ALBERT

Description: Background: Efficacy and safety of iron chelation with deferasirox (Exjade®; DFX) 5 and 10 mg/kg/day (escalated to max: 20 mg/kg/day) in non-transfusion-dependent thalassemia patients, was established in the placebo-controlled, THALASSA study; Taher et al Blood 2012;120:970-977. THETIS added to this evidence by investigating a broader patient population, including non-transfusion-dependent congenital anemia patients and those treated with concomitant medications (eg hydroxyurea) and by evaluating early escalation with higher DFX doses according to liver iron concentration (LIC; max: 30 mg/kg/day). Methods: Patients ≥10 yrs of age with iron overload (LIC ≥5 mg Fe/g dry weight [dw]) and serum ferritin (SF) ≥300 ng/mL were enrolled. Exclusion criteria included: blood transfusions within 6 months of study enrollment or anticipated regular transfusions (unplanned transfusions allowed); Hb S/β thalassemia; active hepatitis B/C; cirrhosis; history of clinically relevant ocular and/or auditory toxicity; on two consecutive measurements: alanine aminotransferase (ALT) 〉5×the upper limit of normal (ULN), serum creatinine 〉ULN, creatinine clearance ≤40 mL/min, or urine protein/urine creatinine ratio 〉1.0 mg/mg. All patients started DFX at 10 mg/kg/day. At week 4, DFX was increased according to baseline (BL) LIC: LIC 〉15, 20 mg/kg/day; LIC 〉7-≤15, 15 mg/kg/day; LIC ≥5-≤7, 10 mg/kg/day. At week 24, DFX was adjusted further: LIC 〉15, +5-10 mg/kg/day (max 30 mg/kg/day); LIC 〉7-≤15, +5 mg/kg/day (max 20 mg/kg/day); LIC ≥3-≤7, same dose. If LIC ULN. All patients with notable renal or liver laboratory values continued treatment. Conclusions: DFX 10 mg/kg/day (escalated to max: 30 mg/kg/day) resulted in significant and clinically relevant reductions in iron overload, with a similar safety profile as reported in THALASSA (in both DFX- and placebo-treated patients). With early dose escalation at week 4 with further adjustment at week 24, patients with a higher iron burden received higher DFX doses. These results support early dose escalation of DFX to optimize chelation in more heavily iron-overloaded patients with non-transfusion-dependent anemias. Disclosures Taher: Novartis: Honoraria, Research Funding. Cappellini:Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Porter:Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Karakas:Novartis: Research Funding. Viprakasit:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GPO, Thailand: Honoraria, Research Funding; Shire: Research Funding. Siritanaratkul:Pfizer: Research Funding; Roche: Research Funding; Novartis: Research Funding; Janssen-Cilag: Research Funding. Kattamis:Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. Wang:Novartis: Employment. Zhu:Novartis: Employment. Joaquin:Novartis: Employment. Uwamahoro:Novartis: Employment.

Description: Background: Although non-transfusion-dependent thalassemias (NTDT) and non-transfusion-dependent congenital or chronic anemias are found in Southern China, they are relatively rare diseases in China and there are little data evaluating iron chelation in Chinese patients. This 1-year analysis from the THETIS study investigated the efficacy and safety of deferasirox in a large subpopulation of Chinese patients. Early escalation of deferasirox doses (max: 30 mg/kg/day) was evaluated according to liver iron concentration (LIC). Methods: THETIS is an open-label, single-arm, multicenter, Phase IV, 5-year study with the primary endpoint after 1 year of treatment. For this subanalysis, Chinese patients ≥10 years of age with iron overload (LIC ≥5 mg Fe/g dry weight [dw] and serum ferritin [SF] ≥300 ng/mL) were enrolled. Exclusion criteria included: blood transfusions within 6 months of study enrollment or anticipated regular transfusions (unplanned transfusions allowed), Hb S/β thalassemia, active hepatitis B/C, cirrhosis, history of clinically relevant ocular and/or auditory toxicity; on two consecutive measurements: alanine aminotransferase 〉5× the upper limit of normal (ULN), serum creatinine 〉ULN, creatinine clearance ≤40 mL/min, or urine protein/urine creatinine ratio 〉1.0 mg/mg. All patients started deferasirox at 10 mg/kg/day. At week 4, deferasirox was increased according to baseline LIC (LIC 〉15, 20 mg/kg/day; LIC 〉7-≤15, 15 mg/kg/day; LIC ≥5-≤7, 10 mg/kg/day). At week 24, deferasirox was adjusted further: LIC 〉15, +5-10 mg/kg/day (max 30 mg/kg/day); LIC 〉7-≤15, +5 mg/kg/day (max 20 mg/kg/day); LIC ≥3-≤7, same dose. If LIC

Description: Background: THALASSA demonstrated consistent efficacy and safety of iron chelation therapy with deferasirox (Exjade®) across underlying non-transfusion-dependent thalassemia syndromes: β thalassemia intermedia (β TI), Hb E/β thalassemia and α thalassemia (Hb H disease); Taher et al AJH 2013;88:503-506. THETIS added to this evidence by investigating a broader patient population (including non-transfusion-dependent congenital anemias and those treated with concomitant medications [eg hydroxyurea]) and by evaluating early escalation with higher deferasirox doses (LIC; max: 30 mg/kg/day) according to baseline liver iron concentration. Here, we report 1-year efficacy and safety findings from THETIS by underlying non-transfusion-dependent anemia. Methods: Patients aged ≥10 years with iron overload (LIC ≥5 mg Fe/g dry weight [dw]) and serum ferritin (SF) ≥300 ng/mL were enrolled. Exclusion criteria included: blood transfusions within 6 months of study enrollment or anticipated regular transfusions (unplanned transfusions allowed); Hb S/β thalassemia; active hepatitis B/C; cirrhosis; history of clinically relevant ocular and/or auditory toxicity; on two consecutive measurements: alanine aminotransferase (ALT) 〉5× the upper limit of normal (ULN), serum creatinine (SCr) 〉ULN, creatinine clearance (CrCl) ≤40 mL/min, or urine protein/urine creatinine ratio (UPCR) 〉1.0 mg/mg. All patients started deferasirox at 10 mg/kg/day. At week 4, deferasirox was increased according to baseline LIC (LIC 〉15, 20 mg/kg/day; LIC 〉7-≤15, 15 mg/kg/day; LIC ≥5-≤7, 10 mg/kg/day). At week 24, deferasirox was adjusted further: LIC 〉15, +5-10 mg/kg/day (max 30 mg/kg/day); LIC 〉7-≤15, +5 mg/kg/day (max 20 mg/kg/day); LIC ≥3-≤7, same dose. If LIC

Description: Thalassemia is one of the most common causes of inherited anemia worldwide. While significant advances has been made in clinical management of thalassemia patients over the past few decades, our knowledge on the factors affecting the quality of life of thalassemia patients is limited. The "IntercontinThal Study" is a collaborative effort to study the quality of life (QoL) and quality of care of thalassemia patients in populations across diverse social and health care systems. Data presented here are from the three participating centers in Canada, Lebanon and Iran. We have gathered study data through: a) QoL questionnaire SF-36 completed by patients, b) a specifically designed and validated questionnaire completed by patients which addressed patient's social status (marriage/relationship status, education, employment status, and access to social support and health care), and c) review of the patients' charts using a data collection form. This form included: patients' demographics, specifics of transfusion therapy and iron chelation, thalassemia-related and other clinical complications (endocrinopathies, bone disease, cardiac disease, hemolysis-related complications, etc.), tissue iron content (liver and cardiac) and/or serum ferritin within the past three years, and splenectomy status. All study questionnaires were translated into Persian (for Iranian patients) and Arabic (for Lebanese patients). Due to the variety of the clinical complications, all clinical complications were aggregated together for statistical analysis. We used univariate and multivariate regression analysis to study the association of predictors and patients' QoL Mental Component Summary (MCS) Score. Ninety seven patients [46 female, 59 transfusion-dependent beta-thalassemia (TDT) and 38 non-transfusion-dependent beta-thalassemia (NTDT)] were included in the analysis. All patients were older than 18 years of age (Mean 32 years, SD: 7 years). In univariate analysis age, access to social support and health care, marriage status, liver iron concentration and ferritin (strongly correlated with each other), and disease-related complications were found to be predictor of QoL MCS scores. In NTDT patients, splenectomy and lower baseline hemoglobin were also significantly associated with reduced QoL. In multivariate analysis, ferritin and age (and clinical complications in TDT patients) were found to independently be associated with reduced QoL. LIC was not found to be an independent factor likely due to the fewer number of patients who had recent LIC assessments. Of interest, patients with NTDT reported better QoL at younger age compared to TDT patients but there was a trend toward worse QoL at older age. Our results provide a better understanding of the factors that affect the QoL of thalassemia patients and highlights the importance of management of body iron in both TDT and specially in NTDT patients. In addition, it confirms the notion that while NTDT patients may not require regular transfusions based on conventional criteria, they may experience significant reduction in QoL especially at older ages. Further efforts to address the health and QoL of NTDT patients are required to improve the outcomes of this often neglected condition. (Funded by a research grant from the Thalassemia Foundation of Canada) Disclosures Taher: Celgene: Research Funding; Novartis: Honoraria, Research Funding.

Description: Background The Philadelphia chromosome−negative classical MPNs (myelofibrosis [MF], polycythemia vera [PV], and essential thrombocythemia [ET]) are associated with a pronounced symptom burden, including fatigue, night sweats, itching, and inactivity that may affect patients' HRQOL. There is a limited real-world evidence from many of the Asian countries, including Middle East, regarding the impact of MPNs on HRQOL, or the economic burden associated with these diseases. MERGE is a multinational, multicenter, nonintervention study conducted in adult patients with MPNs in Asia, including Middle East, Turkey, and Algeria. The present analysis evaluated the impact of MPNs on HRQOL of patients from MERGE and explored the association of HRQOL with the clinical outcomes and resource utilization. Method The MERGE registry included patients with MPN diagnosed as per the World Health Organization 2008 criteria. Patients were planned to be followed up for 2 years (5 visits over the course of study). MPN Symptom Assessment Form Total Symptom Score (MPNSAF TSS) was administered during the routine biannual follow-up visits to assess the HRQOL. MPNSAF TSS score was calculated only for patients who completed at least 6 of the 10 items on the MPNSAF TSS questionnaire. The level of inter-rater agreement between physicians and patients on the proportion of symptomatic patients was assessed through Cohen's Kappa coefficient. Further, an ANCOVA (Analysis of covariance) model was applied to estimate the influence of the baseline variables (age, sex, weight, height, family history of MPNs, comorbidities, time to initial MPNs diagnosis, type of MPN initial diagnosis, baseline hemoglobin and platelet count, Eastern Cooperative Oncology Group Performance Status [ECOG PS], and time since diagnosis to treatment initiation) on the TSS score. Variables with univariate P-value 〈 0.20 were included in the multivariate model. Furthermore, medical resource utilization was assessed by evaluating the inpatient and outpatient visits, hospice care, emergency room visits, and day care. Results Of the 884 eligible patients with MPNs, 169 had MF, 301 had PV, 373 had ET, and 41 had unclassified MPN. During the study, 64% of patients received hydroxyurea, 15% interferon, 15% JAK inhibitors, and 10% anagrelide either alone or in combination. At baseline, the proportion of patients presenting at least 1 of the symptoms was higher in the MF group (96.4%), compared to the total MPN patients (91.8%). In addition, the TSS (mean [SD]) at baseline was highest in the patients with MF (23.5 [17.47]) as compared to patients with ET (14.6 [14.26]) and PV (16.6 [14.84]). During the study duration and follow-up, the TSS remained approximately constant at subsequent visits. Physicians reported a lower proportion of symptomatic patients than the proportion self-reported by patients, although, there was better agreement between physicians and patients for pruritus and night sweats (Kappa, 0.61-0.80) (Table 1) than for other symptoms (Kappa, 0.41-0.60). Across MPN subtypes, inter-rater agreement was lowest for patients with MF compared to patients with ET or PV. In a multivariate adjusted mixed effect regression model, female gender, type of MPN (MF), presence of comorbidities, lower baseline hemoglobin were independently and positively associated with the symptom score values. Overall, 24.3% of the patients had at least 1 inpatient visit, with a mean duration of 11.1 days. Outpatient visits were the most commonly observed healthcare resource used (95.5%), without remarkable change during the follow-up period. Patients with ET had a lower mean number of inpatient visits (mean [SD]: 0.9 [0.77] days), and patients with MF had more outpatient visits (mean [SD]: 5.2 [3.17] visit) on an average, compared to the entire MPN group. Conclusion Despite being on treatment, patients with MPN in MERGE had substantial symptom burden, which did not change over the course of the study. A discordance between physician and patient perception of symptom assessment was seen in this study, indicating that in addition to spleen and hematological investigations, a more systematic assessment such as the use of MPNSAF TSS could help to better evaluate patients' symptoms and understand the disease and its treatment burden. Disclosures Taher: Celgene Corp.: Research Funding; Ionis Pharmaceuticals: Consultancy; Protagonist Therapeutics: Consultancy; La Jolla Pharmaceutical: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Yassin:Novartis: Research Funding. Rippin:Employee of IQVIA - doing consultancy for Novartis: Consultancy. Sadek:Novartis Pharmaceutical Corporation: Employment. Siddiqui:Novartis Pharma AG: Employment, Equity Ownership. Wong:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Background: Iron overload is a significant complication in patients with hereditary hemochromatosis and hereditary hemolytic anemia (esp. sickle cell disease and thalassemia). LJPC-401, a synthetically produced peptide identical to endogenous human hepcidin, is being developed as a therapeutic intervention for iron overload in these conditions. Methods: Phase 1, randomized, double-blind, two-arm, placebo-controlled, single dose escalation, and multiple dose study to assess the safety, tolerability, and pharmacokinetics (PK) /pharmacodynamics (PD) of LJPC-401 in healthy adults. Eligible healthy adults were randomized in a 3:1 ratio to receive either LJPC-401 or placebo as a subcutaneous (SC) injection in single-dose cohorts (Arm A) or a multiple-dose cohort (Arm B, twice weekly for two weeks). Subjects were assigned to receive LJPC-401 at doses of 4, 10, or 20 mg. Serial blood samples were collected up to one-week post dose in the single-dose cohort and up to two weeks in the multiple-dose cohort for PK and PD assessments. PD assessments included effects on serum iron, ferritin, unsaturated iron binding capacity (UIBC), and transferrin saturation (TSAT). Results: Twenty-one healthy adults were randomized and included in analyses (12 from Arm A and 9 from Arm B). In Arm A, dose-related increases in mean baseline-corrected LJPC-401 concentrations were observed following single SC doses of 4, 10, and 20 mg LJPC-401. Peak concentrations were observed at approximately 2 hours postdose for all doses. LJPC-401 concentrations returned to near baseline by approximately 1 day postdose for the 4- and 10-mg dose groups and by 7 days postdose for all groups. In Arm A, dose-dependent decreases in serum iron were observed in all LJPC-401 dose groups, beginning at 2 hours postdose. The largest percent decrease in serum iron for the LJPC-401 groups occurred at the 12-hour postdose timepoint and was a mean (SD) of−56.0% (16.9%) in the 4-mg group, −66.9% (6.1%) in the 10-mg group, and −79.7% (4.1%) in the 20-mg group. Serum iron levels returned to baseline within approximately 24 hours in the 4-mg dose group and within approximately 48 hours after dosing in the 10 and 20 mg dose groups. In Arm B (10 mg dose twice weekly), decreases in mean serum iron from baseline were observed after each dose of LJPC-401. The largest percent decreases in serum iron for the LJPC-401 group was observed at Hours 8 and 12 for the Day 1 dose (mean (SD): −69.1% [9.6%] and −69.2% [17.8%], respectively) and at Hour 12 for the Day 11 dose (−73.0% [13.1%]). Dose-related increases in UIBC were observed, along with dose-related decreases in TSAT, which were similar to those observed for serum iron. Dose-related prolonged increases in serum ferritin were observed. Diurnal variation patterns were seen in endogenous hepcidin and baseline iron levels in placebo subjects. No treatment-emergent serious adverse events were reported. One subject discontinued treatment due to a TEAE (exacerbation of pre-existing atopic dermatitis) two days after initial 10 mg dose. No trends were observed in clinical laboratory data, vital signs, ECGs, or concomitant medications. No subjects tested positive for antibodies specific to LJPC-401. Conclusion: LJPC-401 was well tolerated at single doses between 4 and 20 mg (the highest dose tested), and at doses of 10 mg twice weekly in healthy adults, and resulted in decreases in serum iron levels compared with baseline. Serum ferritin increased over the time course of observations, consistent with an increased distribution of iron into the macrophage compartment, secondary to decreased iron egress into the plasma transferrin compartment. These results warrant further research in longer-term studies. Disclosures Porter: Agios: Honoraria; Novartis: Consultancy; Cerus: Honoraria. Taher:Celgene Corp.: Research Funding; Protagonist Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; La Jolla Pharmaceutical: Research Funding; Ionis Pharmaceuticals: Consultancy. Shen:La Jolla Pharmaceutical Company: Employment, Equity Ownership. Chen:La Jolla Pharmaceutical Company: Employment, Equity Ownership. Chawla:La Jolla Pharmaceutical Company: Employment, Equity Ownership. Tidmarsh:La Jolla Pharmaceutical Company: Employment, Equity Ownership.

Description: Background The Philadelphia chromosome−negative classical myeloproliferative neoplasms ([MPNs], including essential thrombocythemia [ET], polycythemia vera [PV], and myelofibrosis [MF]), are generally associated with a substantial disease burden, often leading to a reduced quality of life (QOL) and shortened survival in many patients (pts). There has been a lack of estimates for the incidence/prevalence and treatment patterns of MPNs in many regions of the world, including countries from South Asia, Asia Pacific, Middle East, and Turkey. Hence, there is a need to establish databases like registries, which would provide information on the "real-world" data in these regions. The MERGE registry was initiated with an objective to collect data on the epidemiological indices of MPNs and existing treatment patterns in Asia, including Middle East, Turkey, and Algeria. This primary descriptive analysis from the MERGE registry was performed to estimate the incidence/prevalence, natural disease course, and treatment patterns of MPNs in these countries. Methods MERGE is a multinational, multicenter, nonintervention study that included adult pts with MPNs, who were diagnosed according to World Health Organization 2008 criteria. The data were collected retrospectively (since diagnosis) and prospectively after enrollment in the study. Disease assessments were scheduled every 6 months up to 5 visits, with a minimum of 2 years of follow-up. Pts who participated or were participating in a randomized clinical trial were allowed. Data were analyzed descriptively. Results In total, 884 MPN pts (ET=373, PV=301, MF=169, and unclassified=41) were included in the full analysis data set. The median age was 58 years (range, 47-66 years; younger compared to other regions) and 50% pts were males. Baseline pt characteristics by MPN subtype are summarized in Table 1. About 57% of pts were diagnosed by incidental finding of abnormal blood results followed by bone marrow evaluation. In these countries, the prevalence and incidence of MPNs are estimated to be 57-81 and 12-15 per 100.000 hospital-patients per year over the last 4 years, respectively. As assessed by MPN Symptom Assessment Form (MPNSAF), 92% of the pts reported at least 1 symptom. At baseline, fatigue was the most common symptom in all 3 MPN subtypes (71% MPN; 78% MF; 71% ET; and 68% PV). Inactivity (64%), early satiety (61%), abdominal discomfort (57%), bone pain (56%), weight loss (52%), night sweats (46%), and fever (29%) were more common in MF; whereas, itching in PV pts (50%). MF pts had the highest total symptom score at baseline (mean [SD], 23.5 [17.47]) as compared to ET (mean [SD], 14.6 [14.26]) and PV pts (mean [SD], 16.6 [14.84]). Overall, 64% of pts had ECOG performance status of 0 and 26% had ECOG 1. During study period, the most common nonpharmacological intervention was red cell transfusion in MF and ET pts, and phlebotomy in PV pts. Splenectomy (n=2) and stem cell transplantation (n=4) were rarely employed (6 MF pts). Hydroxyurea (HU) was the most common first-line therapy in all 3 MPN subtypes (overall, 54%; PV, 61%; ET, 54%; and MF, 39%), followed by aspirin. Other common first-line therapies were anagrelide (10%) and interferon (9%) in ET pts, antineoplastic (6%) and clopidogrel (6%) in PV, and JAK2 inhibitors in MF pts (15%). More than 75% of the induction therapies were monotherapies, with less than 3% of pts receiving 3 or more drug combinations as primary treatment. Patients with MF often received monotherapy (81%), than the other patients with MPN. Median duration of first-line therapy was about 6 months (95% CI, 1-21 months), and first-line therapy discontinuation rates of 35%, 36%, and 30% were noted in ET, PV and MF pts, respectively. Interferon was used in 8% of in the second-line setting. JAK2 inhibitors were more frequently (14%-17%) used in the second-and third-line settings. Conclusions The prevalence and incidence of MPNs in countries from Asia Pacific were derived using the number of pts visiting the corresponding hospitals. Thus, the resulting incidence and prevalence reported here are not directly comparable with the country-based prevalence/incidence and may overestimate the actual values. At baseline, pts with MPNs had significant disease burden. The most common first-line therapy was HU, though discontinuation rates of first-line therapies were high, and JAK2 inhibitors were mostly used in the second-line/third-line settings. Disclosures Yassin: Novartis: Research Funding. Taher:La Jolla Pharmaceutical: Research Funding; Ionis Pharmaceuticals: Consultancy; Celgene Corp.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Protagonist Therapeutics: Consultancy. Kim:Novartis Korea: Honoraria. Rippin:Employee of IQVIA - doing consultancy for Novartis: Consultancy. Sadek:Novartis Pharmaceutical Corporation: Employment. Siddiqui:Novartis Pharma AG: Employment, Equity Ownership. Wong:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.