Journal articles: 'RL 0.8 / 0.5 Pts'

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Brown, Jennifer R., Matthew S. Davids, Jordi Rodon, Pau Abrisqueta, Coumaran Egile, Rodrigo Ruiz-Soto, and Farrukh Awan. "Update On The Safety and Efficacy Of The Pan Class I PI3K Inhibitor SAR245408 (XL147) In Chronic Lymphocytic Leukemia and Non-Hodgkin’s Lymphoma Patients." Blood 122, no. 21 (November 15, 2013): 4170. http://dx.doi.org/10.1182/blood.v122.21.4170.4170.

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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.

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Stein, Anthony Selwyn, Jeffrey Y. C. Wong, Joycelynne Palmer, Margaret O'Donnell, David S. Snyder, Ni-Chun Tsai, Pablo Miguel Parker, et al. "A Phase I Trial of Total Marrow and Lymphoid Irradiation (TMLI)-Based Transplant Conditioning in Patients (Pts) with Relapsed/Refractory Acute Leukemia." Blood 126, no. 23 (December 3, 2015): 735. http://dx.doi.org/10.1182/blood.v126.23.735.735.

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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.

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Siyal, Ali N., Saima Q. Memon, and M. Y. Khuhawar. "Recycling of styrofoam waste: synthesis, characterization and application of novel phenyl thiosemicarbazone surface." Polish Journal of Chemical Technology 14, no. 4 (December 1, 2012): 11–18. http://dx.doi.org/10.2478/v10026-012-0095-0.

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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.

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te Boekhorst, Peter, Claire N. Harrison, Heinz Gisslinger, Dietger Niederwieser, Viktoriya Stalbovskaya, Edric Atienza, Prashanth Gopalakrishna, and Alessandro M. Vannucchi. "A Phase 1b, Open-Label, Dose-Finding Study of Ruxolitinib in Patients with Myelofibrosis (MF) and Baseline Platelet Counts from 50 × 109/L to 99 × 109/L (The EXPAND Study)." Blood 124, no. 21 (December 6, 2014): 1841. http://dx.doi.org/10.1182/blood.v124.21.1841.1841.

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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.

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Thuruthiyil, Divya K., Martin Cawley, and Mohamed Metwaly. "A cone beam CT-based study on fiducial seed migration and planning target volume margin in prostate radiotherapy." Journal of Radiotherapy in Practice 19, no. 4 (November 21, 2019): 315–20. http://dx.doi.org/10.1017/s1460396919000827.

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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.

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Durrant, Simon, Maya Koren-Michowitz, David Lavie, Joaquin Martinez-Lopez, Alessandro M. Vannucchi, Francesco Passamonti, Viktoriya Stalbovskaya, et al. "HARMONY: An Open-Label, Multicenter, 2-Arm, Dose-Finding, Phase 1b Study of the Combination of Ruxolitinib and Buparlisib (BKM120) in Patients with Myelofibrosis (MF)." Blood 124, no. 21 (December 6, 2014): 710. http://dx.doi.org/10.1182/blood.v124.21.710.710.

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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.

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Chan, A., N. Tubiana, V. Ganju, P. Conte, P. Bougnoux, D. Aubert, T. Bourlard, and D. Becquart. "Optimal tolerance of an all-oral combination chemotherapy (CT) of oral vinorelbine (NVBo), capecitabine (C) with/without trastuzumab (T) in metastatic breast cancer (MBC) patients (pts): Safety Results of two international multicenter studies." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10607. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10607.

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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]

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Giona, Fiorina, Angela Amendola, Giovanna Palumbo, Patrizia Pignoloni, Antonio Chistolini, Maria Luisa Moleti, Robert Foà, and Maria Gabriella Mazzucconi. "Inherited and Acquired Thrombophilic Abnormalities in Patients Aged <20 Years with Bcr-Abl Negative Chronic Myeloproliferative Disorders." Blood 112, no. 11 (November 16, 2008): 5249. http://dx.doi.org/10.1182/blood.v112.11.5249.5249.

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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 <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 <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. <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)> 1/9 (11%) pan lang=”EN-US”>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> 3/34 (8,8%) d> 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%)

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Ghanem, Hady, Hagop M. Kantarjian, Richard E. Champlin, Lakshmikanth Katragadda, Gabriela Rondon, Elias J. Jabbour, Alfonso Quintás-Cardama, Sherry A. Pierce, and Jorge E. Cortes. "Outcomes of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (pts) After Surviving 5 Years of Initial Therapy with Interferon Alpha (IFN), Imatinib (IMA) or Allogeneic Stem Cell Transplantation (ASCT)." Blood 120, no. 21 (November 16, 2012): 2001. http://dx.doi.org/10.1182/blood.v120.21.2001.2001.

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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.

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Salzburg, Janina, Birgit Burkhardt, Olga Wachowski, Martin Zimmermann, Reza Parwaresch, Wolf-Dieter Ludwig, Georg Mann, et al. "CNS Involvement in Childhood and Adolescence Non-Hodgkin Lymphoma: Prevalence and Patient’s Outcome Differ According to the Subtype." Blood 106, no. 11 (November 16, 2005): 233. http://dx.doi.org/10.1182/blood.v106.11.233.233.

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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< 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<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.

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Ramadan, Hanadi, Vu H. Duong, Najla H. Al Ali, Eric Padron, Ling Zhang, Jeffrey E. Lancet, Alan F. List, and Rami S. Komrokji. "Eltrombopag Use in Chronic Myelomonocytic Leukemia (CMML) Patients: A Cautionary Tale." Blood 126, no. 23 (December 3, 2015): 2897. http://dx.doi.org/10.1182/blood.v126.23.2897.2897.

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Abstract Introduction Thrombocytopenia is a management challenge for Myelodysplastic syndromes (MDS) patients (pts). The outcome of MDS Pts after hypomethylating agents (HMA) failure is poor. Eltrombopag is an oral, small non-peptide thrombopoietin (TPO) receptor agonist. It has biologically distinct effects in part to its binding site on the TPO receptor that is distinct from that for native TPO and other synthetic agonists. We report our experience among CMML pts treated with eltrombopag in the context of a phase I MDS study. Methods This is a phase I study. Pts are allocated to dose cohorts of 50, 100, 150, 200 mg/day. Key eligibility criteria include confirmed diagnosis of MDS or acute myeloid leukemia (AML) with 20-30% myeloblasts. All pts had HMA failure. The mean platelet count within a month of enrollment must be ≤ 50 X 109/L. Key exclusions include splenic enlargement > 8 cm, bone marrow fibrosis > grade 3. We identified CMML pts and compared the responses and adverse events to MDS patients. Results Among 33 pts enrolled on the phase I study, 7 were CMML pts. Table-1 summarizes baseline characteristics. The median age of CMML pts was 76 years, all were white males. Five pts were CMML-2. Majority were classified as higher risk by IPSS, revised IPSS and MD Anderson model. Four pts were proliferative CMML. Among CMML pts, one received eltrombopag at 50 mg, 2 pts at100 mg, 2 pts at 150 mg, and 2 pts at 200 mg. Three pts completed 8 weeks to be evaluable for response and toxicity. Hematological improvement or better by IWG 2006 criteria (HI+) was observed in 6/26 (23%) MDS pts and 1/7 (14%) CMML pts (p 0.16). The responding CMML pt had bilineage response. Five non CMML pts had a platelet response. Two CMML pts became platelet transfusion independent compared to 4 non CMML pts. The rate of AML transformation was 39% and 29% respectively in MDS and CMML pts (p 0.14). The median OS was 7 months for CMML pts compared to 5 months for non-CMML (p 0.2). Five (71%) CMML pts developed leukocytosis on treatment compared to 3 MDS pts (12%). (p 0.001). (3 out of 5 pts had proliferative type CMML). Leukocytosis developed within first cycle in all pts. In 2 CMML pts, leukocytosis resolved after stopping treatment. Four CMML pts (57%) showed peripheral myeloblasts on treatment compared to 11 (42%) in the MDS group (p 0.2). One CMML pt (14%) developed grade 3 fibrosis from grade 0-1 at baseline compared to 3 MDS pts (12%). Data will be presented on ongoing Next generation sequencing for somatic mutations comparing CMML pts to MDS pts and those who developed leukocytosis/circulating myeloblasts to pts who did not. Conclusions Eltrombopag yielded lower responses in CMML pts after HMA failure compared to MDS pts but namely due to stopping treatment in majority of pts due to leukocytosis or circulating myeloblasts. At the time being, eltrombopag should only be offered to CMML pts in the context of clinical trials. Table 1. Baseline Characteristics CMML (n=7) MDS (n= 26) P value Age Mean 77.5 75 0.20 Gender Male 7 [100%] 18 [69%] 0.09 Race White 7 [100%] 24 [92%] 0.40 ECOG PS 0 1 1 [14%] 6 [86%] 6 [23%] 20 [77%] 0.70 MyeloblastsPlateletsHgbWBC Mean % Mean Mean Mean 9 30 10.5 14 13 22 9.5 3 0.08 0.20 0.20 0.03 Cytogenetic Risk Good Intermediate Poor 4 [57%] 2 [29%] 1 [14%] 15 [56%] 3 [11%] 8 [33%] 0.40 WHO classification RCMD RAEB-1 RAEB-2 RAEB-t (AML) CMML-1 CMMl-2 MDS/MPN-U Del 5q 0 0 0 0 2 [29%] 5 [71%] 0 0 6 [23%] 7 [27%] 11 [42%] 1 [4%] 0 0 0 1 [4%] IPSS Low Int-1 Int-2 High 1 [14%] 0 4 [57%] 2 [29%] 0 11 [42%] 9 [35%] 6 [23%] 0.05 R-IPSS Very low Low Intermediate High Very High 0 1 [14%] 0 5 [72%] 1 [14%] 0 2 [8%] 5 [19%] 9 [35%] 10 [38%] 0.20 Disclosures Padron: Novartis: Speakers Bureau; Incyte: Research Funding. Lancet:Celgene: Consultancy, Research Funding; Amgen: Consultancy; Kalo-Bios: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Boehringer-Ingelheim: Consultancy. List:Celgene Corporation: Honoraria, Research Funding. Komrokji:Pharmacyclics: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Off Label Use: use of eltrombopag in MDS and CMML.

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Zinner, R., F. V. Fossella, M. S. Kies, R. S. Herbst, C. Lu, F. M. Johnson, S. V. Bhat, J. S. Price, C. Cleeland, and X. Wang. "A phase II trial of pemetrexed (P) in patients (pts) with performance status (PS) 2 and 3 as first- and second-line treatment for advanced non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 18149. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.18149.

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18149 P (Alimta) is approved as second-line therapy in pts with advanced NSCLC. In a phase III trial comparing P with docetaxel (D), median survival was 8.3 mos (P) vs 7.9 mos (D); P had a more favorable safety profile than D (Hanna, 2004). There are few data on pts with PS 3, and ASCO 2003 guidelines recommend that chemotherapy be reserved for pts with PS 0, 1 and possibly 2. Since P is well tolerated, PS3 pts may tolerate and benefit from it. In this trial, we treated 20 pts with stage IIIb/IV NSCLC and PS 2–3 who were chemo-naive or had received 1 prior regimen. Pts received P 500 mg/m2 IV D1 Q 3 wks. All pts received folic acid, vitamin B12 and dexamethasone prophylaxis. Serial blood samples were obtained to monitor inflammatory cytokines, and symptoms were monitored using the validated MDASI instrument. All pts were assessable for toxicity-symptoms, and 17 pts were evaluable for response (assessed after first cycle). Pt characteristics: 8 pts were PS 3 (4/8 first line) and 12 pts were PS 2 (6/12 first line). Median age was 69 for PS3 and 68 for PS2. 5/8 PS3 pts and 6/12 PS2 pts were men. 2/8 PS3 pts and 4/12 PS2 pts had stage IIIb. 4/8 PS3 pts and 6/12 PS2 pts were chemo-naive. Grade 3–4 toxicities for PS3/PS2 cohorts were: neutropenia 0/1 pt, anemia 1/2, fatigue 2/0, pneumonia 1/1, hypotension 1/1, neutropenic fever 0/1, atrial fibrillation 1/1. Response rates (RR) in PS3 pts were minor response (MR) 1/8, stable disease (SD) 5/8, progressive disease (PD) 2/8; RR in PS2 pts were partial response (PR) 1/12, MR 2/12, SD 3/12, PD 3/12, inevaluable 3/12. RR by line of therapy: first-line 6/10 SD, 2/10 PD, 2/10 inevaluable, and second-line, 1/10 PR, 2/10 MR, 3/10 SD, 3/10 PD, and 1/10 inevaluable. Reasons for PS3 pts coming off study were progression (4/8), constitutional toxicity (3/8), fatal pulmonary emboli (1/8); PS2 pts came off study due to progression (5/12), constitutional toxicity (2/12), and pneumonia (1/12). 4/12 PS2 pts are still on study. These preliminary data suggest that single-agent P is well-tolerated and has a promising RR in poor PS pts. Total planned accrual is 30 PS3 and 45 PS2 pts. Survival, symptom, cytokine data will be presented. [Table: see text]

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Cristofanilli, Massimo, Stephen R. D. Johnston, Alexey Manikhas, Henry Leonidas Gomez, Oleg Gladkov, Zhimin Shao, Sufia Safina, et al. "A randomized phase II study (VEG108838) of lapatanib plus pazopanib (L+P) versus lapatanib (L) in patients with ErbB2+ inflammatory breast cancer (IBC)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 531. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.531.

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531 Background: ErbB2 amplification is frequently reported in IBC and there is evidence of positive association between ErbB2 and VEGF expression. We evaluated the combination of anti ErbB2 and VEGF therapy in ErbB2+ IBC. Methods: We conducted a multicenter, randomized clinical trial for patients (pts) with relapsed ErbB2+ IBC. Cohort 1: Pts stratified (prior trastuzumab; cutaneous disease only vs systemic) and randomized 1:1 to receive L 1500 mg + placebo or L 1500 mg + P 800 mg, QD. Due to high incidence of Grade 3/4 diarrhea in pts treated with L 1500 mg+ P 800 mg in another study, Cohort 1 was closed after 76 pts randomized. Cohort 2 (87 pts ): Pts were stratified (prior trastuzumab) and randomized 5:5:2 to receive L 1500 mg + placebo or L 1000 mg + P 400 mg (double-blind) or P 800 mg (open-label), respectively, QD. Treatment continued until PD, unacceptable toxicity or death. Primary endpoint was ORR. Secondary endpoints included PFS, OS, and safety. Results: Cohort 1: 76 pts were randomized and treated: L, n=38; L+P, n=38. ORR was 29% for the L arm, and 45% for the L+P arm. Median PFS was 16.1 and 14.3 wks, respectively, for the L and L+P arms. The most frequent Grade ≥3 AEs were diarrhea (0% vs 18%) vomiting (0% vs 8%), ALT increased (0% vs 8%), neutropenia (3% vs 13%), and bilirubin increased (0% vs 5%). Dose reductions due to AE were 3% and 21% and dose interruptions due to AE were 11% and 55% in the L and L+P arms, respectively. Cohort 2: 88 pts were randomized (87 treated): L, n=36; P, n=14; L+P, n=38. The ORR was 47%, 31%, and 58% for the L, P, and L+P arms, respectively. Median PFS was 16.0, 11.4, and 16.0 wks for the L, P, and L+P arms, respectively. The most frequent Grade ≥3 AEs were ALT increased (0%, 0%, 21%), AST increased (0%, 0%, 18%), diarrhea (3%, 8%, 8%), and fatigue (3%, 8%, 8%). Dose reductions due to AE occurred in 0%, 0%, and 13% of pts and dose interruptions due to AE occurred in 22%, 23%, and 39% of pts in the L, P, and L+P arms, respectively. Conclusions: This prospective, randomized study confirmed the clinical activity of lapatinib single agent in metastatic ErbB2+ IBC. Furthermore, we demonstrated increased toxicity associated with the combination without a clinically meaningful improvement in efficacy.

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Kindler, H. L., K. A. Bylow, H. S. Hochster, G. Friberg, K. Micetich, G. Locker, M. Kozloff, M. Moore, W. Sun, and E. E. Vokes. "A randomized phase II study of bevacizumab (B) and gemcitabine (G) plus cetuximab (C) or erlotinib (E) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 4040. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4040.

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4040 Background: In a phase II trial of G + anti-VEGF antibody B in 52 PC pts, we reported a 21% response rate and median survival of 8.8 months (mo) (Kindler, JCO 2005). EGFR inhibitors C and E also have activity in PC. VEGF and EGFR pathways are interdependent; dual inhibition may be synergistic. Methods: We are conducting a multi-center, randomized phase II trial of GBC vs. GBE in advanced PC pts who have: no prior therapy for metastatic disease, PS 0–2, measurable disease, no tumor invasion of duodenum, no bleeding risk. Primary endpoint: response. Trial design: 2 parallel, Simon 2-stage designs; requires 6 responses in 27 evaluable pts for 2nd stage; 63 pts/arm. All pts receive G 1000 mg/m2 over 30 minutes days (D) 1, 8, 15 Q28D; B 10 mg/kg D 1, 15 Q28D. Pts are randomized to C 400 mg/m2 D1, then 250 mg/m2 Q7D, or E 150 mg D1–5, 8–12, 15–26 Q28D. CT scans: Q2 cycles. 58 pts enrolled at 13 sites 9/04–12/05. Pt characteristics: male 66%; median age 61 (range 36–82); PS: 0/1/2: 52%/40%/8%; stage IV 95%; liver metastases 76%. Results: 49 pts (GBC/GBE 24/25) are evaluable for toxicity; 51 pts (27/24) for response. 232 cycles were administered (median 4, range 1–11). Grade ¾ toxicity (%pts GBC/GBE): neutropenia 29%/28%; anemia 4%/16%, thrombocytopenia 8%/24%, DVT-PE 17%/8%, CVA 4%/4%, GI bleed 4%/12%, hypertension 4%/4%, rash 13%/4%, pneumonitis 0%/8%, diarrhea 4%/4%; grade 5: bowel perforation 0%/4%, MI- CVA 0%/4%, other cardiac 4%/0%. Response: GBC 19% (1 complete, 4 partial), GBE 21% (5 partial). Stable disease 59%/67%. Median progression-free survival 3.6/3.6 mo (95%CI: 2.7, 4.7/2.7, 5.9), 6-month survival 41%/38% (95% CI: 11%, 71%/2%, 75%). Conclusion: GBC and GBE are active in advanced PC. Toxicity, principally related to B, is moderate. The trial proceeds to a 2nd stage if 1 more response is observed in each arm. Supported by NCI grant N01-CM-17102. [Table: see text]

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Saussele, Susanne, Michael Lauseker, Alois Gratwohl, Dominik Heim, Dietrich Wilhelm Beelen, Hartmut Döhner, Rainer Schwerdtfeger, et al. "Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in the Imatinib-Era: High Survival Rate Following Allogeneic HSCT after Imatinib Failure: Results of the German CML Study IV." Blood 112, no. 11 (November 16, 2008): 448. http://dx.doi.org/10.1182/blood.v112.11.448.448.

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Abstract Allogeneic HSCT remains an important option for patients with chronic myeloid leukemia (CML) who failed imatinib. Focus has been on second line tyrosine kinase inhibitors (TKI). Little is known on the outcome of HSCT for such patients. In July 2002, the German CML-Study Group activated a prospective randomized trial comparing different imatinib based strategies in chronic phase CML (CP). Elective early HSCT was considered for patients (pts) with EBMT score 0–1 for those with high disease risk, and after imatinib failure. By the end of July 2008, 1197 pts were randomized. In 80 (6,5 %) pts HSCT was documented. 52 pts were male (65%), 23 were high risk pts (28%) according to the Euro score. Median age at diagnosis was 37 years (yrs) (range 16–62), median time to HSCT was 12.6 months (mo, range 3.5–54 mo). EBMT score was 0–1 in 8 (10%), 2 in 10 (12%), 3–4 in 44 (55%) and 5 in 18 pts (23%). Median follow-up after HSCT was 19 mo (range 0–59). Cumulative response rates prior to HSCT were 68% for complete hematologic response, 23% for complete cytogenetic responses, and 9% for major molecular responses. Based on the indication for HSCT three groups were defined: early HSCT (n= 19, 23%; low EBMT score (n=9), high risk pts (n=7), patient request (n=3); HSCT after imatinib failure or intolerance in first CP (n=34, 43%) and HSCT in second CP or higher, accelerated phase or blast crisis (n=27, 34%). 14 pts died, 10 deaths were transplantation related, 4 CML related. Two pts with a molecular relapse were successfully treated with donor lymphocyte infusion in combination with TKI. Overall survival rate at two yrs for group one was 87.8%, for group two 93.8%, and for group three 49.5%. By EBMT score, survival rates were 100% for risk score 0–2, 82.2% for risk score 3–4, and 43.5% for risk score 5. Data from this prospective controlled cohort study clearly show that HSCT remains an attractive and important rescue therapy for CML patients with imatinib failure or intolerance, particularly for those with a low EBMT risk score. HSCT in 1st CP early HSCT HSCT for failure and intolerance in 1st CP Total HSCT in advanced phases N 19 34 53 27 Euro score high 6 8 14 9 intermediate 3 12 15 7 low 10 14 24 11 % male 63 56 60 78 Median age (range) 35 (16–56) 38 (21–56) 37 (16–56) 37 (18–62) Median time to HSCT (Range) (months) 8.5 (4.8–23.6) 17,5 (5.0– 53.7) 12.6 (4.8 53.7) 12.0 (3.5–54.1) EBMT score 0–1 5 3 8 0 2 5 4 9 1 3–4 9 26 35 9 >=5 0 1 1 17 Best response CHR 11/18 28/34 39/52 14/26 CCyR 3/17 10/33 13/50 4/22 MMR 2/17 3/31 5/48 2/19 Response at HSCT BC 0 0 0 24 AP 0 0 0 3 CP 19 34 53 0 HR 11 19 30 0 Ccyr 2 2 4 0 MMR 0 0 0 0 Transplant source Sibling 10 10 20 9 Unrelated 9 24 33 18 Conditioning therapy standard 14 21 35 17 reduced 3 6 9 4 other 2 7 9 6 Source PB 13 26 39 22 BM 6 8 14 5 Dead 2 2 4 10 TRM 2 2 4 6 CML 0 0 0 4 Probability of survival at 2 years after HSCT 87.8% 93.8% 91.4% 49.5%

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Shen, X., R. Ramchandani, B. Dunn, R. Lambert, S. J. Gunst, and R. S. Tepper. "Effect of transpulmonary pressure on airway diameter and responsiveness of immature and mature rabbits." Journal of Applied Physiology 89, no. 4 (October 1, 2000): 1584–90. http://dx.doi.org/10.1152/jappl.2000.89.4.1584.

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We previously demonstrated that airway responsiveness is greater in immature than in mature rabbits; however, it is not known whether there are maturational differences in the effect of transpulmonary pressure (Ptp) on airway size and airway responsiveness. The relationship between Ptp and airway diameter was assessed in excised lungs insufflated with tantalum powder. Diameters of comparable intraparenchymal airway segments were measured from radiographs obtained at Ptp between 0 and 20 cmH2O. At Ptp > 8 cmH2O, the diameters were near maximal in both groups. With diameter normalized to its maximal value, changing Ptp between 8 and 0 cmH2O resulted in a greater decline of airway caliber in immature than mature airways. The increases in lung resistance (Rl) in vivo at Ptp of 8, 5, and 2 cmH2O were measured during challenge with intravenous methacholine (MCh: 0.001–0.5 mg/kg). At Ptp of 8 cmH2O, both groups had very small responses to MCh and the maximal fold increases in Rl did not differ (1.93 ± 0.29 vs. 2.23 ± 0.19). At Ptp of 5 and 2 cmH2O, the fold increases in Rl were greater for immature than mature animals (13.19 ± 1.81 vs. 3.89 ± 0.37) and (17.74 ± 2.15 vs. 4.6 ± 0.52), respectively. We conclude that immature rabbits have greater airway distensibility and this difference may contribute to greater airway narrowing in immature compared with mature rabbits.

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Noga, Stephen J., Janak Choksi, Beiying Ding, Lyndah Dreiling, and Howard Ozer. "Final Results of a Large, Community Based Study Evaluating the Impact of First and Subsequent Cycle Pegfilgrastim on Neutropenic Events in NHL and HD Patients." Blood 108, no. 11 (November 16, 2006): 1153. http://dx.doi.org/10.1182/blood.v108.11.1153.1153.

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Abstract Introduction: Most alterations to chemotherapy (CT) dose and schedule are due to neutropenic events, which mainly occur in the 1st cycle. A nationwide survey found that of 4522 patients (pts) with diffuse, aggressive non-Hodgkin’s lymphoma (NHL) treated with CHOP-like regimens in community practice, 40% experienced CT dose reductions, and 24% experienced CT dose delays (Lyman 2004). The ability of pegfilgrastim to reduce complications of CT-induced neutropenia has been established in clinical trials for pts receiving moderately (Vogel 2005) and highly (Holmes 2002) myelosuppressive CT. This prospective, community-based study evaluated the efficacy of 1st cycle pegfilgrastim in pts with NHL receiving CT in community practice. Methods: Pts ≥ 18 yrs with cancers other than leukemia or MDS were eligible, including those with major comorbidities who are generally not eligible for clinical trials. Key exclusions were weekly CT and concurrent radiotherapy. Pts received pegfilgrastim 6mg ~24 hours after CT in each cycle (up to 8 cycles). Endpoints included neutropenic complications and CT dose reductions and delays. Additionally, average relative dose intensity (ARDI) was calculated for major standard regimens. Point estimates and 95% confidence limits (CL) are provided. Results: This open-label, single-arm study enrolled 2249 pts at 319 sites. Of these, 325 pts with NHL and 46 pts with Hodgkin’s disease (HD) were included in the primary analysis set. The mean (SD) age was 65 (13) years for NHL pts and 41 (14) for HD pts. 69% of NHL pts and 26% HD pts had advanced (III–IV) disease, 90% of NHL pts and 98% of HD pts had ECOG status 0 or 1, and 31% of NHL pts and 26% of HD pts had major comorbidities (eg. vascular disease, diabetes). 49% of NHL pts received standard CHOP ± R (cyclophosphamide, doxorubicin, vincristine, and prednisone ± rituximab) and 78% of HD pts received standard ABVD (bleomycin, dacarbazine, doxorubicin, vinblastine). Few pts experienced neutropenic complications (table). All serious adverse events were consistent with those observed in pts receiving myelosuppressive CT. Conclusions: These results represent ‘real-world’ data as the only major entry criterion for pts was a confirmed diagnosis of malignancy. Pts in our study received myelosuppressive CT with very few neutropenia-related alterations in CT dose and schedule supporting the use of pegfilgrastim from the 1st cycle of CT. Use of pegfilgrastim allowed maintenance of RDI with minimal CT dose delays and reductions. Incidence % (95% CL) NHL HD 1 physician reported; 2standard reference dose and planned cycle length were used to calculate DI in the denominator of RDI Hospitalization related to neutropenia in cycle 1 9 (6, 13) 4 (0.5, 15) Hospitalization related to FN in cycle 1 6 (4, 9) 0 (0, 8) FN in cycle 1 (ANC<0.5×109/L and temperature 38.2°C) 8 (5, 12) 0 (0, 8) Incidence of grade 3/4 neutropenia in cycle 1 37 (32, 42) 4 (0.5, 15) Neutropenia-related IV antibiotic use in cycle 1 9 (6, 12) 4 (0.5, 15) Neutropenia-related CT dose reductions in cycle 21 2 (1, 5) 0 (0, 8) Neutropenia-related CT dose delays in cycle 21 2 (1, 5) 0 (0, 8) ARDI (mean % [SD])2 CHOP ± R every 21 days 77 (23) ABVD every 14 days 83 (26)

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Hansberg, Marion, Stefan O. Schoenland, Anja Mangatter, Sascha Dietrich, Peter Dreger, Kai Neben, Anthony Ho, Hartmut Goldschmidt, and Ute Hegenbart. "Evaluation of Safety and Efficacy of Different Stem Cell Mobilization Regimens in 110 Patients with Light Chain Amyloidosis." Blood 112, no. 11 (November 16, 2008): 3709. http://dx.doi.org/10.1182/blood.v112.11.3709.3709.

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Abstract Introduction: High-dose melphalan (HDM) with autologous hematopoietic stem cell transplantation (SCT) is an effective treatment for patients (pts) with systemic light chain (AL) amyloidosis. Most centers use granulocyte colony-stimulating factor (G-CSF) alone for mobilization of peripheral blood stem cells. The application of mobilization chemotherapy (MC) together with G-CSF might have some advantages, e.g. a higher amount of collected SC and the reduction of the plasma cell load prior to HDM therapy. We have retrospectively analyzed all pts with AL amyloidosis admitted to our centre who received SC mobilization until 2007. Patients and methods: 110 pts received mobilization therapy. Median age was 56 years (range, 35–69 years). Major eligibility criteria were cardiac disease < NYHA stage III and performance status (PS) < 3. Prior to mobilization, 55 pts (50%) had been pre-treated with induction chemotherapy, including 19 pts who had received melphalan. MC was performed with a combination of cyclophosphamide (1g/m2)/adriamycin (60 mg/m2)/dexamethasone (160 mg) (CAD) in 82 pts. The remaining pts received ifosfamide (12 g/m2, Ifo, n=14) or other chemotherapies (n=7). G-CSF (5 ug/kg/day) was started on day 8 after start of MC. Mobilization with G-CSF alone (10 ug/kg/day) was performed in 11 pts (patientxs choice, pts after cardiac transplant). Patients were retrospectively analyzed regarding toxicity and efficacy of SC mobilization as well as hematological reconstitution after HDM. Results: No patient died during mobilization therapy and leukapheresis (LP). Median NCI grade of non-hematological toxicity was 2 and significantly depended of advanced age, lower Karnofsky performance scale and application of Ifo (p<0.05, Table 1). After CAD cardiac toxicity > NCI grade 3 was observed in 3 pts. Main problems of HD-ifo were worsening of kidney function in 8 pts and occurrence of encephalopathy in 7 pts. Due to AL amyloidosis progression 3 pts could not proceed to SC collection and further 5 pts with successful SC collection were not transplanted, respectively. SC mobilization was successful (> 2 × 106 CD34+/kg body weight (BW)) in 105 pts (95%), 4 pts had to be mobilized twice. The median number of collected SC was 8 × 106 CD34+/kg BW (range, 0–46) with a median LP of 1. Previous melphalan treatment and G-SCF mobilization alone were significantly associated with a reduced number of collected SC (p<0.01, Table 1). HDM with SCT was performed in 100 pts with a transplant-related mortality of 3%. Hematological reconstitution was regular: median time to ANC > 1.0/nl 13 days (range, 9–27 days), median time to platelets > 20/nl 11 days (range, 8–102 days). Of note, only one patient received G-CSF post SCT. There was a trend for faster leukocyte recovery for pts receiving more than 6,5 × 106 CD34+ cells/kg BW compared to < 3 × 106 CD34+ cells/kg BW (12 vs. 14 days, p=0.1). One year after SCT 13 pts (16% of evaluable pts) had a reduced platelet count (<150/nl) with a minimum value of 54/nl. This was associated with a lower amount of transplanted SC (p<0.05). Our results differ from those published by Gertz et al., Am J Med, 2002 regarding number of LP (median 2.5) and time to platelet engraftment (14 days). Conclusion: Our analysis shows that MC with CAD is safe and very effective in pts with AL amyloidosis. More than 95% of the CAD pts could proceed to HDM and had a fast and sustained hematological reconstitution after SCT. Due to the non-hematological toxicity Ifo administration can not be recommended. Mobilization with G-CSF alone is also effective and safe but results in lower amount of collected SC. MC with CAD as part of an intensive therapy approach including IC with new agents should be further evaluated in clinical trials. Mobilization therapy (number of pts) Median number of LP Median number of CD34+ cells/kg BW collected Median NCI grade of nonhematological toxicity G-CSF (n=11) 1 (1–2) 5 (0–11) 0 (0–3) CAD (n=82) 1 (1–5) 9 (0–37) 2 (0–4) Ifo (n=14) 1 (1–4) 19 (5–46) 3 (0–3) Mobilization therapy (number of pts) Median number of LP Median number of CD34+ cells/kg BW collected Median NCI grade of non- hematological toxicity G-CSF (n=11) 1 (1–2) 5 (0–11) 0 (0–3) CAD (n=82) 1 (1–5) 9 (0–37) 2 (0–4) Ifo (n=14) 1 (1–4) 19 (5–46) 3 (0–3)

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Tournigand, C., B. Samson, W. Scheithauer, C. Louvet, T. Andre, G. Lledo, J. Latreille, F. Viret, B. Chibaudel, and A. de Gramont. "mFOLFOX-bevacizumab or XELOX-bevacizumab then bevacizumab (B) alone or with erlotinib (E) in first-line treatment of patients with metastatic colorectal cancer (mCRC): Interim safety analysis of DREAM study." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 4077. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4077.

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4077 Background: Anti-VEGF or EGFR inhibitors demonstrated clinical activity in combination with chemotherapy (CT) in mCRC. The DREAM trial compares, after an induction CT of 6 cy of FOLFOX-B or XELOX-B, a maintenance with B ± E. We report here a pre-planned safety analysis of induction (I) and maintenance (M) phase for the first 200 patients. Methods: Patients (pts) with untreated mCRC were randomly assigned to 2 arms (I): mFOLFOX+B (n=100), or mXELOX+B (n=100). mFOLFOX-B: LV 400 mg/m2, Oxaliplatin (ox) 100 mg/m2, B 5 mg/kg d1, 5FU ci 2.4g/m2 46h, q2w, mXELOX-B: Ox 100 mg/m2 d1, capecitabine 2.5 g/m2 d1–7, B 5mg/kg, q2w. To date, 117 pts with a disease control after 6 cy have had a 2nd randomisation (M): B alone (7.5 mg/kg q3w, n=56) or B+E 150 mg/d (n=61) until PD. Results: Pts characteristics were: sex: 124M/76F, median age: 62.4 years (26–80), primary tumors: colon 152, rectum 53, synchronous metastases: 150 pts, > 1 metastase site: 115, PS 0/1: 134/66, Alk. Ph.>UNL: 87 pts, and LDH>UNL: 88pts. For I, 92 pts in mFOLFOX-B and 93 in XELOX-B were evaluable for toxicity (tox). Tox (%) for mFOLFOX-B/XELOX-B were: any toxicity grade (gr) 3 or 4: 21/30; neutropenia gr 3 6/1, gr 4 0/2; febrile neutropenia gr 3 1/1, gr 4 0/1; thrombopenia gr 3 0/1, gr 4 0/2; anemia gr 2 8/15, gr 3 2/1; nausea gr 2 17/15, gr 3 4/6; vomiting gr 2 10/12, gr 3 2/5; mucositis gr 2 6/6, gr 3 0/4; diarrhea gr 2 8/12, gr 3 5/20, gr 4 0/1; neuropathy gr 2 23/17 gr 3 3/1; HFS gr 2 0/7, gr 3 0/2; hypertension gr 2 2/3, gr 3 1/0; proteinuria gr 2 1/5; SAEs 14/25. For M, 56 pts in B and 61 pts in B+E were evaluable. Tox (% B/B+E) were: neutropenia gr 2 0/3; thrombopenia gr 2 2/0; nausea gr 2 2/2, gr 3 2/0; vomiting gr 3 2/0; mucositis gr 2 2/3; diarrhea gr 2 0/6, gr 3 2/6; skin tox gr 1 9/31, gr 2 0/38, gr 3 0/16, gr 4 0/2; proteinuria gr 2 5/5; hypertension gr 1 9/15, gr 2 3/8, gr 3 3/0. Conclusions: This interim safety analysis demonstrated that induction with mFOLFOX-B or XELOX-B as well as maintenance with B or B + E appears to be well-tolerated, without unexpected side effects. The DREAM study is ongoing, with a prolonged induction phase of 6 months (3 mo with ox then 3 mo with fluoropyrimidines-B) before randomisation for maintenance therapy. [Table: see text]

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Tang, Ying Margie, Nneoma Olivia Okoronkwo, Neal Patel, Victor Tsu-Shih Chang, Trent P. Wang, Tanganyika Barnes, Basil Kasimis, Monica McPherson, Barbara Crump, and Fengming Zhong. "Comparison of predictors of survival in colon and rectal cancer patients." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e14681-e14681. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e14681.

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e14681 Background: We studied comorbidity and other predictors of survival for patients (pts) with colorectal cancer (CRC) and compared pts with colon (C) vs rectal (R) cancer (ca). Methods: In an IRB-approved protocol, we reviewed the records of pts diagnosed with CRC at a VA medical center from 01/01/2003 to 12/31/2011 for demographics, stage, grade, ECOG performance status (PS), CEA, Hemoglobin (HGB), and Albumin (ALB) at diagnosis (dx). Comorbidity was assessed with the Charlson Comorbidity Index (CCI), the Cumulative Illness Rating Scales (CIRS), and the Kaplan-Feinstein Index (KFI). Statistical analyses were performed with SAS 9.2/Stata 11.0. We compared the pts with C vs R ca. Results: There were 279 men. 191 pts (68.5%) had C ca and 88 pts (31.5%) had R Ca. The two groups were similar for stage, grade, age, HGB, CEA, ALB, and ECOG PS. For R ca pts, Median (M) CCI is 3.7 (0.4-13.9), M CIRS15 2.5 (0-5), M CIRS16 5 (0-13), M CIRS 17 2.0 (0-8), M CIRS18 0 (0-1), M CIRS19 0 (0-1), and M KFI 1 (0-3). For C ca pts, M CCI is 4.3 (0.9-19.6), M CIRS15 3.0 (0-6), M CIRS16 6.0 (0-13), M CIRS17 2.0 (0-9), M CIRS18 0 (0-1), M CIRS19 0 (0-2), and M KFI 2 (0-3). In univariate analysis, stage, ECOG PS, HGB, and ALB were significant survival predictors in R ca pts. Age, stage, grade, ECOG PS, HGB, CCI, CIRS16, CIRS17, CIRS19 and KFI were significant for C ca pts. Other significant multivariate predictors are summarized in the table. R ca pts are more likely to die (P=0.003, HR=0.51). Conclusions: In this larger population of pts with CRC, we confirmed our previous findings (ASCO 2012 e14125). Grade, stage, ECOG PS, and CIRS 19 are important independent survival predictors for veterans with CRC. Age, grade, stage, ECOG PS, CCI, CIRS 16 and CIRS 19 are independent predictors for colon ca pts. Only Stage and ECOG PS are independent predictors for rectal ca pts. Rectal ca pts are at increased risk of dying. More research is needed to confirm this. Supported by New Jersey Commission for Cancer Research. [Table: see text]

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Jabbour, Elias, Hagop Kantarjian, Ehab Atallah, Gautam Borthakur, William Wierda, Stefan Faderl, Steven Kornblau, and Jorge Cortes. "Impact of Imatinib Mesylate Dose Escalation on Resistance and Sub-Optimal Responses to Standard-Dose Therapy in Patients (pts) with Chronic Myeloid Leukemia (CML)." Blood 110, no. 11 (November 16, 2007): 1035. http://dx.doi.org/10.1182/blood.v110.11.1035.1035.

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Background: Dose escalation has been reported to be of benefit in some pts after standard-dose imatinib failure. This benefit is based on small series of pts with short follow-up. Although dose escalation is also recommended for pts with suboptimal response to imatinib (as defined by the European LeukemiaNet recommendations), the efficacy of this approach has not been reported. Methods: We assessed the long-term efficacy of dose escalation in 102 pts with CML in chronic phase who met the criteria of failure (n=85) or suboptimal (n=9) response to imatinib, or had their dose escalated by physician’s choice for responses better than suboptimal (n=8). Results: Median age was 52 years (range, 18–79). 89 pts were receiving imatinib after interferon failure and 13 as frontline therapy. Median time on imatinib before dose escalation was 19 mos (range, 3–87). Best response to standard-dose imatinib was complete cytogenetic response (CCyR) in 33 (32%), partial (PCyR) in 10 (10%), minor (mCyR) in 14 (14%), complete hematologic response (CHR) in 30 (29%), and partial hematologic response (PHR) in 1 (1%). 86 pts had their dose escalated from 400 to 800 mg/day and 24 from 300 to 600 mg[JC1]. Pts were followed for a median of 50 mos (range 3–83) from dose escalation. Among pts with criteria for failure, 45/61 (74%) treated for cytogenetic resistance (n=31) or relapse (n=30) responded, including complete molecular response (CMR) (n=2), major molecular response (MMR) (n=4), CCyR (n=24), PCyR (n=9), and minor CyR (n=6). Another 24 pts were treated for hematologic resistance (n=5) or relapse (n=19), and 13 (54%) responded: 1 MMR, 2 CCyR, 2 PCyR, 7 CHR, and 1 PHR. Median time to cytogenetic response was 9 mos (range, 2–54). 31/58 (53%) failure pts who responded to dose escalation relapsed after a median of 68 mos (range, 6–79), with relapses in 6/33 pts (18%) who achieved a CCyR. CCyR occurred in 31/77 (40%) pts who escalated to 800mg and 2/9 (22%) of those who escalated to 600mg (p=0.29). Among 9 pts with suboptimal response (8 no MMR at 18 mo, 1 no PCyR at 6 mos), 2 (22%) responded: 1 MMR and 1 PCyR. The later lost his response to minor CyR 2 years after escalation. Among 8 pts with response better than suboptimal, 6 (75%) improved their response to CMR (n=1) and MMR (n=3) from CCyR, and to CCyR (n=2) from PCyR at 3 and 9 mos,respectively. Table 1 summarizes responses and outcome for the 3 categories. Conclusion: Imatinib dose escalation can induce sustained molecular and cytogenetic responses in patients with failure or suboptimal response to standard-dose imatinib. Many of these responses can be durable. Table 1. Outcome after dose escalation (%) 2-year (%) from dose escalation CCyR MMR Transformation Event Loss CCyR EFS TFS EFS=Event-free survival; TFS=Transformation-free survival. * One evaluable pt not in CCyR at dose escalation. **4 evaluable pts not in CCyR at dose escalation Failure 33/85 (39) 7/85 (8) 9/58 (15) 31/58 (53) 6/33 (18) 85 86 Cytogenetic 30/61 (49) 6/61 (10) 4/40 (10) 15/40 (37) 5/30 (17) Hematologic 3/24 (12) 1/24 (4) 5/18 (28) 16/18 (89) 1/3 (33) Suboptimal 0/1* (0) 1/9 (11) 0 (0) 1 (11) 0 (0) 88 100 Other 4/4** (100) 4/8 (50) 0 (0) 0 (0) 0 (0) 100 100

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Scher, Howard I., Glenn Heller, Margaret K. Yu, Thian Kheoh, Weimin Peng, and Johann S. De Bono. "Clinical outcome of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with a post-treatment circulating tumor cell (CTC) of 0 vs CTC > 0: Post hoc analysis of COU-AA-301." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 5015. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.5015.

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5015 Background: Assessment of radiographic response by RECIST in the majority of mCRPC pts is limited by the lack of measurable disease. Changes in CTC counts (CTCs) enumerated using Veridex CellSearch from unfavorable at baseline (BL [≥ 5 cells/7.5 mL]) to favorable (≤ 4) are prognostic for survival, and the test is FDA cleared as an aid in the monitoring of metastatic PC. The CTC cutpoint of ≥ 5 excludes many pts from response assessment. Examining CTCs alone and in combination with other biomarkers as a potential surrogate for clinical benefit was a secondary objective of COU-AA-301, a phase 3 trial of abiraterone acetate + prednisone vs prednisone alone in mCRPC. Methods: Pts from both treatment (tmt) groups with BL CTC > 0 were combined to assess CTC = 0 as a response criterion. Association between CTC response, defined as BL CTC > 0 and post-BL CTC = 0, and clinical outcomes was assessed. CTCs were determined at BL and 4, 8, and 12 wks. Pts with BL CTC > 0 and missing post-tmt CTCs were considered nonresponders. Radiographic response was first assessed at Wk 12. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: Among739 pts with BL CTC > 0, 141 had measurable disease. At Wk 12, 19% (141/739) of pts were CTC responders and 81% (598/739) were CTC nonresponders. Among CTC responders, 74% (104/141) had stable disease or better by RECIST; 26% (37/141) were either not evaluable or had disease progression by RECIST. Median OS was 23.8 and 10.0 mos for CTC responders (n = 141) and nonresponders (n = 598), respectively. Among pts with liver and/or lung metastases, 86% (24/28) of CTC responders at Wk 12 had stable disease or better by RECIST; 14% (4/28) had disease progression by RECIST. Median OS was 19.9 and 7.1 mos for CTC responders (n = 28) and nonresponders (n = 127), respectively. Similar results were observed in Wk 8 CTC responders. Conclusions: For mCRPC pts with BL CTC > 0, CTC response on tmt (CTC = 0) is associated with longer survival and could be considered a response criterion. Additional analysis is required to fully characterize the relationship between CTC = 0 and objective response by RECIST in pts with measurable disease. Clinical trial information: NCT00638690.

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Boku, N., S. Yamamoto, K. Shirao, T. Doi, A. Sawaki, W. Koizumi, H. Saito, K. Yamaguchi, A. Kimura, and A. Ohtsu. "Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): LBA4513. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.lba4513.

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LBA4513 Backgrounds: We conducted a 3-arm phase III study to investigate superiority of CP and non-inferiority of S-1 to 5-FU for advanced gastric cancer in the primary endpoint of overall survival (OS) and secondary endpoints of response rate (RR), time to treatment failure (TTF), non-hospitalized survival (NHS) and toxicities. Methods: Treatments with 5-FU (800mg/m2/d, ci, d1–5, q4w), CP (irinotecan, 70mg/m2, div, d1&15 and cisplatin, 80mg/m2, div, d1, q4w) and S-1 (40mg/m2, b.i.d., d1- 28, q6w) were continued until disease progression or unacceptable toxicities. Tumors were evaluated every two months. With 230 patients (pts) per arm, this study had 80% power to demonstrate 10% superiority of CP and non-inferiority with 5% margin (hazard ratio, HR=1.16) of S-1 and 0.05 study-wise 1-sided alpha. Results: 704 pts having unresectable or recurrent gastric adenocarcinoma with/without target lesions (TL) were randomized between Nov 2000 and Jan 2006. Final analysis was performed in Feb 2007 when 601 pts (85%) were dead. The results of OS are shown in Table . Median TTF/NHS were 2.3M/7.2M for 5-FU, 3.7M/9.5M for CP, and 4.0M/9.2M for S-1. Incidences (%) of grade 4 neutropenia, grade ≥3 febrile neutropenia, infection with neutropenia, anorexia, diarrhea within 6M, and treatment related death (5- FU/CP/S-1) were 0/37/0, 0/9/0, 0/8/0, 13/33/12, 0/9/8, and 0/1.3/0.4. In the subset having TL, RRs of 5-FU/CP/S-1 (n=175/181/175) were 9%/38%/28%, and their median survival times (MST) were 9.0M/12.1M/10.5M and HRs to 5-FU were 0.78 (95%CI, 0.63–0.98) for CP and 0.85 (0.68–1.06) for S-1. In the subset not having TL, the MSTs of 5-FU/CP/S-1 (n=59/55/59) were 13.5M/14.4M/18.1M and HRs were 1.02 (0.68–1.55) for CP and 0.82 (0.55–1.24) for S-1. Conclusions: S-1 showed a significant non-inferiority to 5-FU. Although CP did not show statistically significant superiority to 5-FU in all pts, it may have a benefit for some subgroups such as pts with measurable metastatic diseases. [Table: see text] [Table: see text]

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Fescina, D. R., W. Gradishar, M. Orlando, J. Rubinsak, L. Haney, and Y. Wang. "Phase II study of gemcitabine (Gem) + docetaxel (D) in combination with trastuzumab (T) in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10730. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10730.

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10730 Background: Addition of T to chemotherapy (chemo) is assoc. with improved overall survival (OS) in pts with HER2+ tumors. Combination chemo has shown improvements in PFS and OS over single agent in recent phase III studies. Pre-clinical models suggest that the combination of G and D appears to be synergistic and that either agent is also synergistic with T. Objectives: This multi-institutional study was designed to determine overall RR (primary endpoint), TTP, OS and the toxicity profile of the combination of G + D + T as first-line therapy for MBC pts. Design: Pts with measurable HER2-overexpressing (FISH+) MBC, no prior chemo in the metastatic setting, adequate end-organ function and PS 0–2, received Gem 1,000 mg/m2 over 30 min on days 1 and 8 + D 75 mg/m2 day 1 and T on day 1 (8 mg/kg over 90 min on cycle 1, then 6 mg/kg over 30 min on subsequent cycles) of a 21-day cycle, until progressive disease or undue toxicity. Results: 8 pts have been enrolled over a period of 16 months. Median age: 53 years (range 40–74); ER status ±: 5/3 pts; ECOG PS 0 = 3 pts, 1 = 4 pts, 2 = 1 pt; Prior adjuvant therapy: Chemo ± Hormonal 3, Hormonal only 3, T 1. Sites of Disease: All pts had visceral involvement (Lung 4, Liver 5) and 5 pts ≥ 2 sites of metastatic disease. Total number of cycles administered was 52; median per pt. 7 (range 4–10). Median delivered dose intensity for G, D and T was 91%, 92% and 100% respectively. Toxicity was generally manageable. One pt discontinued therapy due to adverse events (grade 3 pneumonitis). Grade 3/4 neutropenia occurred in 27% and 10% of cycles; no grade 3/4 anemia or thrombocytopenia were recorded; Non-Heme toxicities of grade 2/3, included with dyspnea (0/2 pts), emesis (2/1), fatigue (4/1), diarrhea (1/1), dehydration (0/1), constipation (1/0). Complete alopecia was observed in 2 pts. No symptomatic cardiac toxicity was recorded. Best Overall RR assessment (N = 8): CR 3, PR 4, SD 1, PD 0, for an ORR of 7 out of 8 pts or 88% (95% CI: 47%–100%). Only 3 pts have progressed, and no pt has died. Progression-free survival at 1 year is 58%. Conclusion: According to this limited experience, the combination of G + D + T in front-line MBC is well tolerated and active. Study was discontinued due to slow accrual as of Feb 2004. Supported by Eli Lilly & Company. [Table: see text]

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Dandurand, R. J., L. J. Xu, J. G. Martin, and D. H. Eidelman. "Airway-parenchymal interdependence and bronchial responsiveness in two highly inbred rat strains." Journal of Applied Physiology 74, no. 2 (February 1, 1993): 538–44. http://dx.doi.org/10.1152/jappl.1993.74.2.538.

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To investigate if airway-parenchymal interdependence may account for differing bronchial responsiveness between inbred rat strains, Fisher and Lewis 12-wk-old male rats were anesthetized, tracheostomized, and placed in a pressure plethysmograph. Functional residual capacity, total lung capacity [lung volume at transpulmonary pressure (PL) of 30 cmH2O], and specific compliance were determined and were found to be similar. Rats were paralyzed and mechanically ventilated. Concentration-response curves were constructed by calculating lung resistance (RL) and lung elastance (EL) after nebulization of saline and then doubling doses of methacholine (0.0625–512 mg/ml). In Fisher (n = 8) and Lewis (n = 7) rats RL and EL were again determined at a lung volume corresponding to 2 cmH2O PL above FRC. The doubling, maximal, and half-maximal effective concentrations were determined for RL and EL. The doubling of effective concentrations of RL and EL were significantly less for Fisher rats. Other groups of Fisher (n = 5) and Lewis (n = 5) rats were similarly exposed to three concentrations of methacholine (64, 128, and 256 mg/ml), and determinations of RL and EL were made at lung volume corresponding to PL of 0, 2, 4, and 8 cmH2O. In both groups, Lewis rats exhibited a significant effect of volume on maximal RL and EL, whereas Fisher rats did not. The absence of volume effect on bronchoconstriction in the hyperresponsive Fisher strain is consistent with the hypothesis that altered airway-parenchymal interdependence contributes to bronchial hyperresponsiveness.

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Shirasu, Hiromichi, Takahiro Tsushima, Yutaka Tanizawa, Satoshi Hamauchi, Akiko Todaka, Tomoya Yokota, Nozomu Machida, et al. "Role of surgery for gastric cancer with liver limited multiple metastases." Journal of Clinical Oncology 35, no. 4_suppl (February 1, 2017): 170. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.170.

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170 Background: Although it has been suggested that surgery provides favorable outcome for gastric cancer (GC) patients (pts) with liver limited multiple metastases (LLM), the survival benefit of surgery comparing to systemic chemotherapy (CTx) has yet to be elucidated, especially in pts with LLM. The aim of this study was to explore the role of surgery for GC with LLM. Methods: We retrospectively reviewed the data of consecutive GC pts with LLM who underwent hepatectomy or received systemic CTx as initial therapy at Shizuoka Cancer Center between Dec. 2004 and Dec. 2015. Inclusion criteria were as follows: ECOG PS 0-1; histologically proven adenocarcinoma; synchronous or metachronous LLM; 2 or 3 LLM technically resectable disease; no prior CTx or radiotherapy Pts who were refractory to adjuvant CTx were excluded. Results: Nine of 24 pts who met the inclusion criteria underwent hepatectomy, and 15 pts received CTx. Pts’ background who received hepatectomy versus (vs) CTx was as follows: median age (range), 74 (64-81) vs 59 (42-76) years; male/female, 8/1 vs 14/1 pts; Histology intestinal/diffuse, 9/0 vs 10/5 pts; HER2 positive/negative/unknown 0/0/9 vs 2/5/8 pts; number of liver metastases 2/3, 9/0 vs 9/6; unilobar/bilobar, 5/4 vs 5/10 pts. In hepatectomy group, all 9 pts underwent radical hepatectomy (with gastrectomy for synchronous metastases), and 3 pts received adjuvant CTx. No in-hospital death or severe complication was observed. In CTx group, 11 pts received fluoropyrimidine plus cisplatin therapy, and trastuzumab was combined in 2 pts with HER2 positive tumor. Three pts underwent radical hepatectomy after CTx. Eight pts in hepatectomy group had recurrence. Recurrent sites were remnant liver (7), lymph node (1), and peritoneum (2). With median follow-up time of 47.9 months, median progression free survival was 8.0 months in hepatectomy group and 27.9 months in CTx group (p = 0.02). In CTx group, 3 pts who underwent subsequent radical hepatectomy after CTx had no recurrence or death. Median overall survival was 24.1 months in hepatectomy group and 38.4 months in CTx group (p = 0.15). Conclusions: Initial surgery for GC pts with LLM did not show survival benefit. But radical hepatectomy subsequent to CTx may associate with preferable outcome.

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Cantoni, Silvia, Monica Carpenedo, Maria Gabriella Mazzucconi, Valerio De Stefano, Marco Ruggeri, Nicola Vianelli, Francesco Zaja, et al. "Thrombopoietin Receptor Agonist (TPO-RA) Switch in Adult Primary Immune Thrombocytopenia (ITP) Patients: A Retrospective Collaborative Survey from 8 Italian Hematology Centers." Blood 126, no. 23 (December 3, 2015): 3462. http://dx.doi.org/10.1182/blood.v126.23.3462.3462.

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Abstract Introduction. Availability of the 2 TPO-RAs Romiplostim (Rom) and Eltrombopag (El) offers an effective treatment option for primary ITP patients (pts). However, some pts are either not responsive or lose response - i.e. desired platelet (plt) count achieved but not sustained over time, or experience wide fluctuations in plt count with either TPO-RA. Adverse events may cause treatment discontinuation. Finally, ptÕs preference may be an important issue considering the different route and timing of administration of the two agents. Availability of two TPO-RAs for clinical use, with different molecular structure and site of binding within the TPO receptor, makes it appealing to try switching with the aim of overcoming treatment limitations of either agent. The present survey offers insight into outcome of TPO-RA switching in a group of ITP pts treated at 8 Centers representative of the Italian territory. Patients. Charts of ITP pts on treatment who underwent TPO-RA switch were retrospectively reviewed. Results. Between Jan 2009 and Feb 2015, 57 of 249 pts on TPO-RA (22,9%) underwent switch: El ˆ Rom 26/57 (45.6%), Rom ˆEl 31/57 (54.4%). Median age at 1st TPO-RA administration was 55 yrs (range 16-81); M/F = 23/34. Median disease duration prior to 1st TPO: 58 mos (range 2-648). Median lines of previous therapy 3 (range 1-6; splenectomy: 23/57, 40.4%). Overall 42/57 pts (73,7%) had received maximum product dose as per prescribing information prior to switch. Table 1 summarizes reasons for TPO-RA switch and outcome. Overall, 32/57 pts (56.1%) achieved, regained or maintained a response upon switching. The majority of pts (39/57, 68.5%) were switched for efficacy issues, i.e. failure to respond to 1st TPO (27 pts) or response loss (12 pts); among these 39 pts, 48.7% responded to the 2nd TPO-RA. One pt lost response to Rom because of development of neutralizing antibodies; response was regained upon switching to El. In this subgroup of pts, disease duration and lines of previous therapy (but not splenectomy status) seem to have an impact on response to switching. Each one month increase in disease duration determines a 0.7% decrease in the odds of achieving a response (WaldÕs test p=0.065). More than 2 lines of therapy determine a 72% decrease in the odds of achieving a response (WaldÕs test p=0.077). Either TPO-RA switch sequence was equally effective in yielding response (FisherÕs exact test p=0.752) and age at 1st TPO-RA had no impact on response. Of the 18 pts switched for reasons other than efficacy, 13 (72.2%) maintained a response on the 2nd TPO-RA: 5/6 switched for plt count instability (counts stabilized = 2/5 responding pts), 4/7 switched for ptÕs preference, 4/5 switched for side effects. Four pts (1 plt count instability, 3 ptÕs preference) underwent Òdouble switchÓ (i.e. Rom ˆ El ˆ Rom): re-exposure to Rom was not associated with response loss. Discussion. Switching enables approximately 56% of pts to achieve, regain or maintain a plt response; switching for inefficacy yields lower response rates (48.7%) compared to switching for reasons other than efficacy (72.2%) Plt counts fluctuation stabilized in 40% of pts. Re-exposure to R in the 4 pts who underwent Òdouble switchÓ was not associated with response loss, confirming absence of tachyphylaxis with this TPO-RA. Our results are in line with those reported by Khellaf (Haematologica 2013) and Gonzales-Porras (BJH 2014): TPO-RA switch can be a safe and appealing treatment option for ITP pts who experience suboptimal results with either agent. Table 1. REASON for SWITCHING n (%) NR (%) R (%) CR (%) All 57 (100) 25 (43.9) 14 (24.6) 18 (31.5) El->Rom 26 (45.6) 10 (38) 8 (31) 8 (31) Rom->El 31 (54.4) 10 (48.4) 6 (19.4) 10 (32.3) 1st TPO-RA failure 27 (47.4) 16 (59) 4 (15) 7 (26) El->Rom 15 7 (47) 3 (20) 5* (33) Rom->El 12 9 (75) 1 (8) 2 (17) Loss of response 12 (21.1) 4 (33) 2 (17) 6 (50) El->Rom 4 2 (50) 1 (25) 1 (25) Rom->El 8 2 (25) 1 (12.5) 5 (62.5) Plt count fluctuation 6 (10.5) 1 (17) 3 (50) 2 (33) El->Rom 2 0 1 1 Rom->El 4 1 2 1 PtÕs preference 7 (12.3) 3 (42.9) 2 (28.6) 2 (28.6) El->Rom 0 0 0 0 Rom->El 7 3 2 2 Adverse event¡¡ 5 (8.8) 1 (20.0) 3 (60.0) 1 (20.0) El->Rom 5 1 3 1 Rom->El 0 0 0 0 CR: complete response; R: response; NR: no response (Rodeghiero et al, Blood 2009) *1 NR secondary to neutralizing antibodies development ¡¡1 hepatic enzyme increase, 1 CPK increase; 2 skin rash; 1 retinal thrombosis. Disclosures De Stefano: Janssen Cilag: Research Funding; Shire: Speakers Bureau; Amgen: Speakers Bureau; Bruno Farmaceutici: Research Funding; Novartis: Research Funding, Speakers Bureau; Roche: Research Funding; Celgene: Speakers Bureau; GlaxoSmithKline: Speakers Bureau.

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Orlowski, Robert Z., Bercedis L. Peterson, Ben Sanford, Asher A. Chanan-Khan, Lee M. Zehngebot, Peter R. Watson, Michael A. Caligiuri, and Richard A. Larson. "Bortezomib and Pegylated Liposomal Doxorubicin as Induction Therapy for Adult Patients with Symptomatic Multiple Myeloma: Cancer and Leukemia Group B Study 10301." Blood 108, no. 11 (November 16, 2006): 797. http://dx.doi.org/10.1182/blood.v108.11.797.797.

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Abstract Introduction: The proteasome inhibitor bortezomib in combination with pegylated, liposomal doxorubicin (PLD) has significant activity against relapsed/refractory multiple myeloma (MM). It was therefore of interest to evaluate this combination in previously untreated MM patients (pts) requiring induction chemotherapy. Methods: Patients enrolled onto Cancer and Leukemia Group B study 10301 received bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 of every 21 day cycle, along with PLD at 30 mg/m2 on day 4, for a maximum of eight cycles. Primary objectives were to determine the complete response (CR) + near-CR rate, and also to define the toxicity of this regimen in the front line setting. Secondary objectives included determining the overall response rate, the ability to collect stem cells, and the time to progression and overall survival. Results: Between June, 2004, and October, 2005, a total of 63 pts were enrolled. Adverse event (AE) data were available for 55 pts, with hematologic AEs reaching grade 3 in 14 pts (25%), and grade 4 in 5 pts (9%). Notable hematologic AEs included neutropenia (grade 3 in 16%, and grade 4 in 2% of pts), thrombocytopenia (9% and 5%, respectively), lymphopenia (11% and 2%), and anemia (7% and 2%), though there was only one episode of febrile neutropenia. Non-hematologic toxicities reaching grade 3 were seen in 32 pts (58%), while 5 pts (9%) had grade 4 non-hematologic toxicities. Fatigue (grade 3 in 16%, grade 4 in 0%), sensory neuropathy (11% and 2%, respectively), hand-foot syndrome (9% and 0%), syncope (9% and 0%), motor neuropathy (7% and 0%), dehydration (7% and 0%), rash (7% and 0%), weight loss (5% and 0%), hypotension (5% and 0%), diarrhea (5% and 0%), nausea (5% and 0%), infection (5% and 0%), and dyspnea (5% and 0%) were notable AEs seen in 5% or more of pts. Preliminary response data were available for 57 pts, of whom 9 (16%) achieved a CR or near-CR, while 58% attained at least a partial response (PR). Final response data were available for 29 pts who completed their study-directed therapy, and among these the CR + near-CR rate was 28%, with an overall response rate (PR or better) of 79% in this small cohort. Progression-free and overall survival can not yet be estimated because of a paucity of events at a median of 10 months of follow-up. Stem cell collection data is available for 6 pts after induction therapy with bortezomib and PLD, in whom a median of 13.6 x 106 CD34+ cells/kilogram were mobilized (range 11.2 – 48.6 x 106). Conclusions: These preliminary data suggest that bortezomib and PLD is well-tolerated by chemotherapy-naïve multiple myeloma patients in this study. Moreover, this steroid-free regimen has promising activity, and does not seem to compromise the ability to collect stem cells for later transplantation.

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Falchi, Lorenzo, Michael J. Keating, Susan Lerner, Xuemei Wang, Sara S. Strom, William G. Wierda, and Alessandra Ferrajoli. "Other Cancers in Patients with Chronic Lymphocytic Leukemia Requiring Therapy: Association with Prognostic Factors and Impact On Survival." Blood 120, no. 21 (November 16, 2012): 3896. http://dx.doi.org/10.1182/blood.v120.21.3896.3896.

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Abstract Abstract 3896 Chronic lymphocytic leukemia (CLL) is associated with an increased incidence of other cancers (OC). Potential risk factors for OC in CLL include immune disturbances, shared risk factors, genetic predisposition and chemotherapy. While reports on OC in patients with CLL have been typically descriptive in nature, detailed information regarding the clinical features of OC, relationship with the time of diagnosis of CLL, patient characteristics, prognostic factors and survival have been missing. We report an analysis of OC in pts with CLL requiring therapy, with a post therapy observation time of 5 years or longer. We reviewed our database and selected pts with CLL seen at our center who underwent treatment and who have a follow-up of at least 5 years after therapy. We studied pts with an OC either before or after the diagnosis and/or treatment of CLL and compared them with patients without OC. Richter's transformation of CLL was not considered an OC in this analysis. A total of 1,364 pts with CLL referred between 1963 and 2007 with a median follow up time of 8.2 years (range 5–28) were studied. Among these, we identified 324 pts (24%) with OC. Sixty-eight pts were diagnosed with >1 OC [2 OC (62 pts), 3 OC (4 pts) or 4 OC (2 pts)], for a total of 400 individual OC. Of the 324 pts with OC, OC preceded the diagnosis of CLL in 117 pts (36%), with a median time from OC to CLL of 80 (0–455) months, OC occurred after the diagnosis of CLL but before treatment in 49 pts (15%), with median time from CLL to OC of 22 (0–131) months. OC occurred after treatment of CLL in 158 pts (49%), with a median time from treatment to OC of 94 (0–304) months. The type, frequency and timing of OC are summarized in table 1. Clinical characteristics and traditional prognostic factors were not significantly different between pts with and without OC, with the exception of age, as pts with OC are older than pts without OC at the time of referral (median age: 60 vs 55 years, p<.0001). We next analyzed the distribution of the newer prognostic parameters in these two groups. Fifty-three % of pts with OC had unmutated IGHV genes, 65% were ZAP70+, 22% CD38+, 8% had del17p, 27% del11q, 22% +12, 20% negative FISH, and 23% del13q. Sixty-one % of pts without OC had unmutated IGHV genes, 58% were ZAP70+, 26% CD38+, 6% had del17p, 17% del11q, 22% +12, 26% negative FISH, and 29% del13q. A trend toward significance (p.07) for a higher incidence of del11q was observed in pts with OC. At the time of this analysis 536 (39%) pts have died and 828 (61%) are alive. One hundred seventy six/324 (54%) pts with OC are alive, vs 652/1040 (63%) pts without OC (p<.007). Median overall survival (OS) has not been reached in either pt group at a median follow up of 95 (61–284) months for pts with OC and 98 (61–340) months for pts without OC. Causes of death were: progression of CLL (99), CLL-related complications (121), OC (43), complications of stem cell transplant (16), events unrelated to CLL (39) and unknown causes (218). In pts with OC, the OC itself was the cause of death in 37%. Other causes of death were CLL/CLL-related complications in 44%, complications of stem cell transplant in 8%, and events unrelated to CLL in 11%. In contrast, in pts without OC CLL/CLL-related complications accounted for 83% of deaths, complications of stem cell transplant for 4%, and events unrelated to CLL for 13%. In conclusion, in pts with CLL requiring therapy and with post therapy follow up of >5 years, the incidence of OC is 24%. Among pts with OC, there is a trend for higher number of pts with del11q. In pts with OC, OC itself is a major cause of death, while the vast majority of deaths among pts without OC are caused by CLL or CLL-related complications. Table 1. Distribution of OC (1364 pts). Site of OC 1st case Total cases OC prior/at CLL OC after CLL After diagnosis After treatment NMSC1 124 144 41 26 77 PROSTATE 43 54 18 7 29 MELANOMA 26 34 16 2 16 BREAST 23 26 14 2 10 MDS/AML2 16 18 0 0 18 LUNG 14 21 0 1 20 NEUROENDOCRINE 3 6 1 0 5 HEAD AND NECK 12 16 3 2 11 UROTHELIAL CELL CANCERS 11 12 7 2 3 GI3 (including pancreas and liver) 10 18 4 3 11 KIDNEY 10 11 4 3 4 NHL4 and MM5 8 12 0 0 12 TESTIS/OVARY 6 6 4 0 2 THYROID 6 7 5 1 1 SARCOMAS 4 5 4 0 1 UTERUS 2 3 3 0 0 OTHERS6 6 7 3 0 4 TOTALS 324 400 127 49 224 1 non-melanoma skin cancers; 2 myelodysplastic syndrome/acute myeloid leukemia; 3 gastrointestinal; 4 non-Hodgkin's lymphoma; 5 multiple myeloma; 6 includes: brain, nasopharyngeal, penis carcinoma, mesothelioma, unknown primary. Disclosures: No relevant conflicts of interest to declare.

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Nazha, Aziz, Hagop M. Kantarjian, Jorge E. Cortes, Stefan Faderl, Sherry A. Pierce, Naval G. Daver, Naveen Pemmaraju, et al. "Outcome of Patients with Myelodysplastic Syndrome (MDS) with Bone Marrow (BM) Blasts Between 10 to 30% Treated with Hypomethylating Agents Versus Intensive Chemotherapy." Blood 120, no. 21 (November 16, 2012): 4928. http://dx.doi.org/10.1182/blood.v120.21.4928.4928.

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Abstract Abstract 4928 Background In 2001, the World Health Organization modified the French-American-British (FAB) classification for MDS by folding the refractory anemia with excess blasts in transformation (RAEB-t) category into acute myeloid leukemia (AML). Since then, controversy exists regarding whether this subset of pts should be treated with AML (ie cytotoxic therapy) or MDS therapy (hypomethylating agents, HMA). Furthermore, a subset analysis of the AZA-001 trial has shown that azacitidine prolongs overall survival (OS) compared to intensive chemotherapy (IC) in pts with AML and BM blasts of 20–30%. The purpose of this analysis is to evaluate the clinical outcome and OS of pts with MDS and BM blasts between 10–30% who were treated with HMA vs IC. Patients and Methods We conducted a retrospective analysis of newly diagnosed pts with refractory anemia with excess blasts-2 (RAEB-2) and RAEB-t according to FAB classification criteria that were treated at one institution with frontline therapy between 1/2000 and 10/2011. For the purpose of this analysis, pts were divided into 4 groups based on their treatment: 1) hypomethylating agents (HMA) only (azacitidine and decitabine), 2) hypomethylating agents in combination with investigational drug (HMA-I), 3) intensive chemotherapy (IC, mainly cytarabine based regimens), and 4) investigational agents (I-A). Responses were defined as achieving a complete remission (CR), complete remission without platelet recovery (CRp), or complete remission with incomplete recovery (CRi) as defined by the International Working Group criteria (Cheason BD, J Clin Oncol. 2003). OS was calculated by using the Kaplan-Meier method, and survival curves were compared by using the log-rank test. The Gehan-Wilcoxon method was used to evaluate OS at early time point. Results Three hundred forty-nine pts were included in the final analysis. 53 pts (15%) were treated with HMA, 40 pts (11%) with HMA-I, 237 pts (68%) with IC, and 19 pts (5%) with I-A. Pts' clinical characteristics are summarized in table 1. 20 pts (38%) achieved a response in HMA group, 19 (48%) in HMA-I, 143 (60%) in IC, and 1 (5%) in I-A group (P <0. 001). Response duration was 19. 3 months (m), 14. 7 m, 14. 5 m, and not reached, respectively, (P = 0. 62). 4 weeks mortality was 1 (2%), 2 (5%), 10 (4%) and 2 (11%) respectively, (P = 0. 36). With a median follow up of 37 m (1–96), the median OS was 21. 8 m, 16. 1 m, 14. 6 m, and 15. 8 respectively, (P = 0. 15). The OS was higher in pts who were treated with HMA vs IC by using Gehan-Wilcoxon test (P = 0. 04). In subgroup analysis, pts with BM blasts between 20–30% had higher response rates when they were treated with IC (63%) compared to HMA (44%), HMA-I (38%), and I-A (13%), (P = 0. 008); however, the remission duration 16 m, not reached, 15 m, and 8 m, respectively, (P = 0. 28), and the OS 16 m, 27 m, 24 m, and 8 m respectively, (P = 0. 2) were not significant. Conclusion Although pts with MDS and BM blasts between 10–30% achieved higher response rates when they treated with IC vs HMA, pts with BM blasts between 20–30% had similar OS when they were treated with HMA vs IC. There was a trend toward increased survival early after treatment administration in favor of HMA. This data suggests that IC is not superior to HMA in the treatment of this subgroup of pts. Disclosures: No relevant conflicts of interest to declare.

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Hehlmann, Rudiger, Benjamin Hanfstein, Martin C. Müller, Philipp Erben, Michael Lauseker, Alice Fabarius, Susanne Schnittger, et al. "The prognostic significance of early molecular and cytogenetic response for long-term progression-free and overall survival in imatinib-treated chronic myeloid leukemia (CML)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 6510. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.6510.

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6510 Background: In the face of competing first line treatment options for CML early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of an alternative therapy. We sought to evaluate the prognostic impact of early response landmarks. Methods: A total of 1,303 newly diagnosed imatinib-treated patients (pts) from the randomized CML Study IV were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). Median follow-up was 4.7 years (range 0-9). The BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (BCR-ABLIS). The proportion of Philadelphia-chromosome positive metaphases (Ph+) was determined by conventional metaphase analysis. To confirm the prognostic significance of early molecular response, an independent validation sample of 174 pts treated with imatinib within the IRIS trial was analyzed. Results: The persistence of >10% BCR-ABLIS at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with 1-10% BCR-ABLIS (41% of pts; 5-year OS: 94%; p=0.012), and from a group with <1% BCR-ABLIS (31% of pts; 5-year OS: 97%; p=0.004). By cytogenetics high-risk patients could be identified by the persistence of >35% Ph+ (27% of pts; 5-year OS: 87%) as compared to ≤35% Ph+ (73% of pts; 5-year OS: 95%; p=0.036). At 6 months the >1% BCR-ABLIS group (37% of pts; 5-year OS: 89%) showed inferior survival compared to ≤1% (63% of pts; 5-year OS: 97%; p<0.001); survival of the >0% Ph+ group (34% of pts; 5-year OS: 91%) was inferior to 0% Ph+ (66% of pts; 5-year OS: 97%; p=0.015). Regarding the IRIS pts 3 month BCR-ABLIS >10% (25% of pts; 8-year OS: 81%) was associated with inferior survival compared to ≤10% (75% of pts; 8-year OS: 93%; p=0.011). Conclusions: Failure to achieve the response landmarks of 10% BCR-ABLIS or 35% Ph+ at 3 months of imatinib treatment and 1% BCR-ABLIS or 0% Ph+ at 6 months identifies high-risk patients which might benefit from an early change of therapy.

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Vega-Villegas, M. E., M. C. Galán-Guzmán, J. Gallego-Plazas, A. Cervantes, P. Escudero, J. Tabernero, B. Massutí, V. Alonso-Orduña, D. Asensio, and F. Rivera. "Phase II trial of preoperative irinotecan-cisplatin (IC) followed by concurrent IC and radiotherapy (IC/RT) for locally advanced gastric and esophago-gastric junction adenocarcinoma (LA-G/EGJ-A)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 4059. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4059.

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4059 Background: Long-term survival for LA-G/EGJ-A is poor and could be improved by preoperative chemoradiotherapy. We performed a phase II trial to evaluate IC followed by IC/RT in this setting. Methods: Patients with locally advanced (stage II-IV, M0) G/EGJ-A were included. Main objective was pathological complete response (pCR). Secondary objectives were toxicity, response to preoperative treatment and resection rate. Pretreatment staging included an esophagogram, EUS and CT scan. Two courses of IC (Irinotecan 65mg/m2 and Cisplatin 30mg/m2 d 1 and 8, each 21 d) were given and pts without progression received IC/RT: daily RT (180cGy fractions, total dose: 5040cGy) with concurrent IC (Irinotecan 65mg/m2 and Cisplatin 30mg/m2 d 1, 8, 15 and 22 of RT). Response to preoperative treatment was evaluated with EUS and CT scan 3–4 weeks after the end of radiotherapy. Five to 8 weeks after RT, surgical resection was performed if feasible. Results: Between 2003 and 2005, 40 pts were included: 32 men; median age 65 (45–80); PS (ECOG): 0: 38%, 1: 59%, 2: 3%; Location and resectability: Esophago-gastric Junction: 16 pts (resectable: 11 pts), Stomach: 24 pts (resectable: 13 pts); Stage: II: 13 pts, III: 15 pts, IV: 12 pts. Grade 3–4 toxicity of IC (40 pts evaluable): neutropenia 22 % (febrile 5%), diarrhoea 8%, emesis 5%, asthenia 3%. One pt (3%) died during IC due to progression. All the 33 pts who received IC/RT were evaluable for toxicity (G-3–4): neutropenia 39% (febrile 0%), diarrhoea 0%, emesis 6%, asthenia 26%, thrombocytopenia 6%. Four pts (12%) died during IC/RT (toxicity: 2 pts, progression: 2 pts). Response to preoperative treatment: PR: 6 pts, SD: 21 pts, Prog: 6 pts, No Evaluated: 7 pts. R0 resections were performed in 12 out of 24 (50%) initially resectable pts (pCR: 2 pts) and in 4 out of 16 (25%) initially non-resectable pts (pCR: 0 pts). One pt died during the first 30 days after resection. With a median follow-up of 12 months, 16 pts (40%) are alive with disease, 10 (25%) pts are alive and disease free and 14 pts (35%) have died. Conclusions: Preoperative IC> IC/RT obtained moderate response and resection rates with mild toxicity in LA-G/EGJ-A. Supported by a grant from Prasfarma/Almirall Prodesfarma. [Table: see text]

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Morrison, Vicki A., Sin-Ho Jung, Jeffrey Johnson, Ann LaCasce, Kristie A. Blum, Nancy L. Bartlett, and Bruce D. Cheson. "Salvage Therapy with Bortezomib Plus Lenalidomide for Relapsed/Refractory Mantle Cell Lymphoma: Initial Results of a Phase II Trial (Alliance/CALGB 50501)." Blood 120, no. 21 (November 16, 2012): 3696. http://dx.doi.org/10.1182/blood.v120.21.3696.3696.

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Abstract Abstract 3696 Introduction: The majority of patients (pts) with mantle cell lymphoma (MCL) respond to initial treatment, yet most pts relapse and die from disease. Although stem cell transplantation (SCT) is a treatment option, it is not always curative and many pts are not eligible. Based upon single agent activity of thalidomide and bortezomib in MCL (overall response rates [ORR] approximately 30%), CALGB designed a phase II trial of bortezomib + lenalidomide therapy for pts with relapsed/refractory MCL. Methods: Eligibility criteria included: histologically confirmed MCL (CD5+, CD 23-, cyclin D1+); measurable disease; prior therapy with >1 regimen that may include autologous (not allogeneic) SCT, now with relapsed/refractory disease; no prior radioimmunotherapy, bortezomib, or lenalidomide; ECOG performance status (PS) 0–2; no >grade (gr) 3 peripheral neuropathy. Induction therapy was lenalidomide (20 mg po qd, days [D] 1–14) plus bortezomib (1.3 mg/m2 IV, D 1, 4, 8, 11), given every 21 D for 8 cycles. Pts were restaged at 3 & 6 mos; responding patients (complete and partial responses; [CR+PR]) at 6 mos received maintenance with lenalidomide (15 mg po D 1–14) and bortezomib (1.3 mg/m2 IV, D 1, 8), until disease progression (PD). In 9/09, the protocol was modified to have separate toxicity-related dose reductions for each agent (myelosuppression, decrease lenalidomide; neuropathy, decrease bortezomib). Primary endpoints were ORR (=CR+PR), CR rate; secondary endpoints were event-free- (EFS) (time to progression, all-cause death, or initiation of non-protocol therapy), progression-free- (PFS) (time to progression or all-cause death), and overall survival (OS) (time to death from any cause). The study design considered an ORR <45% too low, and >65% of strong interest. Response and toxicity data were summarized using frequency tables; Kaplan-Meier method was used to analyze survival parameters. The study was activated in 11/07. It temporarily closed for planned interim analysis after accrual of 19 pts, and closed in 7/11, when it reached the accrual goal of 54 pts. Results: Median pt age was 67 (range, 39–83) yrs; 83% were male. 47 (89%) pts had relapsed, and 6 (11%) refractory, disease. 79% of pts had stage IV disease; 21% had B-symptoms; lactate dehydrogenase was elevated in 17 (32%). PS was 0 (62%), 1 (36%), and 2 (2%). Number of prior chemotherapy regimens was: one (60% of pts), 2 (25%), 3 (12%), 4 (2%), and 5 (2%). Prior therapy included rituximab in 46 (85%), radiotherapy in 14 (26%), and SCT in 21 (40%). Median number of protocol therapy cycles received was 4 (range, 1–64); 20 pts (37%) received <2 cycles. Reasons for treatment discontinuation included: PD in 20 pts (38%); no response in 1 (2%); toxicity in 17 (32%); pt refusal in 4 (8%); rising lymphocyte count in 1; physician decision in 1; other treatment in 6 (8%). Best response for the 53 eligible pts was 8 (15%) CR, 13 (25%) PR, 8 (15%) stable disease (SD), 17 (32%) PD; 7 (13%) unevaluable pts were taken off treatment after cycle one. Among the responding pts, 5/8 CR pts and 4/13 PR pts went onto maintenance therapy. Of the responders, 6 CR and 1 PR pts remain in remission. 27 (51%) pts have died (1 treatment-related, 24 with PD, 2 with infections). Median follow-up in the 26 living eligible pts is 2.3 (range, 0.1–3.8) yrs. One-yr EFS, PFS, and OS are 25%, 41%, and 67%, respectively. Gr 3/4 toxicities (% gr 3/% gr 4) were: anemia (8/0), leukopenia (6/0), thrombocytopenia (13/21), fatigue/aesthenia (21/0), dyspnea (9/0), infection (6/0), motor neuropathy (9/0), sensory neuropathy (8/0; gr 2 36%), hypotension (8/0), and thrombosis (6/0). During induction therapy (cycles 1–8), at least >1 lenalidomide or bortezomib dose reduction occurred in 24 (44%) and 29 (54%) pts, respectively, due to adverse events; 21 (39%) pts had dose reductions in both drugs. Conclusion: The ORR of 40% for the combination of lenalidomide + bortezomib was disappointing given the high single agent response rates reported with lenalidomide. The lower than anticipated ORR may be due to inadequate lenalidomide dosing, initial simultaneous dose reductions in both agents for toxicity, or the limited protocol therapy administered in 37% of pts. Due to the small number of pts receiving maintenance therapy, one cannot assess its impact. Future studies with this dose and schedule of lenalidomide + bortezomib are not warranted. Disclosures: No relevant conflicts of interest to declare.

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Zang, Rongyu, Tingyan Shi, Rong Jiang, Hong Pu, Huijuan Yang, Dongsheng Tu, Zhiyuan Dai, et al. "Dose-dense early postoperative intraperitoneal chemotherapy in ovarian cancer: Randomized, phase II trial." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 5514. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5514.

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5514 Background: Dose-dense early postoperative intraperitoneal chemo (DD-EPIC) had been carried out in advanced ovarian cancer (OC) pts in China over the past three decades but it was not proved by a prospective study. This trial was designed to confirm the benefit of DD-EPIC in delaying progression and improving survival. Methods: In a multicenter, phase 2 trial, pts with FIGO IIIC-IV OC and optimal debulking surgery (residual disease ≤1cm) were randomly allocated to receive 4 doses of weekly DD-EPIC with cisplatin (50mg/m2) and etoposide (100mg/m2) followed by 6 cycles of intravenous (iv) chemo with carboplatin and taxane every 3 weeks (DD-EPIC group), or standard iv chemo alone (iv group). (ClinicalTrials.gov, NCT01669226). Results: Between 2009 and 2015, 218 pts were randomized, of whom 215 initiated treatment (106 to DD-EPIC and 109 to iv; for efficacy analyses). Totally, 36 pts (16·7%) were received neoadjuvant chemo. With a median of 61·9 mos follow-up, 122 pts died (54 in DD-EPIC and 68 in iv group). Remarkable OS benefit of DD-EPIC was recorded (67·5 mos for DD-EPIC vs. 46·3 mos for iv; HR 0·70, 95% CI 0·49-1·00, P=0·047). Pts in DD-EPIC had a significantly increased median PFS compared with those in iv group (21·7 vs. 16·8 mos; HR 0·64, 95% CI 0·47-0·86, P=0·003). Median TFST was 25·1 vs. 18·0 mos in favor of DD-EPIC (HR 0·62, 95%CI 0·46-0·83, P=0·002). Similar findings were detected in TSST (42·2 vs. 29·3 mos; HR 0·66, 95%CI 0·47-0·94, P=0·019). Grade 3 and 4 Leucopenia (53·8% vs. 35·2%), anemia (23·6% vs. 5·6%) and gastrointestinal events (10·4% vs. 1·9%) were more common in DD-EPIC ( P=0·006, P<0·001 and P=0·010, respectively). Ninety-one pts were detected by gBRCA testing, with 25·3% of cases carrying deleterious BRCAm, but PFS and OS benefit were observed in patients with BRCA-wild type (HR 0·46 and 0·55, 95%CI 0·27-0·81 and 0·27-1·11, respectively). Conclusions: DD-EPIC with a higher completion rate and acceptable treatment burden was associated with longer OS than standard iv alone. Owing to the benefit of relatively long-term OS, DD-EPIC may be considered as a valuable option for OC, particularly in developing countries and BRCA-wild type pts. Clinical trial information: NCT01669226. [Table: see text]

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Sadhu, Justin S., Erik R. Dubberke, Robert Gatti, Steven M. Devine, and Victoria J. Fraser. "Clostridium Difficile-Associated Disease in Allogeneic Transplant Patients." Blood 104, no. 11 (November 16, 2004): 5095. http://dx.doi.org/10.1182/blood.v104.11.5095.5095.

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Abstract Allogeneic transplant (allo) patients (pts) are at high risk for Clostridium difficile-associated disease (CDAD), yet there are few studies evaluating CDAD in allo pts. We carried out a retrospective chart review of all allo pts who had CDAD on a transplant (tx) unit between 8/01 and 7/03. 37 pts were identified who had CDAD during tx hospitalization (hosp) or after tx during the study period. 17 (46%) were admitted for initial tx, 13 (35%) for infection, and 7 (19%) for other reasons. 15 (40%) had acute leukemia, 6 (16%) lymphoma, 4 (11%) myelodisplastic syndrome, and 12 (32%) other underlying diseases. On admission, 17 (46%) pts were in complete remission, 4 (11%) in partial remission, 7 (19%) in relapse, and 9 (24%) presented with refractory disease. 5 pts (14%) had CDAD before day 0 (median d-2, range d-9 to d-1) and 32 pts (86%) had CDAD after tx (median d+49, d0 to d+3185). In the 60 days prior to CDAD, pts had median 1 (0–4) prior hosp and 15 days (1–50) hospitalized; 36 pts (97%) received antibiotics, 35 (95%) immunosuppressants, 33 (89%) antimotility/narcotic agents, 31 (84%) gastric acid suppression, 23 (62%) chemo, and 14 (38%) TBI. Within 48 hours of CDAD, 31 (86%) pts had diarrhea, 12 (33%) fever, 10 (28%) abdominal tenderness, 7 (19%) abdominal distention, and 7 (19%) hypothermia. 22 pts (59%) had either moderate or severe CDAD. 25 (68%) pts were treated for their primary episode of CDAD with metronizadole (met), 2 (5%) with vancomycin (vanc), 8 (22%) with met and vanc, and 2 (5%) were not treated for CDAD. 32 (86%) pts responded to therapy (median 2 days, range 0–25 days). Of the 32 pts who had CDAD post allo, 3 (9%) had gut graft-versus-host disease (GVHD) before CDAD and 8/29 (28%) developed gut GVHD after CDAD. Those 8 pts developed CDAD median d+114 (range +1 to +278) and gut GVHD d+131 (+1 to +454), with gut GVHD coming median 11 days (0 to 176) after CDAD. 7 pts (19%) died before discharge. The median survival time for all pts was 79 days after CDAD and 205 days after tx. Of the 30 (81%) pts discharged alive, 10 (33%) had recurrent CDAD episodes (median 1, range 1–3). When compared to mild CDAD, patients with severe CDAD had an increased risk of death at one year after CDAD (OR 3.3; CI 1.4–7.6). CDAD in allo pts may be associated with an increased risk of gut GVHD, death, and other adverse outcomes.

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Sorror, Mohamed L., Barry Storer, Brenda M. Sandmaier, David G. Maloney, Georg Franke, Judith Shizuru, Thomas Chauncey, et al. "Allogeneic Hematopoietic Cell Transplantation (HCT) after Nonmyeloablative Conditioning for Patients (pts) Aged ≥60 Years." Blood 112, no. 11 (November 16, 2008): 2162. http://dx.doi.org/10.1182/blood.v112.11.2162.2162.

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Abstract Median ages of pts with most hematological malignancies are beyond 60 years. The advent of nonmyeloablative conditioning regimens has extended the use of allogeneic HCT to these older pts. Here, we retrospectively investigated outcomes among 280 pts aged ≥60 years, given HCT between 1998 and 2006. Results were broken down in 3 age groups 60–64 (n=166), 65–69 (n=90), and ≥70 (n=24) years old, respectively. Pts aged ≥70 years had less preceding chemotherapy, less often failed autologous HCT, more often had related grafts, and had higher comorbidity scores compared to pts in the other two age groups (table 1). Acute leukemias were more frequent and lymphoma/multiple myeloma were less frequent among pts aged ≥70 years old, resulting in higher risk for relapse (Table 1). After HCT, non-relapse mortality, relapse, and progression free survivals at 5-years for all pts were 26%, 41%, and 32% respectively. Five-year Kaplan Meier rate of overall survival was 35%, of those 12% vs. 23% were with vs. without chronic GVHD requiring immunosuppressive therapy, respectively. There were no statistically significant differences in outcomes among the three age groups except for more infections and days of hospitalization among pts aged 65–69 years compared to the other two age groups (Table 2). In multivariate analyses of risk factors, high HCT-comorbidity index (1–2 and ≥3) independently predicted higher NRM (HR: 2.84 and 3.0, respectively, p=0.01) and, not surprisingly, previously defined high relapse risk predicted relapse (HR: 2.17, p=0.06); both predicted worse OS (p=0.005 and p=0.0009, respectively) and PFS (p=0.01 and p=0.02, respectively). Pts given unrelated grafts did as well as recipients of related grafts. In conclusion, nonmyeloablative allogeneic HCT can be curative among pts older than 60 years with resolution of chronic GVHD among a majority of pts. Comorbidities and relapse risk rather than age should be used for benefit-risk assessment. Continued enrollment of elderly pts in prospective studies including unrelated donors is warranted. Table 1: Pt characteristics Age groups, years (60–64) (n=166) (65–69) (n=90) (70–74) (n=24) Median Interval from Dx to HCT, months 19 15 8 Median (range) # of prior regimens 3 (0–14) 3 (0–13) 2 (0–10) Median CD34+ cell number x 106/kg 6.7 6.7 6.5 Median CD3+ cell number x 108/kg 2.9 3.1 3.4 % Prior radiotherapy 18 11 13 Prior HCT Failed 19 12 4 Planned 8 6 4 Positive patient CMV sero-status 58 65 79 HLA-matched related 54 53 83 Donor HLA-matched unrelated 41 44 17 HLA-mismatched unrelated 5 3 0 Conditioning 2 Gy TBI 12 13 21 2 Gy TBI + FLU 88 87 79 HCT-CI scores 0 27 27 15 1–2 30 39 25 3–4 30 17 40 ≥5 13 17 20 Diagnoses Acute leukemia 35 47 62 Chronic leukemia 15 13 13 Lymphoma/myeloma 21 23 8 Myelodysplastic/myeloproliferative 16 16 17 Others 3 1 0 Disease status at HCT CR 46 41 38 PR 15 30 21 Refractory 28 21 33 Relapse 11 8 8 Relapse risk Low 19 17 8 Standard 48 51 38 High 33 32 54 Table 2: Outcomes per age groups HCT Outcomes Age groups, years P* (60–64) (n=166) (65–69) (n=90) (70–74) (n=24) FUO indicates fever of unknown origin *Test for trend μBased on hazard ratio analysis Bacterial 1.4 2.3 1.7 .0004 Rates of Infection episodes per person Viral 0.7 1.1 0.7 NS within 100 days FUO 0.3 0.4 0.1 NS Fungal 0.3 0.2 0.3 NS Median (range) days of hospitalization 1 (0–60) 4.5 (0–179) 0.5 (0–47) NS % Acute GVHD Grades II–IV 52 49 54 NSμ Grades III–IV 16 12 13 NSμ Chronic extensive GVHD 39 45 54 0.05μ NCI-CTC criteria grades III–IV non-hematological toxicities 42 57 50 NSμ Pts with Full donor chimerism at 1-year CD3/CD33/BM 68/ 84/ 80 66/ 83/ 77 67/ 79/ 71 NSμ CR at 2-years 40 47 63 NSμ 5-years Relapse/progression 38 46 46 NSμ 5-years NRM 28 22 29 NSμ 5-years OS 37 36 23 NSμ 5-years PFS 34 31 25 NSμ Patients alive and off all immunosuppression 24 25 5 NSμ

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Robert, Chloé, Leslie Couëdelo, Carole Knibbe, Laurence Fonseca, Charline Buisson, Elisabeth Errazuriz-Cerda, Emmanuelle Meugnier, Emmanuelle Loizon, Carole Vaysse, and Marie-Caroline Michalski. "Rapeseed Lecithin Increases Lymphatic Lipid Output and α-Linolenic Acid Bioavailability in Rats." Journal of Nutrition 150, no. 11 (September 16, 2020): 2900–2911. http://dx.doi.org/10.1093/jn/nxaa244.

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ABSTRACT Background Soybean lecithin, a plant-based emulsifier widely used in food, is capable of modulating postprandial lipid metabolism. With arising concerns of sustainability, alternative sources of vegetal lecithin are urgently needed, and their metabolic effects must be characterized. Objectives We evaluated the impact of increasing doses of rapeseed lecithin (RL), rich in essential α-linolenic acid (ALA), on postprandial lipid metabolism and ALA bioavailability in lymph-cannulated rats. Methods Male Wistar rats (8 weeks old) undergoing a mesenteric lymph duct cannulation were intragastrically administered 1 g of an oil mixture containing 4% ALA and 0, 1, 3, 10, or 30% RL (5 groups). Lymph fractions were collected for 6 h. Lymph lipids and chylomicrons (CMs) were characterized. The expression of genes implicated in intestinal lipid metabolism was determined in the duodenum at 6 h. Data was analyzed using either sigmoidal or linear mixed-effects models, or one-way ANOVA, where appropriate. Results RL dose-dependently increased the lymphatic recovery (AUC) of total lipids (1100 μg/mL·h per additional RL%; P = 0.010) and ALA (50 μg/mL·h per additional RL%; P = 0.0076). RL induced a faster appearance of ALA in lymph, as evidenced by the exponential decrease of the rate of appearance of ALA with RL (R2 = 0.26; P = 0.0064). Although the number of CMs was unaffected by RL, CM diameter was increased in the 30%-RL group, compared to the control group (0% RL), by 86% at 3–4 h (P = 0.065) and by 81% at 4–6 h (P = 0.0002) following administration. This increase was positively correlated with the duodenal mRNA expression of microsomal triglyceride transfer protein (Mttp; ρ= 0.63; P = 0.0052). The expression of Mttp and secretion-associated, ras-related GTPase 1 gene homolog B (Sar1b, CM secretion), carnitine palmitoyltransferase IA (Cpt1a) and acyl-coenzyme A oxidase 1 (Acox1, beta-oxidation), and fatty acid desaturase 2 (Fads2, bioconversion of ALA into long-chain n–3 PUFAs) were, respectively, 49%, 29%, 74%, 48%, and 55% higher in the 30%-RL group vs. the control group (P < 0.05). Conclusions In rats, RL enhanced lymphatic lipid output, as well as the rate of appearance of ALA, which may promote its subsequent bioavailability and metabolic fate.

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Carvajal, Richard D., Jeffrey Alan Sosman, Fernando Quevedo, Mohammed M. Milhem, Anthony Michael Joshua, Ragini Reiney Kudchadkar, Gerald P. Linette, et al. "Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/Gna11 (Gq/11) mutant (mut) uveal melanoma (UM)." Journal of Clinical Oncology 31, no. 18_suppl (June 20, 2013): CRA9003. http://dx.doi.org/10.1200/jco.2013.31.18_suppl.cra9003.

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CRA9003 Background: Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation. We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel, a small molecule inhibitor of MEK1/2 (Ambrosini, CCR 2012). Methods: We conducted a 16 center randomized phase II study of hyd-sulfate sel 75 mg BID vs TMZ 150 mg/m2 daily for 5 days in 28-day cycles (or DTIC 1000 mg/m2 q21 days) for patients (pts) with metastatic UM with a Q209 Gq/11 mut who have not received prior TMZ/DTIC. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall survival (OS) and response rate (RR). Select pts underwent tumor biopsies at baseline and after 14 (+/- 3 days) of sel. Our statistical plan required ≥80 pts randomized and ≥68 events to detect a PFS hazard ratio of 0.6 (p=0.1). Randomization was stratified by mut (Gq vs G11), M stage and number of prior therapies (tx). Tumor assessment occurred every 4 weeks (wks) for 8 wks and then every 8 wks using RECIST 1.1. Pts receiving TMZ who progressed could receive sel (TMZ→sel). Results: 80 pts were randomized. Sel (n=39): median age 66 (range 32-86), 54% male, 54% G11 mut, median ECOG PS 0 (range 0-1), 97% M1c, median prior tx 0 (range 0-2). TMZ (n=41): median age 60 (range 34-81), 63% male, 58% G11 mut, median ECOG PS 0 (range 0-1), 93% M1c, median prior tx 0 (range 0-2). 11/39 (28%) pts on sel experienced grade (gr) 3 toxicity (tox) manageable with dose modification (5 CPK elevation, 3 LFT elevation, 1 rash, 1 lymphopenia, 1 edema). 1/41 (2%) pt on TMZ experienced gr 3 tox (neutropenia). No gr 4/5 tox occurred. 28 pts on sel underwent paired tumor biopsies with inhibition of pERK and cyclinD1 observed by Western blot at day 14. At interim analysis (9/25/12), 55 pts were evaluable with 45 progression events and 16 deaths. Sel (n=27): median PFS 16 wks (95% CI 8-30.9), RR 11%, median OS 11.8 months (95% CI 4.8-not reached). TMZ (n=28): median PFS 4 wks (95% CI 3.7-15), RR 0%, median OS 4.7 months (95% CI 4.3-14.3). TMZ→sel (n=25): median PFS 8.1 wks (95% CI 7-15), RR 0%. Conclusions: Sel is the first drug to ever show improved clinical activity in UM relative to TMZ. Sustained target inhibition is observed with sel. Final results will be presented. Clinical trial information: NCT01143402.

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Lledo, G., P. Michel, L. Dahan, L. Mineur, M. Galais, O. Dupuis, S. Abdiche, N. Jovenin, B. Chibaudel, and A. De Gramont. "Chemoradiation with FOLFOX plus cetuximab in locally advanced cardia or esophageal cancer: Final results of a GERCOR phase II trial (ERaFOX)." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 8. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.8.

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8 Background: Chemoradiotherapy (CRT) for locally advanced cardia and esophageal cancer is based on 5-FU combined with cisplatin, which could be favorably replaced by oxaliplatin (Ox). Cetuximab (C) has demonstrated synergism with both radiotherapy (RT) and platinum-based chemotherapy. ERaFOX trial was evaluating the safety and efficacy of the addition of C to CRT with FOLFOX. Methods: Main inclusion criteria were: stage III squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction; WHO PS 0-1; age 18-80 years; weight loss <15% in the last 6 months. Patients (pts) received 2 cycles of FOLFOX induction therapy (Ox 85 mg/m2/d1, folinic acid 400 mg/m2/d1, 5-FU 2,400 mg/m2/d1-2, q2w) plus C (first infusion 400 mg/m2 then 250 mg/m2, q1w), then RT 50.4 Gy (1.8Gy/d x 28 fractions) with FOLFOX plus C (same doses, except 5-FU 1,800mg/m2/d1-2). Tumor evaluation was performed at the end of CRT (RECIST and endoscopic ultrasonography). The primary endpoint was overall response rate (ORR), with a 50% threshold for efficacy (Simon Minimax two-stage design). Results: From Nov 2007 to Feb 2010, 80 pts were enrolled in 12 centers. The characteristics of the 79 eligible pts were (1 ineligible pt for stage IV disease): male/female 60/19, median age 63 (23-79), PS 0/1/ND 47/31/1, squamous/adenocarcinoma/undifferentiated 53/25/1; esophagus/cardia 74/5; median daily caloric intake 1,720 Kcal (550-3160). 74 pts were treated by CRT (5 pts experienced anaphylaxis during the first cetuximab infusion). ORR (ITT) was achieved in 61 pts (77.2%), 6 pts (7.6%) had stable disease, and 9 pts (11.4%) had disease progression (3 pts were not evaluable). Grade 3-4 toxicities induction therapy/CRT were (%): neutropenia: 7.6/28.4; febrile neutropenia: 0.0/2.7; vomiting: 1.3/4.0; mucositis: 1.3/5.4; diarrhea: 3.8/2.7; dysphagia-esophagitis: 1.3/13.5; rash: 7.6/10.8; allergy 8.9/0.0. One toxic death (1.3%) occurred after CRT related to esophagitis with GI bleeding. Conclusions: Threshold for efficacy was reached with an ORR of 77.2%. Chemoradiotherapy with FOLFOX plus cetuximab is active and has an acceptable toxicity profile in patients with locally advanced cardia or esophageal cancer. No significant financial relationships to disclose.

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Enzinger, P. C., T. Yock, W. Suh, P. Fidias, H. Mamon, N. Choi, N. Lehman, C. Lawrence, T. Lynch, and C. Fuchs. "Phase II cisplatin, irinotecan, cetuximab and concurrent radiation therapy followed by surgery for locally advanced esophageal cancer." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 4064. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4064.

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4064 Background: Weekly irinotecan, cisplatin, and concurrent radiation therapy is a well-tolerated, active regimen in locally advanced esophageal cancer. (Ilson. JCO 2003) Cetuximab, an EGFR inhibitor, is a potent radiation sensitizer in head and neck cancer. (Bonner. Proc ASCO 2004) Methods: In this phase II trial, patients (pts) with T2–4N0–1M0–1A esophageal adenocarcinoma (A) or squamous cell carcinoma (S) receive 5040 cGy/28 fractions of radiation therapy (RT) and concurrent weekly cisplatin 30mg/m2 plus irinotecan 65 mg/m2 on weeks 1, 2, 4, and 5, followed by surgery 4–8 weeks after completion of RT. Additionally, pts receive weekly infusions of cetuximab 250 mg during RT, up to one week before surgery, and for 6 months following surgery. Results: Seventeen pts have been entered: male: female = 14:3, median age 54, ECOG PS 0:1 = 6:11, A:S = 17:0, stage IIA:IIB:III:IVA = 6:1:8:2, tumor location-esophagus-mid:lower:gastroesophageal junction = 1:4:12, >10% weight loss-yes:no = 8:9. Of 17 pts entered, 15 pts have proceeded to surgery, 1 pt died from Aspergillus infection resulting in respiratory failure and sepsis, and 1 pt is pending surgery. Of the 15 pts who underwent surgery, 2 (13%) had a complete pathologic response; pathologic stage for other pts: 0 = 1, I = 3, IIA = 3, IIB = 1, III = 4, IV = 1. Grade III/IV toxicity (17 pts) was: diarrhea 9 pts, neutropenia 9 pts, febrile neutropenia 5 pts, anorexia 5 pts, vomiting 4 pts, fatigue 3 pts, mucositis 1 pt. Chemotherapy dose attenuation was required for diarrhea in 5 pts, for neutropenia in 4 pts, and for folliculitis in 1 pt. One patient was removed from study during week 6 for prolonged diarrhea/ dehydration. Due to the 2-step design of the trial, accrual is on hold pending a 3rd required pathologic CR in the first 17 patients. Conclusions: Compared to other trials of irinotecan, cisplatin, radiation therapy, and surgery in similar groups of esophageal cancer patients, early results for this combination with cetuximab suggest a lower complete response rate and higher overall toxicity. Additional data will be available at ASCO. Supported by Bristol-Myers Squibb. No significant financial relationships to disclose.

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Mitsunaga, Shuichi, Masafumi Ikeda, Hideki Ueno, Kohei Nakachi, Chigusa Morizane, Shunsuke Kondo, Satoshi Shimizu, et al. "Phase I/II study of lenvatinib (E7080), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC): Phase I results." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 231. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.231.

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231 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFR-beta. Maximum tolerated dose (MTD) of lenvatinib for solid tumor pts was determined to be 25 mg once daily dosing (qd). The current study was planned to determined MTDs and pharmacokinetic profiles of lenvatinib in HCC pts with Child-Pugh grade (CP) A and B. Methods: Between Aug. 2009 and Nov. 2011, a total of 20 pts with advanced HCC were enrolled in phase I part (Ph I). Ph I consists of a standard dose escalation design in separate cohorts of CP-A (6 pts per cohort) and CP-B (3+3 pts). The initial dose level of lenvatinib for CP-A and for CP-B was 12 mg qd. Tumor response was assessed by RECIST 1.1. Results: Nine pts with CP-A and 11 pts with CP-B were enrolled and evaluable for safety and efficacy. Pt characteristics: median age: 63.5 years, Male: 85%, HBV: 35% / HCV: 45%. 1/6 pt in 12 mg qd and 2/3 pts in 16 mg qd experienced DLTs (fever/vomiting, hepatic encephalopathy and proteinuria) in the CP-A group. In the CP-B group 2/5 pts in 12 mg qd and 0/6 pt in 8 mg qd experienced DLTs (hepatic encephalopathy and AST increased/hyperbilirubinaemia/creatinine increased). The most common toxicities were hypertension (all grade (Gr):75%, Gr3:50%), diarrhea (all Gr:70%, Gr3:0%), anorexia (all Gr:65%, Gr3:0%), palmar-plantar erythrodysaesthesia syndrome (all Gr:65%, Gr3:5%), fatigue (all Gr:65%, Gr3:0%) and hyperbilirubinaemia (all Gr:50%, Gr3:15%). Confirmed partial responses were observed in 4 pts and stable disease were in 9 pts. Median time to progression was 3.7 mo. Following administration of 12 mg lenvatinib, trough plasma concentrations (Ctrough) of the CP-A (n=5), CP-B (n=2), and pts with other solid tumors were 49.7 ± 23.6 (mean ± standard deviation), 73.7 and 22.8 ± 9.8 ng/mL respectively. Conclusions: The MTD for lenvatinib in advanced HCC pts with CP-A and CP-B are 12 mg qd and 8 mg qd, respectively. Ctrough is substantially higher than in HCC pts than in pts with other solid tumors. Lenvatinib 12 mg qd in HCC pts with CP-A and 8 mg qd in HCC pts with CP-B were associated with manageable toxicity and preliminary evidence of antitumor activity. Clinical trial information: NCT00946153.

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Acs, Peter, Blanche Mavromatis, Metin Ozdemirli, Daniel Hartman, and Bruce Cheson. "Treatment Outcomes in Patients (Pts) with Transformed Chronic Lymphocytic Leukemia (CLL) in One Institution." Blood 106, no. 11 (November 16, 2005): 5031. http://dx.doi.org/10.1182/blood.v106.11.5031.5031.

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Abstract CLL is usually an indolent lymphoproliferative disease; however pts are at risk over time (3-5% yr) of transformation to a more aggressive histology, e.g., prolymphocytic leukemia (PLL), or Richter’s transformation (RT). The outcome of these pts is poor with median overall responses of 5–43%, CR 5–43%, and overall survival of 5–8 months regardless of the chemotherapeutic approach. We report on 15 pts with CLL transformed to PLL or RT treated at our institution over the last 4 years. The median pt age at transformation was 64 (51–79). 9 had PLL, 4 had RT, one had an anaplastic histology, and another with atypical transformation. 7/14 pts were positive for ZAP-70 expression. 10/14 presented with CLL prior to the transformation with a median time of 7 yrs (range 3–27), and had undergone prior therapy with either fludarabine or chlorambucil. Pts were treated with mainly rituximab chemotherapy combinations. One pt who achieved a CR, was consolidated with a matched related donor transplantation and remains disease free for 3 yrs. Conclusion. CR and ORR were higher than reported in the literature. Also, pts treated with rituximab-based combinations achieved longer overall survivals. Rituximab based-combinations should be considered in treating such pts. Whether they would benefit from consolidation therapy needs further investigation. Treatment Based Response and Overall Survival in Patients with Transformed Chronic Lymphocytic Leukemia Treatment # Pts Prev. Tx # Pts CR (%) PR (%) OS after Transformation (Months) Pts, patients; Prev., previously; Tx, treated; CR, complete response; PR, partial response; OS, overall survival; R, rituximab; Flu, fludarabine; Cy, cyclophosphamide PLL R/Flu +/− Cy 2/6 6 67 12 36+, 36+, 36, 24+, 4, 12+ RCHOP or R-EPOCH 2/2 2 0 50 8, 3+ Alemtuzumab 1/1 1 0 100 12+ RT RCHOP or REPOCH 1/4 4 75 25 36+, 30+, 3, 9 Anaplastic RCHOP 1/1 1 100 0 24+ Atypical R/Flu/Cy 1/1 1 100 0 24+ Overall 60 27

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Wagner, A. D., P. Buechner-Steudel, H. Schmalenberg, M. Moehler, O. Kuss, R. Behrens, S. Hahnfeld, G. Kleber, A. Wein, and W. E. Fleig. "Gemcitabine, oxaliplatin and weekly high-dose 5-FU as a 24-hr-infusion in chemonaive patients with advanced or metastatic carcinoma of the gallbladder: Preliminary results of a multicenter phase II-study." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 4129. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4129.

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4129 Background: Combinations of gemcitabine (GEM)/5-FU, GEM/oxaliplatin (LOHP) or 5-FU/LOHP work synergistically in pancreatic and/or colorectal malignancies, and have non-overlapping safety profiles. This phase II-study was designed to evaluate the efficacy and safety of the triple combination GEM/LOHP/5-FU in patients (pts) with advanced or metastatic carcinoma of the gallbladder. Methods: One-stage, multicentre phase II study. Eligibility criteria: chemonaive pts with histologically proven advanced, recurrent or metastatic gallbladder carcinoma (ECOG 0–1; expected survival >3 months; measurable disease; adequate renal, hepatic and bone marrow function). According to the results of our previous phase I-study (Proc ASCO 2003, # 1298), pts were treated with GEM 900mg/m2 as a 30-min infusion, followed by LOHP 65 mg/m2 (2-hr infusion) after a 30 min rest and 5-FU 1500 mg/m2 (24-hr-infusion) on d 1, 8, every 3 weeks. Planned sample size: 35 response evaluable patients. The primary endpoint was tumor response, secondary endpoints were toxicity, median survival, the one-year-survival rate, clinical benefit and quality of life. Results: At time of abstract submission, median follow-up of 35 enrolled pts is 9.8 months. Pt. characteristics: m/f: 11/24, median age 61 (range 42–81), ECOG 0/1: 24/11 (69/31%) pts, locally advanced/metastatic disease 1/32 (3/91%) pts. Analysis of tumor response is still pending. Grade III/IV (NCI-CTC) toxicities occurred in 36/3% of 191 cycles and were: leucopenia 3/1%, neutropenia 4/1%, thrombocytopenia 4/1%, anemia 2/0%, nausea 1/0%, sensory neuropathy 4/0%, asthenia 1/0%, elevated bilirubin 2/0%, AP 4/0%, or elevated SGOT/SGPT 1/0%, edema 1/0%, infection 1/0%, dyspnoe 1/1%. Median survival of all pts is 9.9 months (95% CI: 7.5–11.5), the one-year-survival-rate is 30 % (95% CI: 16–47). Conclusions: GEM/LOHP/5-FU combination therapy is tolerated well in patients with gallbladder cancer. The promising survival data has to be confirmed in a phase III study. (Supported by grants from Eli Lilly and Company, Indianapolis, IN, USA and Sanofi-Synthelabo, Paris, France). [Table: see text]

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Pagano, Livio, Caterina Giovanna Valentini, Pellegrino Musto, Morena Caira, Michela Rondoni, Maria Teresa Van Lint, Anna Candoni, et al. "Systemic Mastocytosis. A GIMEMA Multicenter Survey." Blood 108, no. 11 (November 16, 2006): 4874. http://dx.doi.org/10.1182/blood.v108.11.4874.4874.

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Abstract To evaluate clinical and biological features, treatments and outcome of patients(pts) with Systemic Mastocytosis(SM). A retrospective study (1995–2006) about pts with SM admitted in 14 Italian hematology divisions in tertiary cares or university hospitals. 30 cases of SM were collected(median age 62 y.o.; M/F 14/16) and classified according to the WHO criteria: Mast Cell Leukemia in 14 pts, Aggressive SM in 12 and Indolent in 3; the remaining one had SM with associated clonal non-mast cell-lineage hematologic disease. Skin was the principal extramedullary organ involved (19 pts) followed by spleen(15), liver(13), and cardiovascular system(12). Molecular biology studies were performed in 22 pts: 15 showed the c-kit point mutation D816V; in another patient a different c-kit mutation was found while in 3 pts additional gene defects and karyotype abnormalities were recognized. Treatments were heterogeneous, and the same patient could have received different therapies after failure of the previous one. Imatinib(400 mg/day) was used in 17 pts (11 as first line therapy, 5 and 1 as second and third line respectively); interferon-alpha(3×3 MU s.c. weekly) was employed in 7 patients(4 as first line therapy, 2 as second and 1 as third line); 2-CDA(0.14 mg/kg) was administered in 3 pts(1 as first, 1 as second and 1 as third line therapy); 2 patients underwent HSCT as second and third line respectively. Data about response to treatment are reported in the table. The overall response rate to imatinib was of 30%, registering 1 complete remission(CR) and 4 partial remissions. All but one responsive patients did not present c-kit point mutation. Three pts(10%) died for progression of SM; a fourth patient in CR died for accidental causes. The actuarial Kaplan-Meier curve at 10 years showed an overall-survival of 87%. Conclusions: SM is a rare disease, characterized by severe and life-threatening mediator-related symptoms but with a low mortality rate. D816V c-kit mutation is frequent and associated with resistance against imatinib: only 1 patient showed a CR. Of note 2-CDA has shown interesting clinical response: all 3 treated pts showed a clinical improvement. Because of the rarity of SM, an effective standard of care is lacking. More data are needed to find new and successful therapeutic strategies; it is possible that new tyrosine kinase inhibitors could allow to achieve clinical and molecular remission of disease, crossing resistence to imatinib due to c-kit mutation, in order to improve above all quoad valitudinem prognosis of these pts. Response to treatments. DRUGS CR PR Stable Unrespons. N.E. TOTAL Imatinib 1 4 5 3 4 17 INF-alpha 0 1 1 5 0 7 2-CDA 0 3 0 0 0 3 Conventional CTX 0 1 2 4 1 8 Allo-HSCT 2 0 0 0 0 2 Wait & Watch 0 0 6 2 0 8

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Shirao, K., N. Boku, Y. Yamada, K. Yamaguchi, T. Doi, H. Takiuchi, J. Nasu, K. Nakamura, H. Fukuda, and A. Ohtsu. "Randomized phase III study of 5-fluorouracil continuous infusion (5FUci) versus methotrexate and 5-FU sequential therapy (MF) in gastric cancer with peritoneal metastasis (JCOG0106)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 4545. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4545.

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4545 Background: Gastric cancer (GC) with peritoneal metastasis (PM) often complicates ascites or intestinal stenosis and the prognosis is still poor. Anti-cancer drugs generally can not be administered for such patients (pts) due to the risk of serious and prolonged adverse events. However, 5FU-based chemotherapy is reportedly relatively safe for PM. We conducted a phase III study to investigate the superiority of MF over 5FUci for GC with PM with a primary endpoint of overall survival (OS) and secondary endpoints of toxicities, ingestion-possible survival (IPS) in pts with initially possible ingestion and proportion of ingestive improvement (%II) in pts requiring nutrition support. Methods: Eligibility criteria included pts with histologically proven gastric adenocarcinoma; inoperable or recurrent GC; PM with radiologically confirmed intestinal stenosis or ascites; 20–75 years old; PS 0–2; no prior treatment except surgery or adjuvant chemotherapy. Treatment with 5FUci (800mg/m2/d, civ, d1–5, q4w) or MF (methotrexate, 100mg/m2, iv, followed 3 h later by 5FU, 600mg/m2, iv, with leucovorin rescue, q1w) were continued until disease progression or unacceptable toxicities. Projected sample size was 236 in total, which had 80% power to detect 40% increase of median OS in MF with 1-sided alpha 0.05. Results: A total of 237 pts were randomized between Oct 2002 and Apr 2007. Final analysis was performed in Dec 2008 when 224 pts (95%) were dead. Results of OS are shown in Table . Median IPS was 8.1M for 5FUci(n=102) and 9.0M for MF(n=103) (p=0.60). %II was 41%(7/17) for 5FUci and 57%(8/14) for MF (p=0.48). Frequencies (%) of grade 4 neutropenia, grade >3 febrile neutropenia, infection with neutropenia, anemia, anorexia, diarrhea, abdominal pain within 6M, and treatment related death (5-FUci/MF) were 0/9, 0/3, 0/5, 10/16, 27/34, 1/10, 5/10 and 2/1, respectively. Conclusions: MF could not become new standard therapy for GC with PM. [Table: see text] No significant financial relationships to disclose.

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Petrini, I., M. Lencioni, M. Ricasoli, M. Iannopollo, C. Orlandini, F. Oliveri, F. Filipponi, C. Bartolozzi, M. Del Tacca, and S. Ricci. "A phase II (PhII) trial of sorafenib (S) in combination with 5-fluorouracil (5FU) continuous infusion (c.i.) in patients (pts) with advanced hepatocellular carcinoma (HCC): Preliminary data." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 4592. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4592.

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4592 Background: S, an oral multi-kinase inhibitor that targets Raf-kinase and receptor tyrosine kinases, improved overall survival (OS) and time to progression (TTP) versus placebo in a randomized phase III study in HCC (SHARP study). The safety of S in association with infusional and bolus 5FU regimens was established in a previous PhI study, with no clinically relevant pharmacokinetic interaction between S and 5FU. The present trial was designed to evaluate the safety and efficacy of S with infusional 5FU in HCC pts. Methods: Patients with advanced HCC (not eligible to surgical or locoregional therapies), age≥18 years, Child-Pugh Class A or B, ECOG PS 0–1, without prior systemic treatment for HCC and adequate bone marrow, liver and renal function, were eligible for the study. The primary endpoint is the Disease Control Rate (DCR). Secondary endpoints included response rate, TTP, OS and safety. According to a two-step Simon's model 46 pts were to be accrued. Pts were treated with oral S 400 mg bid continuously and c.i. 5FU 200 mg/sqm/day day 1–14 every 3 weeks. Tumour response was assessed according to RECIST criteria every 9 weeks. Results: Between October 2006 and October 2008 38 pts were enrolled: M-F: 32–6, median age (range): 68(47–83) years, ECOG-PS 0–1: 28–10, Child-Pugh A-B: 35–3, extrahepatic spread: 14 pts, macroscopic vascular invasion: 6 pts. Grade 3/4 (%) toxicities (NCI CTC v 3.0 criteria) included diarrhoea 5/0, stomatitis 21/3, hand foot syndrome 21/0, skin rash 11/0, hypertension 11/0; hyperbilirubinemia 5/3, AST 11/0, ALT 8/0, cardiac toxicity (one cardiac failure, one atrial fibrillation) 5/0 and bleeding (melena) in 3/0. One partial response was observed. Stable disease was obtained in 45% of pts with a median duration of 9.6 months (range 5–18+). Median TTP was 7.6 months (CI 95%=5.3–9.9) and median OS 12.2 months (CI 95%=4.45–19.8). Conclusions: Preliminary results of this PhII study show encouraging disease control rate, TTP and OS in pts with advanced HCC. The S+5FU association is feasible, well tolerated and AEs were predictable and manageable. [Table: see text]

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Strickler, John H., Shannon McCall, Andrew B. Nixon, Herbert Pang, Christel Rushing, Christy Arrowood, Sherri Haley, Kellen Meadows, and Herbert Hurwitz. "Correlation of Src activation with response to dasatinib, capecitabine, oxaliplatin, and bevacizumab in advanced solid tumors." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 11036. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.11036.

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11036 Background: Src inhibition may augment sensitivity to chemotherapy, but in unselected patients (pts) with advanced solid tumors, src inhibitors have shown limited clinical activity. Biomarkers to predict benefit from src inhibitors in advanced solid tumors are not yet known. Methods: 22 pts (dose escalation cohort= 12 pts; colorectal cancer [CRC] expansion cohort= 10 pts) were enrolled in a phase I study to determine the safety and tolerability of the src inhibitor dasatinib with capecitabine, oxaliplatin, and bevacizumab (J Clin Oncol 29: 2011 [suppl; abstr 3586]). Src activation (src-a) was assessed in tumors from 16 evaluable pts. Src-a was measured by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded tumor samples using an antibody that selectively recognizes the active conformation of src (clone 28). A GI pathologist who was blinded to pt outcomes graded membranous src-a using a standard semi-quantitative method. The endpoint of this exploratory analysis was objective response rate ([ORR]= PR+CR). 2-sided Fisher’s Exact test was used to evaluate the association between ORR and src-a. Results: Across all tumor types, 8 tumors had no/faint src-a (IHC=0/1); 8 tumors had moderate/strong src-a (IHC≥2). Benign colonic epithelium had no src-a (IHC=0). The ORR was 75% (6/8) for pts with moderate/strong src-a versus (vs) 0% (0/8) for pts with no/faint src-a (p =0.007). In the CRC expansion cohort, the ORR was 83% (5/6) for patients with moderate/strong src-a vs 0% (0/2) for pts with no/faint src-a (p=0.107); progression free survival range was 7.9-24.4 months for pts with moderate/strong src-a. Conclusions: In this small phase I study, src-a is associated with benefit from the combination of dasatinib and oxaliplatin-based chemotherapy. Further evaluation of dasatinib in patients whose tumors demonstrate high levels of src-a may be warranted. Clinical trial information: NCT00920868.

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Parsons, H. A., M. de La Cruz, M. O. Delgado-Guay, A. E. Akitoye, R. Chacko, V. Poulter, and E. Bruera. "Characteristics of patients who refuse medically appropriate do not resuscitate orders (DNR) upon admission to a palliative care (PC) unit in a comprehensive cancer center." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 9589. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.9589.

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9589 Background: Cardiopulmonary resuscitation (CPR) has limited benefit in advanced cancer patients (pts). Refusal of medically appropriate DNR (maDNR) may cause harm and distress for pts, families, and the medical team. We conducted a retrospective study to determine the frequency of refusals of maDNR in a tertiary PC unit in a comprehensive cancer center, and characterize the differences between maDNR acceptors (A) and refusers (R). Methods: We reviewed 2538 consecutive admissions to the PC unit to find refusals of maDNR. Data were collected regarding demographical/clinical factors, 0–10 Edmonton Symptom Assessment System, DNR, CPR, and death for the first 100 R and 200 A pts. Results: DNR was considered medically appropriate for 2530/2538 (99%) admissions. 2374/2530 admissions were of unique pts, and 100/2374 (4%) refused maDNR. 3/3 (100%) R pts who coded underwent CPR versus 0/87 A pts who coded (0%, p<0.0001). 2/3 CPR pts survived code and were discharged but died in less than 10 days. Median age (62), female gender (54%), and religious affiliation were not different between R and A. African-Americans and pts with head and neck malignancies were more frequently R than others (OR=1.99, CI=1.13–3.51, p=0.02 and OR=2.62, CI=1.05–6.56, p=0.04, respectively). A had more hematological malignancies and advance directives (OR=2.66, CI=1.07–6.63, p=0.02, and OR=2.80, CI=1.68–4.66, p<0.0001, respectively). Multivariate regression analysis revealed that pts with hematologic malignancies (OR 2.69, CI=1.05–6.90 p= 0.04) and advance directives (OR 1.46, CI=1.46–4.27, p= 0.001) were associated with A. R pts presented with median (interquartile range, IR) pain of 7(4–9) vs 5(3–8, p=0.0005) nausea of 2(0–7) vs 1(0–4, p=0.05), and dyspnea of 1(0–5) vs 4(0–7, p=0.002). Median (IR) time between PC consult and death and discharge and death were 143 (49–329) days for R vs 25(10–77) for A (p<0.0001) and 85 (25–206) for R and 18 (8–35) for A (p<0.0001). Conclusions: DNR refusal in pts after PC consult is low, more frequent among African Americans, pts with head and neck cancers, pts with more pain or nausea, and is associated with longer survival. This study demonstrates possible predictors of complicated DNR discussions. No significant financial relationships to disclose.

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Traina, Tiffany A., Denise A. Yardley, Lee Steven Schwartzberg, Joyce O'Shaughnessy, Javier Cortes, Ahmad Awada, Catherine Margaret Kelly, et al. "Overall survival (OS) in patients (Pts) with diagnostic positive (Dx+) breast cancer: Subgroup analysis from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in AR+ triple-negative breast cancer (TNBC) treated with 0-1 prior lines of therapy." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1089. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1089.

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1089 Background: The AR may be a novel therapeutic target for pts with AR-driven TNBC. ENZA, a potent AR inhibitor approved in men with metastatic prostate cancer, was evaluated in this phase 2 study of pts with AR+ TNBC. A genomic signature associated with AR-driven biology was identified; updated OS results in pts treated with 0-1 prior lines of therapy are presented. Methods: This is an open-label, Simon two-stage study (NCT01889238) of ENZA monotherapy in advanced AR+ TNBC (AR > 0% by IHC). Bone-only disease and unlimited prior regimens were allowed; CNS metastases or seizure history were exclusionary. The primary endpoint was clinical benefit rate at 16 weeks (CBR16) in evaluable pts (AR > 10% and ≥1 postbaseline assessment). OS was an exploratory endpoint. Results in intent-to-treat (ITT) and evaluable pts were presented previously (Traina TA et al. J Clin Oncol. 2015;33:1003). Results: 118 pts were enrolled (ITT). CBR16 in 78 evaluable pts was 33.3%. Of the 118 ITT pts, 56 were Dx+ and 62 were Dx–; ≥50% received 0-1 prior lines of therapy (28 Dx+, 37 Dx–). As of 26 Nov 2016 there were 83 deaths (median follow-up 28 mo); median OS (mOS) was 13 mo (95% CI; 8-18). In the Dx+ subgroup there were 32 deaths (mOS 20 mo [95% CI; 13-29]) vs 51 deaths in the Dx– subgroup (mOS 8 mo [95% CI; 5-11]). In pts with 0-1 prior lines of therapy, there were 13 deaths in the Dx+ subgroup (mOS 29 mo [95% CI; 19-not reached] vs 28 in the Dx– subgroup (mOS 10 mo [95% CI; 7-15]). The most common adverse events (AEs) were fatigue and nausea; fatigue was the only grade 3 related AE in > 5% of pts. A multi-covariate Cox analysis identified Dx status (+ vs –) and line of therapy (0-1 vs ≥2) as the only variables significantly associated with OS. Conclusions: In this study, the mOS of pts with Dx+ TNBC who received 0-1 prior lines of therapy appears longer than that of unselected historic controls. ENZA may represent a therapeutic option in pts with AR+ TNBC who would otherwise receive cytotoxic chemotherapy and is currently being evaluated in ENDEAR, a phase 3 study in pts with Dx+ advanced TNBC and 0-1 prior lines of therapy. Clinical trial information: NCT01889238.

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Santini, Daniele, Giuseppe Procopio, Camillo Porta, Calogero Mazzara, Sandro Barni, Andrea Fontana, Alfredo Berruti, et al. "Natural history of malignant bone disease in renal cancer: Final results of an Italian bone metastases survey." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 4627. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4627.

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4627 Background: bone metastases (mts) are an emerging clinical problem in renal cancer patients related to survival increase. We report the final data of largest survey never published in literature. Methods: 398 renal cancer patients (pts) with evidence of bone mts, all died at the moment of study inclusion, have been included. Clinico-pathological data, data on survival and Skeletal Related Events (SRE) data and skeletal related therapies have been collected and statistically analyzed. Results: 286 males/112 females; median age: 63 (16-87); pts with bone mts at the moment of renal cancer diagnosis: 31.4%; pts with single bone mts: 31.1%. Type: lytic 77%, mixed: 14.6%, blastic: 7.6 %. Sites: spine (65.8%), pelvis (38.4%), long bones (31.6%), other (18.8%). Median time to bone mts: 8 months (0-288) (all patients); 24 months (1-288) (pts without bone mts at diagnosis). Pts with at least 1 SRE: 71.1%. Types of SREs: pathologic fracture (12.6%), radiotherapy (61.8%), spinal compression (7.6%), bone surgery (14.8%), hypercalcaemia (3.2%). Median number of SRE for patient: 1 (0-4). Median time to first SRE: 2 (0-72), to second SRE: 4 (0-113), to third SRE: 11 (1-108). Median survival after bone mts diagnosis: 12 (1-178). Median survival after first SRE: 10 (0-144). Median survival in pts with at least one SRE: 14 (1-178); median survival in pts without SREs: 9 (0-62). In according with MKSCC criteria median time to skeletal disease was in patients with good prognosis was 24 (0-288), intermediate was 5 (0-180) and poor prognosis was 0 (0-77). A total of 168 pts received zoledronic acid until performance status worsening or death. 162 pts have been analysed as control group. The median time to first SRE in the zoledronic treated pts was 3 mths (0-101) compared with 1 mth (0 - 25) in the control group (p< 0.05). 5 cases of ONJ have been diagnosed. Conclusions: The present survey is the largest descriptive study concerning the natural history of bone disease in renal cancer patients. The effects of biological therpies on bone met will be presented during the meeting.

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Journal articles on the topic 'RL 0.8 / 0.5 Pts'

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