ALBERT

Description: Abstract 4279 Background: A fraction of patients (up to 30%) with transfusional iron overload on deferasirox (DFX, Exjade®) have less-than-adequate chelation responses at doses above 30 mg/kg/day. Both transfusion burden and adherence play significant roles in observed chelation effectiveness, but a biological difference between good and poor DFX responders is detectable by pharmacokinetic (PK) assessment. Indeed, we have reported that patients with poor responses at doses〉30 mg/kg/d have decreased exposure (area under the concentration:time curve) after a single oral dose of 35 mg/kg (Chirnomas et al, Blood, 2009, 114:4009). In principle, iron status in these individuals could be improved by strategies to reduce iron input or intensify chelation. Here we report results of these strategies for the poor responders of the published PK trial. Patients and Methods: We retrospectively assessed response of ferritin levels and hepatic iron measurements by R2 Ferriscan® MRI to various strategies in the 9 thalassemia (thal) patients (pts) with poor DFX response from the phase 4 PK trial cited above. One sickle cell pt from the trial with documented poor adherence is not included. Strategies were individualized, based on prior dose of DFX, comorbidity (e.g. liver disease or dose-limiting toxicity), transfusion burden, and estimates of pt adherence. Strategies included: splenectomy to reduce transfusion burden (n=2); dose increase (n=5, including 1 with rapid elimination half-life who also received b.i.d. dosing) and combination (“combo”) therapy with DFX and deferoxamine (DFO, n=2). As ferritin values are variable and not normally distributed, log-transformed ferritin values in three successive months from the time of study eligibility determination and after intervention strategies were compared by two-way ANOVA. Liver iron content pre- and post-interventions, was compared by paired t-test. Results: As shown in the figure, ferritin improved in 8/9 pts (p

Description: Between 1995 and 2004, two NIH-sponsored studies (STOP/STOP II) showed that children with sickle cell disease (SCD) and abnormal transcranial Doppler blood flow measurements (high stroke risk) are protected from stroke with regular blood transfusions. Iron overload, which may lead to complications and requires iron removal therapy, was monitored by serum ferritin (SF). Liver iron concentration (LIC) measurement was not mandated by protocol and was performed at investigator discretion. Biopsy dates and lab values were captured during STOP/STOP II, providing an opportunity to validate SF against LIC. 75 LICs on 36 patients (19 female, 17 male) at 8 centers were obtained. No liver biopsy complications were reported. LICs were correlated with STOP/STOP II core laboratory SF and alanine aminotransferase (ALT) obtained within 180 days of LICs. Median age at first biopsy was 11.1 years (range, 4.5–17.8), median time from start of transfusion was 36 months (range, 2–100). Iron removal treatment was initiated a median 23 months (range, 4–108) from start of transfusion, with deferoxamine (n=27), and/or exchange transfusion (n=9). 21 pts (58%) had multiple LIC measures: 2 (n=9), 3 (n=8), 4 (n=2), 5 (n=2). Last LICs on iron removal therapy were obtained a median 72 months (range, 35–124) from start of transfusion. Correlation between SFs and LICs were r=-0.06 (n=18) for first LICs obtained prior to iron removal therapy, r=0.50 (n=17) for last LICs obtained on iron removal therapy, and r=0.51 for all LICs (n=60). Pts with single/last LIC 〉=15 mg/gram dry liver were significantly more likely to have ALTs 〉=45 IU/L compared to those with LICs =15 mg/gram and ALT 〉=45 IU/L tended to have higher SFs then those with normal ALT (mean SF 4927 ng/ml, 95% CI 1739–8115 vs. mean SF 2255 ng/ml, 95% CI 1599–2912). 37% (7/19) of pts with LIC 〉=15 mg/gram had SFs

Description: We present results from a prospective, multicenter, open-label, single-arm study evaluating response of cardiac and liver iron to deferasirox therapy for 18 months. Twenty-eight patients with abnormal T2* and normal left ventricular ejection fraction were enrolled from 4 US centers. All patients initially received deferasirox doses of 30 to 40 mg/kg per day. Patients were severely iron overloaded: mean liver iron concentration (LIC) 20.3 mg Fe/g dry weight, serum ferritin 4417 ng/mL, and cardiac T2* 8.6 ms. In the intent-to-treat population, 48% reached the primary endpoint (cardiac T2* improvement at 18 months, P = not significant). There were 2 deaths: 1 from congestive heart failure and 1 from sepsis. In the 22 patients completing the trial, LIC and cardiac T2* improvements were 16% (P = .06) and 14% (P = .07), respectively. Cardiac T2* improvement (13 patients) was predicted by initial LIC, final LIC, and percentage LIC change, but not initial cardiac T2*. Cardiac iron improved 24% in patients having LIC in the lower 2 quartiles and worsened 8.7% in patients having LIC in the upper 2 quartiles. Left ventricular ejection fraction was unchanged at all time points. Monotherapy with deferasirox was effective in patients with mild to moderate iron stores but failed to remove cardiac iron in patients with severe hepatic iron burdens. This study was registered at www.clinicaltrials.gov as #NCT00447694.

Description: Tens of thousands of transfusion-dependent (eg, thalassemia) patients worldwide suffer from chronic iron overload and its potentially fatal complications. The oral iron chelator deferasirox has become commercially available in many countries since 2006. Although this alternative to parenteral deferoxamine has been a major advance for patients with transfusional hemosiderosis, a proportion of patients have suboptimal response to the maximum approved doses (30 mg/kg per day), and do not achieve negative iron balance. We performed a prospective study of oral deferasirox pharmacokinetics (PK), comparing 10 transfused patients with inadequate deferasirox response (rising ferritin trend or rising liver iron on deferasirox doses 〉 30 mg/kg per day) with control transfusion-dependent patients (n = 5) with adequate response. Subjects were admitted for 4 assessments: deferoxamine infusion and urinary iron measurement to assess readily chelatable iron; quantitative hepatobiliary scintigraphy to assess hepatic uptake and excretion of chelate; a 24-hour deferasirox PK study following a single 35-mg/kg dose of oral deferasirox; and pharmacogenomic analysis. Patients with inadequate response to deferasirox had significantly lower systemic drug exposure compared with control patients (P 〈 .00001). Cmax, volume of distribution/bioavailability (Vd/F), and elimination half-life (t1/2) were not different between the groups, suggesting bioavailability as the likely discriminant. Effective dosing regimens for inadequately responding patients to deferasirox must be determined. This trial has been registered at http://www.clinicaltrials.gov under identifier NCT00749515.

Description: Chronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% ± 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% ± 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% ± 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% ± 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182.

Description: Abstract 5163 Introduction: Deferasirox (Exjade, ICL670) is an orally effective iron chelating agent approved for use in patients 2 years of age and older with transfusional iron overload. While it is effective as a single agent, there are patients who do not attain net negative iron balance despite being at the upper limit of approved dosing (40 mg/kg/day). Deferiprone (Ferriprox, L1) is another orally effective iron chelator. Through a series of metabolic iron balance studies we were able to demonstrate that various regimens involving the combined use of deferiprone and deferoxamine (Desferal, DFO) were capable of placing all patients into net negative iron balance with the potential to adjust dosing schedules and the ratio of drugs to maximize effectiveness while minimizing toxicity. A variety of such regimens are now in widespread clinical use. We have taken the same approach in order to optimize the use of deferasirox. Methods: Six patients with thalassemia major were enrolled in a 34-day metabolic iron balance study wherein deferasirox and deferoxamine were evaluated alone and in combination, each patient serving as his/her own control. Deferoxamine (40 mg/kg) was administered on days 5 – 10 as an 8-hour subcutaneous infusion during the night. On days 15 – 20, deferasirox (30 mg/kg) was given orally, 30 minutes prior to breakfast. Both drugs were given on days 25 – 30, the same doses and dosing schedules being employed. Non drug days allowed for washout of stool iron induced by the previous treatment. The patients consumed a fixed low-iron diet consisting of four individualized meal plans. Daily collections of urine and stool were made and their iron content determined by atomic absorption, a correction being made for all uneaten food. Results: As in previous studies, there was significant patient to patient variability in terms of the amount of drug-induced iron excretion. Combination therapy placed all patients into iron balance exceeding 200% (206% - 270%, mean 251%). The combination was synergistic in two patients (35% and 57%), additive in three patients, and less than additive in one patient. Where iron excretion was more than additive, all of the excess appeared in the urine (a 2.1- and 3.4-fold increase). Deferasirox proved to be less effective than deferoxamine in all six patients (relative iron excretion: 23% - 59%, mean 42%), stool iron excretion in response to the respective drugs being 94% -100% (mean 98%) and 49% - 74% (mean 59%). Net negative iron balance was achieved in 2/6 patients when on deferasirox (iron balance 28% - 129%, mean 72%) and 6/6 patients when infusing deferoxamine (iron balance 125% - 219%, mean 167%). Discussion: These results suggest that chelation therapy can be tailored to the individual needs of each patient, selectively removing iron from different pools while minimizing any side effects. Deferasirox appears to shuttle iron to deferoxamine for excretion in the urine, not unlike the situation when deferiprone and deferoxamine are combined, although the source of the iron may be somewhat different. It is hoped that these results will provide patients with further options to optimize their chelation regimens. Disclosures: Grady: Novartis Pharmaceuticals: Research Funding. Off Label Use: Deferasirox and Deferoxamine are both iron chelating agents. Their use in combination is not indicated on their labeling. Galanello:Novartis Pharmaceuticals: Speakers Bureau. Paley:Novartis Pharmaceuticals: Employment. Giardina:Novartis Pharmaceuticals: Research Funding.

Description: Abstract 5155 Introduction: Deferasirox (Exjade®, Novartis Pharmaceuticals) is an oral iron chelator indicated for the treatment of transfusional iron overload. The recommended mode of administration is to be taken on an empty stomach in water, apple juice or orange juice ≥30 minutes before food. However, there have been post-marketing reports of discontinuation or reduced compliance of deferasirox secondary to palatability and gastrointestinal adverse events. Registration trials with deferasirox did not evaluate different food combinations in an attempt to maintain predictable plasma levels. Early single dose studies suggested that the bioavailability of deferasirox is increased when administered with or before meals, and is positively influenced by fat content, but is not affected by degree of dispersion nor type of liquid. Long-term pharmacokinetic and tolerability studies involving a food effect have not been conducted to date, and the ability of alternate methods of administration to improve patient compliance with iron chelation therapy is unknown. Method: This is an ongoing single-arm, open-label, multi-center study designed to evaluate the palatability, safety, tolerability and pharmacokinetics of deferasirox when administered with food, dispersed in any liquid of choice, or crushed and added to food. The patient population includes patients with transfusional hemosiderosis (minimum entry serum ferritin ≥500 μ g/L) aged 〉2 years with thalassemia major, sickle cell disease (SCD), low or intermediate (INT-1) risk MDS or other anemias, who are on, starting, or resuming treatment with deferasirox. The study began with a 1-month run-in phase with deferasirox dosed according to prescribing information, then a 3-month assessment phase where subjects could choose each week from 5 general administration options including with or without meals, in the morning or evening, crushed and added to a soft food, or mixed in a liquid of choice. Subject diaries are used to record the meal and method of administration at the end of each week. Palatability is assessed with a modified facial hedonic scale, with additional directed questions capturing gastrointestinal side effects. This is a data analysis of the run-in phase. Result: Target enrollment has been met with 65 patients. Baseline data on the first 58 subjects include 8 in the 2 to

Description: Introduction Patients (pts) with sickle cell disease (SCD) experience a heterogeneous clinical course, with a range of symptoms and sequelae. We describe clinical outcomes and treatment patterns from a prospective registry of pediatric and adult pts with SCD. Methods Pts ≥2 years old with HbSS, HbSC, or HbS/β-thalassemia were enrolled from 57 US centers and assessed every 6 months (mos) for up to 3 years. Differences between pediatric and adult pts at 24 mos follow-up are reported. (ClinicalTrials.gov NCT01220115). Results A total of 498 pts completed the baseline visit (74.1% HbSS disease, 15.3% HbSC, and 10.4% HbS/β-thalassemia) (Table 1 ). At baseline, the following conditions were more frequent in adults: avascular necrosis, gallbladder disease, leg ulcers, and pulmonary hypertension. Pediatric pts had more frequent asthma/reactive airway disease, dactylitis, and splenic sequestration. The nature of sickle-related events varied between adult and pediatric pts (Table 2 ). Prior to study, adults had higher frequencies of pain crises, strokes, and priapism, while pediatric pts had more frequent infections and acute chest syndrome (ACS)/pneumonia. On study, a similar proportion of pediatric and adult pts (56.4% overall) were hospitalized, most frequently due to pain, fever, and ACS/pneumonia; a greater proportion of pediatric pts were hospitalized due to fever (P

Description: Background: Clinical studies have shown that some pts with CML-CP who achieve deep, sustained molecular response (MR) on BCR-ABL1 tyrosine kinase inhibitor (TKI) therapy are able to stop treatment and maintain treatment-free remission (TFR). Because more pts achieve deep MR with NIL vs IM, a higher proportion of pts on NIL may be eligible to attempt TFR. Currently, 4 studies (ENESTgoal, ENESTop, ENESTfreedom, and ENESTpath) are evaluating TFR after NIL in pts with CML-CP. ENESTgoal is an open-label phase 2 study of TFR after second-line NIL in pts who achieved major MR (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [IS]) but not MR4.5 (BCR-ABL1IS ≤ 0.0032%) on IM. The MMR to MR4.5 eligibility window was based on the assumption that approximately one-third of pts within this range of MR would achieve MR4.5 within 2 years of switching to NIL on study. Due to slow enrollment and a higher than expected screen failure rate (primarily due to pts not being in the specified MR window), the sample size was reduced to 59 pts, and the NIL consolidation phase was changed to 2 years (Figure). Methods: Adult (aged ≥ 18 years) pts with Philadelphia chromosome-positive CML-CP who achieved MMR but not MR4.5 (confirmed in a central laboratory) after ≥ 1 year of IM therapy were switched to NIL 300 mg twice daily (BID) upon enrollment. On study, pts who achieve MR4.5 within 2 years of switching to NIL and maintain deep MR during a subsequent 2-year NIL consolidation phase are then eligible to attempt TFR (ie, stop NIL). Approximately 20 pts are expected to become eligible to attempt TFR. Real-time quantitative polymerase chain reaction (RQ-PCR) monitoring is performed by a central laboratory every 3 months on study and more frequently during the TFR phase. During the TFR phase, pts with loss of MMR (per protocol amendment) are required to re-initiate NIL. The primary endpoint is the molecular relapse-free rate 6 months after attempting TFR. Herein we present an early analysis of pts who switched from IM to NIL in ENESTgoal. Results: Fifty-nine pts were enrolled by January 9, 2015 (median age, 54 years [range, 26-74 years]); 66% of pts were male, and80% were Caucasian. Baseline Sokal risk scores were as follows: high, 5 pts (9%); intermediate, 9 pts (15%); low, 32 pts (54%); unknown, 13 pts (22%). Median prior IM treatment duration was 64 months (range, 13-163 months). As of the data cutoff date (March 30, 2015), 49 pts (83%) were on study (monitoring phase, n = 32; consolidation phase, n = 16; TFR phase, n = 1), and 10 pts (17%) had discontinued (monitoring phase, n = 8; consolidation phase, n = 2). Reasons for study discontinuation included withdrawn consent (n = 4), adverse events (AE; n = 2 [grade 1 transient ischemic attack and grade 4 pericardial effusion]), unsatisfactory therapeutic effect (n = 2), administrative problems (n = 1), and abnormal laboratory values (n = 1). The median NIL treatment duration on study was 11.5 months (range, 2.7-18.5 months). AEs were reported in 56 pts (95%), the majority of which were low grade. Grade 3/4 AEs included elevated lipase (10%); rash (3%); and elevated amylase, hypophosphatemia, bronchospasm, headache, hyperglycemia, leukocytosis, non-cardiac-related chest pain, small-intestinal obstruction, squamous cell carcinoma, pericardial effusion, and vomiting (2% each). NIL-related AEs (≥ 5%; all-grade) included rash (27%); fatigue (14%); pruritus (12%); lipase increased (10%); abdominal pain and constipation (8% each); fatigue, headache, and palpitations (7% each); and abdominal discomfort, alopecia, nausea, and weight decreased (5% each). There were no QTcF values 〉 500 ms and no deaths. A total of 19 pts (32%) achieved confirmed MR4.5, and the median time to MR4.5 was 119 days (range, 56-448 days). In the consolidation phase, the median follow-up was 153 days (range, 11-434 days), and the median duration of MR4.5 was 97 days (range, 11-434 days). Per the original protocol, 1 pt entered the TFR phase after 1 year of consolidation and had BCR-ABLIS levels of 0.0241% at 60 days and 0.0216% at 90 days after attempting TFR, triggering re-initiation of NIL. Conclusion: After switching from IM to NIL, 32% of pts achieved confirmed MR4.5 with a median treatment duration of 11.5 months. Safety results are consistent with previously reported NIL studies. Results from longer-term follow-up in ENESTgoal and those from other ongoing studies will provide a better understanding of the role of NIL in enabling pts to achieve TFR. Figure 1. Figure 1. Disclosures Ritchie: Incyte: Speakers Bureau; Celgene: Speakers Bureau. Deininger:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Erba:Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Millennium/Takeda: Research Funding; Millennium/Takeda: Research Funding; Celator: Research Funding; Celator: Research Funding; Astellas: Research Funding; Sunesis: Consultancy; Astellas: Research Funding; Pfizer: Consultancy; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Ariad: Consultancy; Daiichi Sankyo: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees; Ariad: Consultancy; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; GlycoMimetics: Other: Data Safety and Monitoring Committees; Jannsen (J&J): Other: Data Safety and Monitoring Committees. Savona:Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Warsi:Novartis Pharmaceutical Corporation: Employment. Paley:Novartis Oncology: Employment. Dautaj:Novartis Pharmaceutical Corporation: Employment. Lin:Novartis: Employment. Mauro:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy.

Description: Background: FMS-like tyrosine kinase-3 (FLT3) mutation is present in approximately one-third of AML patients. Internal tandem duplication mutations of FLT3 (FLT3-ITD) mutation in AML have been associated with poorer prognosis compared to FLT3 wild type (WT). Treatment patterns and outcomes among FLT3 mutated AML patients have not been well understood. Aims: To compare real-world treatment patterns and clinical outcomes in 18-59 year-old patients with FLT3 mutated vs. FLT3 WT AML. Methods: An online medical records review of 209 patients 18-59 years with a confirmed diagnosis of AML in 2010, 2011, or 2012 was conducted by US hematologists/oncologists. Physicians (n=112) with experience treating AML were chosen from a nationally-representative panel to conduct a review of patients’ medical charts. Charts of patients treated in a variety of practice settings (e.g., solo and group practices, teaching and community hospitals, hospital clinics) were abstracted using a secure online portal. Patient characteristics at diagnosis, treatment patterns (induction and consolidation chemotherapy and stem cell transplantation [SCT]) and clinical outcomes (complete remission [CR] and relapse) were compared between FLT3 mutated and WT patients using chi-square tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. Results: Medical records for 104 FLT3 mutated and 105 WT AML patients were reviewed. FLT3 mutation was associated with having poorer risk status at initial AML diagnosis based on National Comprehensive Cancer Network (NCCN) guidelines (p