ALBERT

Description: Background and purpose: There are no currently approved treatments for the vaso-occlusive crises (VOC) associated with sickle cell disease (SCD). In addition to causing pain, vaso-occlusion and the resulting hypoxia cause a reduction in overall life expectancy and increase chronic morbidity. Sevuparin is a novel, non-anticoagulant, low-molecular weight heparin analogue, with a preclinical multi-modal activity profile against VOC relevant targets (i.e. P- and L-selectin, thrombospondin, Von Willebrand factor, fibronectin). Due to its low risk for bleeding side effects, sevuparin can be dosed at levels that were previously unattainable with heparinoids. The present study evaluated whether sevuparin could shorten the time with VOC in hospitalized SCD patients compared to placebo. Patients and methods: This phase II, global, multicenter, randomized, double-blind, placebo-controlled and parallel group clinical trial enrolled patients aged 12 to 50 with a diagnosis of SCD (HbSS, HbSC, HbSβ0-thalassemia, HbSβ+-thalassemia). The study recruited patients across 22 sites in 8 countries (Netherlands, Belgium, Turkey, Oman, Bahrain, Lebanon, Saudi Arabia, and Jamaica). Patients with VOC received sevuparin or placebo (1:1) along with standard of care (SoC) therapy with a requirement for parenteral opioid use. The primary endpoint was time to VOC resolution, measured as the time from IMP start until resolution by fulfilment of the two following criteria: a) freedom from parenteral opioid use (8 ± 2 hours), b) readiness for discharge as judged by the patient or physician (whichever occurred first). In addition to assessing safety, main secondary efficacy measures were related to pain and opioid use. The sample size of 120 VOC resolution events was determined based on an assumed between-arm hazard ratio of 0.60. Results: Overall, 147 subjects were randomized (144 dosed) to sevuparin, n=71 (69); or placebo n=76 (75). The median age of subjects entering the study was 22 years with 72% adults and 62,5 % males. Treatment groups were generally balanced with respect to demographic and baseline characteristics. Sevuparin, infused continuously at 18 mg/kg/day, did not confer any benefit over placebo in the primary endpoint of time to VOC resolution (ITT Cox proportional HR 0.89 (95% CI 0.61-1.30; p = 0.554; Figure 1a), which was also reflected by the secondary endpoint analyses (exemplified in Figure 1b). Most AEs were mild to moderate and transient. The number of SAEs was slightly higher in the placebo group (21/17 [22.4%]; one fatal case with hyperhemolytic crisis) than in the sevuparin group (16/15 [22.1%]). The most commonly reported treatment emergent AEs (TEAEs) are displayed in Table 1. No clinically meaningful differences, imbalances or trends were apparent in TEAEs, laboratory parameters, vital signs, physical examination and ECG data across treatment groups. Conclusions: In this study, one of the largest VOC studies run to date, sevuparin failed to show an improvement of the VOC resolution time and associated measures (pain, opioid use, etc) in patients hospitalized with acute VOC. These results were surprising given both the promise from preclinical models and the clinical efficacy seen with selectin inhibition. It is possible that once full-blown, an acute VOC cannot be limited by sevuparin's mode of action (MoA). The understanding of sevuparin's MoA combined with this negative result may contribute to the notions of VOC causative factors and help inform future therapeutics targeting the VOC. The study is also important given its size and the high patient representation from the eastern Mediterranean and Middle Eastern regions, where SCD is of high prevalence. The comparison of this data with the available data from other VOC studies will be important in helping understand both regional and genetic differences in treatment practices and response to therapeutics. In conclusion, the present study showed that sevuparin treatment was not effective in acute VOC. However, sevuparin's promising safety profile and broad MoA including p-selectin inhibition, may warrant further exploration in the prodromal setting, especially given that sevuparin may be dosed by the patient at home in a convenient, subcutaneous format. Acknowledgements: Modus is grateful for the contributions from Ergomed, the Arabian Gulf University, the study sites, as well as to the patients for participating in this study. Disclosures Al-Khabori: Shire (Takeda): Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; NovoNardisk: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; SOBI: Honoraria; AstraZeneca: Honoraria. Abboud:CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Other: Travel support; Modus: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Inati:Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Research Funding; AstraZeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kristensen:Modus Therapeutics: Employment. Donnelly:Modus Therapeutics: Employment. Ohd:Modus Therapeutics: Employment.

Description: Background Cardiac iron removal is relatively slow and patients with cardiac siderosis can take years to normalize cardiac T2* to 〉20 ms. Prospective comparison of iron chelators are mostly limited to studies of 1-yr duration. CORDELIA is a large randomized trial comparing deferasirox (DFX) with deferoxamine (DFO) in patients with β-thalassemia major (TM), which demonstrated the non-inferiority of DFX vs DFO for cardiac iron removal at 1 yr, with a trend for superiority of DFX (P=0.057). This 1-yr extension was planned to collect additional data on efficacy and safety of DFX and DFO in patients with cardiac siderosis when treated for up to 2 yr. Methods Study design has been reported previously (Pennell Blood 2012; abst 2124). Patients enrolled had cardiovascular magnetic resonance-measured cardiac T2* 6–20 ms, left ventricular ejection fraction (LVEF) ≥56%, and R2-magnetic resonance imaging liver iron concentration (LIC) ≥3 mg Fe/g dw. Patients completing 1 yr were eligible to continue on DFX or DFO as assigned, or to switch treatment on entering the extension if judged by the investigator to be of therapeutic benefit. Target doses were an intensified DFO regimen of 50–60 mg/kg/d sc for 8–12 h, 5–7 d/wk, or DFX at 40 mg/kg/d. Efficacy is reported for changes from core baseline (BL). Safety was monitored continuously. Results for patients continuing with DFX or DFO are reported here. Results In total, 160/197 patients completed 1 yr; 74 patients continued into the extension on DFX (mean age 20.1 ± 6.9 yr; 59.5% male) and 29 patients on DFO (17.0 ± 5.4 yr; 58.6%). At core BL, 29.7% DFX patients had cardiac T2* 33% from BL and 〉 upper limit of normal (ULN) at 2 consecutive values occurred in 2.7% of DFX and 3.4% of DFO patients. Frequency of ALT elevations 〉5 x ULN and 2 x BL were comparable between groups. Discussion Cardiac T2* increased substantially during 2-yr treatment with DFX or DFO. Improvement with DFX was comparable with DFO, although DFO patient numbers were low. The magnitude of cardiac T2* improvement with DFX was consistent with previous long-term studies (Pennell Blood 2010). Mean LVEF was stable and remained within normal limits in both groups. LIC continued to decrease from very high BL levels with DFX and DFO. The reduction in CIC in the extension was similar or possibly greater than in the core, which might relate to the falling LIC. Long-term safety profiles of DFX and DFO were consistent with previous reports. Disclosures: Pennell: Shire: Consultancy, Honoraria; ApoPharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Porter:Celgene: Consultancy; Shire: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Piga:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Wegener:Novartis: Employment. Habr:Novartis: Employment. Shen:Novartis: Employment. Aydinok:Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Background Transfusion-dependent patients with severe cardiac siderosis often require intensive iron chelation therapy for a limited time to facilitate rapid removal of iron from the heart, allowing patients to move from a high-risk (cardiac T2*

Description: Purpose The study is conducted in 29 sickle cell anemia (SCA) patients, who are in ischemic attacks (in vasoocclusive crises period) and in steady state; the level of T helper cells, cytotoxic T cells and natural killer cells were determined and the effect of ischemic attack on clinical prognosis and the immune functions. Materials and Methods In the study, 29 patients with sickle cell anemia in ischemic attacks with painful crises and in steady state and 24 healthy children were chosen in the same age group for control group. These groups were examined with complete blood cells count, Hb electrophoreses and the blood biochemistry. The study was performed by flowcytometric method to find the level of CD3 monoclonal antibody for total T lymphocyte, CD4 monoclonal antibody for T helper cells, CD8 monoclonal antibody for cytotoxic T cells and CD16+56 monoclonal antibodies for natural killer cells in the mentioned groups to compare the statistical data. Findings The average of HbS in ischemic periods in SCA patients are to be found 83±6,6 %. There were decrease in hemoglobin and hematocrit levels in SCA versus control group (p0,05). Results As a result of the study, in the patients with sickle cell anemia whom associated with chronic hemolysis and tissue hypoxia during the ischemic attack, the levels of total T lymphocyte (CD3) was found significantly lower than the control groupp

Description: Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P 〈 .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P 〈 .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P 〈 .001) and 371 ng/mL (n = 147; P 〈 .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

Description: Key Points DFX-DFO combination followed by DFX monotherapy led to a meaningful decrease in myocardial and liver iron in severe siderosis patients. Substantial liver iron reduction may be helpful in patients needing rapid control of liver iron (eg, pretransplant or planned pregnancy).

Description: Background: Sickle cell anemia (SCA) is a monogenic disease resulting in polymerization of hemoglobin in hypoxic conditions. This leads to red blood cell (RBC) membrane damage and sickling, causing vaso-occlusion and hemolysis. Continual, excessive release of lysed RBC contents within the vascular space can activate the inflammasome, a multiprotein oligomer that promotes maturation and secretion of pro-inflammatory cytokines, including interleukin 1-beta (IL-1β). The intravascular inflammation associated with SCA, e.g., increased serum c-reactive protein (CRP) and absolute counts of neutrophils and monocytes, is predictive of long-term morbidity and mortality. Inflammation is a major component of many of the clinical complications of SCA, including vaso-occlusive pain episodes, acute chest syndrome, vascular-endothelial dysfunction, renal disease and other forms of end organ damage. Standard of care for SCA is hydroxyurea, which augments fetal hemoglobin levels and may have some anti-inflammatory effects by reducing neutrophil and monocyte counts. Canakinumab is a fully human monoclonal antibody targeting IL-1ß and blocking its downstream pro-inflammatory activities with potential to ameliorate the inflammatory complications of SCA. Objective:To clinically validate in pediatric and young adult SCA patients the hypothesis that IL-1ß blockade by canakinumab is safe and provides clinical benefits. Methods: A multi-center, randomized, parallel group, double-blind, placebo-controlled trial recruited SCA patients (HbSS or HbS/ß0thalassemia) with history of ≥2 major pain episodes/year, screening baseline detectable pain (using pain e-diaries) and serum high sensitivity CRP level ≥1.0 mg/L. Patients were randomized with 1:1 ratio to receive six monthly s.c. injections of either canakinumab 300 mg (4 mg/kg for patients ≤40 kg) or placebo. The concurrent use of hydroxyurea was a stratification factor at randomization. Outcomes were measured at baseline and at weeks 4, 8, 12, 16, 20, 24, after which all patients moved to open label canakinumab treatment for additional 6 months. Electronic patient reported outcomes included daily pain intensity with a 0-10 cm visual analog scale, school/work absences secondary to SCA, fatigue and analgesic use. The primary outcome was change from baseline in the 4-week average daily pain intensity at week 12. Other secondary and exploratory outcomes included daily activity measured by wrist actigraphy, rate of hospitalization and adverse events, serious adverse events, transcranial Doppler velocities, percent oxygen saturation and laboratory markers of inflammation and hemolysis. Results: A planned interim analysis for futility and safety was performed on the first 30 enrolled patients (canakinumab, n=16; placebo, n=14), of whom 26 patients completed the Week 12 assessments (canakinumab, n=14; placebo, n=12), and 13 patients completed the Week 24 assessments. Enrolled patients (median age 17 years, range 12-20; 19 male, 11 female) were evenly distributed between treatment arms. All except one patient were maintained on a stable hydroxyurea regimen. Baseline overall disease activity levels (median, [range]) included average daily pain 3.93 [0.29, 6.57]; high sensitivity CRP 3.93 mg/L [1, 64.7]; transcranial Doppler velocities 85.0 m/s [23, 267]; hemoglobin 94.8 g/L [73.5, 121]. Futility criteria were not met and no canakinumab-associated safety issues were identified in this first interim analysis. Conclusions: Canakinumab was well tolerated and not associated with any major side effects in SCA. Results from a second interim analysis of study outcomes for all currently enrolled patients (n=49) completing the blinded, 24-week treatment period will be available in November 2019. Disclosures Rees: Agios: Other: Grants; TauRx (methylene blue): Other: Data monitoring committees; Astra Zeneca (ticagrelor): Other: Data monitoring committees; Novartis: Other: Strategic advisory role,Principal investigator,sickle cell disease2.6 Investigator; Emmaus: Other: Strategic advisory role; Celgene: Other: Strategic advisory role; Global Blood Therapeutics: Other: Strategic advisory role; Alnylam: Other: Principal investigator. Dampier:Micelle Biopharma: Consultancy, Research Funding; Merck: Research Funding; Hudson Publishing Company: Consultancy; Global Blood Therapeutics: Consultancy; Ironwood: Consultancy; Epizyme: Consultancy; Modus Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mahlangu:Sanofi Genzyme: Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding; Baxalta: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Biomarin: Research Funding; uniQure: Research Funding; Spark: Consultancy, Speakers Bureau; Chugai: Consultancy; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Freeline Therapeutics: Research Funding; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; World Federation of Haemophilia: Speakers Bureau. Mortier:Novartis Pharma AG: Employment. McNamara:Novartis Pharma AG: Employment. Li:Novartis Pharma AG: Employment. Oliver:Novartis Pharma AG: Employment, Equity Ownership. OffLabel Disclosure: canakinumab use in the treatment of sickle cell anemia.

Description: Objective: In pediatric patients treated for malignancies with chemotherapy or bone marrow transplantation (BMT), the disease and the treatment lead to impaired immunity and loss of immunity continues for a time period after the completion of therapy. Therefore, revaccination of these children is necessary. The aim of this study was to examine the differences between different treatment groups, namely solid tumors, leukemias and BMT patients, for their response to inactivated or subunit or live attenuated vaccines at least 6 months after the cessation of the of treatment. Materials and Method: The study was performed prospectivly in 35 patients with solid tumors (Group I), 32 patients with leukemia (28 ALL, 4 AML) (Group II) and 13 patients after BMT (Group III). Inactivated (Diphtheria, tetanus), subunit (acellular pertussis, hepatitis B, hepatitis A) and live attenuated (measles-mumps-rubella (MMR), varicella) vaccines were applied to patients. Blood samples taken from the all patients before vaccination and 1 month after vaccination. IgG antibodies against measles-mumps-rubella and varicella were evaluated in vitro. Results: For inactivated vaccines, the level of anti diphteria antigen was highly positive in Group I and II, 80% and 71.8% respectively, but only 53.8% of Group III patients were positive before vaccination. After one dose all of these levels became 100%. For tetanus it was the same pattern (84.4% 88.6% and 46.2%, low in Group III). They all reached 100% after vaccination with one dose. Anti pertussis IgGs were low in all 3 groups, 54.3%, 46.9%, 38.5% respectively. These levels were 66.7%, 66.7%, 50% after the vaccination and the differences were meaningful for Groups I and II (p : 0.02 and 0.002), but not for Group III (p : 0.068). In subunit (purified antigen) vaccines, for Hapatitis B, Anti HBs levels were low in all groups (60%, 37.5%, 46.2%) before vaccination. After one dose, 55.6%, 64.3%, 50% became positive, but only after the second dosage 100% of the patients were positive. For Hepatitis A, positive levels of antiHAV IgG before vaccination were 28.6%, 37.5%, 53.8% for the 3 groups. Except for one patient in the BMT group 100% became positive with one dose. Among live, attenuated viruses, measles, rubella, mumps vaccinations were applied. Anti-rubeola IgG levels were positive in 45.7%, 34.4% 15.4% of patients in 3 groups before vaccination. After one dose they all became positive except for one patient in each group, who responded after one more dose. For rubella, 85.7%, 78.1% and 61.5% of patients were positive for anti-rubella IgG before vaccination in respective groups and they all became 100% positive after one dose. Before mumps vaccination, 82.9%, 71.9% and 46.2% of patients were positive for anti-mumps IgG before first dose. 83.3%, 100% and 50% became also positive after one dose, but after the second dosage 100% were positive. 65.7%, 59.4% and 53.8% of the patients were seropositive for antiVZV IgG respectively before vaccination. Except for four cases in Group I, the rest achieved seropositivity after one dose. Conclusion: In our study, after one booster dose of vaccine, all patients had very good antibody response against to diphtheria, tetanus, hepatitis A, rubella vaccines at least 6 months after the cessation of therapy for leukemia and solid tumors and 12 months after BMT. Protection after mumps vaccine was in moderate levels in leukemia and solid tumor groups, but not in BMT group. All groups responded moderately for measles, varicella, pertussis, hepatitis B, some needing one more booster. BMT group seems to be the maximum looser and the least responder after vaccination. The groups showed differences in antibody responses to vaccines, according to age, the time passed after the cessation of treatment and their primary vaccination status. To evaluate the response obtained, following antibody levels for response to vaccination is necessary and a booster should be considered when there is a decrease or loss in these levels. Disclosures Karakas: Novartis: Research Funding.

Description: Introduction Mutations in JAK2 have been implicated in polycythemia vera (PV), essential thrombocythemia (ES), primary myelofibrosis (PMF) as wll as other myeloproliferative disorders. Aim In this study we aimed to investigate the frequency of JAK2V617F mutation on 216 patients with hematologic malignancies in childhood and 176 patients with myeloproliferative disorders in adulthood. Materials and method Patient group consist of 164 ALL and 52 AML patients in childhood and 79 PV, 51 ES, 22 chronic myeloid leukemia patients (CML) and 24 PMF patients in adulthood. These patients followed by Cukurova University, Departments of Pediatric and Adult Hematology, are included in this study. Blood samples were collected in these patients group and DNA was isolated using high pure template preparation kit (Roche) and stored -80oC. Gene mutations were studied using TMB (TıbMolBiol) LightMix Kit JAK2V617F genomic and analyzed by Light Cycler 2.0 Roche Diagnostic, GmBh, Germany in both groups. Findings JAK2V617F mutation was found 1 of 164 ALL patients (0,6%), 0 of 52 AML patients (0%) in childhood. Nevertheless, JAK2V617F mutation was also found 71 of 79 PV patients (89,8%), 22 of 51 ET patients (43,1%), 1 of 22 CML patients (4,5%) and 15 of 24 PMF patients (62,5%) in adulthood. Result As a result we found high frequency of JAK2V617F mutation in PV patients than the other myeloproliferative disorders. JAK2V617F mutation was significantly high in myeloproliferative disorders in adulthood comparing with childhood acute leukemias (p

Description: Lymphomatous involvement of the kidneys is a common manifestation of systemic non-Hodgkin’s lymphoma (NHL). In contrast, lymphoma originating within the kidneys is a rare event in children. In this study we report a case of primary renal lymphoma presenting with acute renal failure in a 14-years-old boy. According to histopathological and immunohistochemical examinations, the diagnosis of B-cell renal lymphoma was established. A fourteen years old boy presented to our Pediatric Hematology - Oncology Unit, with 4-month history of weakness and anorexia. He had mild abdominal pain. Physical examination revealed no significant abdominal or systemic. The laboratory data were white blood cell count 4100/mm3; hemoglobin level 10.8 g/dL, mean corpuscular volume 107 fL; mean corpuscular hemoglobin concentration 33.6 g/dL); platelet count 179,000/mm3;erytrocyte sedimentation rate 50mm/h; blood urea nitrogen level 142 mg/dL; creatinine level 4.85 mg/dL; lactate dehydrogenase level 465 IU/L. There were no pyuria or hematuria, and urinary culture and stain results were negative. An abdominal ultrasonography revealed an increase in bilateral kidney sizes. Abdomen computed tomography scan showed an increase in thickness of renal parenchyma with hypodense appearance and with bilateral mild ectasia in pelvicalyceal system. An ultrasonography guided renal biopsy demonstrated precursor B-cell lymphoblastic lymphoma. Hematoxylin and eosin section of these renal masses revealed neoplastic lymphoma cells with increased nuclear-cytoplasmic ratio, prominent nucleoli and mitotic figures.The lymphoma cells stained positivie for terminal deoxynucleotydyl transferase and B-lymphocyte marker CD10 and CD20 immuno-histochemical stain. Extrarenal abdominal involvement was excluded by imaging techniques. Bone marrow examination was normal. He was diagnosed as non-Hodgkin’s lymphoma, pre B-cell type and was treated with multidrug chemotherapy (induction regimen of prednisolone, vincristine, daunorubicin and L-asparaginase) and prophlactic intratecal methotrexate according to British-French-Munster (BFM) protocol. After the initial therapy, renal function test were improved rapidly and during consolidation and maintenance chemotherapy, they continud as normal. The patient is still in complete remission and was followed normal renal function with no sign of disease recurrence 5 years later diagnosis..In conclusion, diagnose of PRL is difficult. Percutaneous kidney biopsy is the most expeditious method towards the establishment of an early diagnosis for appropriate chemotheraph. Early diagnosis and urgent therapy, with supporting therapy are necessary for good prognosis. Disclosures No relevant conflicts of interest to declare.