Gursel Gunes

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.

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.

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.

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.

Expression Profiles of the Individual Genes Corresponding to the Genes Generated by Cytotoxicity Experiments with Bortezomib in Multiple Myeloma

Objective: Multiple myeloma (MM) is currently incurable due to refractory disease relapse even under novel anti-myeloma treatment. In silico studies are effective for key decision making during clinicopathological battles against the chronic course of MM. The aim of this present in silico study was to identify individual genes whose expression profiles match that of the one generated by cytotoxicity experiments for bortezomib. Materials and Methods: We used an in silico literature mining approach to identify potential biomarkers by creating a summarized set of metadata derived from relevant information. The E-MTAB-783 dataset containing expression data from 789 cancer cell lines including 8 myeloma cell lines with drug screening data from the Wellcome Trust Sanger Institute database obtained from ArrayExpress was “Robust Multi-array analysis” normalized using GeneSpring v.12.5. Drug toxicity data were obtained from the Genomics of Drug Sensitivity in Cancer project. In order to identify individual genes whose expression profiles matched that of the one generated by cytotoxicity experiments for bortezomib, we used a linear regression-based approach, where we searched for statistically significant correlations between gene expression values and IC50 data. The intersections of the genes were identified in 8 cell lines and used for further analysis. Results: Our linear regression model identified 73 genes and some genes expression levels were found to very closely correlated with bortezomib IC50 values. When all 73 genes were used in a hierarchical cluster analysis, two major clusters of cells representing relatively sensitive and resistant cells could be identified. Pathway and molecular function analysis of all the significant genes was also investigated, as well as the genes involved in pathways. Conclusion: The findings of our present in silico study could be important not only for the understanding of the genomics of MM but also for the better arrangement of the targeted anti-myeloma therapies, such as bortezomib.

The Prognosis Of Adult Burkitt's Cell Leukemia In Real-Life Clinical Practice.

Objective: Many studies reported an improved prognosis in patients with Burkitt’s lymphoma obviating the need of stem cell transplantation. However, prognosis of the advanced disease [i.e. Burkitt’s cell leukemia (BCL)] has not been reported with current treatment modalities except for a few prospective trials. The aim of this study is to compare the prognoses of BCL patients with similarly treated and nontransplanted patients with other types of acute lymphoblastic leukemia (ALL) and with ALL patients that underwent allogeneic stem cell transplantation (ASCT) in their first remissions. Materials and Methods: In this retrospective analysis, BCL patients aged between 16 and 63 who were admitted between 2000 and 2014 to the hospitals of Hacettepe or Gazi University and were treated with intensive therapies aimed at cure were included. All ALL patients who were treated with a similar protocol not including transplantation during the same period (NT-ALL group) and all ALL patients who underwent ASCT in the first complete remission during the same period (T-ALL group) served as control groups. Results: The central nervous system or extramedullary involvement rates, lactate dehydrogenase levels, and white blood cell counts at diagnosis were higher in the BCL group than the NT-ALL group and these differences were significant. BCL patients had disease-free survival (DFS) durations comparable with the T-ALL cohort but NT-ALL patients had significantly shorter DFS durations. Both cumulative relapse incidence and cumulative nonrelapse mortality were higher in NT-ALL patients compared to the T-ALL group and BCL patients. Conclusion: DFS in BCL patients treated with a widely accepted modern regimen, R-HyperCVAD, is comparable to results in other ALL patients receiving allogeneic transplantation. Our results are in agreement with a few prospective noncomparative studies suggesting no further need for stem cell transplantation in BCL.

Melanonychia Secondary to Long-Term Treatment with Hydroxycarbamide: An Essential Thrombocytosis Case.

Hydroxycarbamide is used in the treatment of essential thrombocytosis and other myeloproliferative disorders. We report the case of a 63-year-old woman with essential thrombocytosis who had melanonychia after the long-term use of the hydroxycarbamide with a dose of 1000 mg/day. Two years after the initiation of the hydroxycarbamide, our patient had pain on her toes and melanonychia on her nails. Hydroxycarbamide treatment was discontinued because of pain and she was given anagrelide treatment. The pathogenesis of melanonychia secondary to long-term hydroxycarbamide treatment is not yet well understood. Some investigators suggested that genetic factors, induction of melanocytes, and some changes in nail matrix could be the reason of hydroxycarbamide related melanonychia. Our patient has suffered color changes in her nails as well as pain that made us doubtful for a beginning of ulceration besides melanonychia. Maybe early clinical reaction of discontinuation of the drug has prevented more severe side effect like ulceration in our patient. Also side effect of hydroxycarbamide has developed more slowly in our patient compared to other patients in the mentioned study. To conclude, long-term hydroxycarbamide treatment can cause mucocutaneous side effects and more studies should be done in future in order to reveal the underlying mechanism.

Late Onset and Protracted Course of Steroid Refractory Chronic Graft-versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) is one of the most important causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). Occurring in 30% to 70% of patients, cGVHD has a median time to onset of 4 to 6 months and most cases present within 2 years after aHSCT. Here, we present a patient transplanted at the age of 55 who developed refractory cutaneous cGVHD more than 5.5 years after aHSCT.