Academic literature on the topic 'RL 0.8 / 0.5 Pts'

Abstract Background Constitutive activation of phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway by various mechanisms has been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). There is mounting evidence suggesting that along with PI3Kγ, PI3Kα may be involved in CLL/NHL. SAR245408 is a potent and selective inhibitor of all α, γ and δ class I PI3K isoforms. It has been shown to inhibit PI3K signaling and impact tumor growth in preclinical tumor models. The impact of SAR245408 on safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor effect was evaluated in patients with relapsed/refractory CLL and NHL from the Sanofi sponsored phase 1 single-agent study (NCT00486135) [Brown et al. ASH Annual Meeting Abstracts 2011. 118 (21): 2683]. Methods SAR245408 was administered orally, once daily, with continuous dosing in monthly cycles. A total of 25 patients were enrolled at the maximum tolerated dose identified in solid tumor patients as part of the expansion cohort in relapsed/refractory lymphoproliferative malignancies. Plasma cytokines and chemokines were evaluated using the Myriad RBM Human Discovery MAP250+ panel (> 250 analytes) and ELISA assays. Results Among the 25 patients (pts), 40% (n=10) had refractory CLL and 60% (n=15) had various relapsed/refractory lymphomas (R/RL), including follicular lymphoma (FL) (n=5), diffuse large B-cell lymphoma (DLBCL) (n=4), Waldenstrom's macroglobulinemia (WM) (n=3), Hodgkin lymphoma (n=2) and B-cell prolymphocytic leukemia (n=1). The median age was 65 years (range 28–83), and 56% were female. Eighty percent of pts had stage III-IV disease and 48% had bulky disease. Five pts were categorized as having refractory disease and the median number of prior regimens was 1 (range 1-7) for CLL pts and 3 (range 0-9) for R/RL pts. For all 25 patients, the median starting absolute lymphocyte count was 1.15 x 103/μL (range 0.3–37.2), the median starting hemoglobin was 11.4 g/dL (range 9.1–15) and the median platelet count was 162 x 103/μL (range 60–431). The median number of cycles administered in CLL pts was 10 (range 5-24) and 5 (range 1-26) in R/RL pts. Six CLL pts experienced an increase in absolute lymphocyte counts within 2-4 weeks of treatment, as has been seen with other PI3K inhibitors. According to modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response criteria, 4 CLL pts had partial response (PR), 1 had nodal PR with increased lymphocytosis, and 5 had stable disease (SD); the progression free survival (PFS) in the responding pts was 22, 21.2, 15.6 and 15.4 months while in the SD pts was 12.5, 9.2, 7.4, 5.6, 4.6 and 3.6 months. According to the modified International Working Group response criteria, 3 PRs were reported in R/RL pts [1 WM, 1 DLBCL (transformed) and one FL with PFS of 23.7, 18.4 and PFS 4.8 months respectively]. One hundred percent of CLL and 80% of R/RL pts reported grade 3 or higher AEs, with the most common (≥ 10% of patients) including neutropenia, diarrhea, anemia and hypotension. SAR245408 induced a reduction in levels of chemokines involved in lymphocyte trafficking in CLL subjects (n=8), including CXCL13, CCL3, CCL22 and CCL19 (64, 58, 52 and 54% reduction, respectively, p<0.05) similar to what was reported with PI3K δ specific inhibitors. In addition, a reduction of tumor necrosis factor receptor 2 (TNFR2) and interleukin-2 receptor alpha (IL-2Rα) levels was observed (63% reduction each, p<0.01). Conclusions The recommended phase 2 dose of SAR245408 in solid tumor patients was confirmed as safe and tolerable in patients with CLL and R/RL. Single agent SAR245408 demonstrates clinical activity in patients with relapsed or refractory CLL and promising pharmacodynamic effects on chemokine levels involved in lymphocyte trafficking. Disclosures: Brown: Emergent: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Vertex: Consultancy; Novartis: Consultancy; Genzyme: Research Funding; Avila: Consultancy; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy. Off Label Use: The abstract shows scientific information on SAR245408 which is an investigational product developed by Sanofi. This investigational product is not approved by any health authority for any indication. Egile:Sanofi: Employment. Ruiz-Soto:Sanofi: Employment. Awan:Lymphoma Research Foundation: Research Funding; Spectrum Pharmaceuticals Inc.: Speakers Bureau.

Abstract Background: Current hematopoietic cell transplant (HCT) regimens for patients with relapsed refractory acute leukemia have 3-year overall survival (OS) rates for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) of 19% and 16% respectively. Previous studies demonstrated that intensification of total body irradiation (TBI) is not possible due to excessive regimen-related toxicity. Because image-guided targeted radiation therapy (e.g., total marrow and lymphoid irradiation (TMLI)) allows for the precise delivery of radiation through the sculpting of radiation to areas of high risk and disease burden, intensification of radiation dose to target structures as part of a HCT preparative may be possible without increased radiation-related toxicities or non-relapse mortality. Herein we report the results of a phase I trial that combines TMLI (1200-2000 cGy) with fixed doses of etoposide (VP16) and cyclophosphamide (CY); the primary objective is to determine the maximum tolerated dose/recommended phase II dose of TMLI. Methods: TMLI together with VP16 and CY before allogeneic HCT was assessed for patients with relapsed/refractory AML and ALL. TMLI was administered on days -10 to -6, VP16 60 mg/kg (adj bw) on day -5, and CY 100 mg/kg (ideal bw) on day -3. The initial radiation dose was 1200 cGy, delivered in 150 cGy fractions twice daily. The radiation dose was escalated in increments of 150 cGy, up to 1500 cGy, by use of a standard 3x3 design. At this point, the dose was raised in 100 cGy increments to a 2000 cGy maximum with a rolling 6 design. Bone marrow (n=3) or peripheral blood stem cells (n=48) were given on day 0. Tacrolimus and sirolimus were administered for graft versus host disease (GVHD) prophylaxis. Dose limiting toxicity (DLT) was defined according to the Bearman and CTCAE 3.0 scales, the latter for hematologic toxicity. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Median normal organs received 16-60% of the dose (oral cavity 28%, lung 44%, esophagus 33%). Results: From 3/14/2008 to 1/30/2014, 51 patients underwent transplantation on this trial. (See table.) Our phase I trial/safety studies found the TMLI/CY/VP16 conditioning regimen to be well tolerated at TMLI doses up to 2000 cGy; 1-year estimates of non-relapse mortality and overall survival were 8.3% (95% CI: 2.6-18.4) and 54.4% (95% CI: 39.3-67.3) respectively (median follow-up: 23.5 months).Relapsed, progressed, or persistent disease after transplant occurred in 33 patients (bone marrow, 26; extramedullary disease, 6; concurrent bone marrow/extramedullary, 1). Of the 18 patients who were treated with a dose of 1700 cGy or higher, 17 achieved a complete remission at the day +30 evaluation. No radiological-based maximum tolerated dose (MTD) was defined. We determined that the median organ dose at 2000 cGy would be lower than that seen for total body irradiation (TBI), but a higher dose may result in reaching or exceeding TBI organ dose levels. We therefore stopped at 2000 cGy, above which non-targeted organs may no longer be protected. Acute GVHD (aGVHD) developed in 28 (55%) of patients; of those 7 (14%) developed grades 3-4. The most common toxicities across the tested dose levels were grade 1 GI toxicity and grade 2 stomatitis. One patient (treated at 1500cGy) developed grade 3 stomatitis. No additional DLTs were experienced across all dose levels. Conclusion: A dose of 2000 cGy targeted to lymph nodes and marrow in combination with CY and VP16 can be safely administered in the context of related and unrelated HCT, using tacrolimus and sirolimus for GVHD prophylaxis. We did not see increased incidence of aGVHD, and the day +100 NRM rate was <5%. A phase II trial is currently being conducted. Table. Patient characteristics Variable Median (range) or N Age at transplant (yrs) 34 (16-57) Disease diagnosis AML ALL Ph- ALL Ph+ biphenotypic undifferentiated 3313221 Disease status at HSCT 1 RL 2 RL IF 14334 Cytogenetic risk (SWOG criteria) favorable intermediate unfavorable unknown significance 122199 KPS at HSCT 80 (60-100) Donor source sibling HLA matched unrelated mismatched (1 allele) unrelated 25521 WBC at HSCT 1.4 (0.1-14.9) % Blasts in blood at transplant* 4 (0-93) % Blasts in marrow at transplant* 52 (8-98) Extramedullary disease at time of HSCT 11 *Excludes patients with solely extramedullary disease, n=4 Disclosures Stein: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding. Snyder:Incyte: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang: Research Funding; Amgen: Consultancy.

Abstract An attempt has been made to recycle Styrofoam waste to a novel functional polymer, Phenyl thiosemicarbazone surface (PTS). Polystyrene (PS) obtained from Styrofoam waste was acetylated and then condensed to PTS by reacting it with 4-Phenyl-3-thiosemicarbazide ligand and characterized by FT-IR spectroscopy and elemental analysis. Synthesized PTS was applied successfully for the treatment of lead contaminated water by batch extraction method. Sorption variables were optimized (pH 8, adsorbent dose 53mg, initial Pb(II) ion concentration 10mgl-1 and agitation time 90min) by factorial design approach. Lead uptake by PTS was found much sensitive to the pH of Pb(II) ion solution. The maximum removal (99.61%) of Pb(II) ions was achieved at optimum conditions. The Langmuir and D-R isotherm study suggested the monolayer, favorable (RL=0.0001-0.01) and chemisorption (E=20.41±0.12kJmol-1) nature of the adsorption process. The sorption capacity of PTS was found to be 45.25±0.69mgg-1. The FT-IR spectroscopy study showed the involvement of nitrogen and sulphur of thiosemicarbazone moiety of PTS for the uptake of Pb(II) ions by five membered chelate formation.

Abstract BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that has demonstrated superiority over traditional therapies in the treatment of MF. In the 2 phase 3 COMFORT studies, RUX demonstrated rapid and durable reductions in splenomegaly, improved MF-related symptoms and quality of life measures, and improved survival compared with placebo and best available therapy. The aim of EXPAND was to evaluate safety of RUX and establish a maximum safe starting dose (MSSD) in thrombocytopenic MF patients (pts). METHODS: EXPAND is a phase 1b, dose-finding study (NCT01317875) in MF pts with baseline platelet counts (PLTs) 50 to 99 × 109/L. Pts with ≥ 1 episode of PLTs < 100 × 109/L during screening were eligible. A Bayesian logistic regression model was used to guide dose-escalation decisions; intra-pt dose modification was allowed. The study consists of 2 phases: dose escalation and safety expansion. In the dose-escalation phase, doses of RUX investigated included 5 mg bid, 5 mg AM/10 mg PM, 10 mg bid, 10 mg AM/15 mg PM, and 15 mg bid (cohorts C1-5). Pts were assigned to 2 strata based on their baseline PLTs: S1: 75 to 99 × 109/L; S2: 50 to 74 × 109/L. Dose levels in S2 were open only if that dose and the next were deemed safe in S1. In the safety-expansion phase, 20 additional pts (10 per stratum) will be treated at the stratum MSSD. RESULTS: To date, 34 pts (S1, n = 21; S2, n = 13) received treatment across 8 cohorts (S1: C1, n = 4; C2, n = 3; C3, n = 4; C4, n = 4; C5, n = 6; S2: C1, n = 3; C2, n = 3; C3, n = 7). Baseline characteristics were generally balanced across strata: 68% of pts were ≥ 65 y, 41% male, 74% had PMF (24% PPV-MF, 3% PET-MF), and 62% had high-risk MF; spleen length ranged from 5 to 33 cm below the costal margin. Baseline hemoglobin ranged from 83 to 138 g/L in S1 and 77 to 133 g/L in S2; PLTs ranged from 56 to 112 × 109/L in S1 and 47 to 100 × 109/L in S2. As of data cutoff, 9 (43%) and 7 (54%) pts were still receiving treatment in S1 and S2, respectively. The primary reasons for discontinuation were adverse events (AEs; S1, 19% [4]; S2, 23% [3]), deaths (9.5% [2]; 7.7% [1]), disease progression (4.8% [1]; 0), and pt decision (0; 7.7% [1]). Reported AEs were consistent with the known safety profile of RUX (Table). 94% experienced grade 3/4 AEs. AEs leading to discontinuation were all grade 3/4 (S1, 24%; S2, 31%); besides thrombocytopenia (S2, n = 2; S1, n = 0), no other AE led to treatment discontinuation in > 1 pt in either stratum. Three pts in S1 and 1 in S2 had grade 3/4 hemorrhage; 24 pts had AEs requiring dose reduction, most commonly anemia (S1, 14%; S2, 8%) and thrombocytopenia (38%; 77%); the remainder occurred in 1 pt each. Hemoglobin decreases were generally balanced across dose levels: no pt had grade 4 (all grade, 68%; grade 3, 50%). PLT decreases were more frequent with increasing dose: 2 pts (S1/C2) and 3 pts (1 in S2/C2 and 2 in S2/C3) had grade 4 (all grade, 94%; grade 3/4, 53%). Reasons for death included cardiac failure (S1), sudden death (S1), and multi-organ failure (S2). Of 34 pts, 33 (97%) had reductions in palpable spleen length, with complete resolution in 9 pts; 17 pts (50%) had a ≥ 50% reduction as their best response on study (Figure). Results for changes in symptom scores will be presented. CONCLUSIONS: Starting doses of up to 15 mg bid have been tolerated well in MF pts with low PLTs, and the safety in the escalation phase is consistent with findings from previous studies. While the study is still ongoing and proceeding into the expansion phase, preliminary evaluations indicate 15 and 10 mg bid as MSSDs for pts with PLT 75 to 99 × 109/L and 50 to 74 × 109/L, respectively. Table. AEs in ≥ 10% of Pts in Either Stratum % S1 n = 21 S2 n = 13 All Grade Grade 3/4 All Grade Grade 3/4 Abdominal pain 10 5 8 0 Abdominal pain upper 24 0 0 0 Anemia 57 43 31 23 Arthralgia 19 0 8 0 Asthenia 19 10 23 0 Back pain 14 5 23 8 Bronchitis 0 0 23 0 Contusion 5 0 23 0 Cough 10 0 38 0 Decreased appetite 14 0 8 0 Diarrhea 33 0 23 0 Dizziness 19 0 8 0 Dyspnea 5 0 15 0 Epistaxis 24 5 0 0 Fatigue 14 5 8 0 Headache 19 0 23 0 Hyperuricemia 0 0 15 8 Influenza 0 0 15 0 Influenza-like illness 10 0 0 0 Insomnia 14 0 8 0 Muscle spasm 14 0 8 0 Musculoskeletal chest pain 10 0 0 0 Nasopharyngitis 10 0 23 0 Nausea 19 0 8 0 Edema peripheral 14 5 15 0 Oropharyngeal pain 14 0 15 0 Pain in extremity 5 0 23 0 Pollakiuria 10 0 0 0 Procedural pain 10 0 0 0 Pruritus 0 0 23 0 Pyrexia 10 0 23 0 Skin lesion 10 0 0 0 Splenomegaly 10 5 0 0 Thrombocytopeniaa 81 67 85 85 Urinary tract infection 10 0 8 0 Vomiting 14 0 8 0 Weight increased 10 0 0 0 a All pts had grade1/2 thrombocytopenia at study entry. Figure 1 Figure 1. Disclosures te Boekhorst: Novartis: Consultancy. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Gilead: Honoraria; SBio: Consultancy. Gisslinger:AOP ORPHA: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy. Niederwieser:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stalbovskaya:Novartis: Employment, Equity Ownership. Atienza:Novartis: Employment. Gopalakrishna:Novartis: Employment. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

AbstractAim:This study attempts to investigate fiducial marker (FM) migration and calculate the prostate planning target volume (PTV) margin considering the setup errors after translation corrections alone (T) and translation plus rotational corrections (T+R) and anatomy variation with respect to the corrected fiducial position, analysed on cone beam computed tomography (CBCT) images.Methods and materials:CBCT images from 25 patients are analysed for FM movements, setup error and anatomy variation with respect to the seed match positions. Systematic and random components of setup error and prostate movements are used to calculate the PTV margin for CBCT-based FM localisation in two scenarios, translation corrections only and translation plus rotational correction. MTNW887825 soft tissue gold markers (Civco, Orange City, FL, USA) were used with the department-specific immobilisation system and rectal and bladder filling protocols.Results:The average directional inter-marker distance variation is −0·05 ± 0·90 mm. The systematic setup errors for T+R are 0·40, 0·63 and 0·80 mm in right–left (RL), anterior–posterior (AP) and superior–inferior (SI), respectively. The corresponding values for T only are 0·54, 0·69 and 0·90 mm. The systematic prostate movement from T+R corrected FM positions are 0·65, 1·27 and 1·32 mm in the RL, AP and SI directions.Findings:Minimal FM movements are noted from the study. The PTV margins to incorporate the daily T+R corrected setup error and prostate deformation are found to be 2·5, 4·5 and 5·2 mm in the RL, AP and SI directions, respectively. The corresponding margins for T only corrected scenario are found to be 2·8, 4·8 and 5·7 mm.

Abstract BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that has demonstrated improvements in splenomegaly, MF-related symptoms, and quality of life measures and prolonged survival in 2 phase 3 studies. JAK signaling can activate the PI3K/mTOR pathway, and constitutive PI3K activation has been implicated in numerous cancers. Preclinical and early clinical results indicate benefit with inhibition of PI3K in MF. Buparlisib is a pan-PI3K inhibitor with specific and potent activity against class I PI3Ks. The aims of HARMONY are to evaluate the safety of co-administration of RUX and buparlisib in patients (pts) with MF and determine a recommended phase 2 dose (RP2D). METHODS: This is a dose-finding, phase 1b study (NCT01730248) of RUX plus buparlisib in intermediate- or high-risk MF pts. Pts must have palpable splenomegaly ≥ 5 cm below the costal margin and MF symptoms. There are 2 treatment groups (JAK inhibitor–naive pts [arm A] and pts not benefiting from prior JAK inhibition [arm B]) and 2 study phases (dose escalation and expansion). Dose escalation is guided by a Bayesian logistic regression model with overdose control and depends on dose-limiting toxicities in cycle 1 and other safety findings. Each dose level consists of ≥ 3 evaluable pts; the 5 dose levels are (RUX [mg bid]/buparlisib [mg qd]) 10/60, 15/60, 15/80, 20/80, 20/100. 9 evaluable pts are required at the final dose level to determine an RP2D and proceed to the expansion phase; 10 additional pts per arm will be treated at the RP2D. PK of RUX was assessed by LC-MS/MS on day 1 after the first dose of RUX and on days 2 and 8 when administered in combination with buparlisib. RESULTS: To date, 33 pts (arm A, n = 20; arm B, n = 13) have been treated in the dose-escalation phase. Baseline characteristics were (arm A and arm B) median age, 64 y (range, 48-79 y; 45% ≥ 65 y) and 61 y (53-74 y; 31% ≥ 65 y); male, 50% and 62%. RP2D was selected based on tolerability in the investigated dose levels, with additional confirmation from dose-selection recommendations derived through a Bayesian model.Currently, RUX 15 mg bid/buparlisib 60 mg qd was determined as the RP2D in both arms; the study is proceeding into the expansion phase. At data cutoff (April 1, 2014), 15 (75%) and 8 (62%) pts were ongoing in arm A and arm B with a median exposure of 11.3 wk (range, 2.3-48.4 wk) and 19.0 wk (range, 0.6-50.9 wk), respectively. The primary reasons for discontinuation included lack of efficacy (10%) in arm A and AEs (15%) in arm B; all other reasons were in 1 pt each. There was 1 death (arm A) from duodenal ulcers/perforation, assessed as not related to study drugs by the investigator. Despite the short follow-up, a ≥ 50% reduction from baseline in palpable spleen length was achieved by 70% and 54% of pts in arms A and B; 7 pts had a resolution of splenomegaly (6 in arm A; 1 in arm B). All pts with prior JAK inhibitor treatment, including 5 who had no previous spleen length reductions, had reductions with the combination. Hematologic AEs included anemia (all grade [grade 3/4]: arm A, 30% [15%]; arm B, 31% [23%]) and thrombocytopenia (40% [10%]; 62% [39%]). Nonhematologic AEs were primarily grade 1/2 (Table). Overall, 20% and 23% of pts experienced serious AEs; these occurred in 1 pt each, with the exception of pyrexia (n = 2). PK parameters of RUX were comparable when administered alone or in combination with buparlisib, suggesting a lack of impact of buparlisib on RUX PK. CONCLUSIONS: The combination of RUX and buparlisib was well tolerated, with early signs indicating promising efficacy even in pts who have previously failed JAKi; preliminary RP2D was assessed as RUX 15 mg bid/buparlisib 60 mg qd for both arms. Updated efficacy and safety for the dose-escalation phase will be presented (July 1, 2014 data cutoff). Table Nonhematologic AEs in ≥ 2 Pts in Either Arm Pts, % Arm A n = 20 Arm B n = 13 All Grade Grade 3/4 All Grade Grade 3/4 Abdominal distension 15 0 8 0 Abdominal pain 10 0 15 0 Abdominal pain lower 0 0 15 0 Abdominal pain upper 5 0 15 0 Diarrhea 10 0 46 8 Dyspepsia 10 0 0 0 Nausea 10 0 31 0 Stomatitis 15 5 8 8 Vomiting 5 0 15 0 Asthenia 0 0 31 0 Fatigue 10 0 23 0 General health deterioration 0 0 15 0 Edema peripheral 10 0 0 0 Pyrexia 15 0 23 15 Nasopharyngitis 15 0 15 0 Decreased appetite 5 0 46 8 Hyperglycemia 15 5 0 0 Hyperkalemia 5 5 15 0 Arthralgia 20 5 8 0 Pain in extremity 10 0 8 0 Dizziness 5 0 23 0 Anxiety 20 5 15 0 Confusional state 10 0 8 0 Depressed mood 0 0 15 8 Depression 0 0 15 8 Insomnia 5 0 15 0 Epistaxis 5 0 15 0 Hyperhidrosis 0 0 31 0 Night sweats 0 0 23 0 Hypertension 10 5 0 0 Disclosures Durrant: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Yes; Ruxolitinib is a kinase inhibitor indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Buparlisib is an investigational agent. Koren-Michowitz:Novartis: Honoraria, Research Funding. Lavie:Novartis: Membership on an entity's Board of Directors or advisory committees. Martinez-Lopez:Novartis: Research Funding; BMS: Honoraria; Celgene: Honoraria. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Stalbovskaya:Novartis: Employment, Equity Ownership. Atienza:Novartis: Employment. Iommazzo:Novartis: Employment. Gopalakrishna:Novartis: Employment. Gisslinger:AOP ORPHA: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy.

10607 Background: Combination therapy of T and Vinorelbine has recently been reported to be an active and safe regimen for HER2 positive MBC pts. The current safety analysis investigated NBVo and C, which offers the convenience of an all-oral regimen given alone or in combination with T, if pts were HER2 positive, as first-line therapy for MBC patients, KPS ≥ 70%. Methods: In the HER2 negative study ([A]) (IHC 0- 2+/FISH−) 38 pts received: NVBo 60 mg/m2 (Cycle 1) or 80 mg/m2 (from Cycle 2) D1 & D8 and C 2000 (1500 if ≥ 65 y) mg/m2/d D1-D14 every 3 weeks. In the HER2 positive study ([B]) (IHC 2+ or 3+ confirmed by FISH+) 25 pts received : NVBo, and C at the same doses as [A] + T, 4 mg/kg on D 1 as loading dose and then 2 mg/kg i.v. weekly starting on D8. Treatment was continued in both studies till progression. Results: Median age: [A] 61.5y (17 pts ≥ 65 y), [B] 53.0 y (5 pts ≥ 65 y); Prior (neo)adjuvant CT: [A] 21 pts (55.3%), [B] 16 pts (64%); Visceral involvement: [A] 28 pts (73.7%), [B] 22 pts (88%); > 2 metastases: [A] 15 pts (39.5%), [B] 10 pts (40%); Median dose intensity (%): NVBo [A] 45.1 mg/m2/w (90.5%), [B] 39.5 mg/m2/w (75.7%); C [A] 7733 mg/m2/w (87%), [B] 7140 mg/m2/w (83.7%); T [B] 2.1 mg/kg/w (98.1%). NVBo dose escalation to 80 mg/ m2: [A] 33 pts (94.3%), [B] 23 pts (92%). Tolerance: ([A] n = 38 pts, [B] n = 25 pts) (% of pts with G3/4 NCI CTC v2): Neutropenia [A] 29/16, [B] 52/16; Infection with G3/4 neutropenia [A] 3/3, [B] 8/0; Stomatitis [A] 5/3, [B] 0/4; Bilirubin [A] 3/0, [B] 0/0; HF Syndrome [A] 3/0, [B] 8/0; Nausea [A] 3/0, [B] 0/4; Vomiting [A] 10/0, [B] 4/4; Diarrhoea [A] 5/0, [B] 12/4; Ileus [A] 0/0, [B] 4/0; Febrile Neutropenia: [A] 5%, [B] 8%. Efficacy: the preliminary results on the evaluable pts confirm an optimal disease control (CR + PR + SD): [A] 25/27 pts (92.6%), [B] 22/24 pts (91.7%). Conclusion: The combination of NVBo and C can be safely administered in the palliative setting of MBC and calls for further comparative studies vs i.v. combinations. The addition of T in HER2 positive patients does not alter the favourable safety profile. [Table: see text]

Abstract Several associated thrombophilic abnormalities have been reported in adults with Bcr-Abl negative chronic myeloproliferative disorders (CMD), mostly in essential thrombocythemia (ET) and polycythemia vera (PV), while only sporadic data are available in younger patients (pts). In order to identify coagulation abnormalities in very young pts with a diagnosis of CMD, we evaluated different thrombophilic parameters in CMD pts aged &lt;20 years (yrs) at the time of diagnosis. Lupus anticoagulant (KCT and dRVVT), functional protein C (PC), free protein S (PS) antigen, functional antithrombin (AT), homocysteine (HCY), factor V Leiden (FVL) mutation, factor II (FII)G20210A mutation and methylentethrahydrofolate reductase (MTHFR)C677T polymorphisms were investigated. Thirty-four CMD pts (18 M and 16 F) with a median age at diagnosis of 168/12 yrs (range: 3mo-1911/12 yrs), followed at the study Institution, were tested. According to the criteria of the PVSG or WHO, 17 pts had a diagnosis of ET, 8 of PV and 9 of hereditary thrombocythemia (HT). Among the ET cohort, 3 pts were treated with aspirin alone and 14 received cytoreductive therapy. Among the HT cohort, 2 patients received cytoreductive therapy. PV pts were phlebotomized to maintain a hematocrit (Ht) level &lt;50%. The median interval between diagnosis and the time of the study was 8.8 yrs (range: 1 mo-24 yrs). No thrombotic events occurred. Five females with ET or HT became pregnant and had 5 children, 1 of them being affected by HT. At the time of the study, the median platelet (plt) count was 649 × 109/L (range 325–1,712) for ET pts and 1,000 × 109/L (range 602–2,142) for HT pts; the median Ht level for pts with PV was 53% (range 52–60.5%). The KCT ratio (n.v. &lt;1.31) was increased in 5/33 (15%) pts, 4 of them with PV (1 with high dRVVT ratio). Functional PC and free PS levels were decreased in 4/34 (11.7%) pts tested. An increased HCY level was found in 3/8 pts (37.5%) with PV. Of the 34 pts investigated for FVL, FIIG20210A mutations and MTHFRC677T polymorphisms, 1 ET pt was heterozygous for both the FVL and MTHFRC677T mutations and one ET pt showed an isolated FII G20210A mutation. Screening for the C677T polymorphisms in the MTHFR gene revealed that 22/34 pts (64.7%) were heterozygous, 9 of them affected by ET and 8 by HT. In our CMD population of children and young adults, the frequencies of heterozygosis of FIIG20210A mutations (4/34 pts = 11.7%) and MTHFRC677T polymorphisms (64.7%) were higher than those reported in the normal population (about 2.5% and 45%, respectively). Our data demonstrate that an accurate thrombophilic screening is important in young CMD pts in order to better manage this particular category of patients. Coagulation parameter All pts ET pts HT pts PV pts Median KCT ratio (range) No. of pts with increased ratio 0.89 (0.26–1.49) 5/33 (15%) 0.86 (0.26–1.21) 0/16 1.22 (0.77–1.49)&gt; 1/9 (11%) pan lang=”EN-US”&gt;1.31 (0.9–1.41)4/8 (50%) Median dRVVT ratio (range) No. of pts with increased ratio 0.64 (0.26–1.15) 1/34 (2.9%) 0.78 (0.26–0.99) 0/17 0.75 (0.54–0.98) 0/9 0.72 (0.55–1.6) 1/8 (12.5%) Median PC level (range) No. of pts with reduced levels 97 (58–137) 4/34 (11.7%) 97 (62–137) 0/17 (0%) 91 (62–133) 2/9 (22%) 101 (58–116) 2/8 (25%) Median PS level (range) No. of pts with reduced levels 85 (48–113) 4/34 (11.7%) 82 (49–113) 1/17 (5,8%) 84 (63–95) 1/9 (11%) 106 (60–112) 2/8 (25%) Median antithrombin level (range) No. of pts with reduced values 100 (87–197) 0/34 100 (88–197) 0/17 99 (88–197) 0/9 97 (87–100) 0/8 Median HCY level (range) No. of pts with increased levels 9.20(4.6–34.06)/span&gt; 3/34 (8,8%) d&gt; 8.7 (4.6–14.1) 0/17 5.7(4.6–13.5) 0/9 9.8 (4.5–34.06) 3/8 (37.5%) FVL (allele frequency) mutations 1/34 (2.9%) 1/17 (5.8%) 0/9 0/8 FIIG20210A mutations (allele frequency) 4/34 (11.7%) 1/17 (5.8%) 3/9 (33%) 0/8 MTHFRC677T polymorphisms (heterozygosis) 22/34 (64.7%) 9/17 (52.9%) 8/9 (89%) 5/8 (62.5%)

Abstract Abstract 2001 Introduction: IFN and ASCT were the most commonly used treatment modalities for CML before 2001. The introduction of IMA as the preferred treatment for CML changed the treatment paradigms for this disease. CML pts are now expected to live longer and responses are prolonged in most cases. However, long-term outcomes including late relapses, durability of response, side effects, and late development of new medical conditions are largely unknown. Methods: We performed a chart review of pts with CML in CP treated at our institution who have survived at least 5 yrs of their initial IFN or IMA therapy, or 5 yrs after ASCT, to analyze their long-term outcome, risk of late relapse, and emergence of late side effects or new medical health problems. Results: 469 pts with CML CP treated at our institution between 1981 and 2006 survived at least 5 yrs on their initial CML treatment. One hundred twenty five pts are described in this analysis: 25 pts in the IFN group, 50 pts in the IMA group (400 mg/d), and 50 pts in the ASCT group. Pts received their initial treatment a median of 1 month (range, 0.3 to 11), 1 month (range, 0 to 7), and 13 months (range, 1 to 126) from diagnosis, respectively. Median time on initial therapy for the IFN and IMA groups was 6.4 yrs (range, 5–8.5) and 10.8 yrs (range, 5.1–11.5). Characteristics of the pts at time of diagnosis were as follows: hypertension (HTN) was present in 12%, 30% and 2% of the IFN, IMA, and ASCT pts, respectively; cardiac disease in 12%, 8% and 2%, respectively; thyroid disease (Thy) in 8%, 8% and 2%, respectively. Median number of medications (MEDS) per patient at baseline was 1 (range, 0–5), 1 (range, 0–13) and 0 (range, 0–4), respectively. Complete cytogenetic response (CCyR) was obtained in 76% (n=19), 96% (n=48) and 100% (n=50) of the pts, respectively. Time to best CyR was 17.1 months (mos) (range, 6–59.1), 7.2 mos (range, 2.4–64.2) in the IFN and IMA groups, respectively. Loss of cytogenetic response after 5 years occurred in 91% (n=21, 2 pts had no initial response, 2 pts remained in CCyR), 10% (n=5) and 6% (n=3), respectively. Twenty pts (80%) on the IFN cohort were switched to IMA at a median of 7.4 yrs (range, 5.3–13.3) after diagnosis (19 occurring between yrs 2000 and 2001). Of these 20 pts 75% (n=15) achieved MMR or better after a median of 4 yrs (range, 0.6–10.2) on IMA. New medical problems that developed at the 5 year mark were a follows: Thyroid problems in 8%, 0% and 10%, respectively, HTN in 0%, 2% and 14%, respectively; cardiac in 0%, 4% and 0%, respectively; and other in 44%, 22%and 58%, respectively. Median MEDS per patient at the 5 year mark was 2 (range, 0–7), 4 (range, 1–12) and 2 (range, 0–15), respectively. New medical problems that developed by last follow up were a follows: Thyroid problems in 4%, 6% and 0%, respectively; HTN in 4%, 18% and 10%, respectively, cardiac in 8%, 4% and 4%, respectively; osteoporosis in 0%, 0% and 6%, respectively, and other in 44%, 32% and 26%, respectively. Median Meds per patient at last follow up was 4 (range, 0–19), 6 (range, 1–16) and 2 (range, 0–25), respectively. Secondary malignancies occurred in 8%, 10% and 12% of patients, respectively. Pts continued to be on initial treatment in 16% (n=4), 94% (n=47) and 94% (n=47), respectively. At date of last follow up, late relapses (beyond 5 yrs of initial therapy) occurred in 72% (n=18), 8% (n=4) and 2% (n=1), respectively. At median follow up of 18, 11, and 14 yrs respectively, 76% (n=19), 92% (n=46) and 92% (n=46) are alive, 64% (n=16), 86% (n=43) and 90% (n=45) in CCyR. Conclusion: CP CML pts treated with IMA or SCT and surviving 5 yrs beyond initial treatment have low incidence of late relapses. New medical problems including heart disease and secondary malignancies may occur in some pts, but most pts are still alive. Pts with CML require prolonged medical care even in the setting of lasting remissions. Disclosures: Jabbour: BMS: Honoraria; Pfizer: Honoraria, Research Funding; novartis: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Abstract We evaluated the prevalence and clinical significance of CNS involvement in childhood and adolescence Non-Hodgkin Lymphoma (NHL). Between 10/86 and 12/02, 2,086 eligible patients (pts) were registered in the subsequent multicenter trials NHL-BFM86, −90, −95. Median follow up was 6.5 years (0.3–17.7 years). Initial staging included examination of cerebrospinal fluid (CSF) and cranial CT or MRI. CNS involvement was diagnosed in case of CSF blasts, and/or intracerebral mass (ICM), and/or cranial nerve palsy (CNP), not caused by an extradural mass. Epidural NHL without any of the above criteria was not considered as CNS disease. CNS positive (pos) pts with lymphoblastic lymphoma (LBL) received an 8-drug induction, consolidation, re-intensification, and maintenance up to 2 years. CNS therapy included dexamethason, methotrexate (MTX) 5 g/m2 i.v., 13 dosis of intrathecal (i.th.) MTX, and cranial radiotherapy (CRT). CNS pos pts with non-LBL received six 5-day courses based upon vincristine, vindesine, dexamethason, oxazophorins, cytarabine, etoposide, doxorubicin, MTX 5 g/m2 i.v., and intraventricularely or i.th. applied chemotherapy. CRT was omitted since study BFM90, except for pts with anaplastic large cell lymphoma (ALCL). 111 of the 2,086 analyzed NHL pts were initially diagnosed as CNS pos. 1,933 pts were CNS negative (neg) and in 42 pts the CNS status was questionable or not evaluable due to incomplete diagnostics. Prevalence and outcome of CNS pos pts according to NHL subtypes were as follows. In the total group, the probability of event free survival at 5 years (pEFS) was 63 ± 5% for CNS pos pts compared to 81 ± 1% for CNS neg pts with stage III/IV NHL (n=1,323) (p&lt; 0.0001). In LBL pts pEFS was 81 ± 10% for CNS pos pts and 84 ± 2% for CNS neg pts with stage III/IV (n=359) (p=0.54), while in Burkitt/B-ALL pEFS was 60 ± 5 % for CNS pos pts versus 85 ± 1% for CNS neg pts with stage III/IV (n=599) (p&lt;0.0001). For CNS pos Burkitt/B-ALL pts pEFS was 57 ± 7% for 57 pts with and was 67 ± 10% for 24 pts without bone marrow involvement (p=0.31). Total LBL (T-, pB-) Burkitt/B-ALL PMLBL* DLBL° ALCL Others *primary mediastinal large B-cell lymphoma, °diffuse large B-cell lymphoma Number of pts 2086 433 1003 40 222 215 173 CNS pos pts 111 16 81 0 4 5 5 Percentage 5,3% 3,7% 8,1% 0 1,8% 2,3% 2,9% Chracteristics and outcome of CNS pos pts CSF blasts +/ − others 81 13 60 0 1 4 3 ICM (without CSF blasts) 18 2 11 0 2 1 2 CNP 12 1 10 0 1 0 0 Death unrelated to tumor 6 0 6 0 0 0 0 Relapse/Nonresponse 30 2 24 0 0 2 2 CNS involved 18 1 15 0 0 2 0 In summary, CNS-disease was most frequent in pts with Burkitt/B-ALL, while it was rare in DLBL pts. In Burkitt/B-ALL, CNS pos pts had a worse outcome compared to CNS neg pts with advanced stage disease, while in LBL pts outcome was comparable for CNS pos and CNS neg pts.

Three hundred eighty-six patients with acute myocardial infarction received up to 150 mg rt-PA (single chain) IV either over 8 h (60mg over 1 h, 20 mg/h for 2 h,10 mg/h for 5 h)(173 pts) or over"5h(1 mg/kg over 1 h, remainder over 4 h) (213 pts),before randomization to early or late angioplasty. Blood was collected on a lyophilized mixture of citrate and the t-PA inhibitor D-Phe-Pro-Arg-CH2C1 (PPACK), to maximally prevent in vitro fibrinolytic activation and concomitant fibrinogen degradation. The plasma rt-PA level increased to 2.4±2.0 /μg/ml(mean +SD)and 1.7 ±1.3 /μg/ml after 3h and to 1.0 ±1.8 and 1.0 ±0.9 /μg/ml at the end of the infusion.Fibrinogen levels (coagulation rate assay) fell to 5 ± 28 and 52 ± 27% at 3 h and to53 ± 28 and 47 μ 26% at the endof infusion.Fibrinogen degradation productsincreased to 32 /μg/ml (median, with 10 and 90 percentile values of 2 and 512 /μg/ml) after 3h and to3 2 /μg/1 (median, with 10 and 90 percentile values of 2and 512 ug/ml) at the end of infusion. The fibrinogen decreased to below 1 g/1 in 23% of patients and b e low 0-5 g/1 in 11% after 3 h infusion with corresponding values of 33% and 12%at the end of infusion.Thus, at the infusion rates required for rapid coronary artery reperfusion in man, rt-PA remains relatively fibrin-specific. The cause of the extensive fibrinogen depletion occurring in some patients remains to be further investigated.