ALBERT

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: 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: Abstract 4903 Anaplastic large cell lymphoma (ALCL) accounts for approximately 10% of the childhood lymphomas. ALCL is characterized by peripheral, mediastinal or intra-abdominal lymph node involvement or extranodal involvement. We report a child with ALCL with unusual localization. An eleven-year-old boy had been admitted to the another university hospital with left knee pain and swelling for 15 days. The left knee joint punction had been done, and osteomyelitis had been diagnosed, and treated with antibiotics. However, there had been no recovery from his complaints, and left knee synoviectomy had been done. This operation had revealed anaplastic large cell lymphoma in the intraarticular soft tissue of the left knee. Then, he was referred to our hematology and oncology clinic for advanced therapy. There was nothing significant in the background and family history. Physical examination showed a 3 cm mass arising from the left knee joint with lobulated contours. PET-CT showed the left inguinal lymph node involvement, only. Chemotherapy according to ALCL 99 protocol was started because of the tumor was not resectable. After the first course of therapy, tumor mass was reduced apparently. By the end of his second chemotherapy course, tumor was not detectable. Now, he completed his therapy, and he is on follow-up without any complaint or recurrence for 18 months. In conclusion, to the best of our knowledge, this is the first reported case with ALCL originating from the intraarticular soft tissue which was treated successfully. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Chronic blood transfusions impact the liver due to accumulation of iron, leading to tissue damage, collagen formation and portal fibrosis. Long-term chelation therapy has been shown to be associated with stability or improvement of liver fibrosis and necroinflammation in heavily iron-overloaded patients with β thalassemia, independently of reductions in liver iron concentration (LIC) (Deugnier et al Gastroenterology 2011;141:1202-1211). It was also shown that changes in alanine aminotransferase (ALT, an indicator of hepatocellular damage) mirrored changes in LIC, with significant decreases in ALT seen in LIC responders. Here, we evaluated the effect of long-term chelation therapy on hepatocyte iron score (HIS), and the correlation of HIS and liver iron ratio (LIR) with ALT, to determine if the location of iron within the liver impacts liver function. Methods: Study design, inclusion and exclusion criteria for studies 107 and 108 have been described previously (Deugnier et al, 2011). β thalassemia patients who had liver biopsy assessment at start of deferasirox treatment and after at least 3 years, were included in this analysis. Iron deposits were assessed according to size, cellular and lobular locations in Rappaport's acinus leading to three different scores: HIS (range 0-12), sinusoidal iron score (SIS, range 0-4) and portal iron score (PIS, range 0-4). The LIR, used to assess the relative amount of hepatocytic to total liver iron, was calculated as HIS/(HIS + SIS + PIS) x 100%. LIC was determined by liver biopsy. Correlation between ALT and HIS, and ALT and LIR was assessed using Pearson correlation coefficients. Baseline (BL) in these analyses refers to start of deferasirox treatment. Patients who received deferoxamine during the first year are referred to as the crossover cohort. Assessments were performed according to LIC response (see Table). Results: Of 671 β thalassemia patients enrolled, 470 received chelation therapy for at least 3 years. Of these patients, 219 had histological biopsy data at BL and after at least 3 years of treatment. For all patients (n=219), mean absolute change ± standard deviation (SD) in HIS from BL (16.7 ± 7.4) to end of study (EOS; 11.8 ± 7.8) was -5.0 ± 9.3 (95% confidence interval [CI]; -6.3, -3.8), with a mean relative change of -18.1% (95% CI; -27.7, -8.5). In the crossover cohort (n=94), the mean absolute change in HIS from BL (15.1 ± 7.1) to EOS (11.6 ± 8.0) was -3.8 ± 9.3 (95% CI; -5.8, -1.8), with a mean relative change of -10.4% (95% CI; -26.8, 6.0). Among LIC responders, the mean absolute change of HIS from BL (18.6 ± 7.4) to EOS (9.9 ± 7.2) was -8.7 ± 7.6 (95% CI; -10.1, -7.4); mean relative change -43.5% (95% CI; -51.7, -35.4). Among LIC non-responders, the mean absolute change of HIS from BL (13.0 ± 5.9) to EOS (14.4 ± 7.9) was 1.6 ± 8.2 (95% CI; -0.3, 3.5); mean relative change 26.9% (95% CI; 6.9, 47.0; Table). Correlation of HIS versus ALT: At BL and EOS, HIS showed a weak positive correlation with ALT in LIC responders (n=125, R=0.27 and n=126, R=0.31, respectively) and moderate correlation in non-responders (n=72, R=0.36 and n=72, R=0.43). Similarly, absolute change in HIS showed a weak correlation with change in ALT in LIC responders (n=125; R=0.17) with a moderate correlation in non-responders (n=72; R=0.44; Figure). Correlation of LIR versus ALT: At BL and EOS, LIR showed no correlation with ALT in LIC responders (n=121; R=-0.07 and n=122; R=0.04, respectively) and non-responders (n=70; R=-0.14 and n=70; R=-0.05, respectively). Absolute change in LIR showed a weak negative correlation with change in ALT in LIC responders (n=121; R=-0.25) and no correlation in non-responders (n=70; R=0.02). Discussion: Long-term iron chelation therapy is associated with improvement of liver function as measured by ALT in iron-overloaded patients with β thalassemia. Absolute change in HIS correlated with change in ALT in both LIC responders and non-responders. Although this correlation was weak to moderate, this finding supports the importance of excess iron removal from hepatocytes in order to improve ALT levels. By contrast, LIR which represents the proportion of HIS to total liver iron, showed no correlation. These results suggest that the improvement in liver function seen during chelation therapy may partly be due to the decrease in iron stored in hepatocytes. Further studies are warranted to investigate the mechanisms by which iron chelation therapy may improve liver function. Disclosures Cappellini: Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Kattamis:ApoPharma: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Han:Novartis: Employment. El-Ali:Novartis: Employment. Porter:Celgene: Consultancy; Shire: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Description: ICL670 (deferasirox) is an investigational once-daily oral iron chelator that has demonstrated the ability to induce sustained, clinically relevant reductions in liver iron content (LIC) in heavily transfused patients with β-thalassemia and iron overload. The efficacy and safety of ICL670 is being assessed in a multicenter, randomized, open-label Phase III study in comparison with deferoxamine (DFO) in patients aged ≥2 years with β-thalassemia and transfusional hemosiderosis. Between March and November 2003, 587 patients began treatment (296 on ICL670; 291 on DFO) in the following 12 countries : Italy (200), Turkey (87), Tunisia (68), US (48), Greece (46), Germany (27), Argentina (24), Belgium (24), Brazil (20), UK (18), Canada (13) and France (12). Based on LIC at baseline (2–3, 〉3–7, 〉7–14 and 〉14 mg Fe/g dw), patients were randomized in a 1:1 ratio to receive either oral ICL670 once daily at doses of 5, 10, 20 or 30 mg/kg, respectively, or subcutaneous DFO at doses of 20–60 mg/kg/day for 5 days/week. Treatment was for one year initially, to be followed by an extension phase during which patients randomized to DFO may switch to ICL670. LIC, the primary outcome variable, was assessed at baseline by liver biopsy or, in some children, non-invasively by magnetic susceptometry using a Superconducting QUantum Interference Device (SQUID). LIC will be reassessed after 12 months of therapy in each patient using the same methodology as at baseline. Liver biopsies are analyzed at a single center (Rennes, France) and SQUID assessments are performed in 3 centers (Turin, Italy; Hamburg, Germany; Oakland, US). At baseline, median (25–75th percentiles) LIC was 13.0 mg Fe/g dw (7.2–21.0) by biopsy and 5.6 (4.0–7.7) in those patients assessed by SQUID. Total body iron balance will be assessed to determine the relative chelation efficacies of ICL670 and DFO. A summary of patient demographics and baseline characteristics (median values or no. of pts) is given in the table. ICL670 has been well tolerated with mild, transient gastrointestinal complaints as the main AEs with a suspected relationship to study drug. As of May 2004, 8 patients on ICL670 and 2 on DFO had discontinued therapy due to AEs. The key efficacy and safety data from the initial 12 months of therapy for all randomized patients will be available late November 2004. Treatment group (by initial dose) ICL670 (n=296) Deferoxamine (n=291) 10 mg/kg n = ≤ 94 20 mg/kg n = 83 30 mg/kg n = 119

Description: Abstract 4063 Poster Board III-998 Background In a large, 1-yr Phase 3 clinical trial, patients (pts) with β-thalassemia (aged ≥2 yrs) were randomized to receive deferasirox (Exjade®) or deferoxamine (DFO), with doses assigned according to baseline liver iron concentration (LIC). Pts completing the 1-yr core were permitted to enter a 4-yr extension; those receiving deferasirox continued on this therapy (deferasirox cohort), while those receiving DFO crossed over to deferasirox (crossover cohort). This analysis evaluates the efficacy and safety of deferasirox over 5 yrs. Methods Based on analyses showing that iron burden and transfusional iron intake need to be considered for appropriate dosing of deferasirox, dose adjustments were permitted in the extension to ensure optimal dosing. Deferasirox dose in the extension was initially based on dose response in the core (deferasirox cohort only) and end-of-core LIC (biopsy or SQUID); subsequent adjustments in steps of 5–10 mg/kg/day were based on serum ferritin (SF) levels and safety markers. Efficacy was assessed by monthly SF levels and LIC at baseline, end of 1-year core and end of study (EOS) (or upon discontinuation). Safety was assessed by incidence and type of adverse events (AEs) and changes in laboratory parameters. Results 296 pts (deferasirox cohort) and 259 pts (crossover cohort) received ≥1 dose of deferasirox; 181 (61%) & 190 (73%) pts from each cohort respectively completed the extension. Most common reasons for discontinuation: consent withdrawal (n=62) and AEs (n=43). Most common AEs leading to discontinuation: increased ALT [n=5], increased transaminases [n=4], glycosuria [n=4]. 2 deaths occurred during the extension in the deferasirox cohort (cardiac failure, cardiomyopathy); 2 in the crossover cohort (cardio-respiratory arrest, road traffic accident); none considered to be related to study drug. Median duration of deferasirox treatment was 61.2 & 48.1 mths in deferasirox & crossover cohorts, respectively. At start of deferasirox, mean LIC was 14.0 ± 9.8 & 10.4 ± 7.6 mg Fe/g dry weight (dw) and median SF was 2211 & 1758 ng/mL in deferasirox and crossover cohorts, respectively. Transfusion requirements at start of deferasirox were comparable; most pts (81% & 83%, respectively) receiving 7–14 mL/kg/mth. Mean deferasirox dose during study: 21.6 ± 6.4 & 23.2 ± 5.9 mg/kg/d (final actual dose: 24.4 ± 8.7 & 27.0 ± 8.0 mg/kg/d) in deferasirox and crossover groups, respectively. Most pts were receiving 15–

Description: Abstract 4838 Background: Regularly transfused patients including those with MDS and AA inevitably accumulate iron in various tissues, hence the importance of iron chelation to prevent end organ dysfunction. Studies of iron chelation in MDS and AA have mostly used serum ferritin as an efficacy indicator; LIC data, a more direct measure of clinical benefit are limited in these patients. Here, we report results from a 1-year Phase II, multicenter study evaluating the effect of deferasirox (DFX) on LIC in iron-overloaded patients with MDS, AA, and other rare anemias. Methods: Patients aged ≥2 yrs with transfusional iron overload due to low/intermediate (Int-1) risk MDS, AA and other congenital or acquired anemias were enrolled. Patients with thalassemia and SCD were excluded. Patients required a lifetime transfusion history of ≥20 units of packed red blood cells (RBC) or serum ferritin 〉1000 ng/mL. DFX was administered at a starting dose of 20 mg/kg/day; some patients started on 10 or 30 mg/kg/day based on transfusion requirements and therapeutic goals. Dose adjustments were based on serum ferritin trends and safety parameters. Primary endpoint was absolute change in LIC assessed by R2 MRI (Ferriscan®) from baseline (BL) to 1 year. Secondary objectives included analyses of change in serum ferritin, iron balance and safety. Results: 102 patients (MDS n=42 [41.2%], AA n=29 [28.4%] and other rare anemias n=31 [30.4%]) were enrolled. Median age was 56.5 yrs (range 2–85 yrs). 68 (67%) patients completed 1 year of treatment. Average actual dose (mean ± SD) was 18.5 ± 5.6 mg/kg/day; 64 patients (62.7%) received an average dose of 15–7–ULN at 2 consecutive visits) compared with 18 of the remaining 83 patients (21.7%) who did not receive CyA. Conclusions: A large proportion of patients in this study with transfusion-dependent Low/Int-1 risk MDS, AA and other rare anemias had severe liver iron overload (LIC ≥15 mg Fe/g dw). 1 year of DFX treatment significantly reduced iron burden, as assessed by both LIC and serum ferritin; with iron excretion 2–3 times higher than iron intake. Furthermore, change in LIC correlated with change in serum ferritin and ALT, a clinically relevant indicator of liver function. Overall the DFX safety profile was consistent with that from previous studies. Renal function in patients receiving DFX and concomitant CyA should be closely monitored as previously noted in the EPIC trial. Disclosures: Kohgo: Kyorin Pharma: Research Funding; Sapporo Brewery: Research Funding; Asahikasei Kurare Medical: Research Funding; Chugai Roche: Research Funding; Novartis: Research Funding, Speakers Bureau. Sanz:Novartis: Speakers Bureau. Helou:Novartis: Employment. Habr:Novartis: Employment. Malet:Novartis: Employment. Glaser:Novartis: Employment. Wiktor-Jedrzejczak:Novartis: Honoraria, Research Funding; Janssen-Cilag: Honoraria.

Description: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with the survival rates up to 80–90%, but in high-risk patients the survival rate is still unsatisfactory. The aim of this study is to analyze the pediatric ALL data of a single pediatric university center between 1987–2005 retrospectively to identify risk factors effecting the event free survival (EFS). In order to determine the risk factors possibly effecting the survival, we analyzed gender, age, physical examination findings, blood cell count, FAB morphology, immunophenotyping results, translocations and extramedullary involvement. During the same period, chemotherapy regimens used and response to these protocols were also analyzed. A total of 372 cases [220 male (60%) and 151 female (41%)] were diagnosed and treated in our center between 1987–2005. The age distribution was as follows: 7% patients under 2 years, 68% between 2–10 years, 25% above 10 years of age. At diagnosis, 76% patients had a hemoglobin level 10.000/mm3, 74% platelet 50.000/mm3 and platelet count

Description: Abstract 4365 Fibrinolytic system plays a role in tumor growth, invasion and metastasis in cancer. High levels of plasminogen activator inhibitor-1 (PAI-1) which is a part of fibrinolytic system is a sign of poor prognosis in a number of cancer types. Acute lymphoblastic leukemia (ALL) is the most frequent malignant disease of childhood. Risk groups of ALL are used to determine treatment strategies in childhood ALL. In this study, we aimed to ascertain the prognostic and predictive roles of PAI-1 and vitronectin in children with ALL, and their relationship with risk groups of ALL. In the literature, there are few studies with PAI-1, but no study with vitronectin and ALL in children. In this study, we analyzed the plasma PAI-1 and vitronectin levels of 37 recently diagnosed ALL patients (age range: 9 months–17 years), and 25 age-matched healthy children as a control group by using the ELISA technique. The mean PAI-1 levels was 27.36±16.53 ng/ml, vitronectin levels 97.54±29.82% in the ALL group; and, 23.60±10.44 ng/ml, 85.50±20.85% in the control group, respectively. It was found that the plasma vitronectin levels of ALL group was high as nearly statistically significant (p=0.06). Although, the PAI-1 levels of ALL group was higher than the control group, there was no statistically significance (p=0.27). The ALL group was divided into three risk groups (standard, moderate, and high) according to the BFM protocol. When the standard and moderate-high risk groups are compared with control group, the vitronectin levels of standard risk group was higher than the control group (p=0.048), but no difference was found for PAI-1 levels (p=1.00). There was no significant difference for vitronectin levels (p=0.76), and PAI-1 levels (p=0.25) between moderate-high risk groups and the control group, although PAI-1 levels were higher in moderate-high risk groups. In conclusion, we could not find any relationship between the parameters of fibrinolytic system and ALL risk groups except the vitronectin levels of standard risk group, new studies are needed. Disclosures: No relevant conflicts of interest to declare.

Description: Immunological disturbances have been reported in thalassemia and the possibility has been raised that these may be consequences of blood transfusion and iron overload. These disturbances are augmentation of the number of supressor T cells (CD8), decreased number and activity of helper T cells (CD4) and impaired activity of NK (natural killer) cells. Iron overload causes toxic tissue changes through the release of free radicals and induces oxidative stress. According to Fenton and Haber-Weiss reactions, iron plays a catalytic role occuring hydroxyl radicals (OH*) which are very reactive free radicals. Antioxidants, like vitamin E, vitamin C and selenium, may modulate oxidative damage. In the present study; firstly, normal lymphocytes mitogen responses and NK activity were investigated by colorimetric MTT test in 26 thalassemia patients and 10 healthy volunteers as control. Secondly, lymphocytes were incubated with vitamin E ( 150, 50, 15 mg/ml), vitamin C (200, 100, 20mg/ml) and selenium (10−5, 10−6, 10−7 M). Finally, lymphocytes mitogen responses and NK activity are investigated. The results were statistically analyzed comparing with controls and healthy volunteers. It was found decreased NK activity of thalassemia patients in comparison with healthy volunteers. The concentration of 10−7 M of selenium enhanced NK activity at the E:T (effector/target) ratio of 50:1 The concentration of 200 mg/ml of vitamin C enhanced NK activity at the E:T ratio of 10:1, 25:1 and 50:1. However, vitamin E decreased NK activity of both thalassemia patients and healhty volunteers. The concentration of 50 mg/ml vitamin E decreased NK activity at the E:T ratio of 5:1 in thalassemia patients and the concentration of 15 mg/ml of vitamin E decreased NK activity at the E:T ratio of 5:1 in healhty volunteers. It was not found any differences between thalassemia patients and healthy volunteers in lymphocytes mitogen responses. The concentration of 200 mg/ml of vitamin C decreased lymphocytes mitogen response against PHA. In conclusion, we suggest that vitamin C and selenium supplementation are required in patients with thalassemia for augmentation of NK cell activity.