Paley, Carole

Abstract Introduction: Recent reviews indicate that transfusional hemosiderosis may be associated with an increased risk of mortality in lower-risk pts with MDS. This trial is designed to evaluate the efficacy and long-term safety of deferasirox (Exjade®, ICL670) in MDS. Deferasirox is an oral iron chelator approved for use in pts with transfusional iron overload. Methods: This is a Phase II, open-label, 3-yr clinical trial in 55 US centers, enrolling 150 pts (aged ≥18 years) with Low- or Int-1-risk MDS (by IPSS criteria) and transfusional iron overload (serum ferritin ≥1000 ng/mL and >20 units RBC transfusions). Deferasirox dosing is 20–30 mg/kg/day. Serum ferritin, iron, transferrin and transferrin saturation are being assessed at screening and monthly in yr 1, then quarterly in yrs 2 and 3, while labile plasma iron (LPI) is assessed quarterly in yr 1. In addition, creatinine, calculated creatinine clearance, echocardiograms and endocrine and hematological status are being assessed. This report describes baseline data in these pts. Results: As of June 2006, 84 pts have enrolled. Demographic data are available from 79 pts: median age 71 years (range 47–87); sex (52 male, 27 female); ethnicity (74 Caucasian, 2 Black, 2 Hispanic, 1 Oriental); and IPSS Risk Group (Low: 22 pts; Int-1: 56 pts). Iron status is summarized in the table: Parameter n Mean ± SD Median Range Normal range n/a, not applicable Serum ferritin,μg/L 84 3779 ± 4070 2951 1160–36280 12–370 Serum iron, μg/dL 84 205 ± 64 201 48–409 37–180 Transferrin, mg/dL 82 153 ± 31 152 83–244 190–375 Transferrin saturation, % 83 85 ± 15 91 20–94 15–50 LPI, μmol/L 38 0.52 ± 0.63 0.25 0–2.9 0 Total transfusions, n 78 63.3 ± 66.3 41.5 14–435 n/a Years of transfusion 75 3.4 ± 1.9 3 1–12 n/a Baseline concurrent therapies: 5-azacytidine (Vidaza): 5 pts; lenalidomide (Revlimid): 1 pt. Calculated creatinine clearance: normal (>80 mL/min): 37 pts; mildly abnormal (51–80 mL/min): 30 pts; moderately abnormal (30–50 mL/min): 9 pts. Hematological parameters: Anemia was present in all pts; other cytopenias included: neutropenia (<1800/μL): 13 pts, thrombocytopenia (<100,000/μL): 15 pts; neutropenia and thrombocytopenia: 12 pts. A total of 53 pts had received chelation prior to enrolling: 51 deferoxamine (Desferal®); and 2 deferasirox. Conclusions: Despite the prior availability of deferoxamine, these baseline data demonstrate significant levels of iron overload among transfused pts with myelodysplasia. Serum iron, ferritin and LPI are all well above the clinically significant thresholds associated with increased complications. Since recent data has suggested that iron overload may be a poor prognostic indicator in MDS, increased attention to maintaining appropriate iron balance is warranted. The recent availability of an oral iron chelator may be more acceptable to MDS pts and their physicians. This ongoing trial is designed to assess the long-term efficacy, safety, and clinical benefits of deferasirox in pts with MDS.

Abstract INTRODUCTION: The majority of patients (pts) with MDS require red blood cell transfusions, which can result in iron overload and its clinical sequelae. The US03 trial is designed to evaluate the long-term efficacy and safety of the once-daily, oral iron chelator, deferasirox (DFX), in pts with lower-risk MDS. In this ongoing study 93/176 pts have now completed 12 months of treatment. METHODS: US03 is a Phase II, open-label, 3-year trial in pts with Low- or Int-1 IPSS-risk MDS and transfusional iron overload (serum ferritin [SF] 1000 μg/L and >20 units RBC transfusions), with serum creatinine (SCr) 2-fold the upper limit of normal (ULN). Initial DFX dose was 20 mg/kg/day and could be increased to 40 mg/kg/day based on tolerability and response. SF was monitored monthly; labile plasma iron (LPI), the reactive species of non-transferrin-bound iron, was assessed quarterly. BASELINE FEATURES: 176 pts were enrolled at 45 centers. Mean age: 70 years (range 21–90); 105 men and 71 women; IPSS Low risk (n=47; 27%); Int-1 (n=126; 72%); other (n=3; 2%). Mean baseline iron status was: SF, 3397 μg/L (863–36,280); LPI, 0.4 μmol/L (0.0–3.6). Forty-one percent of pts had elevated LPI at baseline (≥0.5 μmol/L). Mean number of lifetime prior transfusions: 63; mean duration of transfusions: 3.5 years (0–34). MDS therapy at study entry included azacitidine, hydroxyurea, lenalidomide, thalidomide or decitabine in 25 pts, and growth factors in 48 pts. Calculated creatinine clearance was normal (>80 mL/min) in 77 pts and abnormal (abn) in 99: mildly abn (51– 80 mL/min) in 71; moderately abn (30–50 mL/min) in 25; severely abn (<30 mL/min) in 3. RESULTS: Over 12 months, the mean dose of DFX was 21 mg/kg/day, and the mean transfusion rate was 3.4 units/month. Mean SF±SEM (μg/L) values at baseline, 3, 6, 9 and 12 months were 3397±233 (n=176), 3057±144 (n=143), 2802±128 (n=126), 2635±148 (n=109) and 2501±139 (n=93), respectively. In pts with elevated baseline LPI, sustained suppression of mean LPI to the normal range was achieved after 3 months of treatment. The figures show reductions (±SEM) in SF, and in LPI in pts with baseline LPI ≥0.5 μmol/L. Hematological improvement by IWG 2000 criteria was achieved in 8 pts (5%): erythroid response in 5 (major 3; minor 2); platelet in 1 (major); neutrophil in 1 (major); and combined platelet and neutrophil in 1. SAFETY: Of 173 pts, 18 (10%) discontinued DFX because of suspected adverse events (AEs), and an additional 5 (3%) because of serious AEs (SAEs). The most common AEs were diarrhea (n=9), rash (n=3) and nausea (n=2), while the most common SAEs were rash (n=2) and diarrhea (n=1). Of 147 pts with normal baseline SCr, 26 (18%) increased >ULN on at least two occasions (3.0 mg/dL max SCr). There were 9/172 (5%) and 22/168 (13%) new onset cases of grade 3–4 thrombocytopenia and neutropenia, respectively, none suspected to be related to DFX; 7 and 11 of these pts, respectively, were receiving other MDS treatment therapies, including lenalidomide, decitabine, hydroxyurea and azacitidine. There were 17 deaths (10%), due to sepsis/infection (n=8), disease progression (n=4), intracranial bleed (n=2), cardio-respiratory arrest (n=2) and renal failure (n=1), all thought to be unrelated to DFX. CONCLUSIONS: In these heavily iron-overloaded pts, DFX was generally well tolerated. New onset cytopenias were consistent with the underlying disease. A 2-year extension phase of this study will assess the long-term safety and efficacy of DFX as well as the clinical impact on cardiac, hepatic and endocrine function. Figure Figure

Abstract INTRODUCTION: The majority of patients (pts) with MDS become red blood cell (RBC) transfusion dependent with escalating risk for transfusional hemosiderosis and its adverse effect on morbidity and mortality. The US03 trial is designed to evaluate long-term efficacy and safety of the oral iron chelator, deferasirox (DFX), in pts with lower risk MDS. In this ongoing study 53 pts have completed 12 months’ (mos) treatment. METHODS: US03 is a Phase II, open-label, 3-year trial in pts with Low- or Int-1 IPSS risk MDS and transfusional iron overload (SF ≥1000 μg/L and >20 units RBC transfusions [tx]), with serum creatinine (SCr) ≤2-fold the upper limit of normal (ULN). Initial DFX dose was 20 mg/kg/day and could be increased to 40 mg/kg/day based on tolerability and response. SF was monitored monthly; LPI, the reactive species of non-transferrin-bound iron, was assessed quarterly. BASELINE FEATURES: 176 pts were enrolled at 45 centers. Mean age was 70 years (range, 21−90), including 102 men, 71 women; and IPSS risk groups of Low 46 pts (27%), Int-1 123 (71%), other 4 (2%). Mean baseline iron status: SF 3398 μg/L (range, 863−36,280); LPI 0.4 μmol/L (0.0−3.6); mean lifetime txs prior to study, 63; years of prior tx 3.5 (0−34). MDS therapy at study entry included chemotherapy, 22 pts; growth factors, 46. Estimated creatinine clearance: normal (>80 mL/min), 77 pts; mild (51−80 mL/min), 68; moderate, (30–50 mL/min) 25; severe (<30 mL/min) 2. Over 12 mos the mean dose was 21 mg/kg/day, and the mean tx rate was 4.1 units/mo. Forty percent of pts had elevated LPI at baseline (≥0.5 μmol/L). RESULTS: Mean SF±SD (μg/L) values: baseline 3398±3088; 3 mos 3065±1743; 6 mos 2775±1355; 9 mos 2759±1562; 12 mos 2603±1336. Sustained suppression of mean LPI to the normal range was achieved after 3 mos of treatment. (Figure shows changes in SF and LPI). Hematologic improvement by IWG criteria: 5 pts (6%); erythroid response: 3 (major 1; minor 2); platelet 2 (major); neutrophil 1 (major). SAFETY: Of 165 pts, only 10 (6%) discontinued secondary to suspected adverse events (AEs), and 7 (4%) serious AEs. There were 11 deaths (7%), all unrelated to DFX. Of 140 pts with normal baseline SCr, 35 (25%) increased >ULN (2.2 mg/dL max SCr). SCr increased >33% above baseline in 11 pts (8%) abnormal at baseline. New onset of thrombocytopenia and neutropenia were 52/165 (32%) and 22/165 (13%), respectively. CONCLUSIONS: DFX therapy decreased mean SF over 1 year in this heavily iron-replete MDS population. Trough LPI normalized in 100% of pts over 12 mos, indicating 24-hour sustained suppression. DFX had a manageable safety profile in this population; new cytopenias were consistent with hematologic progression of MDS. Recent reviews show a 30% increase in hazard ratio for every 500 ng/mL increase in SF >1000 ng/mL; NCCN guidelines recommend consideration of iron chelation in iron-overloaded MDS pts. Ongoing assessments evaluating cardiac, hepatic and endocrine function will evaluate the impact of iron reduction on morbidity and mortality in MDS. Figure Figure

Abstract Introduction Myelofibrosis (MF) is a chronic myeloid neoplasm in which 75% of patients have anemia and 25% are erythrocyte transfusion-dependent (TD) (Emanuel et. al. JCO 2012). MF patients receiving chronic transfusions are at risk of multiple co-morbid conditions and iron overload may develop with potential for end-organ damage. Iron chelating therapies (ICTs) help eliminate iron surplus by binding with plasma iron to form a non-toxic conjugate that can be safely excreted from the body. The objective of this study was to examine transfusion patterns and incidence of MF-related complications in TD MF patients treated with vs. without ICT from a US managed care perspective. Methods Two commercial claims databases, Truven Health Analytics MarketScan (2000-2012) and PharMetrics Integrated Database (2001-2012) were used to address the study objectives. Patients with ≥2 MF ICD-9 diagnosis codes (238.76, 289.83) ≥30 days apart, ≥18 years at the time of the first observed diagnosis for MF, and ≥6 months of continuous enrollment prior to the first observed evidence of transfusion dependency (index date), defined as ≥3 transfusion events within any 3-month period, were included (modified Gale et al. Criteria). A transfusion event was defined as a unique day when ≥1 procedure code for packed red blood cells, whole blood, or exchange transfusion was recorded. Frequency of transfusions and time from first evidence of TD to initiation of ICT were analyzed. Incidence of MF-related complications was assessed using incidence rates (IR) and compared between TD patients with vs. without ICT using adjusted incidence rate ratios (aIRR), adjusting for baseline comorbidities and complications. Results Characteristics of MF patients receiving ICT: Of the 571 TD MF patients who met the inclusion criteria, 103 (18%) received ICT and 468 (82%) did not. Mean (SD) age was similar between the two groups (with ICT: 67.2 (10.4) vs. without ICT: 66.6 (11.7), p=0.65), but the proportion of men was higher in the ICT group (with ICT: 70.9% vs. without ICT: 58.3%, p=0.02). The mean (SD) observation time was longer for patients with ICT than without ICT (months, 22.2 [13.9] vs. 12.6 [11.6], p<0.001). A greater proportion of TD patients without ICT had a history of essential thrombocythemia (with ICT: 11.7% vs. without ICT: 20.9%), whereas the proportion of patients with prior polycythemia vera was similar between the two groups (with ICT: 11.7% vs. without ICT: 13.7%). Differences in TD MF patients by utilization of ICT: Overall, patients without ICT were generally more ill than those with ICT (Charlson Comorbidity Index [CCI], with ICT: 1.8 vs. without ICT: 2.3, p=0.01). The mean (SD) number of transfusion events per year was similar between the two groups with 22.4 (19.5) events/year in the group with ICT compared to 22.2 (28.5) events/year in the group without ICT (p=0.94). Among patients receiving ICT, therapy was initiated after a median time of 5.6 months following the first evidence of TD. TD patients with ICT had lower rates of thrombocytopenia (aIRR: 0.54; 95% confidence interval [CI]: 0.40-0.74) and pancytopenia (aIRR: 0.53; 95% CI: 0.37-0.76), but higher rates of anemia (aIRR: 1.61; 95% CI: 1.27-2.02). The incidence of other MF-related complications considered was similar between the two groups. Conclusion In this first analysis of the utilization of ICT amongst MF patients whom are TD we identified several important differences between those receiving ICT compared to those who do not. Whether these difference are a result of ICT, or a reflection of whether physician practice leads to ICT utilization in certain subsets of MF patients (i.e. those with less thrombocytopenia/leukopenia) could not be assessed with the current data. Potential short term and long term benefits of ICT in MF need to be validated in prospective clinical trials. Disclosures Vekeman: Novartis Pharmaceuticals: Research Funding. Cheng:Novartis Pharmaceuticals: Research Funding. Sasane:Novartis Pharmaceuticals: Employment. Huynh:Novartis Pharmaceuticals: Research Funding. Kaminsky:Novartis Pharmaceuticals: Research Funding. Duh:Novartis Pharmaceuticals: Research Funding. Paley:Novartis Pharmaceuticals: Employment. Mesa:Novartis Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Gilead Sciences: Research Funding; CTI: Research Funding; Celgene: Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Lilly: Research Funding.

Abstract Abstract 630 Introduction: Medical treatment options for myelofibrosis (MF) are palliative in nature. Short of allogeneic stem cell transplantation, no therapies are available that are curative or confer a survival benefit. Panobinostat (PAN; LBH589) is a potent pan-deacetylase inhibitor that belongs to a structurally novel cinnamic hydroxamic acid class of compounds. Preclinical studies demonstrated that treatment with PAN alone depletes the levels of JAK2V617F (JAK2) and signaling downstream through STAT3 and 5, AKT, and c-RAF/MAPK in human MPN progenitor cells, including those from patients (pts) with MF (Blood 2009; 114:5024). In a prior phase IA/II study of PAN in pts with advanced hematologic malignancies, among 12 pts with MF evaluable for response, 4 pts demonstrated durable clinical improvement. Methods: In this phase II trial, approximately 50 adult pts with primary MF, post essential thrombocythemia, or post polycythemia vera MF who have an International Prognostic Scoring System -MF score of 2 or 3 along with either symptomatic splenomegaly (>10 cm below the costal margin [BCM]) or anemia, enrolled. Initial PAN dose is 40 mg three times a week until disease progression or unacceptable toxicity with dose adjustments as required. Response is assessed using the International Working Group criteria. Peripheral blood samples are collected for correlative science studies at 7 time points during treatment; pre-dose on the first day of the study, 6 and 24 hours after the first dose, pre-dose on the first day of cycles 2, 4 and 6, and at the end of the study. The correlative studies include the determination of JAK2V617F allelic burden, immunoblot analyses of the protein expression of p-STAT3, p-STAT5, p-AKT, p-ERK1/2, p-PIM, as well as of their un-phosphorylated counterparts. Also, protein levels of HSP70 and acetylated (Ac)-α-tubulin, as well as the mRNA expression of JAK2 and PRV-1 genes were determined. Results: As of August 12, 2010, 31 pts (24 JAK2 mutated, 7 JAK2 wild type) have been enrolled in the trial. The majority of pts required dose reduction. Adverse events observed are consistent with the known safety profile of PAN. Correlative studies have been performed on MPN cells from19 patients. As compared to the pre-treatment levels, treatment with PAN (for 6 and/or 24 hours) resulted in varying levels of depletion of p-STAT3, p-STAT5, p-AKT, p-ERK1/2 and p-PIM protein. A decline in JAK2 and PRV1 mRNA levels (20 to 80%) was also observed. Conversely, PAN treatment induced Ac-α-tubulin and HSP70 levels, consistent with HDAC6 and HSP90 inhibition. This was associated with decline in the protein levels of AKT, PIM1 and STAT3. PAN treatment also reduced MCL-1 and Bcl-xL, while inducing BIML levels. Notably, of the 10 patients in whom it has been determined, PAN treatment depleted the allelic burden of JAK2V617F by an amount ranging between 10 to 90%. Conclusions: Consistent with its role as a pan-deacetylase inhibitor, PAN exerts in vivo anti-MPN cell activity, as was highlighted by the decrease in the allelic burden of JAK2V617F. Further patient enrollment is ensuing, and more mature clinical toxicity and efficacy data will be presented. Disclosures: DeAngelo: Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. Paley:Novartis: Employment. Snyder:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees. Ondovik:Novartis: Employment. Rine:Novartis: Employment.

SummaryMyelofibrosis (MF) is a Philadelphia chromosome–negative stem cell myeloproliferative neoplasm (MPN) associated with cytopenias, splenomegaly, constitutional symptoms, and poor prognosis. MF patients commonly express JAK2 V617F mutation and activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Agents targeting the JAK/STAT pathway have demonstrated efficacy in patients with MF. This study evaluated panobinostat, a pan‐deacetylase inhibitor that depletes JAK2 V617F levels and JAK/STAT signalling in MPN cells, in patients with primary MF, post–essential thrombocythaemia MF, and post–polycythaemia vera MF. Patients received panobinostat 40 mg administered three times per week. Dose reductions were permitted for toxicities. The primary endpoint was response rate at 6 months using International Working Group for Myelofibrosis Research and Treatment (IWG‐MRT) consensus criteria. Analyses of peripheral blood cells from treated patients revealed that panobinostat inhibited JAK/STAT signalling, decreased inflammatory cytokine levels, and decreased JAK2 V617F allelic burden. However, panobinostat was poorly tolerated at the dose and schedule evaluated, and only 16 of 35 patients completed ≥2 cycles of treatment. One patient (3%) achieved an IWG‐MRT response. Common adverse events were thrombocytopenia (71·4%) and diarrhoea (80·0%). Although molecular correlative analyses suggested that panobinostat inhibits key intracellular targets, limited clinical activity was observed because of poor tolerance.