1129 Poster Board I-151 Background Nilotinib is a selective and potent BCR-ABL inhibitor, developed through structure-based drug design, indicated for the treatment of Philadelphia chromosome positive (Ph+) CML patients in CP or accelerated phase (AP) resistant or intolerant to prior therapy including imatinib. Recently, 24-month follow-up data from the pivotal nilotinib 2101 study demonstrated achievement of rapid and durable cytogenetic responses in the majority of patients and an excellent overall survival (OS) rate of 87%. The current update focuses on the major molecular response (BCR-ABL transcript levels ≤ 0.1% according to the international scale; MMR) of patients treated with nilotinib. Methods Imatinib-resistant and -intolerant CML-CP patients (n=321) were treated with nilotinib 400 mg twice daily and followed for at least 24 months. In this report, the efficacy parameters studied were: rate of MMR, rate of major and complete cytogenetic response (MCyR, CCyR), time to and duration of response, time to progression (TTP), and OS. Efficacy parameters were also analyzed based on the presence or absence of a CHR at study entry. Results The median duration of exposure to nilotinib was 18.7 months (< 1.0–36.5), with 62% of patients on therapy for at least 12 months and 42% on therapy for ≥ 24 months. Median dose intensity of nilotinib was 788.5 mg/day, very close to planned dosing. Overall, 58% of patients required dose interruption (defined conservatively ≥ 1 day of interruption regardless of reason) with a median cumulative duration of interruption of 20 days (4% of days of exposure). Importantly, 73% of patients that required treatment interruptions resumed treatment after interruption at the planned dose. The achievement of MMR in imatinib-resistant and -intolerant CML-CP patients who had BCR-ABL transcript levels available post-baseline (n=294) were included in this efficacy analysis (Table). Of these patients, 105/294 (36%) entered the study with a CHR and 189/294 (64%) did not have a CHR at study entry. The overall MMR rate was 28%; MMR was higher in patients with CHR at study entry (38% vs. 22%). Overall, CCyR was achieved in 46% of patients, among whom 56% achieved MMR. Median time to MMR was 5.6 months. Overall, 77% and 84% of responding patients maintained MCyR and CCyR at 24 months, respectively. Overall (n=321), the estimated rate of progression-free survival (PFS), defined as progression to AP/BC or discontinuation due to progression or death, at 24 months was 64%, however, only 9 patients (3%) progressed to AP/BC based on actual laboratory values. PFS rate at 24 months was higher for patients with baseline CHR (77%) compared with patients without CHR at study entry (56%). OS at 24 months is 87% for the entire patient population. The safety profile of nilotinib remains unchanged at 24 months of follow-up. The majority of first episodes of grade 3/4 bilirubin and lipase elevations occurred within the first month of therapy and were brief in duration (median duration 15 days). The incidences of hepatic and pancreatic disorders on nilotinib were 1.3 and 1.7 per 100-patient years of therapy and no cumulative risk of hepatic and pancreatic events was observed in this population with longer follow-up. Importantly, discontinuations due to hepatobiliary adverse events were uncommon (n=2; < 1.0%). Conclusions Nilotinib therapy led to the achievement of MMR in a majority of patients with CCyR, and in 38% of patients with CHR at study entry. Furthermore, the response and outcomes of patients treated with nilotinib was higher in patients with CHR at baseline suggesting that patients with imatinib resistance and intolerance who lost cytogenetic response but not hematologic response have a more favorable response compared to those patients who have lost hematologic response when switched to nilotinib. Overall, the safety profile of nilotinib remains well-tolerated with long-term follow-up. At 24 months, nilotinib therapy remains an effective and tolerable therapy for patients with imatinib-resistant or -intolerant CML. Disclosures Kantarjian: Novartis: Research Funding. Giles:Novartis: Consultancy, Research Funding; BMS: Research Funding; Merck: Research Funding; Clavis: Research Funding. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria. Pinilla-Ibarz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Larson:Novartis: Consultancy, Honoraria, Research Funding. Gattermann:Novartis, Celgene: Honoraria, Participation in Advisory Boards on deferasirox clinical trials, Research Funding. Ottmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Radich:Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Martinelli:Novartis: Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Shou:Novartis: Employment. Gallagher:Novartis: Employment, Equity Ownership. Wang:Novartis: Employment. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria.

BACKGROUNDAlthough central nervous system (CNS) prophylaxis in patients with leukemia has reduced the incidence of CNS disease recurrence, it still is reported to occur in approximately 5–10% of cases, resulting in a median survival of 6 months. Craniospinal irradiation (CSI) has been shown to improve survival in children who develop a CNS recurrence of acute lymphocytic leukemia (ALL). However, to the authors' knowledge, the role of CSI in adults with a CNS recurrence of leukemia is unknown.METHODSA retrospective review of adult patients treated with CSI for a CNS recurrence of leukemia identified 16 patients treated between 1986 and 2001. The median age of the patients was 34 years (range, 16–58 years). The diagnoses included seven patients with acute myelogenous leukemia (AML), eight patients with ALL, and one patient with chronic myelogenous leukemia in blast crisis. All patients had achieved a complete disease remission prior to the CNS recurrence. Eleven patients had an isolated CNS recurrence and 5 patients had concurrent disease identified in the blood/bone marrow. The median dose of radiation was 24 grays (Gy) (range, 18–34.5 Gy) to the cranium and 18 Gy (range, 15–30 Gy) to the spine. The median fraction size was 1.8 Gy (range, 1.5–2.0 Gy) to the cranium and 1.5 Gy (range, 1.5–2.0 Gy) to the spine. Fifteen patients were also treated with intrathecal chemotherapy.RESULTSOne patient failed to complete radiation treatment because of disease progression. Thirteen patients achieved a complete response in the cerebrospinal fluid (CSF). The median time to disease progression was 3 months from the first day of CSI and 7 months from CNS recurrence. The median survival was 4 months and 9 months, respectively. No CNS recurrences occurred, but there were 11 bone marrow failures, 2 patients without recurrence at > 5 years, and 3 deaths without a documented site of failure. Thirteen patients had no evidence of disease in the CSF until their death or the time of last follow‐up.CONCLUSIONSCSI with or without intrathecal chemotherapy appears to be effective at eliminating leukemia in the craniospinal axis. However, the eradication of disease in the CNS was not found to be effective at preventing disease recurrence in the bone marrow, and despite improved control of disease in the CNS, adult patients with a CNS recurrence still had a poor prognosis. Furthermore, the rapidly fatal course of disease prevented an assessment of the durability of CNS response to irradiation. Cancer 2004. © 2004 American Cancer Society.

337 Background: 12-month results from TOPS showed an advantage for the high dose (800mg/day, HD-IM) arm for: (1) time to achievement of major molecular response (MMR); MMR rates at 3 and 6 months (mos); and (2) complete cytogenetic response (CCyR) at 6 mos (Guilhot et al. [TOPS] ASH 2008). There was no significant difference in the MMR rates at 12 mos, the primary endpoint, and results support 400 mg/day as the standard initial dose for imatinib (SD-IM) in CML-CP pts. The purpose of this update is to assess the outcome of the two arms at 24 mos, as well as the impact of dose intensity (DI) and dose interruption on pts outcome. Methods: 476 pts with newly diagnosed CML-CP were randomized 2:1 to receive HD-IM (n = 319) or SD-IM (n = 157) at 103 sites in 19 countries. The endpoints assessed at 24 mos were: rates of CCyR and MMR, event-free (EFS), progression-free (PFS), and overall survival (OS). CCyR and MMR rates were calculated based on pts with available assessments at specified timepoints. Adverse events (AE) and laboratory results were also monitored. Additional analyses were performed using DI (< 600 mg/d and ≥ 600 mg/d) and number of dose interruptions (periods of zero dose of > 5 days) as variables. In the trial dose interruptions were specified as an AE management strategy prior to dose reduction. Results: At 24 mos, 129/157 (82%) of SD-IM and 247/319 (77%) of HD-IM pts remained on study treatment. There was no significant difference in rates of MMR at 12 mos (SD-IM: 40% vs. HD-IM: 46%), 18 mos (52% vs 47%) or 24 mos (54% vs 51%) (intention to treat analysis). There was no significant difference in the cumulative rates of CCyR at 24 mos (76% in each arm). Overall, 9 (6%) pts on SD-IM and 15 (5%) pts on HD-IM had experienced an event (loss of complete hematologic response, loss of major cytogenetic response, progression to accelerated phase and blast crisis, or death due to any cause). There were no significant differences in estimated EFS (SD-IM: 95% vs. HD-IM: 95%), PFS (97% vs. 98%), or OS (97% vs. 98%) at 24 mos. The most common grade 3/4 hematologic AEs were neutropenia (17.8% vs. 28.2%) and thrombocytopenia (8.9% vs. 19.9%), and for the most part occurred during the first 12 mos. The most common grade 3/4 nonhematologic toxicities for SD-IM and HD-IM were rash (2.5% vs 5.7%), diarrhea (1.3% vs 6.0%) and myalgia (0.6% vs 3.5%), respectively. The most common reasons for discontinuation in both arms were AEs (4.5% vs. 10.7%) and unsatisfactory therapeutic effect (7.0% vs 7.2%). Median DI was 400 mg/d in the SD-IM arm and 728 mg/d in the HD-IM arm. Dose interruptions for > 5 days occurred more frequently in the HD-IM arm (71% vs. 44%). Pts in both arms combined who had ≤ 1 dose interruption during the first 12 mos achieved higher MMR rates at 12 (57.1% vs 33.3% for ≤ 1 vs > 1 interruption; P < 0.0001) and 18 mos (72.6 vs. 46.8; P < 0.0001), faster time to MMR (P = 0.0002), and higher CCyR rates at 12 mos (88.8 vs 63.8; P < 0.0001), compared with pts who had > 1 dose interruption during the same period. On the SD-IM arm pts with ≤ 1 (vs > 1) dose interruption also had higher MMR rates at 12 and 18 mos (12 mos: 49.6% vs 22.2%, P = 0.04; 18 mos: 70.9% vs 50%, P = NS). Comparing pts in the HD-IM arm with DI ≥ 600mg/d for the first 12 mos vs DI < 600 mg/d, the MMR rates at 12 mos (62.4% vs 34.1%, P < 0.0001) and 18 mos (75.2% vs 40.3%, P < 0.0001) were higher, the time to MMR was faster (P < 0.0001), duration of MMR was longer (P = 0.0141) and CCyR rates at 12 mos (89.6% vs 70.3%, P < 0.0001) were higher for pts with DI ≥ 600mg/d. Conclusions: TOPS continues to confirm the safety and efficacy of 400 mg/day IM for newly diagnosed pts with CML-CP, with very similar results to IRIS. HD-IM was also safe and generally well tolerated, but overall did not result in better outcomes at milestones up to 24 months. Frequent or prolonged dosage interruptions on IM adversely affect patient outcomes and should be avoided. These data emphasize the importance of maintaining dose intensity in CML-CP pts treated with imatinib. The TOPS study will continue to assess the impact of dose intensity on long-term outcomes. Disclosures: Baccarani: Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pane:Novartis: Research Funding; Ministero dell'Università/PRIN: Research Funding; Regione Campania: Research Funding; Ministero della Salute/Progetto integrato Oncologia: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Jin:Novartis: Employment. Krahnke:Novartis: Employment, Equity Ownership. Rudoltz:Novartis: Employment, Equity Ownership. Radich:Novartis: Consultancy, Honoraria, Research Funding. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria.

864 Background: Despite the availability of novel ABL tyrosine kinase inhibitors ( TKI ) in addition to imatinib mesylate, the acquisition of the T315I BCR-Abl mutation remains a major cause of resistance to registered therapeutic compounds. Some patients (Pts) may also fail therapy with ≥ 2 TKI and need additional treatment. PHA-739358 is a small ATP competitive molecule that specifically inhibits Aurora A, B and C kinases. PHA-739358 possesses high affinity binding capacity to both wild-type Abl and Abl/T315I in in vitro assays. Methods: An international, multicenter, open-label, single agent, non-comparative, phase I study is being conducted in adult Pts with advanced Chronic Myeloid Leukemia (Accelerated AP-CML/Blastic phase BP-CML) and Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) resistant or intolerant to imatinib and/or 2nd generation c-Abl therapy. Primary objective of the study is to determine the Maximum Tolerated Dose (MTD) and the Dose Limiting Toxicity (DLTs) during the first cycle. Two schedules were planned. Schedule A (PHA-739358 given as daily 3-hrs iv infusion for 7 consecutive days, every 2 wks) is open. Schedule B, not yet started, foresees a more aggressive approach and is currently being amended. Results: Twenty-three Pts with CML and Ph+ ALL have been treated so far (4 with AP-CML; 8 with BP-CML and 11 with Ph+ALL). Five dose levels have been tested: 90 (N=7); 120 (N=4); 150 (N=6); 180 (N=3) and 200 (N=3) mg/m2. Only one DLT occurred at 90 mg/m2 (NCI-CTC AE Gr3 fainting). Presently the MTD has not been defined. Fifteen out of 23 Pts have confirmation of BCR-Abl T315I mutation. A response occurred in 6/14 Pts, including 3 cytogenetic (1 complete, 1 partial, 1 minimal), 5 hematologic, and 1 clinical improvement (reduction in extramedullary disease mass). One severely pretreated (chemotherapy+Imatinib, SCT, Dasatinib and Donor Lymphocyte Infusion) pt with T315I mutated Ph+ALL reached Complete Hematological Response since Cycle (Cy) 4, Complete Cytogenetic Response since Cy 8 and Molecular Response (BCR/ABL undetectable transcripts) since Cy 9. Treatment continues after 10+ months. Last cycles were given every 4 wks due to mild/moderate transaminitis. This Pt at baseline showed: Peripheral Blood Blasts=0%; Bone Marrow (BM) blasts= 33%; % of Ph+ Metaphases = 80%. Two additional Pts (AP-CML and Ph+ ALL) achieved cytogenetic responses, one minimal and one partial reached at Cy2 and Cys 1-6, respectively. Another Pt (BP-CML) who received multiple transplants (3 times) and progressed after Imatinib, Dasatinib, Bosutinib, Nilotinib and Homoharringtonine, with 4 cycles of PHA-739358 had significant improvement of a large extramedullary lesion in the left neck impeding breathing and swallowing. Significant but transient reduction in the White Blood Cells (8/13 pts) and peripheral blood blast counts (3/13 Pts) were obtained with PHA-739358. An acceptable tolerability and safety profile characterized the study therapy: max non-hematological tox (regardless of causality) was as follows (most frequent Adverse events ≥ 30 %): diarrhoea 57% (CTC Gr 3 one Pt), pyrexia 50%; headache 43% (CTC Gr 3 one Pt); dyspnoea 36% (CTC Gr 3 one Pt ) and nausea 36%. Data analysis ongoing. Conclusions: The preliminary results obtained with our study show that PHA-739358 can elicit significant response with clinical benefit in severely pretreated populations of Pts affected with advanced leukemias resistant/intolerant to Imatinib and other 2nd generation TKI. Disclosures: Schafhausen: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Speakers Bureau; Novartis: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau. Latini:Nerviano Medical Sciences: Employment. Capolongo:Nerviano Medical Sciences: Employment. Laffranchi:Nerviano Medical Sciences: Employment. Comis:Nerviano Medical Sciences: Employment.

3917 Poster Board III-853 Background Patients with Myelofibrosis (MF) suffer from significant fatigue, constitutional symptoms and splenomegaly (Mesa et. al. Cancer 2007) not improved by current therapy. The MF-SAF is a 19 item self administered instrument specific to MF associated symptoms previously validated for use at a single time point (Mesa et. al. Leukemia Research 2009). We sought to assess the performance characteristics of the MF-SAF when administered sequentially in the context of a prospective clinical trial. Methods Sequential MF patients enrolled in the prospective, uncontrolled Phase II, trial were given a 15 item modified MF-SAF to complete at enrollment, and after 15 days, 1 month, 2 months, 3 months and every 3 months thereafter. The MF-SAF was scored as previously published on a 0 (absent) to 10 (maximal) scale. Cross validation of serial change in MF-SAF scores was undertaken by comparison to objective measurements made as part of the therapeutic drug trial. Results Patients Eighty six MF patients were enrolled and had 2 or more MF-SAF instruments completed to allow for sequential analysis. Patients were of a median age (65 years), gender distribution (35 % females), and disease subtype (53 % PMF) typical for a clinical trial in MF. Baseline MF-SAF Responses: Baseline assessment of the most frequent MF abnormalities reported by patients completing the MF-SAF (see Table 1) confirmed the wide prevalence of MF associated symptoms, and their significant severity. General fatigue was the most frequent symptom cited (91%), while cough was the least frequently observed symptom (44%). 95% of patients had at least 2 symptoms present on the MF-SAF. Serial MF-SAF Changes in Response to Therapy Therapy with INCB018424 resulted in a significant and rapid reduction in MF associated symptoms with 46% to 85% of patients experiencing improvement in a given symptom. The greatest improvements in MFSAF score improvements were reported by patients experiencing abdominal discomfort, night sweats, pruritus and fever (see Table 1), and corresponded to significant improvements in the individual MF symptom scales as well as the patient's overall assessment of quality of life (QOL). Correlation of MF-SAF to Objective Changes during INCB018424 Therapy Objective measurements obtained on the INCB018424 trial included MRI measurements of splenic reduction, the six minute walk test (6MWT) for inactivity, and serial weights. Reduction in spleen size (by ≥ 35% by volume or ≥ 50% by palpable length) corresponded to improvement in MF-SAF scores of abdominal discomfort and fatigue (50% of patients, median score decrease of -1.2, and -1.8, respectively). Improvement in the 6MWT by > 50 meters was associated with a 2-fold greater improvement in inactivity score on the MF-SAF compared to subjects who improved 6MWT performance by <50 meters. Finally, improvements in weight loss and fever were corroborated by objective measurements made at physician visits on the trial. Conclusions The MF-SAF is a brief, easily self administered, MF specific instrument which was successfully administered sequentially in the conduct of a large Phase II clinical trial. The significant symptomatic improvements reported by patients in the open label trial of INCB018424 corresponded to both improvements in symptom specific scores on the MF-SAF and objective measurements. Further validation of the MF-SAF will be possible by inclusion in upcoming randomized placebo controlled trials in MF patients. Parallel trials performed in MF patients should consider use of this instrument to allow for comparisons. Disclosures: Levy: Incyte Corporation: Employment, Equity Ownership. Vaddi:Incyte Corporation: Employment, Equity Ownership. Erickson-Viitanen:Incyte Corporation: Employment, Equity Ownership. Verstovsek:Incyte: Research Funding.