ALBERT

Description: Introduction: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with variable clinical course. Several studies have been conducted to predict outcome in patients with CLL and also have been going on. A proliferation inducing ligand (APRIL) has been shown to involve in survival and resistance to apoptosis in CLL, and APRIL molecule has been investigated as a prognostic marker in CLL patients. However, there are limited and controversial data regarding APRIL and its impact on prognosis in CLL. We aimed to compare serum APRIL levels in CLL patients with those of age and gender matched healthy subjects, and to investigate the relationship between APRIL and the other common prognostic factors, and to determine whether serum APRIL levels predict time to first treatment in CLL. Methods: After ethical approval and informed consent were obtained, between May and December 2012, venous blood samples were driven from 96 CLL patients’ and 25 healthy controls’, and serum APRIL levels were measured by ELISA. Demographic data and the prognostic markers were obtained from the patients’ files, and patients have been followed for a minimum of 12 months. We tested the correlation between APRIL with the, clinical and biological parameters, and used the log rank test to compare their Kaplan Meier curves. Results: Patients were divided into three groups: Treatment naive (group A, n=49), chemotherapy receiving (group B, n=25) and who had previously received chemotherapy (group C, n=22). Median APRIL level was higher in group A (2.78 vs 1.29; p=0.034) and group C (3.54 vs 1.29; p=0.001) when compared to healthy controls, but was not different in group B (1.56 vs 1.29; p=0.3) (Figure 1). Serum APRIL level in group A was negatively correlated with hemoglobin levels (r=-0.298; p=0.037) and platelet counts (r=-0.321; p=0.025) whereas no correlation with age, Rai and Binet stages, lymphocyte counts, β2-microglobulin and CD38 levels were detected. Group A patients were also divided into 2 subgroups (APRIL levels low, n=20 and APRIL levels high, n=29) using median natural logarithm of serum APRIL level as cut off. April low and high subgroups were similar with respect to demographic data and prognostic factors. Median time to first treatment was not reached in the APRIL low group, but was 104 months in the APRIL high group (p=0.13, log-rank test). Conclusions: Among the treatment naive patients, serum APRIL levels only negatively correlate with hemoglobin levels and platelet counts. These correlations seem to be associated with tumor burden rather than the prognosis, because APRIL levels were not different in chemotherapy receiving patients compared to healthy controls. Since a median survival time could not be reached in the APRIL low group, short follow up time might be an explanation why the APRIL levels did not predict the time to first treatment. In conclusion, our findings let us to think APRIL levels are not a useful marker to predict prognosis in patients with CLL. Figure 1. Median APRIL levels of CLL patients and healthy controls (ng/mL) Figure 1. Median APRIL levels of CLL patients and healthy controls (ng/mL) Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1692 Background: There has been a remarkable improvement in the management of chronic myeloid leukemia (CML) after imatinib mesylate (IM) became available in the market, but there is still a group of patients who are resistant to imatinib. Although point mutations in the BCR-ABL kinase domain is the most common mechanism for resistance in patients with CML receiving tyrosine kinase inhibitor (TKI) therapy, there are several mechanisms that can play a role in the resistance to TKIs. Multi drug resistance gene (MDR1) [ABCB1 (ATP-binding cassette, sub-family B (MDR/TAP), member 1) ] product is an ATP-driven efflux pump contributing to the pharmacokinetics of drugs that are P-glycoprotein (P-gp) substrates and to the multidrug resistance of cancer cells. More than 50 single nucleotide polymorphisms (SNPs) have been identified concerning the MDR1 gene, and SNP polymorphisms may affect the expression and function of the P-gp. The SNPs T1236C, G2677T/A, and C3435T are the most common variants in the coding region of ABCB1. Imatinib is a substrate of P-gp-mediated efflux, and P-gp mediated drug efflux can play a role in IM resistance. So identifying these SNPs may allow to predict the drug disposition and responses to IM in CML patients. The aim of the study was to identify the C3435T SNP variants, and the associations between MDR1 C3435T polymorphism and IM efficacy in our CML patients. Methods: Between December 2010 and March 2011, 110 chronic phase (CP) CML patients who consecutively visited our outpatient clinic were enrolled in this study. Hematologic, cytogenetic and molecular response patterns to IM as well as the association between MDR1 C3435T polymorphism and responses to imatinib were evaluated in our patient cohort. MDR1 C3435T polymorphisms were detected by real-time polymerase chain reaction (RT-PCR). We could assess complete cytogenetic response (CCyR) and major molecular response (MMR) in one hundred and six patients (96%) among these 110 patients. The differences in genotype frequencies in all patients taking imatinib treatment was determined by using the chi-square test. All tests were two-sided, and p

Description: Introduction: Imatinib mesylate (IM) is the first tyrosine kinase inhibitor (TKI) licensed for the treatment of chronic myeloid leukemia (CML). Severe bone marrow fibrosis (BMF) has been reported in excess of 40% of the patients with CML at diagnosis. Before TKIs became available, BMF which emerged at diagnosis and/or in the late periods of the disease was defined to be a poor prognostic factor, and it contributed significantly to morbidity and mortality from 10% to 30% in patients with CML. The relationship between BMF and both disease progression and prognosis has been the subject of re-evaluation after the introduction of IM therapy. In patients with CML, it has not been clearly demonstrated yet, whether IM improves the poor prognostic effect of fibrosis, and prevents the new BMF development or not. Aim: The purpose of this study was to evaluate the effects of IM therapy on BMF formation, and the prognostic significance of BMF in patients with CML. Material and Methods: One hundred and thirty-five CML patients were enrolled in the study. Patients' demographics, Sokal risk scores, molecular and cytogenetic responses and follow-up periods were noted from the patients' files retrospectively. All pre- and post-IM bone marrow biopsy samples, which were stained with hematoxylin and eosin, were re-evaluated for the current analysis. Grading of BMF was according to the European consensus decisions, graded as 0-III. The term "last bone marrow biopsy" (LBMB) is referred to a biopsy, which was performed at 18th months or later on during IM treatment. Results: The median age was 44 years (range, 18-92 years), and 78 patients (58%) were male. One hundred and twenty-eight patients (95%) were in chronic phase [CP], 4 patients (3%) were in accelerated phase [AP], and 3 patients (2%) were in blast crisis [BC] at the time of IM initiation. Out of 128 CML-CP patients, one hundred and twenty patients (93%) were in early CP, whereas 8 (7%) were in late CP. The percentage of low, intermediate, and high Sokal risk scores were 35%, 43%, and 22%, respectively. Before IM was initiated, thirty-one patients had received previous treatment modalities (hydroxyurea (HU) in twenty-one, and 10 patients had received interferon plus HU. he median duration of IM treatment was 45 months (range, 2-106 months). The rates of complete hematological response (CHR) at 3rd month, complete cytogenetic response (CCyR) at 12th month, and major molecular response (MMR) at 18th month were 92.4%, 71.6%, and 67.6%, respectively. BMF before the initiation of IM therapy was grade 0 in 52 patients (39%), grade I in 39 patients (29%), grade II in 28 patients (21%), and grade III in 16 patients (12%). There was a positive correlation between the Sokal risk scores and the grades of BMF at diagnosis (r:0.313, p

Description: Abstract 4603 Background Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in the Western world with an annual incidence of 5/100,000. The clinical course of the disease is highly variable; while some CLL patients experience a stable clinical course that will never affect their morbidity or mortality, some of them will eventually progress and require chemotherapy. In addition to the traditional prognostic markers (e.g. Rai and Binet staging systems), more recently, mutational status of the variable regions of the immunoglobulin heavy chains (IgVH), chromosomal aberrations, CD38 expression and Zeta-chain-associated protein kinase 70 (ZAP-70) expression are used to better determine the prognosis in CLL patients. A novel CLL-specific gene, CLL Up-regulated gene 1 (CLLU1) that uniquely overexpressed in CLL patients, was recently demonstrated. It has been shown that CLLU1 mRNA expression levels in CLL patients predict time to initiation of therapy as well as overall survival (OS), and CLLU1 is highly up-regulated in poor-risk groups. The aim of this study is to investigate the relationship between CLLU1 levels and well known prognostic parameters and, to determine the importance of CLLU1 gene on prognosis and clinical course in our CLL patients. Methods 116 (46 female, 70 male) CLL patients who consecutively visited our outpatient clinic between May 2009 and March 2010 were enrolled in the study. Median age was 60 years (range, 30–87 years). Blood samples were drawn from the patients for CLLU1 determination, and CLLU1 levels were determined by RT-PCR method. CLLU1 expression level was counted both in CLL patients and healthy B cells as the difference between CLLU1 and abl (taken as an house keeping gene) gene. Then, they are transformed as folds which is the ratio between CLLU1 level in CLL patients and that in healthy B cells. Patients with CLLU1 expression exceeding the CLLU1 expression of normal (CD19+) B-cells were taken as positive. Each patient was followed for at least one year for survival data. For the statistical analysis, student’s t-test, Mann-Whitney U test and Pearson correlation were used. p

Description: Introduction: Recent studies indicate an increased risk for developing low bone mineral density (BMD) in patients with haemophilia. This has been suggested to result from less physical activity, and impaired vitamin D metabolism due to viral liver disease. Here we present the preliminary results of an ongoing study aiming to identify the risk factors for impaired bone health in adult haemophilia patients. Material and Method: Twenty-nine severe and 7 moderate haemophilia A and B patients were included in the study. Patient characteristics were given in Table-1. All patients had haemophilic arthropathy in ≥1 joints and were on prophylactic factor replacement therapy except 2 on demand patients. None of the patients had decompensated chronic liver disease. Eleven patients had a history of joint intervention (RAS or joint replacement). None of the patients had received on vitamin D supplementation. DEXA scans to screen BMD, blood chemical analysis including liver and kidney function tests, vit. D (25 hydroxy vitamin D) calcium, parathormone, alkaline phosphatase were obtained from all patients at study entry. Results: Osteoporosis and/or osteopenia according to WHO criteria were detected by DEXA scans in 2/3 of the patients. Twenty-six patients (72%) had vit. D levels below 20ng/mL, with half of them having levels less than 10ng/mL. Median lumbar and femur T scores were in the osteopenia range, being -1.2 and -2.2, respectively. Osteoporosis/penia rates and vit. D levels did not significantly differ between patients with severe and moderate haemophilia. However, patients with severe haemophilia had lower lumbar T scores (p=0.048) and seemed to acquire low BMD 2 times more likely than moderate haemophiliacs. Patients with a history of joint intervention had significantly lower vit. D levels (p=0.005) and 1.4 times more risk for low BMD. Conclusion: Preliminary results of our study are in line with the recent literature indicating an increased frequency for osteopenia and osteoporosis in patients with haemophilia. Despite their young age our cohort of patients had lower BMD and vitamin D levels than the age-matched healthy population. This is an interesting finding in a country like Turkey where the average yearly total number of hours of bright sunshine is over 3000. Data at hand suggest increased risk for reduced BMD especially in severe haemophiliacs with impaired joint mobility. The most probable underlying cause for reduced BMD seems to be haemophilic arthropathy related inactivity. Furthermore, impaired bone health seems to be partially associated with less sunlight exposure, which is probably a result of increased home confinement of patients with haemophilia due to joint disease. The study is still recruiting. We hope to clarify other questions regarding factors influencing bone health in haemophiliacs when the study is completed and additional data on radiological and physical examination as well as on quality of life are obtained. Table. Patient Characteristics (n=36) Age, years (median [range]) 35 [20 - 55] Type of haemophilia ( A/B), n 32/4 Genotype (severe/moderate), n 29/7 Factor activity level, % (median [range]) 0.4 [0.1 - 4.2] Type of treatment (prophylaxis/on demand) 34/2 Annual bleeding rate (median [range]) 4 [1 - 12] Joint replacement, number of patients (%) 7 (19) Radioactive synoviectomy, number of patients (%) 7 (19) Any joint intervention, number of patients (%) 11 (30.5) Lumbar T scores (median [range]) -1.2 [-5.2 - 1] Femur T scores (median [range]) -2.2 [-3.9 - 0.6] Vit. D, ng/mL (median [range]) 10.5 [1.3 - 45] Calcium, mg/dL (median [range]) 9.6 [8.9 - 10.2] Alkaline phosphatase, U/L (median [range]) 91.5 [53 - 177] Parathormon, pg/mL (median [range]) 39 [20 - 179] Haemoglobin, g/dL (median [range]) 14.75 [8.9 - 16] Osteopenia, number of patients (%) 12 (33) Osteoporosis, number of patients (%) 12 (33) HBV/HCV/HIV, n 1/11/0 Disclosures No relevant conflicts of interest to declare.

Description: Background: Ibrutinib has become a widely used drug in the management of B-cell lymphoproliferative neoplasms (BLPNs). Past or active HBV infection is an exclusion criteria for the clinical trials of ibrutinib and for patients (pts) treated outside clinical trials there are contradictory data or suggestions concerning hepatitis B virus (HBV) prophylaxis. In this study, we evaluated the real-life data on the outcome of HBV infection status of pts with BLPNs receiving ibrutinib. Methods: Demographic features, previous treatments (including rituximab (RTX)) and follow-up durations, HBV infection and reactivation status, prophylaxis information, serum transaminase and total bilirubin levels of the pts were noted retrospectively. Past HBV infection was defined as concurrent detectable HBV core IgG antibody (Ab) (anti-HBc IgG) and undetectable HBV surface Ag (HbsAg) ± HBV surface Ab (anti-HBs). Active HBV infection was defined as HbsAg and/or HBV core IgM Ab (anti-HBc IgM) positivity. Quantitative HBV-DNA PCR results are also recorded, when available. Results: Twenty-seven consecutive pts were included, and pts' characteristics are displayed in Table 1. Median durations of ibrutinib therapy and entire follow-up were 9 and 108 months, respectively. All pts had received RTX prior to ibrutinib. Among the 27 patients, 8 had past HBV infection, while 2 had active HBV infection. HBV prophylaxis or treatment was started before ibrutinib in 5 pts, and simultaneously with ibrutinib in one. The remaining 4 pts with past HBV infection were not given any prophylaxis. Among these 4 cases with anti-HBc IgG positivity, three were also positive for anti-HBs. Currently, these 4 pts, including the one with a negative anti-HBs status, are at the 2nd, 4th, 12th, and 16th cycles of ibrutinib. To date, no signs of HBV reactivation was detected in our cohort. Discussion & Conclusion: All pts in our cohort had received RTX containing regimens prior to ibrutinib. In our analysis, 5 pts were under HBV prophylaxis or treatment when ibrutinib was started. Two of these had active HBV infection. Simultaneous HBV prophylaxis was started with ibrutinib for one pt and the remaining 4 pts with past HBV infection (anti-HBs + anti-HBc IgG positivity) did not receive any prophylaxis, but they were planned to be followed by monitoring the anti-HBs titers. In a study, 21 BLPN pts (10 treated with RTX previously) with occult HBV infection with a median follow-up of 9.5 months treated with ibrutinib without anti-HBV prophylaxis, and only two HBV reactivations were reported (Hammond et al. Blood. 2018;131(17):1987-1989). In another study, no HBV reactivation was detected in 7 CLL pts with past HBV infection, with a median follow-up duration of 25 months under ibrutinib, without any anti-viral prophylaxis (Tedeschi et al. Leuk Lymphoma. 2017; 58(12):2966-2968). The increase in the number of pts treated with ibrutinib, is followed by the awareness about the infectious complications including HBV reactivation. The consecutive use of RTX and ibrutinib has increased the risk of HBV-related complications. This issue has become more important in areas with a higher prevalence of HBV. Although the number of pts is limited and follow-up periods are relatively short, our results may indicate that pts with occult HBV infection treated with ibrutinib for BLPNs, might only be closely followed for HBV reactivation, rather than routine anti-HBV prophylaxis. Since pts with previous RTX exposure are likely to lose anti-HBs antibodies, ibrutinib-treated pts with both anti-HBs and anti-HBc IgG positivity should be closely monitored for possible risk of HBV reactivation. Anti-viral prophylaxis under ibrutinib therapy might still be an option for the selected cases. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 4429 Background Imatinib mesylate (IM) is considered the mainstay of chronic myeloid leukemia (CML) treatment for almost a decade. The primary goal of the study is to share data of a substantial number of CML patients followed at one center. Methods We analyzed data from 177 CML patients who were treated in our institution and received IM for at least 24 months. They were stratified into low, intermediate and high risk groups based on Sokal score. Early chronic phase (ECP) (within one year from diagnosis to IM start), late chronic phase (LCP) (≥ 12 months from diagnosis), and accelerated phase (AP) CML patients were included in the study. Patients were evaluated for hematologic, cytogenetic and molecular responses, event-free survival (EFS) and overall survival (OS), frequency of adverse events. Results The median age was 51.2 years (range, 22–86 years), with 77 females and 100 males. Patients were followed for a median of 60 months (range, 24–116 months). IM was started at a dose of 400 mg daily. 97.7% were in chronic phase, and 2.3% were in accelerated phase.75.1% of chronic phase CML patients were in early and 24.9% in late chronic phase. 42% of patients were low Sokal risk, 44% intermediate and 14% were high risk patients. 12% of the patients did not receive any prior therapy, 1% had received prior therapy with interferon (IFN), 73% were treated with hydroxyurea (HU) (mostly short course) and 14% with both HU and IFN. Complete hematologic response (CHR) was achieved in 90% of patients at 3 months (median time, 2.02 months). Cumulative rates of cytogenetic and molecular responses at 6, 12, 18 and 24 months are summarized in Table 1. Complete cytogenetic response (CCyR) was achieved in a significantly higher proportion of patients within the low and intermediate Sokal risk group (79.4%, 85.2%) compared with the high risk patients (14.3%, p=0.001). There was a significant difference in the complete molecular response (CMR) ratio achieved by low, intermediate and high Sokal risk patients (70.4%, 63.8% and 33.3%, p

Description: Background: Management of surgical procedures in people with hemophilia (PwH) has always been a major concern. Insufficient hemostatic control might be an important cause of morbidity and mortality. However, the success of surgical procedures does not only depend on appropriate replacement of the missing factor. Pre- and post-operative interventions, laboratory monitoring, care and rehabilitation of the patient are important. Therefore, surgical procedures in hemophilia patients should be performed in full-fledged hospitals capable of providing a multidisciplinary approach as a "Comprehensive Hemophilia Treatment Center". The aim of our study is to evaluate the outcomes of major surgical procedures (MSPs) among PwH who were followed at Cerrahpasa Medical Faculty. Methods: All MSPs performed on PwH between 2004 and 2017 were included. Baseline activated partial thromboplastin time (aPTT)and factor levels prior to MSP, inhibitor screening and (if any) the inhibitor titration results together with complete blood count, blood group and liver function tests were retrospectively obtained from patient files. The type of MSP, amount of factor concentrates given prior to, during and after the operation, the factor levels and aPTT results following factor replacement; complications developing during or after surgery, and information on the type of treatment modality prior to surgery (on demand vs. prophylaxis) were noted. The amount of factor concentrates administered to patients was determined in units per kilogram. Results: Of the 39 patients included in the study (37 hemophilia A and two hemophilia B) 20 were severe, 7 were moderate and 12 were mild hemophilia (Table 1). The median age at the time of MSP was 37 (20-61) years. A total of 49 MSPs were performed, two patients had 3 surgeries, six patients had 2 surgeries, and 30 patients had one surgery. Fifteen surgical procedures were performed in two, one surgical procedure was performed in three, and 33 operation procedures were performed in one operation area. There were no significant differences in complication rates between hemophilia types (A vs. B), severities (severe vs. moderate vs. mild) and number of operated regions (1 vs. 〉1). In our study, general surgery (n=15) and orthopedic (n=10) operations were the most frequently performed MSPs (Table 2). There was no significant difference in complication rates among surgical branches. Complications were observed in a total of 6 (12%) MSPs, and one patient was deceased due to sepsis. Complication rates were 16% and 11% for MSPs done in PwH with and without inhibitors, respectively (p=non-significant). Factor consumption (U/kg) was highest in patients undergoing orthopedic surgery, followed by cardiovascular and neurosurgical operations. Factor utilization was significantly less for operations done in general surgery, urology and ear, nose and throat departments (p

Description: Background: Although it may vary between different registries, the median age of chronic myeloid leukemia (CML) at diagnosis is between 50-60 years, and approximately 40% of the patients (pts) are diagnosed after age 60 [Hoffmann et al. Leukemia. 2015;29(6):1336-43]. Tyrosinekinase inhibitors (TKIs) have revolutionized the treatment of CML and currently pts with CML may expect to live close to normal lifespan. So the number of elderly CML pts with various potentialcomorbidities started to increase, which then brings out the issues regarding TKI toxicities, medication adherence and responses to TKI treatment. Aim: The aim of this study was to evaluate the efficacy and safety ofimatinib treatment in the elderly population (pts equal to or older than 60 years) with CML and to compare these data with younger pts (pts 〈 60 years). Patients and Methods: Pts diagnosed and followed in our clinic with CML were enrolled in the study. Patient demographics, dose and duration ofimatinib therapy, disease risk scores, cytogenetic and molecular responses,comorbidities, adverse events (AEs), follow-up durations and outcomes were evaluated from files of the pts, retrospectively. TheCharlsoncomorbidity index (CCI) of each patient was calculated as stated before [Breccia et al.Haematologica. 2011;96(10):1457-61]. Results: The patient cohort was consisted of 158 pts with a median age of 44 years (range, 18 - 83 years). Group A consisted of thirty-three pts who were equal to or older than 60 years (Fig. 1), and there were 125 pts (Group B) who were 〈 60 years of age (Table 1). The two groups were balanced regarding gender, disease stage, treatments prior to TKI therapy, and the starting dose ofimatinib. There were more pts with intermediate and highSokal risk scores in Group A than that of Group B (p