Ayse Isik

EUTOS CML prognostic scoring system predicts ELN-based ‘event-free survival’ better than Euro/Hasford and Sokal systems in CML patients receiving front-line imatinib mesylate

Abstract Objectives The validity of the three currently used chronic myeloid leukemia (CML) scoring systems (Sokal CML prognostic scoring system, Euro/Hasford CML scoring system, and the EUTOS CML prognostic scoring system) were compared in the CML patients receiving frontline imatinib mesylate. Patients and methods One hundred and fourty-three chronic phase CML patients (71 males, 72 females) taking imatinib as frontline treatment were included in the study. The median age was 44 (16–82) years. Median total and on-imatinib follow-up durations were 29 (3.8–130) months and 25 (3–125) months, respectively. Results The complete hematological response (CHR) rate at 3 months was 95%. The best cumulative complete cytogenetic response (CCyR) rate at 24 months was 79.6%. Euro/Hasford scoring system was well-correlated with both Sokal and EUTOS scores (r = 0.6, P < 0.001 and r = 0.455, P < 0.001). However, there was only a weak correlation between Sokal and EUTOS scores (r = 0.2, P = 0.03). The 5-year median estimated event-free survival for low and high EUTOS risk patients were 62.6 (25.7–99.5) and 15.3 (7.4–23.2) months, respectively (P < 0.001). This performance was better than Sokal (P = 0.3) and Euro/Hasford (P = 0.04) scoring systems. Overall survival and CCyR rates were also better predicted by the EUTOS score. Discussion EUTOS CML prognostic scoring system, which is the only prognostic system developed during the imatinib era, predicts European LeukemiaNet (ELN)-based event-free survival better than Euro/Hasford and Sokal systems in CML patients receiving frontline imatinib mesylate. This observation might have important clinical implications.

A Rare but Serious Side Effect of Levofloxacin Hypoglycemia in a geriatric patient

Drugs should always be considered in the differential diagnosis of hypoglycemia. Fluoroquinolones have rarely been associated with hypoglycemia (1,2). Levofloxacine, which belongs to the fluoroquinolone group of antibiotics, has previously been reported to cause hypoglycemia in only one patient who was also receiving oral antidiabetic drugs (2). Herein, we describe an elderly patient with hypoglycemia associated with levofloxacine therapy who did use oral antidiabetic drugs or insulin. A 64-year-old female with type 2 diabetes treated only by diet was interned for urinary infection and pneumonia. She had no history of malabsorbtion or oral intolerance. The patient’s weight was 84 kg, and she was 157 cm tall (corresponding to a BMI of 34.1 kg/m2). Her current medications included coraspin, omeprazole, and atorvastatin. Cefuroxime 3 × 750 mg/day i.v. was started. During cefuroxime therapy, her blood glucose levels were within normal limits with diet. …

Bone marrow fibrosis may be an effective independent predictor of the ‘TKI drug response level’ in chronic myeloid leukemia

Abstract Objectives The aim of this study was to assess bone marrow (BM) fibrosis and dysplasia in chronic myeloid leukemia (CML) patients receiving the first-generation tyrosine kinase inhibitor (TKI), imatinib, or second-generation TKIs, dasatinib, and nilotinib. We further investigated whether CML under TKI is associated with dysplastic BM changes during the clinicopathological course of the disease. Methods In total, pre-treatment BM paraffin blocks of biopsy specimens were available for 41 adult patients diagnosed with chronic phase CML. Post-treatment BM aspirate clot and core biopsy samples were reviewed for fibrosis and dyshematopoiesis. Results Overall, 13 (31.7%) patients achieved a complete cytogenetic response with imatinib treatment, with no events. In 25 patients, imatinib was discontinued owing to primary or secondary resistance. In patients with initial dysmyelopoiesis, the rate of BM fibrosis was 82.4 versus 47.6% for other patient groups (P = 0.02). Overall, 24 patients with newly diagnosed CML showed marrow fibrosis, among which 19 (79.1%) had imatinib resistance. However, only 5 out of 15 patients (33.5%) without marrow fibrosis had imatinib resistance (P = 0.08). Discussion Our findings indicate that BM fibrosis is an independent predictor of the ‘TKI drug response level’ in CML and support its inclusion as a critical pathobiological parameter for decision-making with regard to TKI drug selection de novo, calculation of prognosis at the onset of disease, and monitoring response to TKI in the long-term disease course of CML.

Gabapentin induced edema in a geriatric patient.

To the Editor: Gabapentin is a novel drug used increasingly in the management of complex pain syndromes and used as an anticonvulsant and as treatment for neuropathic pain, fibromyalgia, and the pain of spinal stenosis. We describe a patient receiving gabapentin for neuropathic pain who developed edema during treatment with gabapentin that it was necessary to discontinue treatment. A 76-year-old man presented with bilateral pretibial edema for 3 weeks. The patient was receiving gabapentin 300 mg/d for neuropathic pain for 6 weeks. His medical history was unremarkable, and he was not receiving any drug other than gabapentin. He denied alcohol use and smoking. Physical examination was normal, except pitting edema just below the knee in the bilateral legs. His renal, liver, and thyroid function test and urinalysis results and serum albumin level were normal. His chest radiography and echocardiography results were also normal. Abdominal ultrasonography and venous Doppler revealed nothing abnormal. We felt that the edema was due to gabapentin and thus discontinued the medication. Within 3 days of discontinuing gabapentin, the edema disappeared. On rechallenge, the edema reappeared within 5 days, and the gabapentin was permanently discontinued with resolution and no recurrence of edema. Given that there are many possible causes of edema, we could not find any in this patient’s presenting history and physical or laboratory workup, other than the gabapentin. Given the time course over which his edema developed, it seems likely that gabapentin is the primary cause. To our knowledge, this is the second report in the literature. Although the exact mechanism of action remains largely unknown, the analgesic effect of gabapentin is thought to be due to +-aminobutyric acid mimetic and calcium channel-blocking properties. It is well known that calcium channel blockers, especially amlodipine, may cause edema. We think that gabapentin might cause edema in a similar manner as calcium channel blockers do. The use of the Naranjo probability scale indicated a highly probable relationship between edema and gabapentin in this patient. Further studies to examine etiopathology in patients who develop edema while taking gabapentin are clearly needed. In conclusion, gabapentin may have been responsible for the case of edema presented in this report. The patient in question developed edema shortly after initiating gabapentin therapy, which was promptly resolved upon the cessation of gabapentin. However, further case reports are clearly needed to confirm our findings, elucidate the mechanism, and determine the dose at which edema becomes an issue.

Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic hematopoietic stem cell transplantation for acute leukemia patients: A single center experience

Due to the high transplant related morbidity and mortality (TRM), relatively younger acute leukemia patients that have a good performance status and no comorbidity are eligible for myeloablative conditioning (MAC) followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). The outcomes of 84 consecutive adult patients with ALL (n=38) or AML (n=46) who underwent allo-HSCT from their HLA-identical siblings were evaluated retrospectively. The median age at transplantation was 34 (17-58 years) for the whole patient population. Of these, 24 patients received a MAC and 60 patients received a fludarabine-based reduced intensity conditioning regimen (RIC). After a median follow-up of 32 months (range, 1-119), for the entire group, the 3-year estimated overall survival (OS) was 57.5% and the disease-free survival (DFS) was 51.5%. The OS for ALL and AML patients were 53.9% vs 62.1%: and DFS were 50.5% and 53.4%, respectively. The 3-year estimated OS for RIC and MAC patients were 63.2% and 41.7%; and DFS were 57.1% and 34.7%, respectively. In ALL patients, conditioning regimens (RIC vs MAC) led to similar OS and DFS; however, in AML patients both OS (70.1% vs 21.4%) and DFS (59.3% vs 42.9%) were found to be higher in RIC patients compared to MAC recipients. Overall, the TRM at day 100 was 1.7% and has increased up to 5.1% at 1st year. In multivariate analysis, the diagnosis (p=0.03) and RIC regimen (p=0.027) were the prognostic variables for prolonged OS in all patients; and RIC regimen (p=0.031) was the only prognostic factor for prolonged OS in AML patients. The first complete remission (CR1) was correlated with a prolonged DFS as an independent variable for all patients (p=0.09). Eleven of the RIC patients (18.3%) and 6 of the MAC patients (25%) developed acute graft-versus-host disease (GvHD). Seventeen of the RIC patients (33.3%) and 4 of the MAC patients (16.7%) developed chronic GvHD. In conclusion, RIC conditioning regimens may provide a longer OS and DFS, especially in patients with AML who are in first CR, not eligible for MAC conditioning.

Clinical and pathological correlations of marrow PUMA and P53 expressions in myelodysplastic syndromes.

p53 is a key regulator of apoptosis. p53 upregulated modulator of apoptosis (PUMA) is a critical mediator of p53‐dependent and independent apoptosis. The objective of this study was to evaluate the relationship of p53 and PUMA to the prognosis of MDS. Bone marrow biopsies of MDS patients at the time of diagnosis (n = 76) and at the time of transformation (n = 19) were included in the study group. The expression of p53 and PUMA was evaluated using immunohistochemistry. When compared to the control group, both p53 (p < 0.001) and PUMA (p = 0.012) expression levels were significantly higher in MDS group. In MDS group, there was a moderate positive correlation between p53 and PUMA expressions. PUMA expression was not correlated with event free and overall survival. However, overall survival was significantly lower in cases with p53 expression in more than 50% of the cells. There was an increase in PUMA expression in cases that showed transformation as compared to the initial diagnostic bone marrows but was not statistically significant. The correlation that existed between p53 and PUMA was lost in transformed cases. Our results showed that PUMA and p53 expressions are increased in MDS marrows compared to normal marrows. PUMA expression increases further during transformation while the expression of p53 is not significantly altered which suggests that PUMA alterations might be a late event during the evolution of MDS.

Co-expression of t(15;17) and t(8;21) in a Case of Acute Promyelocytic Leukemia: Review of the Literature

Additional chromosomal abnormalities in acute myelogenous leukemia have been identified as one of the most important prognostic factors. Favorable chromosomal changes such as t(8;21), inv(16), and t(15;17) are associated with higher rates of complete remission and event-free survival. Translocation (15;17) characterizes acute promyelocytic leukemia (APL) (French-American-British class M3) in almost all patients. Secondary chromosomal abnormalities are also present in approximately 23%-29% of patients with newly diagnosed APL. The prognostic implications of t(8;21) and other secondary cytogenetic aberrations in APL are reviewed here. We present a 47-year-old woman diagnosed with APL whose initial cytogenetic analysis included both t(8;21) and t(15;17). The initial induction chemotherapy included 3 days of idarubicin (12 mg/m2/day) and daily all-trans retinoic acid (ATRA; 45 mg/m2/day). At the sixth week of treatment, a control bone marrow biopsy was found to be normocellular, t(15;17) bcr3 and t(8;21) were negative, and t(15;17) bcr1 fusion transcripts were reduced from 5007 (1.78525699%) copies per 1 µg RNA to 40 (0.00062020%) with real-time quantitative polymerase chain reaction. Consolidation with 4 days of idarubicin (5 mg/m2/day), ATRA (45 mg/m2/day for 15 days), and cytarabine (1 g/m2/day for 4 days) was then started. However, the patient became pancytopenic and had neutropenic fever after consolidation treatment. Unfortunately, she died 3 months after the time of APL diagnosis, due to acute respiratory distress syndrome-like respiratory problems and multiorgan dysfunction requiring respiratory support and hemodialysis. Conflict of interest:None declared.

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.

Portal vein thrombosis secondary to Klebsiella oxytoca bacteriemia

Ebru Uz1, Alıcı Özlem2, Özlem Şahin Balçık3, Mehmet Kanbay1, Ayşe Işık4, Burak Uz4, Arif Kaya4, Ali Koşar3 1Department of Nephrology, Fatih University School of Medicine, Ankara, Turkey 2Department of Infectious Diseases, Fatih University School of Medicine, Ankara, Turkey 3Department of Hematology, Fatih University School of Medicine, Ankara, Turkey 4Department of Internal Medicine, Fatih University School of Medicine, Ankara, Turkey

Long-Term Sustained Hemorrhage Due to Bone Marrow Biopsy Successfully Treated With Topical Ankaferd Hemostat in a Bleeding-Prone Patient With Secondary Amyloidosis:

We have read with great interest the recent article published in the Clinical and Applied Thrombosis Hemostasis journal by Cakarer et al in which the authors suggested that topical Ankaferd blood stopper (ABS) application could be a safe and effective measurement for the bleedings of dental invasive procedures even under anticoagulant therapy without discontinuation of the antithrombotic medication. On average, 66.7% of the ABS-treated dental extraction sockets achieved hemostasis in less than 1 minute, while 80% of the nontreated sockets achieved hemostasis longer than 1 minute. Furthermore, there were no side effects associated with ABS use except a metallic taste in the mouth lasting for approximately 5 minutes. This investigation brilliantly indicates the efficacy of ABS for the clinical bleedings in the setting of acquired hemorrhagic diathesis. Hereafter, we would like to share our experience about topical ABS to control long-term sustained resistant site bleeding due to the bone marrow biopsy procedure in a bleeding-prone patient with secondary amyloidosis. Amyloid diseases can generally be associated with potentially life-threatening hemorrhages. Pathobiological factors contribute to abnormal bleeding tendency in amyloid diseases are heterogeneous depending on the type of amyloidosis and the pattern of organ involvement. A 31-year-old male Turkish patient with familial Mediterranean fever (FMF), secondary renal amyloidosis, and chronic kidney failure had presented with palor, lassitude, fatigue, thrombocytopenia, and deep anemia. His medications included L-thyroxine 1 0.1mg and colchium dispert 1-2 1 orally (po) daily. His familiy history was unremarkable and his parents were nonconsanguineous. In the physical examination, he had a significant pale appearance with numerous petechiaes in the upper body and both extremities. Moreover, massive splenomegaly (16 cm palpable below the left costal margin and extending to the inguinal and pelvic areas) with hypersplenism also complicated the clinical picture. Peripheral blood examination disclosed the hemoglobin level of 8.8 g/dL (13.6-17.2), white blood cell count of 9.0 10/mL (4.3-10.3), with 6.4 10/mL absolute count (70.6%) of neutrophils, and platelet count of 41 10/mL (156-373). Peripheral blood smear showed 61% neutrophils, 38% lymphocytes, 1% eosinophils, poikilocytosis, hypochromia, anisocytosis, and decreased platelets. Nutritional and hemolytic anemia were ruled out. Baseline hemostatic parameters revealed the prolonged prothrombin time (international normalized ratio [INR]=1.4; N: 0.86-1.20) and increased D-dimer (5.88 m/mL; N: 0-0.48) compatible with chronic disseminated intravascular coagulation (DIC). Meanwhile, coagulation factor (F) levels were as follows; factor VIII (FVIII): 57% (N: 53-170), FIX: 42% (N: 60-170), FXI: 59% (N: 70-150), FV: 17% (N: 70120), FVII: 41% (N: 70-130), FX: 32% (N: 70-120), and antithrombin III: 67% (N: 80-120). Platelet function tests were abnormal with ADP (2 mmol/L), ADP (6 mmol/L), epinephrine (10 mmol/L), and collagen (1 ug/mL). Bone marrow aspiration and biopsy have been performed at the spina iliaca posterior superior region of the iliac crest in order to assess amyloidosis. Bone marrow histopathology was normocellular and depicted increments in the megakaryocytes and plasma cells (7%-8%). Amyloid accumulation was detected around the blood vessels with crystal violet staining.