxidant Content in Synthetic Gastric Fluids

Introduction. Ankaferd hemostat (ABS) is the first topical haemostatic agent involving the red blood cell-fibrinogen interactions. The antihemorrhagic efficacy of ABS has been tested in controlled clinical trials. The drug induces the formation of an encapsulated complex protein web with vital erythroid aggregation. The aim of this study is to detect the essential toxicity profile and the antioxidant molecules inside ABS. Methods. The pesticides were analyzed by GC-MS and LC-MS. The determination by ICP-MS after pressure digestion was performed for the heavy metals. HPLC was used for the detection of mycotoxins. Dioxin Response Chemically Activated Luciferase Gene Expression method was used for the dioxin evaluation. TOF-MS and spectra data were evaluated to detect the antioxidants and other molecules. Results. TOF-MS spectra revealed the presence of several antioxidant molecules (including tocotrienols, vitamin E, tryptophan, estriol, galangin, apigenin, oenin, 3,4-divanillyltetrahydrofuran, TBHQ, thymol, BHA, BHT, lycopene, glycyrrhetinic acid, and tomatine), which may have clinical implications in the pharmacobiological actions of ABS. Conclusion. The safety of ABS regarding the presence of heavy metals, pesticides, mycotoxins, GMO and dioxins, and PCBs was demonstrated. Thus the present toxicological results indicated the safety of ABS. The antioxidant content of ABS should be investigated in future studies.

Effect of postremission high dose cytarabine-based consolidation chemotherapy before allogenic stem cell transplantation in outcomes of acute myeloid leukemia patients

BACKGROUND AND AIM This is a retrospective study aiming to investigate the effect of the number of high dose cytarabine-based chemotherapy (HiDAC) courses in patients with acute myeloid leukemia before allogenic stem cell transplantation (ASCT). MATERIALS AND METHODS A total of 110 patients with acute myeloid leukemia who received ASCT between 2001 and 2018 were included in the study. RESULTS Of the 110 patients, 25 (23%) patients received one course of HiDAC, 42 (38%) patients received two courses of HiDAC, 34 (31%) patients received three courses of HiDAC and 9 (8%) patients received four courses of HiDAC. Median follow-up for survivors was 71 months (range 4-186) for all patients. The 3-year overall survival for patients who received one course of HiDAC and patients who received more than one course of HiDAC were 49% and 70%, respectively (p = 0.29). The 3-year disease free survival (DFS) for patients who received one course of HiDAC and patients who received more than one course of HiDAC were 38% and 66%, respectively (p = 0.05). There was no statistically significant difference in OS between patients who received one or more than one consolidation chemotherapy. But there was nearly a statistically significant difference between patients who received one or more than one consolidation chemotherapy in DFS. CONCLUSION In conclusion, the administration of more than one consolidation chemotherapy may provide longer DFS, however the number of consolidation chemotherapy is not associated with statistically significant differences in overall outcomes.

Sole Infrequent Karyotypic Aberration Trisomy 6 in a Patient with Acute Myeloid Leukemia and Breast Cancer in Remission

Thank you very much for your valuable comments and sharing your experience. We agree for your contribution. In thalassemia patients, several transplantation centers categorised risk factors prior to allogenic hematopoietic stem cell transplantation. Pesaro classification assigned patients to three arms according to the absence or presence of one, two or three risk factors: hepatomegaly > 2 cm, portal fibrosis, and irregular chelation history [1]. It should be kept in mind that in a study by Ghavamzadeh et al., liver iron overload did not change after transplant (p=0.61) but hepatic fibrosis progressed (p=0.01) [2]. Allogeneic stem cell transplantation did not reduce liver iron overload and in fact liver fibrosis increased. Also steps for reducing iron overload should be taken in the post transplant setting [3]. Iron overload is still an essential issue in both pre and post transplant settings. Survival in transfusion-dependent thalassemia patients can be improved with proper understanding of the pathophysiology of thalassemia and iron toxicity.